Platelets in a blood smear

Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).

The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.

Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.

So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.

The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.

The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.

The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.

The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.

The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.

However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.

The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.

Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.

And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”

They described the development of the platform in Blood. 

Platelets in a blood smear

Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).

The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.

Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.

So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.

The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.

The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.

The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.

The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.

The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.

However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.

The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.

Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.

And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”

They described the development of the platform in Blood. 

Platelets in a blood smear

Investigators from more than 50 institutions across the globe have developed a high-throughput sequencing platform—the ThromboGenomics platform—targeting 63 genes relevant for inherited bleeding, thrombotic, and platelet disorders (BPDs).

The investigators say this platform provides a “comprehensive and cost-effective strategy” to diagnose BPDs and has a high sensitivity to detect and “shortlist” the causal variants when known to be in a BPD gene.

Molecular analysis is often unavailable for patients with BPDs, with the exception of hemophilia and von Willebrand disease, and this causes delays, often inconclusive molecular diagnoses, and compromises treatment.

So to address this unmet diagnostic need, the investigators sequenced 159 and 137 samples from cases with and without previously known causal BPD variants, respectively.

The platform, along with the processing and filtering methods, has a high sensitivity—100% based on the 159 samples with known causal variants.

The investigators report that the sensitivity remains high even when the variants are unknown—greater than 90% based on 61 samples.

The platform’s variant approach also has a high specificity of greater than 99.5% because it reduces the number of candidates requiring consideration.

The ThromboGenomics platform is already being used by the National Health Service in the United Kingdom.

The platform can identify single nucleotide variants, short insertions/deletions, and large copy number variants. They are then subjected to automated filtering and prioritized for diagnosis, resulting in an average of 5.34 candidate variants per individual.

However, the platform cannot identify inversions, and approximately 45% of severe hemophilia A cases are due to inversions. So the investigators recommend that a simple polymerase chain reaction-based test be performed to exclude those cases prior to high-throughput sequencing.

The investigators indicated that during validation of the ThromboGenomics platform, 13 new BPD genes were found.

Use of the platform, they believe, will reduce the diagnostic delay in reaching a conclusive molecular diagnosis for BPD patients.

And further, they believe that “by facilitating provision of a definitive diagnosis, our platform will bring substantial benefits to the estimated 2 million BPD cases worldwide.”

They described the development of the platform in Blood. 

Reverse total shoulder arthroplasty (RTSA) has become a reliable treatment option for many pathologic conditions of the shoulder, including rotator cuff arthropathy, proximal humerus fractures, and others.^1-4 While the treatment outcomes have generally been reported as good, some concern exists over the postoperative range of motion (ROM) in patients following RTSA, including external rotation.^5-7 The original RTSA design was introduced by Neer in the 1970s and has undergone many modifications since that time.^1,2 The original Grammont-style prosthesis involved medialization of the glenoid, inferiorizing the center of rotation (with increased deltoid tensioning), and a neck-shaft angle of 155°.^1,8 While clinical results of the 155° design were encouraging, concerns arose over the significance of the common finding of scapular notching, or contact between the scapular neck and inferior portion of the humeral polyethylene when the arm is adducted.^9,10

To address this concern, a prosthesis design with a 135° neck-shaft angle was introduced.¹¹ This new design did significantly decrease the rate of scapular notching, and although some reported a concern over implant stability with the 135° prosthesis, recent data has shown no difference in dislocation rates between the 135° and 155° prostheses.³ A different variable that has not been evaluated between these prostheses is the active ROM that is achieved postoperatively, and the change in ROM from pre- to post-RTSA.^12,13 As active ROM plays a significant role in shoulder function and patient satisfaction, the question of whether a significant difference exists in postoperative ROM between the 135° and 155° prostheses must be addressed.

The purpose of this study was to perform a systematic review investigating active ROM following RTSA to determine if active postoperative ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. The authors hypothesize that there will be no significant difference in active postoperative ROM between the 135° and 155° prostheses, and that the difference between preoperative and postoperative ROM (that is, the amount of motion gained by the surgery) will not significantly differ between the 135° and 155° prostheses.

Methods

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist.¹⁵ Systematic review registration was performed using the PROSPERO international prospective register of systematic reviews (registration date 3/9/15, registration number CRD42015017367).¹⁶ Two reviewers independently conducted the search on March 7, 2015 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (((((reverse[Title/Abstract]) AND shoulder[Title/Abstract]) AND arthroplasty[Title/Abstract]) NOT arthroscopic[Title/Abstract]) NOT cadaver[Title/Abstract]) NOT biomechanical[Title/Abstract]. English language Level I-IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine¹⁷) clinical studies that reported the type of RTSA prosthesis that was used as well as postoperative ROM with at least 12 months follow-up were eligible. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject publications were discovered, the study with the longer duration of follow-up or larger number of patients was included. Level V evidence reviews, letters to the editor, basic science, biomechanical studies, arthroscopic shoulder surgery, imaging, surgical technique, and classification studies were excluded. Studies were excluded if both a 135° and 155° prosthesis were utilized and the outcomes were not stratified by the humeral inclination. Studies that did not report ROM were excluded.

A total of 456 studies were located, and, after implementation of the exclusion criteria, 65 studies from 2005-2015 were included in the final analysis (Figure). Subjects of interest in this systematic review underwent a RTSA. Studies were not excluded based on the surgical indications (rotator cuff tear arthropathy, proximal humerus fractures, osteoarthritis) and there was no minimum follow-up or rehabilitation requirement. Study and subject demographic parameters analyzed included year of publication, journal of publication, country and continent of publication, years of subject enrollment, presence of study financial conflict of interest, number of subjects and shoulders, gender, age, the manufacturer and type of prosthesis used, and the degree of the humeral inclination (135° vs 155° humeral cup). Preoperative ROM, including forward elevation, abduction, external rotation with the arm adducted, and external rotation with the arm at 90° of abduction, were recorded. The same ROM measurements were recorded for the final follow-up visit that was reported. Internal rotation was recorded, but because of the variability with how this measurement was reported, it was not analyzed. Clinical outcome scores and complications were not assessed. Study methodological quality was evaluated using the Modified Coleman Methodology Score (MCMS).¹⁸

Statistical Analysis

Descriptive statistics were calculated, including mean ± standard deviation for quantitative continuous data and frequencies with percentages for qualitative categorical data. ROM comparisons between 135° and 155° components (pre- vs postoperative for each and postoperative between the 2) were made using 2 proportion z-test calculator (http://in-silico.net/tools/statistics/ztest) using alpha .05 because of the difference in sample sizes between compared groups.

Results

Sixty-five studies with 3302 patients (3434 shoulders) were included in this study. There was a total of 1211 shoulders in the 135° lateralized glenosphere group and 2223 shoulders in the 155° group. The studies had an average MCMS of 40.4 ± 8.2 (poor), 48% of studies reported a conflict of interest, 32% had no conflict of interest, and 20% did not report whether a conflict of interest existed or not. The majority of studies included were level IV evidence (85%). Mean patient age was 71.1 ± 7.6 years; 29% of patients were male and 71% were female. No significant difference existed between patient age at the time of surgery; the average age of patients in the 135° lateralized glenosphere group was 71.67 ± 3.8 years, while the average patient age of patients in the 155° group was 70.97 ± 8.8 years. Mean follow-up for all patients included in this study was 37.2 ± 16.5 months. Of the 65 studies included, 3 were published from Asia, 4 were published from Australia, 24 were from North America, and 34 were from Europe. Of the individual countries whose studies were included, the United States had 23 included studies, France had 13 included studies, and Italy had 4 included studies. All other countries had <4 studies included.

Patients who received either a 135° or a 155° prosthesis showed significant improvements in external rotation with the arm at the side (P < .05), forward elevation (P < .05), and abduction (P < .05) following surgery (Table). When comparing the 135° and 155° groups, patients who received a 135° prosthesis showed significantly greater improvements in external rotation with the arm at the side (P < .001) and had significantly more overall external rotation postoperatively (P < .001) than patients who received a 155° prosthesis. The only preoperative ROM difference between groups was the 155° group started with significantly more forward elevation than the 135°group prior to surgery (P = .002).

Discussion

RTSA is indicated in patients with rotator cuff tear arthropathy, pseudoparalysis, and a functional deltoid.^1,2,4 The purpose of this systematic review was to determine if active ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. Forward elevation, abduction, and external rotation all significantly improved following surgery in both groups, with no significant difference between groups in motion or amount of motion improvement, mostly confirming the study hypotheses. However, patients in the 135° group had significantly greater postoperative external rotation and greater amount of external rotation improvement compared to the 155° group.

Two of the frequently debated issues regarding implant geometry is stability and scapular notching between the 135° and 155° humeral inclination designs. Erickson and colleagues3 recently evaluated the rate of scapular notching and dislocations between the 135° and 155° RTSA prostheses. The authors found that the 135° prosthesis had a significantly lower incidence of scapular notching vs the 155° group and that the rate of dislocations was not significantly different between groups.³ In the latter systematic review, the authors attempted to evaluate ROM between the 135° and 155° prostheses, but as the inclusion criteria of the study was reporting on scapular notching and dislocation rates, many studies reporting solely on ROM were excluded, and the influence of humeral inclination on ROM was inconclusive.³ Furthermore, there have been no studies that have directly compared ROM following RTSA between the 135° and 155° prostheses. While studies evaluating each prosthesis on an individual level have shown an improvement in ROM from pre- to postsurgery, there have been no large studies that have compared the postoperative ROM and change in pre- to postoperative ROM between the 135° and 155° prostheses.^11,13,19,20

One study by Valenti and colleagues²¹ evaluated a group of 30 patients with an average age of 69.5 years who underwent RTSA using either a 135° or a 155° prosthesis. Although the study did not directly compare the 2 types of prostheses, it did report the separate outcomes for each prosthesis. At an average follow-up of 36.4 months, the authors found that patients who had the 135° prosthesis implanted had a mean increase in forward elevation and external rotation of 53° and 9°, while patients who had the 155° showed an increase of 56° in forward elevation and a loss of 1° of external rotation. Both prostheses showed a significant increase in forward elevation, but neither had a significant increase in external rotation. Furthermore, scapular notching was seen in 4 patients in the 155° group, while no patients in the 135° group had evidence of notching.

The results of the current study were similar in that both the 135° and 155° prosthesis showed improvements in forward elevation following surgery, and the 135° group showed a significantly greater gain in external rotation than the 155° group. A significant component of shoulder function and patient satisfaction following RTSA is active ROM. However, this variable has not explicitly been evaluated in the literature until now. The clinical significance of this finding is unclear. Patients with adequate external rotation prior to surgery likely would not see a functional difference between prostheses, while those patients who were borderline on a functional amount of external rotation would see a clinically significant benefit with the 135° prosthesis. Studies have shown that the 135° prosthesis is more anatomic than the 155°, and this could explain the difference seen in ROM outcomes between the 2 prostheses.¹⁹ Ladermann and colleagues²² recently created and evaluated a 3-dimensional computer model to evaluate possible differences between the 135° and 155° prosthesis. The authors found a significant increase in external rotation of the 135° compared to the 155°, likely related to a difference in acromiohumeral distance as well as inlay vs onlay humeral trays between the 2 prostheses. The results of this study parallel the computer model, thereby validating these experimental results.

It is important to understand what the minimum functional ROM of the shoulder is (in other words, the ROM necessary to complete activities of daily living (ADLs).²³ Namdari and colleagues²⁴ used motion analysis software to evaluate the shoulder ROM necessary to complete 10 different ADLs, including combing hair, washing the back of the opposite shoulder, and reaching a shelf above their head without bending their elbow in 20 patients with a mean age of 29.2 years. They found that patients required 121° ± 6.7° of flexion, 46° ± 5.3° of extension, 128° ± 7.9° of abduction, 116° ± 9.1° of cross-body adduction, 59° ± 10° of external rotation with the arm 90° abducted, and 102° ± 7.7° of internal rotation with the arm at the side (external rotation with the arm at the side was not well defined).²⁴ Hence, while abduction and forward elevation seem comparable, the results from the current study do raise concerns about the amount of external rotation obtained following RTSA as it relates to a patients’ ability to perform ADLs, specifically in the 155° prosthesis, as the average postoperative external rotation in this group was 20.5°. Therefore, based on the results of this study, it appears that, while both the 135° and 155° RTSA prostheses provide similar gain in forward elevation and abduction ROM as well as overall forward elevation and abduction, the 135° prosthesis provides significantly more external rotation with the arm at the side than the 155° prosthesis.

Limitations

Although this study attempted to look at all studies that reported active ROM in patients following a RTSA, and 2 authors performed the search, there is a possibility that some studies were missed, introducing study selection bias. Furthermore, the mean follow-up was over 3 years following surgery, but the minimum follow-up requirement for studies to be included was only 12 months. Hence, this transfer bias introduces the possibility that the patient’s ROM would have changed had they been followed for a standard period of time. There are many variables that come into play in evaluating ROM, and although the study attempted to control for these, there are some that could not be controlled for due to lack of reporting by some studies. Glenosphere size and humeral retroversion were not recorded, as they were not reliably reported in all studies, so motion outcomes based on these variables was not evaluated. Complications and clinical outcomes were not assessed in this review and as such, conclusions regarding these variables cannot be drawn from this study. Finally, indications for surgery were not reliably reported in the studies included in this paper, so differences may have existed between surgical indications of the 135° and 155° groups that could have affected outcomes.

Conclusion

Patients who receive a 135° RTSA gain significantly more external rotation from pre- to postsurgery and have an overall greater amount of external rotation than patients who receive a 155° prosthesis. Both groups show improvements in forward elevation, external rotation, and abduction following surgery.

Reverse total shoulder arthroplasty (RTSA) has become a reliable treatment option for many pathologic conditions of the shoulder, including rotator cuff arthropathy, proximal humerus fractures, and others.^1-4 While the treatment outcomes have generally been reported as good, some concern exists over the postoperative range of motion (ROM) in patients following RTSA, including external rotation.^5-7 The original RTSA design was introduced by Neer in the 1970s and has undergone many modifications since that time.^1,2 The original Grammont-style prosthesis involved medialization of the glenoid, inferiorizing the center of rotation (with increased deltoid tensioning), and a neck-shaft angle of 155°.^1,8 While clinical results of the 155° design were encouraging, concerns arose over the significance of the common finding of scapular notching, or contact between the scapular neck and inferior portion of the humeral polyethylene when the arm is adducted.^9,10

To address this concern, a prosthesis design with a 135° neck-shaft angle was introduced.¹¹ This new design did significantly decrease the rate of scapular notching, and although some reported a concern over implant stability with the 135° prosthesis, recent data has shown no difference in dislocation rates between the 135° and 155° prostheses.³ A different variable that has not been evaluated between these prostheses is the active ROM that is achieved postoperatively, and the change in ROM from pre- to post-RTSA.^12,13 As active ROM plays a significant role in shoulder function and patient satisfaction, the question of whether a significant difference exists in postoperative ROM between the 135° and 155° prostheses must be addressed.

