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Hashimoto’s Thyroiditis and Lymphoma
A “heightened index of suspicion” is called for when a patient with Hashimoto’s thyroiditis (HT) presents with an enlarging neck mass, say researchers from Tan Tock Seng Hospital, Singapore, in a case report. According to the researchers, because the complication of thyroid lymphoma is rare, physicians commonly forgotten it. But primary thyroid lymphomas (PTLs) have a 60-fold risk in patients with HT.
Related: Study Points to Risk Factors for Lymphoma
Hashimoto’s thyroiditis typically is treated successfully with thyroxine. The study patient, however, began to lose weight and developed a mass in her neck that was diagnosed as diffuse large B-cell lymphoma. Previously, research suggested that having HT for ≥ 20 years increased the risk of thyroid lymphoma, but small studies have found that the interval between diagnosis of HT and diagnosis of thyroid lymphoma might be shorter—4 to 9 years, the researchers note. They cite another study that found the median interval was 18 months, as with their patient. Symptoms usually last from a few days to 36 months before diagnosis; in the study patient, symptoms of compression occurred over 2 to 3 weeks.
That shorter time frame may indicate that ultrasonography surveillance should be started early and done periodically, the researchers say, to detect lymphoma development as soon as possible. Radiologic imaging is helpful but “only serves as an adjunct to the diagnosis.” Histologic diagnosis is still needed for definitive diagnosis.
Timely diagnosis and early treatment mean the prognosis can be good for PTL, with relatively high survival rates after chemotherapy and radiotherapy. In this case, the patient underwent 6 cycles of chemotherapy with adjuvant radiotherapy. She then was maintained on thyroxine 75 µg daily. She remains euthyroid and disease free 1 year after completing her cancer treatment.
Source:
Chiang B, Cheng S, Seow CJ. BMJ Case Rep. 2016;pii:bcr2016217568.
doi: 10.1136/bcr-2016-217568.
A “heightened index of suspicion” is called for when a patient with Hashimoto’s thyroiditis (HT) presents with an enlarging neck mass, say researchers from Tan Tock Seng Hospital, Singapore, in a case report. According to the researchers, because the complication of thyroid lymphoma is rare, physicians commonly forgotten it. But primary thyroid lymphomas (PTLs) have a 60-fold risk in patients with HT.
Related: Study Points to Risk Factors for Lymphoma
Hashimoto’s thyroiditis typically is treated successfully with thyroxine. The study patient, however, began to lose weight and developed a mass in her neck that was diagnosed as diffuse large B-cell lymphoma. Previously, research suggested that having HT for ≥ 20 years increased the risk of thyroid lymphoma, but small studies have found that the interval between diagnosis of HT and diagnosis of thyroid lymphoma might be shorter—4 to 9 years, the researchers note. They cite another study that found the median interval was 18 months, as with their patient. Symptoms usually last from a few days to 36 months before diagnosis; in the study patient, symptoms of compression occurred over 2 to 3 weeks.
That shorter time frame may indicate that ultrasonography surveillance should be started early and done periodically, the researchers say, to detect lymphoma development as soon as possible. Radiologic imaging is helpful but “only serves as an adjunct to the diagnosis.” Histologic diagnosis is still needed for definitive diagnosis.
Timely diagnosis and early treatment mean the prognosis can be good for PTL, with relatively high survival rates after chemotherapy and radiotherapy. In this case, the patient underwent 6 cycles of chemotherapy with adjuvant radiotherapy. She then was maintained on thyroxine 75 µg daily. She remains euthyroid and disease free 1 year after completing her cancer treatment.
Source:
Chiang B, Cheng S, Seow CJ. BMJ Case Rep. 2016;pii:bcr2016217568.
doi: 10.1136/bcr-2016-217568.
A “heightened index of suspicion” is called for when a patient with Hashimoto’s thyroiditis (HT) presents with an enlarging neck mass, say researchers from Tan Tock Seng Hospital, Singapore, in a case report. According to the researchers, because the complication of thyroid lymphoma is rare, physicians commonly forgotten it. But primary thyroid lymphomas (PTLs) have a 60-fold risk in patients with HT.