The purpose of this study was to perform a systematic review investigating active ROM following RTSA to determine if active postoperative ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. The authors hypothesize that there will be no significant difference in active postoperative ROM between the 135° and 155° prostheses, and that the difference between preoperative and postoperative ROM (that is, the amount of motion gained by the surgery) will not significantly differ between the 135° and 155° prostheses.

Methods

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist.¹⁵ Systematic review registration was performed using the PROSPERO international prospective register of systematic reviews (registration date 3/9/15, registration number CRD42015017367).¹⁶ Two reviewers independently conducted the search on March 7, 2015 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (((((reverse[Title/Abstract]) AND shoulder[Title/Abstract]) AND arthroplasty[Title/Abstract]) NOT arthroscopic[Title/Abstract]) NOT cadaver[Title/Abstract]) NOT biomechanical[Title/Abstract]. English language Level I-IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine¹⁷) clinical studies that reported the type of RTSA prosthesis that was used as well as postoperative ROM with at least 12 months follow-up were eligible. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject publications were discovered, the study with the longer duration of follow-up or larger number of patients was included. Level V evidence reviews, letters to the editor, basic science, biomechanical studies, arthroscopic shoulder surgery, imaging, surgical technique, and classification studies were excluded. Studies were excluded if both a 135° and 155° prosthesis were utilized and the outcomes were not stratified by the humeral inclination. Studies that did not report ROM were excluded.

A total of 456 studies were located, and, after implementation of the exclusion criteria, 65 studies from 2005-2015 were included in the final analysis (Figure). Subjects of interest in this systematic review underwent a RTSA. Studies were not excluded based on the surgical indications (rotator cuff tear arthropathy, proximal humerus fractures, osteoarthritis) and there was no minimum follow-up or rehabilitation requirement. Study and subject demographic parameters analyzed included year of publication, journal of publication, country and continent of publication, years of subject enrollment, presence of study financial conflict of interest, number of subjects and shoulders, gender, age, the manufacturer and type of prosthesis used, and the degree of the humeral inclination (135° vs 155° humeral cup). Preoperative ROM, including forward elevation, abduction, external rotation with the arm adducted, and external rotation with the arm at 90° of abduction, were recorded. The same ROM measurements were recorded for the final follow-up visit that was reported. Internal rotation was recorded, but because of the variability with how this measurement was reported, it was not analyzed. Clinical outcome scores and complications were not assessed. Study methodological quality was evaluated using the Modified Coleman Methodology Score (MCMS).¹⁸

Statistical Analysis

Descriptive statistics were calculated, including mean ± standard deviation for quantitative continuous data and frequencies with percentages for qualitative categorical data. ROM comparisons between 135° and 155° components (pre- vs postoperative for each and postoperative between the 2) were made using 2 proportion z-test calculator (http://in-silico.net/tools/statistics/ztest) using alpha .05 because of the difference in sample sizes between compared groups.

Results

Sixty-five studies with 3302 patients (3434 shoulders) were included in this study. There was a total of 1211 shoulders in the 135° lateralized glenosphere group and 2223 shoulders in the 155° group. The studies had an average MCMS of 40.4 ± 8.2 (poor), 48% of studies reported a conflict of interest, 32% had no conflict of interest, and 20% did not report whether a conflict of interest existed or not. The majority of studies included were level IV evidence (85%). Mean patient age was 71.1 ± 7.6 years; 29% of patients were male and 71% were female. No significant difference existed between patient age at the time of surgery; the average age of patients in the 135° lateralized glenosphere group was 71.67 ± 3.8 years, while the average patient age of patients in the 155° group was 70.97 ± 8.8 years. Mean follow-up for all patients included in this study was 37.2 ± 16.5 months. Of the 65 studies included, 3 were published from Asia, 4 were published from Australia, 24 were from North America, and 34 were from Europe. Of the individual countries whose studies were included, the United States had 23 included studies, France had 13 included studies, and Italy had 4 included studies. All other countries had <4 studies included.

Patients who received either a 135° or a 155° prosthesis showed significant improvements in external rotation with the arm at the side (P < .05), forward elevation (P < .05), and abduction (P < .05) following surgery (Table). When comparing the 135° and 155° groups, patients who received a 135° prosthesis showed significantly greater improvements in external rotation with the arm at the side (P < .001) and had significantly more overall external rotation postoperatively (P < .001) than patients who received a 155° prosthesis. The only preoperative ROM difference between groups was the 155° group started with significantly more forward elevation than the 135°group prior to surgery (P = .002).

Discussion

RTSA is indicated in patients with rotator cuff tear arthropathy, pseudoparalysis, and a functional deltoid.^1,2,4 The purpose of this systematic review was to determine if active ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. Forward elevation, abduction, and external rotation all significantly improved following surgery in both groups, with no significant difference between groups in motion or amount of motion improvement, mostly confirming the study hypotheses. However, patients in the 135° group had significantly greater postoperative external rotation and greater amount of external rotation improvement compared to the 155° group.

Two of the frequently debated issues regarding implant geometry is stability and scapular notching between the 135° and 155° humeral inclination designs. Erickson and colleagues3 recently evaluated the rate of scapular notching and dislocations between the 135° and 155° RTSA prostheses. The authors found that the 135° prosthesis had a significantly lower incidence of scapular notching vs the 155° group and that the rate of dislocations was not significantly different between groups.³ In the latter systematic review, the authors attempted to evaluate ROM between the 135° and 155° prostheses, but as the inclusion criteria of the study was reporting on scapular notching and dislocation rates, many studies reporting solely on ROM were excluded, and the influence of humeral inclination on ROM was inconclusive.³ Furthermore, there have been no studies that have directly compared ROM following RTSA between the 135° and 155° prostheses. While studies evaluating each prosthesis on an individual level have shown an improvement in ROM from pre- to postsurgery, there have been no large studies that have compared the postoperative ROM and change in pre- to postoperative ROM between the 135° and 155° prostheses.^11,13,19,20

One study by Valenti and colleagues²¹ evaluated a group of 30 patients with an average age of 69.5 years who underwent RTSA using either a 135° or a 155° prosthesis. Although the study did not directly compare the 2 types of prostheses, it did report the separate outcomes for each prosthesis. At an average follow-up of 36.4 months, the authors found that patients who had the 135° prosthesis implanted had a mean increase in forward elevation and external rotation of 53° and 9°, while patients who had the 155° showed an increase of 56° in forward elevation and a loss of 1° of external rotation. Both prostheses showed a significant increase in forward elevation, but neither had a significant increase in external rotation. Furthermore, scapular notching was seen in 4 patients in the 155° group, while no patients in the 135° group had evidence of notching.

The results of the current study were similar in that both the 135° and 155° prosthesis showed improvements in forward elevation following surgery, and the 135° group showed a significantly greater gain in external rotation than the 155° group. A significant component of shoulder function and patient satisfaction following RTSA is active ROM. However, this variable has not explicitly been evaluated in the literature until now. The clinical significance of this finding is unclear. Patients with adequate external rotation prior to surgery likely would not see a functional difference between prostheses, while those patients who were borderline on a functional amount of external rotation would see a clinically significant benefit with the 135° prosthesis. Studies have shown that the 135° prosthesis is more anatomic than the 155°, and this could explain the difference seen in ROM outcomes between the 2 prostheses.¹⁹ Ladermann and colleagues²² recently created and evaluated a 3-dimensional computer model to evaluate possible differences between the 135° and 155° prosthesis. The authors found a significant increase in external rotation of the 135° compared to the 155°, likely related to a difference in acromiohumeral distance as well as inlay vs onlay humeral trays between the 2 prostheses. The results of this study parallel the computer model, thereby validating these experimental results.

It is important to understand what the minimum functional ROM of the shoulder is (in other words, the ROM necessary to complete activities of daily living (ADLs).²³ Namdari and colleagues²⁴ used motion analysis software to evaluate the shoulder ROM necessary to complete 10 different ADLs, including combing hair, washing the back of the opposite shoulder, and reaching a shelf above their head without bending their elbow in 20 patients with a mean age of 29.2 years. They found that patients required 121° ± 6.7° of flexion, 46° ± 5.3° of extension, 128° ± 7.9° of abduction, 116° ± 9.1° of cross-body adduction, 59° ± 10° of external rotation with the arm 90° abducted, and 102° ± 7.7° of internal rotation with the arm at the side (external rotation with the arm at the side was not well defined).²⁴ Hence, while abduction and forward elevation seem comparable, the results from the current study do raise concerns about the amount of external rotation obtained following RTSA as it relates to a patients’ ability to perform ADLs, specifically in the 155° prosthesis, as the average postoperative external rotation in this group was 20.5°. Therefore, based on the results of this study, it appears that, while both the 135° and 155° RTSA prostheses provide similar gain in forward elevation and abduction ROM as well as overall forward elevation and abduction, the 135° prosthesis provides significantly more external rotation with the arm at the side than the 155° prosthesis.

Limitations

Although this study attempted to look at all studies that reported active ROM in patients following a RTSA, and 2 authors performed the search, there is a possibility that some studies were missed, introducing study selection bias. Furthermore, the mean follow-up was over 3 years following surgery, but the minimum follow-up requirement for studies to be included was only 12 months. Hence, this transfer bias introduces the possibility that the patient’s ROM would have changed had they been followed for a standard period of time. There are many variables that come into play in evaluating ROM, and although the study attempted to control for these, there are some that could not be controlled for due to lack of reporting by some studies. Glenosphere size and humeral retroversion were not recorded, as they were not reliably reported in all studies, so motion outcomes based on these variables was not evaluated. Complications and clinical outcomes were not assessed in this review and as such, conclusions regarding these variables cannot be drawn from this study. Finally, indications for surgery were not reliably reported in the studies included in this paper, so differences may have existed between surgical indications of the 135° and 155° groups that could have affected outcomes.

Conclusion

Patients who receive a 135° RTSA gain significantly more external rotation from pre- to postsurgery and have an overall greater amount of external rotation than patients who receive a 155° prosthesis. Both groups show improvements in forward elevation, external rotation, and abduction following surgery.

Reverse total shoulder arthroplasty (RTSA) has become a reliable treatment option for many pathologic conditions of the shoulder, including rotator cuff arthropathy, proximal humerus fractures, and others.^1-4 While the treatment outcomes have generally been reported as good, some concern exists over the postoperative range of motion (ROM) in patients following RTSA, including external rotation.^5-7 The original RTSA design was introduced by Neer in the 1970s and has undergone many modifications since that time.^1,2 The original Grammont-style prosthesis involved medialization of the glenoid, inferiorizing the center of rotation (with increased deltoid tensioning), and a neck-shaft angle of 155°.^1,8 While clinical results of the 155° design were encouraging, concerns arose over the significance of the common finding of scapular notching, or contact between the scapular neck and inferior portion of the humeral polyethylene when the arm is adducted.^9,10

To address this concern, a prosthesis design with a 135° neck-shaft angle was introduced.¹¹ This new design did significantly decrease the rate of scapular notching, and although some reported a concern over implant stability with the 135° prosthesis, recent data has shown no difference in dislocation rates between the 135° and 155° prostheses.³ A different variable that has not been evaluated between these prostheses is the active ROM that is achieved postoperatively, and the change in ROM from pre- to post-RTSA.^12,13 As active ROM plays a significant role in shoulder function and patient satisfaction, the question of whether a significant difference exists in postoperative ROM between the 135° and 155° prostheses must be addressed.

The purpose of this study was to perform a systematic review investigating active ROM following RTSA to determine if active postoperative ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. The authors hypothesize that there will be no significant difference in active postoperative ROM between the 135° and 155° prostheses, and that the difference between preoperative and postoperative ROM (that is, the amount of motion gained by the surgery) will not significantly differ between the 135° and 155° prostheses.

Methods

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist.¹⁵ Systematic review registration was performed using the PROSPERO international prospective register of systematic reviews (registration date 3/9/15, registration number CRD42015017367).¹⁶ Two reviewers independently conducted the search on March 7, 2015 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (((((reverse[Title/Abstract]) AND shoulder[Title/Abstract]) AND arthroplasty[Title/Abstract]) NOT arthroscopic[Title/Abstract]) NOT cadaver[Title/Abstract]) NOT biomechanical[Title/Abstract]. English language Level I-IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine¹⁷) clinical studies that reported the type of RTSA prosthesis that was used as well as postoperative ROM with at least 12 months follow-up were eligible. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject publications were discovered, the study with the longer duration of follow-up or larger number of patients was included. Level V evidence reviews, letters to the editor, basic science, biomechanical studies, arthroscopic shoulder surgery, imaging, surgical technique, and classification studies were excluded. Studies were excluded if both a 135° and 155° prosthesis were utilized and the outcomes were not stratified by the humeral inclination. Studies that did not report ROM were excluded.

A total of 456 studies were located, and, after implementation of the exclusion criteria, 65 studies from 2005-2015 were included in the final analysis (Figure). Subjects of interest in this systematic review underwent a RTSA. Studies were not excluded based on the surgical indications (rotator cuff tear arthropathy, proximal humerus fractures, osteoarthritis) and there was no minimum follow-up or rehabilitation requirement. Study and subject demographic parameters analyzed included year of publication, journal of publication, country and continent of publication, years of subject enrollment, presence of study financial conflict of interest, number of subjects and shoulders, gender, age, the manufacturer and type of prosthesis used, and the degree of the humeral inclination (135° vs 155° humeral cup). Preoperative ROM, including forward elevation, abduction, external rotation with the arm adducted, and external rotation with the arm at 90° of abduction, were recorded. The same ROM measurements were recorded for the final follow-up visit that was reported. Internal rotation was recorded, but because of the variability with how this measurement was reported, it was not analyzed. Clinical outcome scores and complications were not assessed. Study methodological quality was evaluated using the Modified Coleman Methodology Score (MCMS).¹⁸

Statistical Analysis

Descriptive statistics were calculated, including mean ± standard deviation for quantitative continuous data and frequencies with percentages for qualitative categorical data. ROM comparisons between 135° and 155° components (pre- vs postoperative for each and postoperative between the 2) were made using 2 proportion z-test calculator (http://in-silico.net/tools/statistics/ztest) using alpha .05 because of the difference in sample sizes between compared groups.

Results

Sixty-five studies with 3302 patients (3434 shoulders) were included in this study. There was a total of 1211 shoulders in the 135° lateralized glenosphere group and 2223 shoulders in the 155° group. The studies had an average MCMS of 40.4 ± 8.2 (poor), 48% of studies reported a conflict of interest, 32% had no conflict of interest, and 20% did not report whether a conflict of interest existed or not. The majority of studies included were level IV evidence (85%). Mean patient age was 71.1 ± 7.6 years; 29% of patients were male and 71% were female. No significant difference existed between patient age at the time of surgery; the average age of patients in the 135° lateralized glenosphere group was 71.67 ± 3.8 years, while the average patient age of patients in the 155° group was 70.97 ± 8.8 years. Mean follow-up for all patients included in this study was 37.2 ± 16.5 months. Of the 65 studies included, 3 were published from Asia, 4 were published from Australia, 24 were from North America, and 34 were from Europe. Of the individual countries whose studies were included, the United States had 23 included studies, France had 13 included studies, and Italy had 4 included studies. All other countries had <4 studies included.

Patients who received either a 135° or a 155° prosthesis showed significant improvements in external rotation with the arm at the side (P < .05), forward elevation (P < .05), and abduction (P < .05) following surgery (Table). When comparing the 135° and 155° groups, patients who received a 135° prosthesis showed significantly greater improvements in external rotation with the arm at the side (P < .001) and had significantly more overall external rotation postoperatively (P < .001) than patients who received a 155° prosthesis. The only preoperative ROM difference between groups was the 155° group started with significantly more forward elevation than the 135°group prior to surgery (P = .002).

Discussion

RTSA is indicated in patients with rotator cuff tear arthropathy, pseudoparalysis, and a functional deltoid.^1,2,4 The purpose of this systematic review was to determine if active ROM following RTSA differs between the 135° and 155° humeral inclination prostheses, and to determine if there is a significant difference between the change in preoperative and postoperative ROM between the 135° and 155° prostheses. Forward elevation, abduction, and external rotation all significantly improved following surgery in both groups, with no significant difference between groups in motion or amount of motion improvement, mostly confirming the study hypotheses. However, patients in the 135° group had significantly greater postoperative external rotation and greater amount of external rotation improvement compared to the 155° group.

Two of the frequently debated issues regarding implant geometry is stability and scapular notching between the 135° and 155° humeral inclination designs. Erickson and colleagues3 recently evaluated the rate of scapular notching and dislocations between the 135° and 155° RTSA prostheses. The authors found that the 135° prosthesis had a significantly lower incidence of scapular notching vs the 155° group and that the rate of dislocations was not significantly different between groups.³ In the latter systematic review, the authors attempted to evaluate ROM between the 135° and 155° prostheses, but as the inclusion criteria of the study was reporting on scapular notching and dislocation rates, many studies reporting solely on ROM were excluded, and the influence of humeral inclination on ROM was inconclusive.³ Furthermore, there have been no studies that have directly compared ROM following RTSA between the 135° and 155° prostheses. While studies evaluating each prosthesis on an individual level have shown an improvement in ROM from pre- to postsurgery, there have been no large studies that have compared the postoperative ROM and change in pre- to postoperative ROM between the 135° and 155° prostheses.^11,13,19,20

One study by Valenti and colleagues²¹ evaluated a group of 30 patients with an average age of 69.5 years who underwent RTSA using either a 135° or a 155° prosthesis. Although the study did not directly compare the 2 types of prostheses, it did report the separate outcomes for each prosthesis. At an average follow-up of 36.4 months, the authors found that patients who had the 135° prosthesis implanted had a mean increase in forward elevation and external rotation of 53° and 9°, while patients who had the 155° showed an increase of 56° in forward elevation and a loss of 1° of external rotation. Both prostheses showed a significant increase in forward elevation, but neither had a significant increase in external rotation. Furthermore, scapular notching was seen in 4 patients in the 155° group, while no patients in the 135° group had evidence of notching.

The results of the current study were similar in that both the 135° and 155° prosthesis showed improvements in forward elevation following surgery, and the 135° group showed a significantly greater gain in external rotation than the 155° group. A significant component of shoulder function and patient satisfaction following RTSA is active ROM. However, this variable has not explicitly been evaluated in the literature until now. The clinical significance of this finding is unclear. Patients with adequate external rotation prior to surgery likely would not see a functional difference between prostheses, while those patients who were borderline on a functional amount of external rotation would see a clinically significant benefit with the 135° prosthesis. Studies have shown that the 135° prosthesis is more anatomic than the 155°, and this could explain the difference seen in ROM outcomes between the 2 prostheses.¹⁹ Ladermann and colleagues²² recently created and evaluated a 3-dimensional computer model to evaluate possible differences between the 135° and 155° prosthesis. The authors found a significant increase in external rotation of the 135° compared to the 155°, likely related to a difference in acromiohumeral distance as well as inlay vs onlay humeral trays between the 2 prostheses. The results of this study parallel the computer model, thereby validating these experimental results.

It is important to understand what the minimum functional ROM of the shoulder is (in other words, the ROM necessary to complete activities of daily living (ADLs).²³ Namdari and colleagues²⁴ used motion analysis software to evaluate the shoulder ROM necessary to complete 10 different ADLs, including combing hair, washing the back of the opposite shoulder, and reaching a shelf above their head without bending their elbow in 20 patients with a mean age of 29.2 years. They found that patients required 121° ± 6.7° of flexion, 46° ± 5.3° of extension, 128° ± 7.9° of abduction, 116° ± 9.1° of cross-body adduction, 59° ± 10° of external rotation with the arm 90° abducted, and 102° ± 7.7° of internal rotation with the arm at the side (external rotation with the arm at the side was not well defined).²⁴ Hence, while abduction and forward elevation seem comparable, the results from the current study do raise concerns about the amount of external rotation obtained following RTSA as it relates to a patients’ ability to perform ADLs, specifically in the 155° prosthesis, as the average postoperative external rotation in this group was 20.5°. Therefore, based on the results of this study, it appears that, while both the 135° and 155° RTSA prostheses provide similar gain in forward elevation and abduction ROM as well as overall forward elevation and abduction, the 135° prosthesis provides significantly more external rotation with the arm at the side than the 155° prosthesis.

Limitations

Although this study attempted to look at all studies that reported active ROM in patients following a RTSA, and 2 authors performed the search, there is a possibility that some studies were missed, introducing study selection bias. Furthermore, the mean follow-up was over 3 years following surgery, but the minimum follow-up requirement for studies to be included was only 12 months. Hence, this transfer bias introduces the possibility that the patient’s ROM would have changed had they been followed for a standard period of time. There are many variables that come into play in evaluating ROM, and although the study attempted to control for these, there are some that could not be controlled for due to lack of reporting by some studies. Glenosphere size and humeral retroversion were not recorded, as they were not reliably reported in all studies, so motion outcomes based on these variables was not evaluated. Complications and clinical outcomes were not assessed in this review and as such, conclusions regarding these variables cannot be drawn from this study. Finally, indications for surgery were not reliably reported in the studies included in this paper, so differences may have existed between surgical indications of the 135° and 155° groups that could have affected outcomes.

Conclusion

Patients who receive a 135° RTSA gain significantly more external rotation from pre- to postsurgery and have an overall greater amount of external rotation than patients who receive a 155° prosthesis. Both groups show improvements in forward elevation, external rotation, and abduction following surgery.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Patients with chronic myeloid leukemia (CML) who received tyrosine kinase inhibitors (TKIs) had 1.7 times the rate of arterial or venous vascular events of population-based controls in a large retrospective cohort study.

In addition, second-generation TKIs were associated with higher rates of myocardial infarction than was first-generation imatinib, Dr. Torsten Dahlén of Karolinska University Hospital Solna, Stockholm, and his associates reported. Although absolute numbers of cardiovascular events were low, physicians “should be aware of these risk factors when initiating TKI therapy in patients with CML,” the authors wrote in a study published online June 13 in the Annals of Internal Medicine .

Tyrosine kinase inhibitors have “revolutionized” the prognosis of CML and are generally well tolerated, the researchers noted. But case reports and follow-up studies of clinical trial participants have raised concerns about cardiovascular toxicities with second-generation TKIs, such as nilotinib, they added.

To further study the issue, the investigators compared 896 patients in Sweden who were diagnosed with CML between 2002 and 2012 with 4,438 age- and sex-matched controls from the national population register. By crosschecking both groups against a national patient database, the investigators calculated rates of venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular ischemia, and other arterial thromboses (Ann. Intern. Med. 2016 Jun 13. doi: 10.7326/M15-2306).

A total of 846 CML patients (94%) received a TKI during a median of 4.2 years of follow-up, the investigators reported. First-line therapy usually consisted of imatinib (89%), followed by nilotinib (9%) and dasatinib (1%).

The TKI cohort had 78 arterial and venous events during 3,969 person-years of follow-up, compared with 250 events during 21,917 person-years of follow-up for controls, for a statistically significant incidence rate ratio (IRR) of 1.7 (95% confidence interval, 1.3-2.2). Individual IRRs for arterial and venous events also reached statistical significance at 1.5 (95% CI, 1.1-2.1) and 2.0 (95% CI, 1.2-3.3), respectively. Deep venous thrombosis and myocardial infarction accounted for most of the excess risk, with IRRs of 2.2 (95% CI, 1.1-4.4) and 1.9 (95% CI, 1.3-2.7), respectively.

When investigators looked only at the TKI cohort, they found that the rates of arterial thromboembolic events were highest for nilotinib (29 events per 1,000 person-years), followed by dasatinib (19 events per 1,000 person-years) and imatinib (13 events per 1,000 person-years). Nilotinib also was associated with a substantially higher rate of all arterial and venous events (42/1,000 person-years) than dasatinib (20/1,000 person-years) and imatinib (16/1,000 person-years).

Furthermore, nilotinib and dasatinib were associated with higher rates of myocardial infarctions (29 and 19 per 1,000 person-years, respectively) and cerebrovascular ischemic events (11 and 4 events per 1,000 person-years, respectively) than was imatinib (8 events per 1,000 person-years and 4 events per 1,000 person-years, respectively). However, the absolute numbers of events were too small to allow for statistical comparisons, the researchers said.

“The observed increase in thrombotic events may be related to CML itself, the treatment administered, or both,” they noted, but “the prevalence of myocardial infarction in patients with CML before diagnosis was similar to that of the control population, [which] might indicate a treatment-related association.”

Among the 31 patients on TKIs who had a myocardial infarction, 26 (84%) had been previously diagnosed with at least one risk factor for cardiovascular disease, including diabetes (19%), atrial fibrillation (26%), angina pectoris (39%), hypertension (55%), and hyperlipidemia (23%).

Most patients who received nilotinib or dasatinib had previously received imatinib, meaning that they could have had more advanced disease that increased their risk of adverse events, according to the researchers.

“The small number of events also leads us to exercise caution in drawing any strong conclusions,” they added. “Future data from the Swedish CML register will provide more robust evidence regarding the risks of individual drugs as exposure time increases.”

The researchers received no funding for the work. Dr. Dahlén disclosed grant support from Merck outside the submitted work. Two coinvestigators disclosed ties to Ariad, Bristol-Myers, Novartis, and Squibb.

Developing a high-efficiency operating room (OR) is both a challenging and rewarding goal for any healthcare system. The OR is traditionally a high-cost/high-revenue environment¹ and operative efficacy has been correlated with low complication rates and surgical success.² An efficient OR is one that maximizes utilization while providing safe, reproducible, cost-effective, high-quality care. Total joint arthroplasty (TJA) has occupied the center stage for OR efficiency research, in part due to increasing demands from our aging population³ and economic pressures related to high implant costs, decreased reimbursement, and competition for market shares when OR time and space are limited.

A PubMed search on OR efficiency in TJA shows a disproportionately high focus on surgical technique, such as use of patient-specific instrumentation (PSI), computer-assisted surgery (CAS), minimally invasive surgery, and closure with barbed suture. In a retrospective review of 352 TKA patients who had PSI vs conventional instrumentation, DeHaan and colleagues⁴ found that PSI was associated with significantly decreased operative and room turnover times (20.4 minutes and 6.4 minutes, respectively). In another prospective multicenter study, Mont and colleagues⁵ showed a reduction in surgical time by 8.90 min for navigated total knee arthroplasty (TKA) performed with single-use instruments, cutting blocks, and trials. Other investigators compared PSI to CAS in TKA and found PSI to be 1.45 times more profitable than CAS, with 3 PSI cases performed in an 8-hour OR day compared to 2 CAS cases.⁶

There is no question that improved surgical technique can enhance OR efficiency. However, this model, while promising, is difficult to implement on a wide scale due to surgeon preferences, vendor limitations, and added costs related to the advanced preoperative imaging studies, manufacturing of the custom guides, and maintenance of navigation equipment. In addition, while interventions such as the use of barbed suture have the potential for speeding closure time, the time saved (4.7 minutes in one randomized trial)⁷ may not be enough to affect major utilization differences per OR per day. These technologies are also frequently employed by high-volume surgeons with high-volume teams and institutions.

Ideally, we need investment in the human capital and a collective change in work cultures to produce high-quality, well-choreographed, easily reproducible routines. An efficient OR requires the synchronous involvement of a large team of individuals, including hospital administrators, surgery schedulers, surgeons, anesthesiologists, preoperative holding area staff, OR nurses, surgical attendants, sterile processing personnel, and recovery room nurses. Case schedulers should match allocated block time with time required for surgery based on the historical performance of the individual surgeon, preferably scheduling similar cases on the same day. Preoperative work-up and medical clearance should be completed prior to scheduling to avoid last-minute cancellations. Patient reminders and accommodations for those traveling from long distances can further minimize late arrivals. Prompt initiation of the perioperative clinical pathway upon a patient’s check-in is important. The surgical site should be marked and the anesthesia plan confirmed upon arrival in the preoperative holding area. Necessary products need to be ready and/or administrated in time for transfer to the OR. These include prophylactic antibiotics, coagulation factors (eg, tranexamic acid), and blood products as indicated. Spinal anesthesia, regional nerve blocks, and intravenous (IV) lines should be completed before transfer to the OR. A “block room” close to the OR can allow concurrent induction of anesthesia and has been shown to increase the number of surgical cases performed during a regular workday.⁸ Hair clipping within the surgical site and pre-scrubbing of the operative extremity should also be performed prior to transfer to the OR in order to minimize micro-organisms and dispersal of loose hair onto the sterile field.