Related: Study Points to Risk Factors for Lymphoma
Hashimoto’s thyroiditis typically is treated successfully with thyroxine. The study patient, however, began to lose weight and developed a mass in her neck that was diagnosed as diffuse large B-cell lymphoma. Previously, research suggested that having HT for ≥ 20 years increased the risk of thyroid lymphoma, but small studies have found that the interval between diagnosis of HT and diagnosis of thyroid lymphoma might be shorter—4 to 9 years, the researchers note. They cite another study that found the median interval was 18 months, as with their patient. Symptoms usually last from a few days to 36 months before diagnosis; in the study patient, symptoms of compression occurred over 2 to 3 weeks.
That shorter time frame may indicate that ultrasonography surveillance should be started early and done periodically, the researchers say, to detect lymphoma development as soon as possible. Radiologic imaging is helpful but “only serves as an adjunct to the diagnosis.” Histologic diagnosis is still needed for definitive diagnosis.
Timely diagnosis and early treatment mean the prognosis can be good for PTL, with relatively high survival rates after chemotherapy and radiotherapy. In this case, the patient underwent 6 cycles of chemotherapy with adjuvant radiotherapy. She then was maintained on thyroxine 75 µg daily. She remains euthyroid and disease free 1 year after completing her cancer treatment.
Source:
Chiang B, Cheng S, Seow CJ. BMJ Case Rep. 2016;pii:bcr2016217568.
doi: 10.1136/bcr-2016-217568.
Hepatitis infection raises non-Hodgkin lymphoma risk in HIV patients
HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma, according to new research published in Annals of Internal Medicine.
Lead author Qing Wang, PhD, of the Basel Institute for Clinical Epidemiology & Biostatistics at University Hospital Basel, Switzerland, and her coauthors said there is growing evidence of an association between both chronic hepatitis B virus infection (HBV) and chronic hepatitis C virus infection (HCV), and non-Hodgkin lymphoma, with chronic immune activation and B cell proliferation suggested as potential mechanisms. However, the impact of chronic coinfection in individuals with HIV is unclear.
Researchers undertook a cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe. Of these participants, 1,336 had chronic HBV and 7,506 had chronic HCV infection, and more than three-quarters (77%) later started treatment with antiretroviral therapy.
After 13 months of follow-up in the treatment-naive group and 50 months in the antiretroviral group, there were 252 cases of non-Hodgkin lymphoma in the treatment-naive group and 310 cases in the treated group (Ann Intern Med. 2016 Oct 17. doi: 10.7326/M16-0240).
Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk (95% confidence interval, 1.08-2.82) and those with hepatitis C showed a 73% greater risk (95% CI, 1.21-2.46) of non-Hodgkin lymphoma compared to treated individuals with neither coinfection. However, the differences in non-Hodgkin lymphoma rates in treatment-naive HBV and HCV coinfected individuals were not significant, which the authors suggested could be due to lower numbers of events and limited follow-up.
“The median CD4 count at the time of NHL diagnosis was less than 0.250 x 109 cells/L in both ART-naive and treated patients coinfected with HBV and HCV, indicating that coinfected patients with NHL initiate ART late or have insufficient HIV viral control and immune recovery that may be due to multiple reasons,” the authors wrote. “This unfavorable constellation is aggravated by the fact that chronic HBV infection attenuates immune recovery in ART-treated patients; whether this is also the case for chronic HCV infection is less clear.”
The authors said routine screening for chronic HBV and HCV infection, in conjunction with early diagnosis and treatment of HIV infection, was essential to reduce morbidity and mortality from non-Hodgkin lymphoma.
“Our findings provide strong evidence that HCV coinfected patients with poor immune status or restoration (CD4 count lower than 0.250 x 109 cells/L) are at high risk for NHL and death and deserve high priority for access to well-tolerated, interferon-free, direct-acting antiviral treatment programs similar to those for patients with advanced liver fibrosis or cirrhosis.”
The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma, according to new research published in Annals of Internal Medicine.
Lead author Qing Wang, PhD, of the Basel Institute for Clinical Epidemiology & Biostatistics at University Hospital Basel, Switzerland, and her coauthors said there is growing evidence of an association between both chronic hepatitis B virus infection (HBV) and chronic hepatitis C virus infection (HCV), and non-Hodgkin lymphoma, with chronic immune activation and B cell proliferation suggested as potential mechanisms. However, the impact of chronic coinfection in individuals with HIV is unclear.
Researchers undertook a cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe. Of these participants, 1,336 had chronic HBV and 7,506 had chronic HCV infection, and more than three-quarters (77%) later started treatment with antiretroviral therapy.
After 13 months of follow-up in the treatment-naive group and 50 months in the antiretroviral group, there were 252 cases of non-Hodgkin lymphoma in the treatment-naive group and 310 cases in the treated group (Ann Intern Med. 2016 Oct 17. doi: 10.7326/M16-0240).
Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk (95% confidence interval, 1.08-2.82) and those with hepatitis C showed a 73% greater risk (95% CI, 1.21-2.46) of non-Hodgkin lymphoma compared to treated individuals with neither coinfection. However, the differences in non-Hodgkin lymphoma rates in treatment-naive HBV and HCV coinfected individuals were not significant, which the authors suggested could be due to lower numbers of events and limited follow-up.
“The median CD4 count at the time of NHL diagnosis was less than 0.250 x 109 cells/L in both ART-naive and treated patients coinfected with HBV and HCV, indicating that coinfected patients with NHL initiate ART late or have insufficient HIV viral control and immune recovery that may be due to multiple reasons,” the authors wrote. “This unfavorable constellation is aggravated by the fact that chronic HBV infection attenuates immune recovery in ART-treated patients; whether this is also the case for chronic HCV infection is less clear.”
The authors said routine screening for chronic HBV and HCV infection, in conjunction with early diagnosis and treatment of HIV infection, was essential to reduce morbidity and mortality from non-Hodgkin lymphoma.
“Our findings provide strong evidence that HCV coinfected patients with poor immune status or restoration (CD4 count lower than 0.250 x 109 cells/L) are at high risk for NHL and death and deserve high priority for access to well-tolerated, interferon-free, direct-acting antiviral treatment programs similar to those for patients with advanced liver fibrosis or cirrhosis.”
The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma, according to new research published in Annals of Internal Medicine.
Lead author Qing Wang, PhD, of the Basel Institute for Clinical Epidemiology & Biostatistics at University Hospital Basel, Switzerland, and her coauthors said there is growing evidence of an association between both chronic hepatitis B virus infection (HBV) and chronic hepatitis C virus infection (HCV), and non-Hodgkin lymphoma, with chronic immune activation and B cell proliferation suggested as potential mechanisms. However, the impact of chronic coinfection in individuals with HIV is unclear.
Researchers undertook a cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe. Of these participants, 1,336 had chronic HBV and 7,506 had chronic HCV infection, and more than three-quarters (77%) later started treatment with antiretroviral therapy.
After 13 months of follow-up in the treatment-naive group and 50 months in the antiretroviral group, there were 252 cases of non-Hodgkin lymphoma in the treatment-naive group and 310 cases in the treated group (Ann Intern Med. 2016 Oct 17. doi: 10.7326/M16-0240).
Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk (95% confidence interval, 1.08-2.82) and those with hepatitis C showed a 73% greater risk (95% CI, 1.21-2.46) of non-Hodgkin lymphoma compared to treated individuals with neither coinfection. However, the differences in non-Hodgkin lymphoma rates in treatment-naive HBV and HCV coinfected individuals were not significant, which the authors suggested could be due to lower numbers of events and limited follow-up.
“The median CD4 count at the time of NHL diagnosis was less than 0.250 x 109 cells/L in both ART-naive and treated patients coinfected with HBV and HCV, indicating that coinfected patients with NHL initiate ART late or have insufficient HIV viral control and immune recovery that may be due to multiple reasons,” the authors wrote. “This unfavorable constellation is aggravated by the fact that chronic HBV infection attenuates immune recovery in ART-treated patients; whether this is also the case for chronic HCV infection is less clear.”
The authors said routine screening for chronic HBV and HCV infection, in conjunction with early diagnosis and treatment of HIV infection, was essential to reduce morbidity and mortality from non-Hodgkin lymphoma.