Upon arrival of the patient to the OR, instrument tables based on the surgeon preference cards should be opened, instrument count and implant templating completed, necessary imaging displayed, and OR staff ready with specific responsibilities assigned to each member. Small and colleagues⁹ showed that using dedicated orthopedic staff familiar with the surgical routine decreased operative time by 19 minutes per procedure, or 1.25 hours for a surgeon performing 4 primary TJAs per day. Practices such as routine placement of a urinary catheter should be seriously scrutinized. In a randomized prospective study of patients undergoing total hip arthroplasty under spinal anesthesia, Miller and colleagues¹⁰ found no benefit for indwelling catheters in preventing urinary retention. In another randomized prospective study, Huang and colleagues¹¹ found the prevalence of urinary tract infections was significantly higher in TJA patients who received indwelling urinary catheters.

A scrub nurse familiar with the instruments, their assembly, and the sequence of events can ensure efficient surgical flow. The scrub nurse needs to anticipate missing or defective tools and call for them, ideally before the incision is made. Direct comparison studies are needed to assess the efficacy of routine intraoperative imaging vs commercially available universal cup alignment guides or clinical examinations in determining acceptable component positioning and limb length. Following component implantation and before wound closure, the circulating nurse should initiate the process of acquisition of a recovery room bed, make sure dressing supplies and necessary equipment are available, and call for surgical attendants. Lack of surgical attendants, delayed transfer from the OR table to hospital bed, and prolonged acquisition of a recovery room bed have been identified as major OR inefficiencies in a retrospective study by Attarian and colleagues.¹²

In summary, time is the OR’s most valuable resource.¹³ We believe that a consistent, almost automated attitude to the above procedures decreases variability and improves efficiency. By providing clear communication of the surgical needs with the team, having consistent anesthesia and nursing staff, implementing consistent perioperative protocols, and insuring that all necessary instruments and modalities are available prior to starting the procedure, we were able to sustainably increase OR throughput in a large teaching hospital.^9,14 This process, however, requires constant review to identify and eliminate new gaps, with each member of the team sharing a frank desire to improve. In this regard, hospital administrators share the duty to facilitate the implementation of any necessary changes, allocation of needed resources, and rewarding good effort, which could ultimately increase staff satisfaction and retention. Because efficiency is the ratio of benefits (eg, revenue, safety, etc.) to investment (eg, implant costs, wages, etc.), raises the question: what would be the effect of transitioning from hourly-wage to a salary-based system for key support staff? Unlike hourly-wage personnel, who have no incentive for productivity, a salaried employee assigned to a high-efficiency OR will inherently strive for improvement, employing higher organizational skills to accomplish a common goal. To our knowledge, there is no published data on this topic.

Developing a high-efficiency operating room (OR) is both a challenging and rewarding goal for any healthcare system. The OR is traditionally a high-cost/high-revenue environment¹ and operative efficacy has been correlated with low complication rates and surgical success.² An efficient OR is one that maximizes utilization while providing safe, reproducible, cost-effective, high-quality care. Total joint arthroplasty (TJA) has occupied the center stage for OR efficiency research, in part due to increasing demands from our aging population³ and economic pressures related to high implant costs, decreased reimbursement, and competition for market shares when OR time and space are limited.

A PubMed search on OR efficiency in TJA shows a disproportionately high focus on surgical technique, such as use of patient-specific instrumentation (PSI), computer-assisted surgery (CAS), minimally invasive surgery, and closure with barbed suture. In a retrospective review of 352 TKA patients who had PSI vs conventional instrumentation, DeHaan and colleagues⁴ found that PSI was associated with significantly decreased operative and room turnover times (20.4 minutes and 6.4 minutes, respectively). In another prospective multicenter study, Mont and colleagues⁵ showed a reduction in surgical time by 8.90 min for navigated total knee arthroplasty (TKA) performed with single-use instruments, cutting blocks, and trials. Other investigators compared PSI to CAS in TKA and found PSI to be 1.45 times more profitable than CAS, with 3 PSI cases performed in an 8-hour OR day compared to 2 CAS cases.⁶

There is no question that improved surgical technique can enhance OR efficiency. However, this model, while promising, is difficult to implement on a wide scale due to surgeon preferences, vendor limitations, and added costs related to the advanced preoperative imaging studies, manufacturing of the custom guides, and maintenance of navigation equipment. In addition, while interventions such as the use of barbed suture have the potential for speeding closure time, the time saved (4.7 minutes in one randomized trial)⁷ may not be enough to affect major utilization differences per OR per day. These technologies are also frequently employed by high-volume surgeons with high-volume teams and institutions.

Ideally, we need investment in the human capital and a collective change in work cultures to produce high-quality, well-choreographed, easily reproducible routines. An efficient OR requires the synchronous involvement of a large team of individuals, including hospital administrators, surgery schedulers, surgeons, anesthesiologists, preoperative holding area staff, OR nurses, surgical attendants, sterile processing personnel, and recovery room nurses. Case schedulers should match allocated block time with time required for surgery based on the historical performance of the individual surgeon, preferably scheduling similar cases on the same day. Preoperative work-up and medical clearance should be completed prior to scheduling to avoid last-minute cancellations. Patient reminders and accommodations for those traveling from long distances can further minimize late arrivals. Prompt initiation of the perioperative clinical pathway upon a patient’s check-in is important. The surgical site should be marked and the anesthesia plan confirmed upon arrival in the preoperative holding area. Necessary products need to be ready and/or administrated in time for transfer to the OR. These include prophylactic antibiotics, coagulation factors (eg, tranexamic acid), and blood products as indicated. Spinal anesthesia, regional nerve blocks, and intravenous (IV) lines should be completed before transfer to the OR. A “block room” close to the OR can allow concurrent induction of anesthesia and has been shown to increase the number of surgical cases performed during a regular workday.⁸ Hair clipping within the surgical site and pre-scrubbing of the operative extremity should also be performed prior to transfer to the OR in order to minimize micro-organisms and dispersal of loose hair onto the sterile field.

Upon arrival of the patient to the OR, instrument tables based on the surgeon preference cards should be opened, instrument count and implant templating completed, necessary imaging displayed, and OR staff ready with specific responsibilities assigned to each member. Small and colleagues⁹ showed that using dedicated orthopedic staff familiar with the surgical routine decreased operative time by 19 minutes per procedure, or 1.25 hours for a surgeon performing 4 primary TJAs per day. Practices such as routine placement of a urinary catheter should be seriously scrutinized. In a randomized prospective study of patients undergoing total hip arthroplasty under spinal anesthesia, Miller and colleagues¹⁰ found no benefit for indwelling catheters in preventing urinary retention. In another randomized prospective study, Huang and colleagues¹¹ found the prevalence of urinary tract infections was significantly higher in TJA patients who received indwelling urinary catheters.

A scrub nurse familiar with the instruments, their assembly, and the sequence of events can ensure efficient surgical flow. The scrub nurse needs to anticipate missing or defective tools and call for them, ideally before the incision is made. Direct comparison studies are needed to assess the efficacy of routine intraoperative imaging vs commercially available universal cup alignment guides or clinical examinations in determining acceptable component positioning and limb length. Following component implantation and before wound closure, the circulating nurse should initiate the process of acquisition of a recovery room bed, make sure dressing supplies and necessary equipment are available, and call for surgical attendants. Lack of surgical attendants, delayed transfer from the OR table to hospital bed, and prolonged acquisition of a recovery room bed have been identified as major OR inefficiencies in a retrospective study by Attarian and colleagues.¹²

In summary, time is the OR’s most valuable resource.¹³ We believe that a consistent, almost automated attitude to the above procedures decreases variability and improves efficiency. By providing clear communication of the surgical needs with the team, having consistent anesthesia and nursing staff, implementing consistent perioperative protocols, and insuring that all necessary instruments and modalities are available prior to starting the procedure, we were able to sustainably increase OR throughput in a large teaching hospital.^9,14 This process, however, requires constant review to identify and eliminate new gaps, with each member of the team sharing a frank desire to improve. In this regard, hospital administrators share the duty to facilitate the implementation of any necessary changes, allocation of needed resources, and rewarding good effort, which could ultimately increase staff satisfaction and retention. Because efficiency is the ratio of benefits (eg, revenue, safety, etc.) to investment (eg, implant costs, wages, etc.), raises the question: what would be the effect of transitioning from hourly-wage to a salary-based system for key support staff? Unlike hourly-wage personnel, who have no incentive for productivity, a salaried employee assigned to a high-efficiency OR will inherently strive for improvement, employing higher organizational skills to accomplish a common goal. To our knowledge, there is no published data on this topic.

Developing a high-efficiency operating room (OR) is both a challenging and rewarding goal for any healthcare system. The OR is traditionally a high-cost/high-revenue environment¹ and operative efficacy has been correlated with low complication rates and surgical success.² An efficient OR is one that maximizes utilization while providing safe, reproducible, cost-effective, high-quality care. Total joint arthroplasty (TJA) has occupied the center stage for OR efficiency research, in part due to increasing demands from our aging population³ and economic pressures related to high implant costs, decreased reimbursement, and competition for market shares when OR time and space are limited.

A PubMed search on OR efficiency in TJA shows a disproportionately high focus on surgical technique, such as use of patient-specific instrumentation (PSI), computer-assisted surgery (CAS), minimally invasive surgery, and closure with barbed suture. In a retrospective review of 352 TKA patients who had PSI vs conventional instrumentation, DeHaan and colleagues⁴ found that PSI was associated with significantly decreased operative and room turnover times (20.4 minutes and 6.4 minutes, respectively). In another prospective multicenter study, Mont and colleagues⁵ showed a reduction in surgical time by 8.90 min for navigated total knee arthroplasty (TKA) performed with single-use instruments, cutting blocks, and trials. Other investigators compared PSI to CAS in TKA and found PSI to be 1.45 times more profitable than CAS, with 3 PSI cases performed in an 8-hour OR day compared to 2 CAS cases.⁶

There is no question that improved surgical technique can enhance OR efficiency. However, this model, while promising, is difficult to implement on a wide scale due to surgeon preferences, vendor limitations, and added costs related to the advanced preoperative imaging studies, manufacturing of the custom guides, and maintenance of navigation equipment. In addition, while interventions such as the use of barbed suture have the potential for speeding closure time, the time saved (4.7 minutes in one randomized trial)⁷ may not be enough to affect major utilization differences per OR per day. These technologies are also frequently employed by high-volume surgeons with high-volume teams and institutions.

Ideally, we need investment in the human capital and a collective change in work cultures to produce high-quality, well-choreographed, easily reproducible routines. An efficient OR requires the synchronous involvement of a large team of individuals, including hospital administrators, surgery schedulers, surgeons, anesthesiologists, preoperative holding area staff, OR nurses, surgical attendants, sterile processing personnel, and recovery room nurses. Case schedulers should match allocated block time with time required for surgery based on the historical performance of the individual surgeon, preferably scheduling similar cases on the same day. Preoperative work-up and medical clearance should be completed prior to scheduling to avoid last-minute cancellations. Patient reminders and accommodations for those traveling from long distances can further minimize late arrivals. Prompt initiation of the perioperative clinical pathway upon a patient’s check-in is important. The surgical site should be marked and the anesthesia plan confirmed upon arrival in the preoperative holding area. Necessary products need to be ready and/or administrated in time for transfer to the OR. These include prophylactic antibiotics, coagulation factors (eg, tranexamic acid), and blood products as indicated. Spinal anesthesia, regional nerve blocks, and intravenous (IV) lines should be completed before transfer to the OR. A “block room” close to the OR can allow concurrent induction of anesthesia and has been shown to increase the number of surgical cases performed during a regular workday.⁸ Hair clipping within the surgical site and pre-scrubbing of the operative extremity should also be performed prior to transfer to the OR in order to minimize micro-organisms and dispersal of loose hair onto the sterile field.

Upon arrival of the patient to the OR, instrument tables based on the surgeon preference cards should be opened, instrument count and implant templating completed, necessary imaging displayed, and OR staff ready with specific responsibilities assigned to each member. Small and colleagues⁹ showed that using dedicated orthopedic staff familiar with the surgical routine decreased operative time by 19 minutes per procedure, or 1.25 hours for a surgeon performing 4 primary TJAs per day. Practices such as routine placement of a urinary catheter should be seriously scrutinized. In a randomized prospective study of patients undergoing total hip arthroplasty under spinal anesthesia, Miller and colleagues¹⁰ found no benefit for indwelling catheters in preventing urinary retention. In another randomized prospective study, Huang and colleagues¹¹ found the prevalence of urinary tract infections was significantly higher in TJA patients who received indwelling urinary catheters.

A scrub nurse familiar with the instruments, their assembly, and the sequence of events can ensure efficient surgical flow. The scrub nurse needs to anticipate missing or defective tools and call for them, ideally before the incision is made. Direct comparison studies are needed to assess the efficacy of routine intraoperative imaging vs commercially available universal cup alignment guides or clinical examinations in determining acceptable component positioning and limb length. Following component implantation and before wound closure, the circulating nurse should initiate the process of acquisition of a recovery room bed, make sure dressing supplies and necessary equipment are available, and call for surgical attendants. Lack of surgical attendants, delayed transfer from the OR table to hospital bed, and prolonged acquisition of a recovery room bed have been identified as major OR inefficiencies in a retrospective study by Attarian and colleagues.¹²

In summary, time is the OR’s most valuable resource.¹³ We believe that a consistent, almost automated attitude to the above procedures decreases variability and improves efficiency. By providing clear communication of the surgical needs with the team, having consistent anesthesia and nursing staff, implementing consistent perioperative protocols, and insuring that all necessary instruments and modalities are available prior to starting the procedure, we were able to sustainably increase OR throughput in a large teaching hospital.^9,14 This process, however, requires constant review to identify and eliminate new gaps, with each member of the team sharing a frank desire to improve. In this regard, hospital administrators share the duty to facilitate the implementation of any necessary changes, allocation of needed resources, and rewarding good effort, which could ultimately increase staff satisfaction and retention. Because efficiency is the ratio of benefits (eg, revenue, safety, etc.) to investment (eg, implant costs, wages, etc.), raises the question: what would be the effect of transitioning from hourly-wage to a salary-based system for key support staff? Unlike hourly-wage personnel, who have no incentive for productivity, a salaried employee assigned to a high-efficiency OR will inherently strive for improvement, employing higher organizational skills to accomplish a common goal. To our knowledge, there is no published data on this topic.