“Our findings provide strong evidence that HCV coinfected patients with poor immune status or restoration (CD4 count lower than 0.250 x 109 cells/L) are at high risk for NHL and death and deserve high priority for access to well-tolerated, interferon-free, direct-acting antiviral treatment programs similar to those for patients with advanced liver fibrosis or cirrhosis.”
The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point: HIV-infected individuals on antiretroviral therapy who also have chronic coinfection with hepatitis B or C virus have an increased risk of developing non-Hodgkin lymphoma.
Major finding: Antiretroviral-treated patients with chronic hepatitis B showed a significant 74% greater risk and those with hepatitis C showed a 73% greater risk of non-Hodgkin lymphoma, compared to treated individuals with neither coinfection.
Data source: A cohort study of 52,479 treatment-naive individuals with HIV infection, using 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe.
Disclosures: The study was supported by the European Union Seventh Framework Programme, Schweizerische Krebsliga, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales (ANRS), Paris; the HIV Monitoring Foundation, Amsterdam; and the Augustinus Foundation, Copenhagen. Eleven authors declared grants, personal fees, and other support from pharmaceutical companies including those involved in the manufacture of HIV and hepatitis drugs. No other conflicts of interest were reported.
Study Points to Risk Factors for Lymphoma
Certain lifestyle, dietary, environmental, serologic, and genetic factors may raise the risk of non-Hodgkin lymphoma (NHL), according to researchers who reviewed 40 years of follow-up data from the Nurses’ Health Study (NHS).
Related: Exercise Lowers Risk of Some Cancers
The researchers, from Brigham and Women’s Hospital, Harvard, and Boston University, all in Massachusetts, aimed to highlight the NHS’s contributions to epidemiologic knowledge of endometrial, ovarian, pancreatic, and hematologic cancers. They focused on findings that identified novel risk factors or markers of early detection or helped clarify discrepant literature.
Because the researchers say severe immune compromise is the “strongest, best-established risk factor” for NHL, they studied factors that might lead to subclinical immune dysregulation, such as diet, body mass index (BMI), and supplement use. They found several risk factors and biomarkers for NHL and more than 35 distinct tumors in that category, including chronic lymphocytic leukemia. Trans fats and red meat, for instance, doubled the risk of NHL. The researchers also found a higher risk for women who reported long-term multivitamin use. However, they found no risk associated with diet or sugar-sweetened soda or aspartame or with dietary intake of vitamin D.
Related: IBD and the Risk of Oral Cancer
Greater adiposity during childhood and adolescence was significantly associated with NHL. The researchers also observed a 19% increased risk of all NHL per 5 kg/m2 increase in BMI in young adulthood. Interestingly, taller women also had a higher risk of NHL.
The researchers conducted one of the first prospective studies to evaluate a putative inverse association of NHL risk with exposure to ambient ultraviolet radiation. They found, “contrary to expectation,” a 10% to 20% increased risk of NHL among women with the highest (vs lowest) ultraviolet-B exposure at baseline and birth, 15 years, and 30 years.
In investigating biomarkers, the researchers noted a “suggestive increase” in chronic lymphocytic leukemia risk associated with an Epstein-Barr virus antibody profile indicative of poor host immune control of the virus.
Related: Sexual Orientation and Cancer Risk
The researchers have established several working groups to study cancers, such as NHL and multiple myeloma. They also are collecting archival tissue specimens for NHL, multiple myeloma, and Hodgkin lymphoma, for better evaluation of factors related to the unique molecular subsets of hematologic tumors.
Source:
Birmann BM, Barnard ME, Bertrand KA, et al. Am J Public Health. 2016;106(9):1608-1615.
doi: 10.2105/AJPH.2016.303337.
Certain lifestyle, dietary, environmental, serologic, and genetic factors may raise the risk of non-Hodgkin lymphoma (NHL), according to researchers who reviewed 40 years of follow-up data from the Nurses’ Health Study (NHS).
Related: Exercise Lowers Risk of Some Cancers
The researchers, from Brigham and Women’s Hospital, Harvard, and Boston University, all in Massachusetts, aimed to highlight the NHS’s contributions to epidemiologic knowledge of endometrial, ovarian, pancreatic, and hematologic cancers. They focused on findings that identified novel risk factors or markers of early detection or helped clarify discrepant literature.
Because the researchers say severe immune compromise is the “strongest, best-established risk factor” for NHL, they studied factors that might lead to subclinical immune dysregulation, such as diet, body mass index (BMI), and supplement use. They found several risk factors and biomarkers for NHL and more than 35 distinct tumors in that category, including chronic lymphocytic leukemia. Trans fats and red meat, for instance, doubled the risk of NHL. The researchers also found a higher risk for women who reported long-term multivitamin use. However, they found no risk associated with diet or sugar-sweetened soda or aspartame or with dietary intake of vitamin D.
Related: IBD and the Risk of Oral Cancer
Greater adiposity during childhood and adolescence was significantly associated with NHL. The researchers also observed a 19% increased risk of all NHL per 5 kg/m2 increase in BMI in young adulthood. Interestingly, taller women also had a higher risk of NHL.
The researchers conducted one of the first prospective studies to evaluate a putative inverse association of NHL risk with exposure to ambient ultraviolet radiation. They found, “contrary to expectation,” a 10% to 20% increased risk of NHL among women with the highest (vs lowest) ultraviolet-B exposure at baseline and birth, 15 years, and 30 years.
In investigating biomarkers, the researchers noted a “suggestive increase” in chronic lymphocytic leukemia risk associated with an Epstein-Barr virus antibody profile indicative of poor host immune control of the virus.
Related: Sexual Orientation and Cancer Risk
The researchers have established several working groups to study cancers, such as NHL and multiple myeloma. They also are collecting archival tissue specimens for NHL, multiple myeloma, and Hodgkin lymphoma, for better evaluation of factors related to the unique molecular subsets of hematologic tumors.
Source:
Birmann BM, Barnard ME, Bertrand KA, et al. Am J Public Health. 2016;106(9):1608-1615.
doi: 10.2105/AJPH.2016.303337.
Certain lifestyle, dietary, environmental, serologic, and genetic factors may raise the risk of non-Hodgkin lymphoma (NHL), according to researchers who reviewed 40 years of follow-up data from the Nurses’ Health Study (NHS).
Related: Exercise Lowers Risk of Some Cancers
The researchers, from Brigham and Women’s Hospital, Harvard, and Boston University, all in Massachusetts, aimed to highlight the NHS’s contributions to epidemiologic knowledge of endometrial, ovarian, pancreatic, and hematologic cancers. They focused on findings that identified novel risk factors or markers of early detection or helped clarify discrepant literature.
Because the researchers say severe immune compromise is the “strongest, best-established risk factor” for NHL, they studied factors that might lead to subclinical immune dysregulation, such as diet, body mass index (BMI), and supplement use. They found several risk factors and biomarkers for NHL and more than 35 distinct tumors in that category, including chronic lymphocytic leukemia. Trans fats and red meat, for instance, doubled the risk of NHL. The researchers also found a higher risk for women who reported long-term multivitamin use. However, they found no risk associated with diet or sugar-sweetened soda or aspartame or with dietary intake of vitamin D.
Related: IBD and the Risk of Oral Cancer
Greater adiposity during childhood and adolescence was significantly associated with NHL. The researchers also observed a 19% increased risk of all NHL per 5 kg/m2 increase in BMI in young adulthood. Interestingly, taller women also had a higher risk of NHL.
The researchers conducted one of the first prospective studies to evaluate a putative inverse association of NHL risk with exposure to ambient ultraviolet radiation. They found, “contrary to expectation,” a 10% to 20% increased risk of NHL among women with the highest (vs lowest) ultraviolet-B exposure at baseline and birth, 15 years, and 30 years.
In investigating biomarkers, the researchers noted a “suggestive increase” in chronic lymphocytic leukemia risk associated with an Epstein-Barr virus antibody profile indicative of poor host immune control of the virus.
Related: Sexual Orientation and Cancer Risk
The researchers have established several working groups to study cancers, such as NHL and multiple myeloma. They also are collecting archival tissue specimens for NHL, multiple myeloma, and Hodgkin lymphoma, for better evaluation of factors related to the unique molecular subsets of hematologic tumors.