Since Neer and colleagues¹ first reported in 1982, glenoid loosening persists as a common cause of anatomic total shoulder arthroplasty (TSA) failure.^1-4 Currently, cemented, all-polyethylene glenoid components are the gold standard, and minimum clinical survival of 10 to 15 years is expected.^3,5 Several clinical studies^5-9 and in vitro biomechanical studies¹⁰ have suggested an advantage of pegged over keeled glenoid components, but glenoid component loosening remains a frequent complication,¹¹ with the cement–implant interface suggested as the weak link of fixation.^10,12 In addition to mechanical loosening, poor cement penetration and heat-induced necrosis have been postulated as contributing to glenoid component loosening.^13,14

Because of these potential complications, there is a growing consideration to minimize or abandon cement fixation and rely on biological fixation to polyethylene for long-term component stability.¹⁵ A newer pegged glenoid component design consists of traditional, peripherally located pegs designed for cement fixation as well as a central, uncemented, fluted, interference-fit peg that allows for bony ingrowth. Short-term clinical studies have shown that bony ingrowth into the space between the flutes can be achieved with a hybrid cementation technique and that, when that occurs, excellent outcomes are likely.^13,16-19 The immediate in vivo stability of this implant design upon initial implantation, before the cement has cured, has prompted some surgeons to consider implanting the device without cement. In a recent series in which this implant design was used without cement, clinical and radiographic results were promising.¹⁵

Despite the widespread clinical use, little biomechanical work has been done to characterize initial fixation of all-polyethylene pegged glenoid implants. We conducted a study to compare glenoid micromotion in an all-polyethylene, centrally fluted pegged glenoid component as a function of 3 fixation techniques: cementless interference-fit fixation, hybrid partial cementation based on manufacturer recommendations, and full cementation to simulate a gold-standard, traditional, cemented, pegged design.

Materials and MethodsBiomechanical Testing

The biomechanical testing methodology used in this study was based on previous studies20-23 and on ASTM standard F2028-1224 using polyurethane bone substitute 0.24 g/cm³ (Pacific Research Laboratories) with ultimate strength of 4.9 MPa and compressive modulus of 123 MPa for component implantation. This material was selected because its mechanical properties are similar to those of cancellous glenoid bone in primary shoulder arthroplasty,25 and it minimizes variability with use of cadaveric specimens. Components were mounted on an MTS 858 Mini-Bionix II materials testing frame (Figure 1). A static compressive load of 756 N (170 lb) was applied via a mass-pulley system simulating the joint compressive force the shoulder is likely to experience during higher load activities.^24,26 The glenoid component was positioned on a linear bearing to allow for joint compression.

Test Groups and Cement Fixation Techniques

All-polyethylene pegged glenoid components (Anchor Peg Glenoid, size 44; DePuy Orthopaedics) were used for biomechanical testing (Figure 1). Polyurethane blocks were reamed with a size 44 reamer until the superior-inferior distance reached 33 mm, ensuring complete seating of implant. Three fixation-technique groups were formed: interference-fit, hybrid cement, and fully cemented. Interference-fit fixation was done without polymethylmethacrylate (PMMA) cement. In hybrid fixation, 2 cm³ of PMMA (SpeedSet Cement, Stryker Orthopaedics) was injected (using a catheter tip syringe) into the peripheral peg holes and manually pressurized; the central peg was press-fit into polyurethane bone substitute. In the fully cemented group, both peripheral and central peg holes received PMMA; the peripheral peg holes were cemented as in hybrid fixation, and the central peg hole was injected with 3 cm³ of PMMA, which was then manually pressurized. The humeral head component (Global Advantage, 44×18 mm; DePuy Synthes) was mounted on the test frame actuator and centrally located within the glenoid at the start of the test.

Determination of Humeral Head Translation via Subluxation Testing

Humeral head subluxation distance, simulating a humeral head rim loading event, was calculated on the basis of preliminary tests outlined in the ASTM standard.²⁴ Three glenoids (1 per fixation technique) were mounted on the test frame with a humeral head positioned centrally within the glenoid. After the joint compressive force was applied, the humeral head was translated along the true superior axis of the glenoid at a rate of 50 mm/min. Testing software was used to record humeral head displacement and load data at a frequency of 100 Hz. Humeral head subluxation displacement was determined at the end of the linear region of the force versus displacement response. This distance, averaged from the 3 subluxation tests, was used as the subluxation distance during cyclic testing.

Determination of Glenoid Component Motion via Cyclic Testing

After subluxation displacement was determined, glenoid components were mounted on the test frame (5 per fixation technique) and subjected to 50,000 cycles of humeral head translation at a frequency of 2 Hz. Amplitude of the humeral head displacement against the glenoid component followed a sinusoidal pattern with maxima and minima represented by the subluxation displacement (positive and negative, respectively). Glenoid edge compression/distraction of the superior edge and glenoid inferior/superior translation were monitored with 2 variable resistance reluctance transducers (Microminiature DVRT; 4.5-µm resolution; MicroStrain) secured to the glenoid component and testing fixture.

Microminiature DVRT measurements of glenoid motion were taken for 5 consecutive cycles at cycles 1, 20, 100, 500, 1000, 5000, 10,000, 15,000, 20,000, 30,000, 40,000, and 50,000. Distraction-compression displacement and superior-inferior translation measurements were recorded relative to the glenoid position with the humeral head at the neutral position at a given cycle. Final glenoid micromotion data were calculated from the mean of consecutive cycles at each cycle time point.

Statistical Analysis

Glenoid motion results are reported as means and standard deviations. Comparisons with 2 factors of fixation technique and number of cycles for glenoid distraction, glenoid compression, and absolute glenoid translation were characterized with 2-way analysis of variance (SigmaPlot Version 11.0; Systat Software), with the Holm-Šídák test used for post hoc determination of significant relationships.

Results

Under subluxation testing, the humeral head translation distance at the end of the linear region was determined to be 0.50 mm. Subsequently for cyclic testing, the humeral head was then translated 0.50 mm from the neutral position of the humeral head along both the superior and inferior axes of the glenoid. All glenoids successfully completed the entire 50,000 cycles of testing. For the glenoid component, Figure 2 depicts distraction and compression, and Figure 3 depicts superior-inferior translation.

Glenoid Component Distraction

Overall, mean (SD) glenoid distraction was significantly higher for interference-fit fixation, 0.21 (0.10) mm, than for hybrid cement fixation, 0.16 (0.05) mm (P < .001), and fully cemented fixation, 0.09 (0.07) mm (P < .001). It was also significantly higher for hybrid fixation than fully cemented fixation (P < .001). From cycle 1000 to cycle 50,000, distraction was significantly higher for interference-fit fixation than for fully cemented fixation at each time point (P < .05).

Glenoid Component Compression

Mean (SD) compression was significantly higher for hybrid cement fixation, 0.31 (0.13) mm, than for interference-fit fixation, 0.17 (0.07) mm (P < .001), and fully cemented fixation, 0.17 (0.08) mm (P < .001). No significant difference was found between interference-fit and fully cemented fixation (P = .793) (Figure 2). At cycles 1, 20, 100, and 500, compression was significantly higher for hybrid fixation than for fully cemented fixation (P < .05). In addition, at cycle 500, it was significantly higher for hybrid fixation than for interference-fit fixation (P < .05).

Glenoid Component Translation

Mean (SD) glenoid translation was significantly lower for fully cemented fixation, 0.10 (0.04) mm, than for interference-fit fixation, 0.13 (0.04) mm (P < .001), and hybrid cement fixation, 0.13 (0.03) mm (P < .001), with all time points considered. There was no significant difference between interference-fit and hybrid fixation (P = .343). Initial translation at cycle 1 was significantly higher for interference-fit and hybid fixation than for fully cemented fixation.

Discussion

Despite advances in glenoid component design, glenoid loosening remains the most common cause of anatomical TSA failure. Recent implants have been designed to take advantage of an all-polyethylene component while providing long-lasting fixation through bony ingrowth into a central peg. In a study of the hybrid cementation technique drescribed here, Groh¹⁷ found no glenoid loosening or radiolucent lines but discovered fingerlike projections of bone between the flanges of the implant in 24 (29%) of 83 cases. Churchill and colleagues¹⁶ also reported bony ingrowth into the central peg in 15 (75%) of 20 patients. Furthermore, Arnold and colleagues13 reported complete bony ingrowth (6/6 inter-fin compartments) in 23 (71%) of 35 shoulders at a mean of 43 months. Wirth and colleagues¹⁹ reported increased radiodensity between the flanges of the central peg in 30 of 44 cases (68%) and osteolysis around the central peg in 3 of 44 cases (7%) at 3 years.

There are also reports of successful bony ingrowth associated with all-polyethylene components implanted without cement. In a canine study using an early ingrowth implant design, Wirth and colleagues²⁷ showed that, though initial fixation was superior with a cemented, keeled implant, pullout strength of the uncemented, pegged implant improved over time and eventually far surpassed that of the cemented, keeled implant owing to both the loosening of the cemented component and the bony ingrowth into the central peg component. Furthermore, Anglin and colleagues¹⁰ confirmed that component micromotion was lower with pegged glenoid components than with keeled components in a biomechanical model. De Wilde and colleagues¹⁵ recently reported on a series of uncemented, central fluted peg glenoids implanted in 34 patients followed clinically and with computed tomography for a minimum of 24 months. The investigators found bony ingrowth into the central peg in 27 (79%) of 34 patients and no signs of loosening in 30 (88%) of 34 patients. Incomplete lucencies around 1 or 2 peripheral pegs were found in 2 (6%) of 34 patients, and complete lucencies around 2 or more peripheral pegs were found in 2 (6%) of 34 patients. However, there was no statistical difference in clinical outcome between patients with and without loosening.

With this type of implant, initial fixation that provides stability while minimizing micromotion under biomechanical loading likely is crucial for attaining bony growth within the central peg flanges. To our knowledge, this is the first biomechanical study to compare micromotion using 3 different fixation methods with a central fluted peg glenoid component design. Of all these fixation methods, fully cemented fixation yielded the most stable glenoid throughout testing with respect to the evaluated parameters. However, this method is not necessarily clinically applicable, as a fully cemented glenoid would inhibit any bony growth within the central flange, which is necessary for long-term biological fixation. Our data showed that, though glenoid distraction was significantly lower with hybrid cement fixation, this fixation method exhibited significantly higher glenoid compression. In addition, there were no significant differences between glenoid components with hybrid fixation and glenoid components with interference-fit fixation with respect to component translation in the superior-inferior direction. These findings may indicate that initial fixation is not significantly improved by the addition of cement to the peripheral pegs in a glenoid component with a central fluted peg design.

The interference fit of the central peg is primarily responsible for conferring long-term implant stability,^13,27 which is ultimately achieved by bony formation between the flutes of the peg. Other authors have reported that, for bony ingrowth to occur, micromotion between the bone–implant interface must not exceed 20 to 150 µm.^28-30 Other than for interference-fit distraction at more than 1000 cycles and hybrid cement fixation compression at each time point throughout testing, our data fall within the reported upper limits of micromotion to support bony ingrowth. Increased micromotion in the interference-fit fixation group is seen at later time points and may be caused by the inability to simulate the potential fixation gained from bony ingrowth allowed with this surgical technique. Research is needed to further explain this increase in distraction.

Results from this study must be interpreted with caution because of limitations of the in vitro testing methodology. This biomechanical model using bone substitute characterizes glenoid fixation at time zero, directly after implantation, followed by repetitive cyclic loading simulating 5 years of implant service. This differs from the clinical scenario in which the shoulder undergoes postoperative immobilization or protected motion during which the early phases of bony remodeling are likely occurring. Furthermore, simulation of 5 years of implant service may not be necessary for an implant that is expected to achieve ultimate fixation by bony ingrowth within the first several months after implantation. Use of this implant without cement is classified off-label, and surgeons should take this into consideration during implantation. Last, this study could not simulate the effect of bony ingrowth on fixation, though our experimental technique of cementing the central peg may be a gross approximation of a fully ingrown central peg and its expected rigid fixation.

Fully cemented fixation of a polyethylene glenoid is superior to hybrid cement fixation and interference-fit fixation with respect to early glenoid micromotion. However, the long-term stability of a fully cemented polyethylene glenoid component remains a clinical concern, as fixation is achieved by bony ingrowth around the central fluted peg of the implant. In this study, interference-fit and hybrid fixation had equivocal component micromotion in biomechanical testing. Our findings suggest that cementation of the peripheral pegs confers no additional initial stability over an uncemented interference-fit technique in a biomechanical model. More research is needed to further evaluate interference-fit fixation as a viable option for implantation of a central fluted, all-polyethylene glenoid component.

Since Neer and colleagues¹ first reported in 1982, glenoid loosening persists as a common cause of anatomic total shoulder arthroplasty (TSA) failure.^1-4 Currently, cemented, all-polyethylene glenoid components are the gold standard, and minimum clinical survival of 10 to 15 years is expected.^3,5 Several clinical studies^5-9 and in vitro biomechanical studies¹⁰ have suggested an advantage of pegged over keeled glenoid components, but glenoid component loosening remains a frequent complication,¹¹ with the cement–implant interface suggested as the weak link of fixation.^10,12 In addition to mechanical loosening, poor cement penetration and heat-induced necrosis have been postulated as contributing to glenoid component loosening.^13,14

Because of these potential complications, there is a growing consideration to minimize or abandon cement fixation and rely on biological fixation to polyethylene for long-term component stability.¹⁵ A newer pegged glenoid component design consists of traditional, peripherally located pegs designed for cement fixation as well as a central, uncemented, fluted, interference-fit peg that allows for bony ingrowth. Short-term clinical studies have shown that bony ingrowth into the space between the flutes can be achieved with a hybrid cementation technique and that, when that occurs, excellent outcomes are likely.^13,16-19 The immediate in vivo stability of this implant design upon initial implantation, before the cement has cured, has prompted some surgeons to consider implanting the device without cement. In a recent series in which this implant design was used without cement, clinical and radiographic results were promising.¹⁵

Despite the widespread clinical use, little biomechanical work has been done to characterize initial fixation of all-polyethylene pegged glenoid implants. We conducted a study to compare glenoid micromotion in an all-polyethylene, centrally fluted pegged glenoid component as a function of 3 fixation techniques: cementless interference-fit fixation, hybrid partial cementation based on manufacturer recommendations, and full cementation to simulate a gold-standard, traditional, cemented, pegged design.

Materials and MethodsBiomechanical Testing

The biomechanical testing methodology used in this study was based on previous studies20-23 and on ASTM standard F2028-1224 using polyurethane bone substitute 0.24 g/cm³ (Pacific Research Laboratories) with ultimate strength of 4.9 MPa and compressive modulus of 123 MPa for component implantation. This material was selected because its mechanical properties are similar to those of cancellous glenoid bone in primary shoulder arthroplasty,25 and it minimizes variability with use of cadaveric specimens. Components were mounted on an MTS 858 Mini-Bionix II materials testing frame (Figure 1). A static compressive load of 756 N (170 lb) was applied via a mass-pulley system simulating the joint compressive force the shoulder is likely to experience during higher load activities.^24,26 The glenoid component was positioned on a linear bearing to allow for joint compression.

Test Groups and Cement Fixation Techniques

All-polyethylene pegged glenoid components (Anchor Peg Glenoid, size 44; DePuy Orthopaedics) were used for biomechanical testing (Figure 1). Polyurethane blocks were reamed with a size 44 reamer until the superior-inferior distance reached 33 mm, ensuring complete seating of implant. Three fixation-technique groups were formed: interference-fit, hybrid cement, and fully cemented. Interference-fit fixation was done without polymethylmethacrylate (PMMA) cement. In hybrid fixation, 2 cm³ of PMMA (SpeedSet Cement, Stryker Orthopaedics) was injected (using a catheter tip syringe) into the peripheral peg holes and manually pressurized; the central peg was press-fit into polyurethane bone substitute. In the fully cemented group, both peripheral and central peg holes received PMMA; the peripheral peg holes were cemented as in hybrid fixation, and the central peg hole was injected with 3 cm³ of PMMA, which was then manually pressurized. The humeral head component (Global Advantage, 44×18 mm; DePuy Synthes) was mounted on the test frame actuator and centrally located within the glenoid at the start of the test.

Determination of Humeral Head Translation via Subluxation Testing

Humeral head subluxation distance, simulating a humeral head rim loading event, was calculated on the basis of preliminary tests outlined in the ASTM standard.²⁴ Three glenoids (1 per fixation technique) were mounted on the test frame with a humeral head positioned centrally within the glenoid. After the joint compressive force was applied, the humeral head was translated along the true superior axis of the glenoid at a rate of 50 mm/min. Testing software was used to record humeral head displacement and load data at a frequency of 100 Hz. Humeral head subluxation displacement was determined at the end of the linear region of the force versus displacement response. This distance, averaged from the 3 subluxation tests, was used as the subluxation distance during cyclic testing.

Determination of Glenoid Component Motion via Cyclic Testing

After subluxation displacement was determined, glenoid components were mounted on the test frame (5 per fixation technique) and subjected to 50,000 cycles of humeral head translation at a frequency of 2 Hz. Amplitude of the humeral head displacement against the glenoid component followed a sinusoidal pattern with maxima and minima represented by the subluxation displacement (positive and negative, respectively). Glenoid edge compression/distraction of the superior edge and glenoid inferior/superior translation were monitored with 2 variable resistance reluctance transducers (Microminiature DVRT; 4.5-µm resolution; MicroStrain) secured to the glenoid component and testing fixture.

Microminiature DVRT measurements of glenoid motion were taken for 5 consecutive cycles at cycles 1, 20, 100, 500, 1000, 5000, 10,000, 15,000, 20,000, 30,000, 40,000, and 50,000. Distraction-compression displacement and superior-inferior translation measurements were recorded relative to the glenoid position with the humeral head at the neutral position at a given cycle. Final glenoid micromotion data were calculated from the mean of consecutive cycles at each cycle time point.

Statistical Analysis

Glenoid motion results are reported as means and standard deviations. Comparisons with 2 factors of fixation technique and number of cycles for glenoid distraction, glenoid compression, and absolute glenoid translation were characterized with 2-way analysis of variance (SigmaPlot Version 11.0; Systat Software), with the Holm-Šídák test used for post hoc determination of significant relationships.

Results

Under subluxation testing, the humeral head translation distance at the end of the linear region was determined to be 0.50 mm. Subsequently for cyclic testing, the humeral head was then translated 0.50 mm from the neutral position of the humeral head along both the superior and inferior axes of the glenoid. All glenoids successfully completed the entire 50,000 cycles of testing. For the glenoid component, Figure 2 depicts distraction and compression, and Figure 3 depicts superior-inferior translation.

Glenoid Component Distraction

Overall, mean (SD) glenoid distraction was significantly higher for interference-fit fixation, 0.21 (0.10) mm, than for hybrid cement fixation, 0.16 (0.05) mm (P < .001), and fully cemented fixation, 0.09 (0.07) mm (P < .001). It was also significantly higher for hybrid fixation than fully cemented fixation (P < .001). From cycle 1000 to cycle 50,000, distraction was significantly higher for interference-fit fixation than for fully cemented fixation at each time point (P < .05).

Glenoid Component Compression

Mean (SD) compression was significantly higher for hybrid cement fixation, 0.31 (0.13) mm, than for interference-fit fixation, 0.17 (0.07) mm (P < .001), and fully cemented fixation, 0.17 (0.08) mm (P < .001). No significant difference was found between interference-fit and fully cemented fixation (P = .793) (Figure 2). At cycles 1, 20, 100, and 500, compression was significantly higher for hybrid fixation than for fully cemented fixation (P < .05). In addition, at cycle 500, it was significantly higher for hybrid fixation than for interference-fit fixation (P < .05).

Glenoid Component Translation

Mean (SD) glenoid translation was significantly lower for fully cemented fixation, 0.10 (0.04) mm, than for interference-fit fixation, 0.13 (0.04) mm (P < .001), and hybrid cement fixation, 0.13 (0.03) mm (P < .001), with all time points considered. There was no significant difference between interference-fit and hybrid fixation (P = .343). Initial translation at cycle 1 was significantly higher for interference-fit and hybid fixation than for fully cemented fixation.

Discussion

Despite advances in glenoid component design, glenoid loosening remains the most common cause of anatomical TSA failure. Recent implants have been designed to take advantage of an all-polyethylene component while providing long-lasting fixation through bony ingrowth into a central peg. In a study of the hybrid cementation technique drescribed here, Groh¹⁷ found no glenoid loosening or radiolucent lines but discovered fingerlike projections of bone between the flanges of the implant in 24 (29%) of 83 cases. Churchill and colleagues¹⁶ also reported bony ingrowth into the central peg in 15 (75%) of 20 patients. Furthermore, Arnold and colleagues13 reported complete bony ingrowth (6/6 inter-fin compartments) in 23 (71%) of 35 shoulders at a mean of 43 months. Wirth and colleagues¹⁹ reported increased radiodensity between the flanges of the central peg in 30 of 44 cases (68%) and osteolysis around the central peg in 3 of 44 cases (7%) at 3 years.

There are also reports of successful bony ingrowth associated with all-polyethylene components implanted without cement. In a canine study using an early ingrowth implant design, Wirth and colleagues²⁷ showed that, though initial fixation was superior with a cemented, keeled implant, pullout strength of the uncemented, pegged implant improved over time and eventually far surpassed that of the cemented, keeled implant owing to both the loosening of the cemented component and the bony ingrowth into the central peg component. Furthermore, Anglin and colleagues¹⁰ confirmed that component micromotion was lower with pegged glenoid components than with keeled components in a biomechanical model. De Wilde and colleagues¹⁵ recently reported on a series of uncemented, central fluted peg glenoids implanted in 34 patients followed clinically and with computed tomography for a minimum of 24 months. The investigators found bony ingrowth into the central peg in 27 (79%) of 34 patients and no signs of loosening in 30 (88%) of 34 patients. Incomplete lucencies around 1 or 2 peripheral pegs were found in 2 (6%) of 34 patients, and complete lucencies around 2 or more peripheral pegs were found in 2 (6%) of 34 patients. However, there was no statistical difference in clinical outcome between patients with and without loosening.

With this type of implant, initial fixation that provides stability while minimizing micromotion under biomechanical loading likely is crucial for attaining bony growth within the central peg flanges. To our knowledge, this is the first biomechanical study to compare micromotion using 3 different fixation methods with a central fluted peg glenoid component design. Of all these fixation methods, fully cemented fixation yielded the most stable glenoid throughout testing with respect to the evaluated parameters. However, this method is not necessarily clinically applicable, as a fully cemented glenoid would inhibit any bony growth within the central flange, which is necessary for long-term biological fixation. Our data showed that, though glenoid distraction was significantly lower with hybrid cement fixation, this fixation method exhibited significantly higher glenoid compression. In addition, there were no significant differences between glenoid components with hybrid fixation and glenoid components with interference-fit fixation with respect to component translation in the superior-inferior direction. These findings may indicate that initial fixation is not significantly improved by the addition of cement to the peripheral pegs in a glenoid component with a central fluted peg design.

The interference fit of the central peg is primarily responsible for conferring long-term implant stability,^13,27 which is ultimately achieved by bony formation between the flutes of the peg. Other authors have reported that, for bony ingrowth to occur, micromotion between the bone–implant interface must not exceed 20 to 150 µm.^28-30 Other than for interference-fit distraction at more than 1000 cycles and hybrid cement fixation compression at each time point throughout testing, our data fall within the reported upper limits of micromotion to support bony ingrowth. Increased micromotion in the interference-fit fixation group is seen at later time points and may be caused by the inability to simulate the potential fixation gained from bony ingrowth allowed with this surgical technique. Research is needed to further explain this increase in distraction.

Results from this study must be interpreted with caution because of limitations of the in vitro testing methodology. This biomechanical model using bone substitute characterizes glenoid fixation at time zero, directly after implantation, followed by repetitive cyclic loading simulating 5 years of implant service. This differs from the clinical scenario in which the shoulder undergoes postoperative immobilization or protected motion during which the early phases of bony remodeling are likely occurring. Furthermore, simulation of 5 years of implant service may not be necessary for an implant that is expected to achieve ultimate fixation by bony ingrowth within the first several months after implantation. Use of this implant without cement is classified off-label, and surgeons should take this into consideration during implantation. Last, this study could not simulate the effect of bony ingrowth on fixation, though our experimental technique of cementing the central peg may be a gross approximation of a fully ingrown central peg and its expected rigid fixation.

Fully cemented fixation of a polyethylene glenoid is superior to hybrid cement fixation and interference-fit fixation with respect to early glenoid micromotion. However, the long-term stability of a fully cemented polyethylene glenoid component remains a clinical concern, as fixation is achieved by bony ingrowth around the central fluted peg of the implant. In this study, interference-fit and hybrid fixation had equivocal component micromotion in biomechanical testing. Our findings suggest that cementation of the peripheral pegs confers no additional initial stability over an uncemented interference-fit technique in a biomechanical model. More research is needed to further evaluate interference-fit fixation as a viable option for implantation of a central fluted, all-polyethylene glenoid component.

Since Neer and colleagues¹ first reported in 1982, glenoid loosening persists as a common cause of anatomic total shoulder arthroplasty (TSA) failure.^1-4 Currently, cemented, all-polyethylene glenoid components are the gold standard, and minimum clinical survival of 10 to 15 years is expected.^3,5 Several clinical studies^5-9 and in vitro biomechanical studies¹⁰ have suggested an advantage of pegged over keeled glenoid components, but glenoid component loosening remains a frequent complication,¹¹ with the cement–implant interface suggested as the weak link of fixation.^10,12 In addition to mechanical loosening, poor cement penetration and heat-induced necrosis have been postulated as contributing to glenoid component loosening.^13,14

Because of these potential complications, there is a growing consideration to minimize or abandon cement fixation and rely on biological fixation to polyethylene for long-term component stability.¹⁵ A newer pegged glenoid component design consists of traditional, peripherally located pegs designed for cement fixation as well as a central, uncemented, fluted, interference-fit peg that allows for bony ingrowth. Short-term clinical studies have shown that bony ingrowth into the space between the flutes can be achieved with a hybrid cementation technique and that, when that occurs, excellent outcomes are likely.^13,16-19 The immediate in vivo stability of this implant design upon initial implantation, before the cement has cured, has prompted some surgeons to consider implanting the device without cement. In a recent series in which this implant design was used without cement, clinical and radiographic results were promising.¹⁵

Despite the widespread clinical use, little biomechanical work has been done to characterize initial fixation of all-polyethylene pegged glenoid implants. We conducted a study to compare glenoid micromotion in an all-polyethylene, centrally fluted pegged glenoid component as a function of 3 fixation techniques: cementless interference-fit fixation, hybrid partial cementation based on manufacturer recommendations, and full cementation to simulate a gold-standard, traditional, cemented, pegged design.

Materials and MethodsBiomechanical Testing

The biomechanical testing methodology used in this study was based on previous studies20-23 and on ASTM standard F2028-1224 using polyurethane bone substitute 0.24 g/cm³ (Pacific Research Laboratories) with ultimate strength of 4.9 MPa and compressive modulus of 123 MPa for component implantation. This material was selected because its mechanical properties are similar to those of cancellous glenoid bone in primary shoulder arthroplasty,25 and it minimizes variability with use of cadaveric specimens. Components were mounted on an MTS 858 Mini-Bionix II materials testing frame (Figure 1). A static compressive load of 756 N (170 lb) was applied via a mass-pulley system simulating the joint compressive force the shoulder is likely to experience during higher load activities.^24,26 The glenoid component was positioned on a linear bearing to allow for joint compression.

Test Groups and Cement Fixation Techniques

All-polyethylene pegged glenoid components (Anchor Peg Glenoid, size 44; DePuy Orthopaedics) were used for biomechanical testing (Figure 1). Polyurethane blocks were reamed with a size 44 reamer until the superior-inferior distance reached 33 mm, ensuring complete seating of implant. Three fixation-technique groups were formed: interference-fit, hybrid cement, and fully cemented. Interference-fit fixation was done without polymethylmethacrylate (PMMA) cement. In hybrid fixation, 2 cm³ of PMMA (SpeedSet Cement, Stryker Orthopaedics) was injected (using a catheter tip syringe) into the peripheral peg holes and manually pressurized; the central peg was press-fit into polyurethane bone substitute. In the fully cemented group, both peripheral and central peg holes received PMMA; the peripheral peg holes were cemented as in hybrid fixation, and the central peg hole was injected with 3 cm³ of PMMA, which was then manually pressurized. The humeral head component (Global Advantage, 44×18 mm; DePuy Synthes) was mounted on the test frame actuator and centrally located within the glenoid at the start of the test.

Determination of Humeral Head Translation via Subluxation Testing

Humeral head subluxation distance, simulating a humeral head rim loading event, was calculated on the basis of preliminary tests outlined in the ASTM standard.²⁴ Three glenoids (1 per fixation technique) were mounted on the test frame with a humeral head positioned centrally within the glenoid. After the joint compressive force was applied, the humeral head was translated along the true superior axis of the glenoid at a rate of 50 mm/min. Testing software was used to record humeral head displacement and load data at a frequency of 100 Hz. Humeral head subluxation displacement was determined at the end of the linear region of the force versus displacement response. This distance, averaged from the 3 subluxation tests, was used as the subluxation distance during cyclic testing.

Determination of Glenoid Component Motion via Cyclic Testing

After subluxation displacement was determined, glenoid components were mounted on the test frame (5 per fixation technique) and subjected to 50,000 cycles of humeral head translation at a frequency of 2 Hz. Amplitude of the humeral head displacement against the glenoid component followed a sinusoidal pattern with maxima and minima represented by the subluxation displacement (positive and negative, respectively). Glenoid edge compression/distraction of the superior edge and glenoid inferior/superior translation were monitored with 2 variable resistance reluctance transducers (Microminiature DVRT; 4.5-µm resolution; MicroStrain) secured to the glenoid component and testing fixture.

Microminiature DVRT measurements of glenoid motion were taken for 5 consecutive cycles at cycles 1, 20, 100, 500, 1000, 5000, 10,000, 15,000, 20,000, 30,000, 40,000, and 50,000. Distraction-compression displacement and superior-inferior translation measurements were recorded relative to the glenoid position with the humeral head at the neutral position at a given cycle. Final glenoid micromotion data were calculated from the mean of consecutive cycles at each cycle time point.

Statistical Analysis

Glenoid motion results are reported as means and standard deviations. Comparisons with 2 factors of fixation technique and number of cycles for glenoid distraction, glenoid compression, and absolute glenoid translation were characterized with 2-way analysis of variance (SigmaPlot Version 11.0; Systat Software), with the Holm-Šídák test used for post hoc determination of significant relationships.

Results

Under subluxation testing, the humeral head translation distance at the end of the linear region was determined to be 0.50 mm. Subsequently for cyclic testing, the humeral head was then translated 0.50 mm from the neutral position of the humeral head along both the superior and inferior axes of the glenoid. All glenoids successfully completed the entire 50,000 cycles of testing. For the glenoid component, Figure 2 depicts distraction and compression, and Figure 3 depicts superior-inferior translation.

Glenoid Component Distraction

Overall, mean (SD) glenoid distraction was significantly higher for interference-fit fixation, 0.21 (0.10) mm, than for hybrid cement fixation, 0.16 (0.05) mm (P < .001), and fully cemented fixation, 0.09 (0.07) mm (P < .001). It was also significantly higher for hybrid fixation than fully cemented fixation (P < .001). From cycle 1000 to cycle 50,000, distraction was significantly higher for interference-fit fixation than for fully cemented fixation at each time point (P < .05).

Glenoid Component Compression

Mean (SD) compression was significantly higher for hybrid cement fixation, 0.31 (0.13) mm, than for interference-fit fixation, 0.17 (0.07) mm (P < .001), and fully cemented fixation, 0.17 (0.08) mm (P < .001). No significant difference was found between interference-fit and fully cemented fixation (P = .793) (Figure 2). At cycles 1, 20, 100, and 500, compression was significantly higher for hybrid fixation than for fully cemented fixation (P < .05). In addition, at cycle 500, it was significantly higher for hybrid fixation than for interference-fit fixation (P < .05).

Glenoid Component Translation

Mean (SD) glenoid translation was significantly lower for fully cemented fixation, 0.10 (0.04) mm, than for interference-fit fixation, 0.13 (0.04) mm (P < .001), and hybrid cement fixation, 0.13 (0.03) mm (P < .001), with all time points considered. There was no significant difference between interference-fit and hybrid fixation (P = .343). Initial translation at cycle 1 was significantly higher for interference-fit and hybid fixation than for fully cemented fixation.

Discussion

Despite advances in glenoid component design, glenoid loosening remains the most common cause of anatomical TSA failure. Recent implants have been designed to take advantage of an all-polyethylene component while providing long-lasting fixation through bony ingrowth into a central peg. In a study of the hybrid cementation technique drescribed here, Groh¹⁷ found no glenoid loosening or radiolucent lines but discovered fingerlike projections of bone between the flanges of the implant in 24 (29%) of 83 cases. Churchill and colleagues¹⁶ also reported bony ingrowth into the central peg in 15 (75%) of 20 patients. Furthermore, Arnold and colleagues13 reported complete bony ingrowth (6/6 inter-fin compartments) in 23 (71%) of 35 shoulders at a mean of 43 months. Wirth and colleagues¹⁹ reported increased radiodensity between the flanges of the central peg in 30 of 44 cases (68%) and osteolysis around the central peg in 3 of 44 cases (7%) at 3 years.

There are also reports of successful bony ingrowth associated with all-polyethylene components implanted without cement. In a canine study using an early ingrowth implant design, Wirth and colleagues²⁷ showed that, though initial fixation was superior with a cemented, keeled implant, pullout strength of the uncemented, pegged implant improved over time and eventually far surpassed that of the cemented, keeled implant owing to both the loosening of the cemented component and the bony ingrowth into the central peg component. Furthermore, Anglin and colleagues¹⁰ confirmed that component micromotion was lower with pegged glenoid components than with keeled components in a biomechanical model. De Wilde and colleagues¹⁵ recently reported on a series of uncemented, central fluted peg glenoids implanted in 34 patients followed clinically and with computed tomography for a minimum of 24 months. The investigators found bony ingrowth into the central peg in 27 (79%) of 34 patients and no signs of loosening in 30 (88%) of 34 patients. Incomplete lucencies around 1 or 2 peripheral pegs were found in 2 (6%) of 34 patients, and complete lucencies around 2 or more peripheral pegs were found in 2 (6%) of 34 patients. However, there was no statistical difference in clinical outcome between patients with and without loosening.

With this type of implant, initial fixation that provides stability while minimizing micromotion under biomechanical loading likely is crucial for attaining bony growth within the central peg flanges. To our knowledge, this is the first biomechanical study to compare micromotion using 3 different fixation methods with a central fluted peg glenoid component design. Of all these fixation methods, fully cemented fixation yielded the most stable glenoid throughout testing with respect to the evaluated parameters. However, this method is not necessarily clinically applicable, as a fully cemented glenoid would inhibit any bony growth within the central flange, which is necessary for long-term biological fixation. Our data showed that, though glenoid distraction was significantly lower with hybrid cement fixation, this fixation method exhibited significantly higher glenoid compression. In addition, there were no significant differences between glenoid components with hybrid fixation and glenoid components with interference-fit fixation with respect to component translation in the superior-inferior direction. These findings may indicate that initial fixation is not significantly improved by the addition of cement to the peripheral pegs in a glenoid component with a central fluted peg design.

The interference fit of the central peg is primarily responsible for conferring long-term implant stability,^13,27 which is ultimately achieved by bony formation between the flutes of the peg. Other authors have reported that, for bony ingrowth to occur, micromotion between the bone–implant interface must not exceed 20 to 150 µm.^28-30 Other than for interference-fit distraction at more than 1000 cycles and hybrid cement fixation compression at each time point throughout testing, our data fall within the reported upper limits of micromotion to support bony ingrowth. Increased micromotion in the interference-fit fixation group is seen at later time points and may be caused by the inability to simulate the potential fixation gained from bony ingrowth allowed with this surgical technique. Research is needed to further explain this increase in distraction.

Results from this study must be interpreted with caution because of limitations of the in vitro testing methodology. This biomechanical model using bone substitute characterizes glenoid fixation at time zero, directly after implantation, followed by repetitive cyclic loading simulating 5 years of implant service. This differs from the clinical scenario in which the shoulder undergoes postoperative immobilization or protected motion during which the early phases of bony remodeling are likely occurring. Furthermore, simulation of 5 years of implant service may not be necessary for an implant that is expected to achieve ultimate fixation by bony ingrowth within the first several months after implantation. Use of this implant without cement is classified off-label, and surgeons should take this into consideration during implantation. Last, this study could not simulate the effect of bony ingrowth on fixation, though our experimental technique of cementing the central peg may be a gross approximation of a fully ingrown central peg and its expected rigid fixation.

Fully cemented fixation of a polyethylene glenoid is superior to hybrid cement fixation and interference-fit fixation with respect to early glenoid micromotion. However, the long-term stability of a fully cemented polyethylene glenoid component remains a clinical concern, as fixation is achieved by bony ingrowth around the central fluted peg of the implant. In this study, interference-fit and hybrid fixation had equivocal component micromotion in biomechanical testing. Our findings suggest that cementation of the peripheral pegs confers no additional initial stability over an uncemented interference-fit technique in a biomechanical model. More research is needed to further evaluate interference-fit fixation as a viable option for implantation of a central fluted, all-polyethylene glenoid component.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

LOS ANGELES – In the clinical experience of Dr. Ian C. Lavery, prevention efforts are the best defense against local recurrence of rectal cancer.

“This means adjuvant treatment, if necessary, neoadjuvant treatment, and a meticulous surgical operation,” Dr. Lavery of the department of colorectal surgery at the Cleveland Clinic said at the annual meeting of the American Society of Colon and Rectal Surgeons. “If the circumferential resection margin is negative, the local recurrence rate is 10% or less. If it’s positive, local recurrence goes up to 78%. Even when we attempt to do the perfect total mesorectal excision, local recurrence is in the order of 4%.”

Selective use of radiotherapy in the neoadjuvant setting appears to be reducing the incidence of local recurrence, “certainly in the short term,” he added. “In the long term, I’m not sure we know the true answer to that yet. Using other techniques like washing the rectal stump out, the use of stapling, and en-bloc resection if necessary [can help prevention efforts].”

The incidence of local rectal cancer recurrence is reported to be between 3% and 50%, but neither curative nor palliative treatment is standardized. “When you get local recurrence after a rectal cancer operation, it’s a disaster,” Dr. Lavery said. “It may cause intractable pain, bleeding, perforation, obstruction, and sepsis – all incredibly difficult things to manage.”

Patients who develop a local recurrence of rectal cancer are often asymptomatic. A digital rectal exam (DRE) may or may not identify a recurrence and carcinoembryonic antigen levels are helpful on some occasions. According to Dr. Lavery, optimal surveillance consists of a clinical examination including DRE, endoscopy, blood tests, CT scans, MRI, and PET scans. “If they were all to be done routinely it would increase the detection earlier rather than later,” he said.

CT and MRI appear to be about 85% accurate but both modalities are “very poor at detecting peritoneal disease,” he said. PET scans for recurrent carcinoma have been shown to change the management in 20%-56% of cases (Ann Surg Oncol. 1997 Dec; 4:613-20).

While follow-up of patients who have undergone surgery for local rectal cancer is generally favored, there is no consensus on what the ideal follow-up timeline should be. “In my opinion, the more intensive follow-up is going to be better than the cursory conventional follow-up examination,” Dr. Lavery said. “One of the big reasons for that is the vast majority of recurrences are extraluminal so they may be difficult to feel. Doing endoscopy, you can’t see them if they’re extraluminal.”

The goal in treating recurrent rectal cancer is to improve quality of life, he continued, as the common symptoms include obstruction, pain, bleeding, bowel discharge, or perforation/abscess. Optimal treatment involves striving for tumor-free margins after the operation. “This may require en bloc resection of an adjacent prostate, bladder, lateral pelvic wall,” he said. “But clinically and radiologically, it’s very difficult to identify those patients that have a potentially R0 resection.”

Curative treatment is possible if the recurrence is locally resectable and the patient has minimal comorbidities. “The potential morbidity after the surgery has to be acceptable, considering the severity of the problem that we’re dealing with,” Dr. Lavery noted. “Distant disease also complicates the issue.”

Reasons to avoid resection include rigid tumor fixation, leg lymphedema, major vessel encasement, bilateral ureteric involvement, extensive para-aortic lymph node involvement, and radicular pain. “If you embark on one of these cases, you want to make it at least the first if not the only case of the day,” Dr. Lavery advised. “Anticipate the need for assistance during the operation, but above all, make sure you have optimal exposure to do the surgery.” He reported having no financial disclosures.

[email protected]

LOS ANGELES – In the clinical experience of Dr. Ian C. Lavery, prevention efforts are the best defense against local recurrence of rectal cancer.

“This means adjuvant treatment, if necessary, neoadjuvant treatment, and a meticulous surgical operation,” Dr. Lavery of the department of colorectal surgery at the Cleveland Clinic said at the annual meeting of the American Society of Colon and Rectal Surgeons. “If the circumferential resection margin is negative, the local recurrence rate is 10% or less. If it’s positive, local recurrence goes up to 78%. Even when we attempt to do the perfect total mesorectal excision, local recurrence is in the order of 4%.”

Selective use of radiotherapy in the neoadjuvant setting appears to be reducing the incidence of local recurrence, “certainly in the short term,” he added. “In the long term, I’m not sure we know the true answer to that yet. Using other techniques like washing the rectal stump out, the use of stapling, and en-bloc resection if necessary [can help prevention efforts].”

The incidence of local rectal cancer recurrence is reported to be between 3% and 50%, but neither curative nor palliative treatment is standardized. “When you get local recurrence after a rectal cancer operation, it’s a disaster,” Dr. Lavery said. “It may cause intractable pain, bleeding, perforation, obstruction, and sepsis – all incredibly difficult things to manage.”

Patients who develop a local recurrence of rectal cancer are often asymptomatic. A digital rectal exam (DRE) may or may not identify a recurrence and carcinoembryonic antigen levels are helpful on some occasions. According to Dr. Lavery, optimal surveillance consists of a clinical examination including DRE, endoscopy, blood tests, CT scans, MRI, and PET scans. “If they were all to be done routinely it would increase the detection earlier rather than later,” he said.

CT and MRI appear to be about 85% accurate but both modalities are “very poor at detecting peritoneal disease,” he said. PET scans for recurrent carcinoma have been shown to change the management in 20%-56% of cases (Ann Surg Oncol. 1997 Dec; 4:613-20).

While follow-up of patients who have undergone surgery for local rectal cancer is generally favored, there is no consensus on what the ideal follow-up timeline should be. “In my opinion, the more intensive follow-up is going to be better than the cursory conventional follow-up examination,” Dr. Lavery said. “One of the big reasons for that is the vast majority of recurrences are extraluminal so they may be difficult to feel. Doing endoscopy, you can’t see them if they’re extraluminal.”

The goal in treating recurrent rectal cancer is to improve quality of life, he continued, as the common symptoms include obstruction, pain, bleeding, bowel discharge, or perforation/abscess. Optimal treatment involves striving for tumor-free margins after the operation. “This may require en bloc resection of an adjacent prostate, bladder, lateral pelvic wall,” he said. “But clinically and radiologically, it’s very difficult to identify those patients that have a potentially R0 resection.”

Curative treatment is possible if the recurrence is locally resectable and the patient has minimal comorbidities. “The potential morbidity after the surgery has to be acceptable, considering the severity of the problem that we’re dealing with,” Dr. Lavery noted. “Distant disease also complicates the issue.”

Reasons to avoid resection include rigid tumor fixation, leg lymphedema, major vessel encasement, bilateral ureteric involvement, extensive para-aortic lymph node involvement, and radicular pain. “If you embark on one of these cases, you want to make it at least the first if not the only case of the day,” Dr. Lavery advised. “Anticipate the need for assistance during the operation, but above all, make sure you have optimal exposure to do the surgery.” He reported having no financial disclosures.

[email protected]

LOS ANGELES – In the clinical experience of Dr. Ian C. Lavery, prevention efforts are the best defense against local recurrence of rectal cancer.

“This means adjuvant treatment, if necessary, neoadjuvant treatment, and a meticulous surgical operation,” Dr. Lavery of the department of colorectal surgery at the Cleveland Clinic said at the annual meeting of the American Society of Colon and Rectal Surgeons. “If the circumferential resection margin is negative, the local recurrence rate is 10% or less. If it’s positive, local recurrence goes up to 78%. Even when we attempt to do the perfect total mesorectal excision, local recurrence is in the order of 4%.”

Selective use of radiotherapy in the neoadjuvant setting appears to be reducing the incidence of local recurrence, “certainly in the short term,” he added. “In the long term, I’m not sure we know the true answer to that yet. Using other techniques like washing the rectal stump out, the use of stapling, and en-bloc resection if necessary [can help prevention efforts].”

The incidence of local rectal cancer recurrence is reported to be between 3% and 50%, but neither curative nor palliative treatment is standardized. “When you get local recurrence after a rectal cancer operation, it’s a disaster,” Dr. Lavery said. “It may cause intractable pain, bleeding, perforation, obstruction, and sepsis – all incredibly difficult things to manage.”

Patients who develop a local recurrence of rectal cancer are often asymptomatic. A digital rectal exam (DRE) may or may not identify a recurrence and carcinoembryonic antigen levels are helpful on some occasions. According to Dr. Lavery, optimal surveillance consists of a clinical examination including DRE, endoscopy, blood tests, CT scans, MRI, and PET scans. “If they were all to be done routinely it would increase the detection earlier rather than later,” he said.

CT and MRI appear to be about 85% accurate but both modalities are “very poor at detecting peritoneal disease,” he said. PET scans for recurrent carcinoma have been shown to change the management in 20%-56% of cases (Ann Surg Oncol. 1997 Dec; 4:613-20).

While follow-up of patients who have undergone surgery for local rectal cancer is generally favored, there is no consensus on what the ideal follow-up timeline should be. “In my opinion, the more intensive follow-up is going to be better than the cursory conventional follow-up examination,” Dr. Lavery said. “One of the big reasons for that is the vast majority of recurrences are extraluminal so they may be difficult to feel. Doing endoscopy, you can’t see them if they’re extraluminal.”

The goal in treating recurrent rectal cancer is to improve quality of life, he continued, as the common symptoms include obstruction, pain, bleeding, bowel discharge, or perforation/abscess. Optimal treatment involves striving for tumor-free margins after the operation. “This may require en bloc resection of an adjacent prostate, bladder, lateral pelvic wall,” he said. “But clinically and radiologically, it’s very difficult to identify those patients that have a potentially R0 resection.”

Curative treatment is possible if the recurrence is locally resectable and the patient has minimal comorbidities. “The potential morbidity after the surgery has to be acceptable, considering the severity of the problem that we’re dealing with,” Dr. Lavery noted. “Distant disease also complicates the issue.”

Reasons to avoid resection include rigid tumor fixation, leg lymphedema, major vessel encasement, bilateral ureteric involvement, extensive para-aortic lymph node involvement, and radicular pain. “If you embark on one of these cases, you want to make it at least the first if not the only case of the day,” Dr. Lavery advised. “Anticipate the need for assistance during the operation, but above all, make sure you have optimal exposure to do the surgery.” He reported having no financial disclosures.

[email protected]

Applying the more stringent SPRINT criteria to a general population of persons with hypertension would yield a significant reduction in the number of people meeting their treatment goals, although those who do would achieve a significant reduction in their risk of cardiovascular disease, a study published June 13 in the Journal of the American College of Cardiology has found.

Min Jung Ko, Ph.D., of the National Evidence-Based Healthcare Collaborating Agency in Seoul, Korea, and coauthors explored the relative impacts of SPRINT target of less than 120 mm Hg for hypertension treatments with the 2014 hypertension recommendations of the Eighth Joint National Committee of less than 140 mm Hg, using data from 13,346 individuals in the Korean National Health and Nutrition Examination Survey of 2008-2013, and 67,965 individuals in the Korean National Health Insurance Service health examinee cohort of 2007.

©Ingram Publishing/thinkstockphotos.com

The investigators found that 11.9% of adults with hypertension would meet the treatment goals of the SPRINT criteria, compared with 70.8% who would meet the 2014 recommendations.

However, the analysis showed that those who met the more aggressive SPRINT treatment goal of systolic BP below 120 mm Hg also had the lowest 10-year risk of a major cardiovascular event (6.2%), compared with 7.7% in those who met the 2014 targets but not the SPRINT targets, and 9.4% in those who failed to meet the 2014 treatment targets (J Am Coll Cardiol. 2016 Jun 13. doi 10.1016/j.jacc.2016.03.572).

After adjustment for factors such as age, diabetes, chronic kidney disease, hyperlipidemia, body mass index, and smoking, the least-controlled group showed a 62% increase in the risk of cardiovascular events, compared with the SPRINT criteria group. Those who met the 2014 criteria had a 17% greater risk than those who met the SPRINT criteria.

“Despite greater cardiovascular protection with intensive BP lowering, achieving SPRINT-defined BP goals might not be easy or practical because the target BP was not met in more than one-half of the participants in the intensive-treatment group,” the authors wrote.

Individuals who were older, female, or had diabetes, chronic kidney disease, or prevalent cardiovascular disease were more likely to meet the stricter goals of SPRINT (Systolic Blood Pressure Intervention Trial), in which combined cardiovascular events occurred in 5.2% of patients treated to a target systolic blood pressure of less than 120 mm Hg and 6.8% of patients treated to a target of less than 140 mm Hg (N Engl J Med. 2015;373:2103-16).

Researchers also noted a significant linear association between lesser blood pressure control and an increased risk of myocardial infarction and stroke, although there was no significant trend seen relating to cardiovascular or all-cause mortality. The authors noted that this was the opposite to what was observed in the original SPRINT trial, where there was a reduction in cardiovascular mortality and heart failure but only a modest, nonsignificant impact on MI or stroke.

“Although the exact reasons remain unclear, this discrepancy might be explained in part by differences in study design, population characteristics, clinical practice pattern, or race or ethnic groups,” they suggested. “The generalizability of the SPRINT experience to multiple groups of various ethnic backgrounds warrants further investigations and is likely to be of considerable interest.”

Unlike the SPRINT trial, the Korean analysis did not look into the potential adverse effects of more aggressive blood pressure–lowering, but the authors noted that the SPRINT trial did see an increased incidence of more serious adverse events, including hypotension, syncope, and acute kidney injury.

“Therefore, beyond the BP target per se, several important factors should be considered for optimal BP management in the contemporary medical setting; for example, an integrated and systematic assessment of combined risk factors and baseline cardiovascular risk, concomitant preventive medical therapies, cost-effectiveness, clinician-patient discussions of the potential benefits and harms, or the clinical judgment of the treating physician.”

The National Evidence-Based Healthcare Collaborating Agency, Seoul, South Korea, funded the study. No conflicts of interest were declared.

Applying the more stringent SPRINT criteria to a general population of persons with hypertension would yield a significant reduction in the number of people meeting their treatment goals, although those who do would achieve a significant reduction in their risk of cardiovascular disease, a study published June 13 in the Journal of the American College of Cardiology has found.

Min Jung Ko, Ph.D., of the National Evidence-Based Healthcare Collaborating Agency in Seoul, Korea, and coauthors explored the relative impacts of SPRINT target of less than 120 mm Hg for hypertension treatments with the 2014 hypertension recommendations of the Eighth Joint National Committee of less than 140 mm Hg, using data from 13,346 individuals in the Korean National Health and Nutrition Examination Survey of 2008-2013, and 67,965 individuals in the Korean National Health Insurance Service health examinee cohort of 2007.

©Ingram Publishing/thinkstockphotos.com

The investigators found that 11.9% of adults with hypertension would meet the treatment goals of the SPRINT criteria, compared with 70.8% who would meet the 2014 recommendations.

However, the analysis showed that those who met the more aggressive SPRINT treatment goal of systolic BP below 120 mm Hg also had the lowest 10-year risk of a major cardiovascular event (6.2%), compared with 7.7% in those who met the 2014 targets but not the SPRINT targets, and 9.4% in those who failed to meet the 2014 treatment targets (J Am Coll Cardiol. 2016 Jun 13. doi 10.1016/j.jacc.2016.03.572).

After adjustment for factors such as age, diabetes, chronic kidney disease, hyperlipidemia, body mass index, and smoking, the least-controlled group showed a 62% increase in the risk of cardiovascular events, compared with the SPRINT criteria group. Those who met the 2014 criteria had a 17% greater risk than those who met the SPRINT criteria.

“Despite greater cardiovascular protection with intensive BP lowering, achieving SPRINT-defined BP goals might not be easy or practical because the target BP was not met in more than one-half of the participants in the intensive-treatment group,” the authors wrote.

Individuals who were older, female, or had diabetes, chronic kidney disease, or prevalent cardiovascular disease were more likely to meet the stricter goals of SPRINT (Systolic Blood Pressure Intervention Trial), in which combined cardiovascular events occurred in 5.2% of patients treated to a target systolic blood pressure of less than 120 mm Hg and 6.8% of patients treated to a target of less than 140 mm Hg (N Engl J Med. 2015;373:2103-16).

Researchers also noted a significant linear association between lesser blood pressure control and an increased risk of myocardial infarction and stroke, although there was no significant trend seen relating to cardiovascular or all-cause mortality. The authors noted that this was the opposite to what was observed in the original SPRINT trial, where there was a reduction in cardiovascular mortality and heart failure but only a modest, nonsignificant impact on MI or stroke.

“Although the exact reasons remain unclear, this discrepancy might be explained in part by differences in study design, population characteristics, clinical practice pattern, or race or ethnic groups,” they suggested. “The generalizability of the SPRINT experience to multiple groups of various ethnic backgrounds warrants further investigations and is likely to be of considerable interest.”

Unlike the SPRINT trial, the Korean analysis did not look into the potential adverse effects of more aggressive blood pressure–lowering, but the authors noted that the SPRINT trial did see an increased incidence of more serious adverse events, including hypotension, syncope, and acute kidney injury.

“Therefore, beyond the BP target per se, several important factors should be considered for optimal BP management in the contemporary medical setting; for example, an integrated and systematic assessment of combined risk factors and baseline cardiovascular risk, concomitant preventive medical therapies, cost-effectiveness, clinician-patient discussions of the potential benefits and harms, or the clinical judgment of the treating physician.”

The National Evidence-Based Healthcare Collaborating Agency, Seoul, South Korea, funded the study. No conflicts of interest were declared.

Applying the more stringent SPRINT criteria to a general population of persons with hypertension would yield a significant reduction in the number of people meeting their treatment goals, although those who do would achieve a significant reduction in their risk of cardiovascular disease, a study published June 13 in the Journal of the American College of Cardiology has found.

Min Jung Ko, Ph.D., of the National Evidence-Based Healthcare Collaborating Agency in Seoul, Korea, and coauthors explored the relative impacts of SPRINT target of less than 120 mm Hg for hypertension treatments with the 2014 hypertension recommendations of the Eighth Joint National Committee of less than 140 mm Hg, using data from 13,346 individuals in the Korean National Health and Nutrition Examination Survey of 2008-2013, and 67,965 individuals in the Korean National Health Insurance Service health examinee cohort of 2007.

©Ingram Publishing/thinkstockphotos.com

The investigators found that 11.9% of adults with hypertension would meet the treatment goals of the SPRINT criteria, compared with 70.8% who would meet the 2014 recommendations.

However, the analysis showed that those who met the more aggressive SPRINT treatment goal of systolic BP below 120 mm Hg also had the lowest 10-year risk of a major cardiovascular event (6.2%), compared with 7.7% in those who met the 2014 targets but not the SPRINT targets, and 9.4% in those who failed to meet the 2014 treatment targets (J Am Coll Cardiol. 2016 Jun 13. doi 10.1016/j.jacc.2016.03.572).

After adjustment for factors such as age, diabetes, chronic kidney disease, hyperlipidemia, body mass index, and smoking, the least-controlled group showed a 62% increase in the risk of cardiovascular events, compared with the SPRINT criteria group. Those who met the 2014 criteria had a 17% greater risk than those who met the SPRINT criteria.

“Despite greater cardiovascular protection with intensive BP lowering, achieving SPRINT-defined BP goals might not be easy or practical because the target BP was not met in more than one-half of the participants in the intensive-treatment group,” the authors wrote.

Individuals who were older, female, or had diabetes, chronic kidney disease, or prevalent cardiovascular disease were more likely to meet the stricter goals of SPRINT (Systolic Blood Pressure Intervention Trial), in which combined cardiovascular events occurred in 5.2% of patients treated to a target systolic blood pressure of less than 120 mm Hg and 6.8% of patients treated to a target of less than 140 mm Hg (N Engl J Med. 2015;373:2103-16).

Researchers also noted a significant linear association between lesser blood pressure control and an increased risk of myocardial infarction and stroke, although there was no significant trend seen relating to cardiovascular or all-cause mortality. The authors noted that this was the opposite to what was observed in the original SPRINT trial, where there was a reduction in cardiovascular mortality and heart failure but only a modest, nonsignificant impact on MI or stroke.

“Although the exact reasons remain unclear, this discrepancy might be explained in part by differences in study design, population characteristics, clinical practice pattern, or race or ethnic groups,” they suggested. “The generalizability of the SPRINT experience to multiple groups of various ethnic backgrounds warrants further investigations and is likely to be of considerable interest.”

Unlike the SPRINT trial, the Korean analysis did not look into the potential adverse effects of more aggressive blood pressure–lowering, but the authors noted that the SPRINT trial did see an increased incidence of more serious adverse events, including hypotension, syncope, and acute kidney injury.

“Therefore, beyond the BP target per se, several important factors should be considered for optimal BP management in the contemporary medical setting; for example, an integrated and systematic assessment of combined risk factors and baseline cardiovascular risk, concomitant preventive medical therapies, cost-effectiveness, clinician-patient discussions of the potential benefits and harms, or the clinical judgment of the treating physician.”

The National Evidence-Based Healthcare Collaborating Agency, Seoul, South Korea, funded the study. No conflicts of interest were declared.