Source:
Birmann BM, Barnard ME, Bertrand KA, et al. Am J Public Health. 2016;106(9):1608-1615.
doi: 10.2105/AJPH.2016.303337.
Managing MGUS Consultations Electronically—A Single Center Experience
Non-visit electronic consultations (NVCs) are an important component of care for VA patients requiring sub-specialty consultation but not requiring urgent face to face evaluation. Here we specifically analyzed referrals for monoclonal gammopathy of undetermined significance (MGUS), since this is a diagnosis that requires ongoing surveillance once identified. It is an ideal model to study utilization and effectiveness of NVCs over time.
We identified 615 electronic hematology consultation encounters from 1/1/11-12/31/11 at our institution. Of these, 37 (6%) were consults for MGUS. Patient records were evaluated up to 5 years following the original consultation. We found that 16% (6/37) of MGUS patients subsequently had a face to face evaluation. 4 of these were due to onset of malignancy (3 multiple myeloma and 1 non-Hodgkin lymphoma). Over the 5 year study period, 51% (19/37) have been one-time consults while 32% (12/37) have utilized multiple NVCs. Typical recommendations at our institution for MGUS include yearly SPEP, serum free light chain assessment, and a baseline skeletal survey. Bone marrow biopsy is not routinely recommended for low-risk patients. Surveillance and re-consultation by a specialist is at the discretion of the referring provider.
22 of 37 MGUS patients had a documented skeletal survey. Of the 15 without evaluation, 7 had M-protein values that were only positive by immunofixation, while 4 were IgM cases. We do not routinely promote DEXA, though 14% of MGUS patients also had a DEXA (for any reason). In addition, the majority of MGUS patients (28/37) were found to have documented 25-OH vitamin D levels. Among these, only 4 had a mean vitamin D level that would be considered deficient (under 20 ng/mL).
Overall, we describe a cohort of MGUS patients initially identified via electronic consultation at our institution. With an average study follow-up of only 4-5 years, we identified 4 cases of malignancy (10.8% of MGUS NVCs), demonstrating the importance of careful evaluation of MGUS cases referred for specialty consultation. Areas of uncertainty that require further attention include: 1) skeletal surveys in patients with scant monoclonal protein, 2) routine promotion of DEXA and 3) targeted vitamin D supplementation practices among MGUS patients.
Non-visit electronic consultations (NVCs) are an important component of care for VA patients requiring sub-specialty consultation but not requiring urgent face to face evaluation. Here we specifically analyzed referrals for monoclonal gammopathy of undetermined significance (MGUS), since this is a diagnosis that requires ongoing surveillance once identified. It is an ideal model to study utilization and effectiveness of NVCs over time.
We identified 615 electronic hematology consultation encounters from 1/1/11-12/31/11 at our institution. Of these, 37 (6%) were consults for MGUS. Patient records were evaluated up to 5 years following the original consultation. We found that 16% (6/37) of MGUS patients subsequently had a face to face evaluation. 4 of these were due to onset of malignancy (3 multiple myeloma and 1 non-Hodgkin lymphoma). Over the 5 year study period, 51% (19/37) have been one-time consults while 32% (12/37) have utilized multiple NVCs. Typical recommendations at our institution for MGUS include yearly SPEP, serum free light chain assessment, and a baseline skeletal survey. Bone marrow biopsy is not routinely recommended for low-risk patients. Surveillance and re-consultation by a specialist is at the discretion of the referring provider.
22 of 37 MGUS patients had a documented skeletal survey. Of the 15 without evaluation, 7 had M-protein values that were only positive by immunofixation, while 4 were IgM cases. We do not routinely promote DEXA, though 14% of MGUS patients also had a DEXA (for any reason). In addition, the majority of MGUS patients (28/37) were found to have documented 25-OH vitamin D levels. Among these, only 4 had a mean vitamin D level that would be considered deficient (under 20 ng/mL).
Overall, we describe a cohort of MGUS patients initially identified via electronic consultation at our institution. With an average study follow-up of only 4-5 years, we identified 4 cases of malignancy (10.8% of MGUS NVCs), demonstrating the importance of careful evaluation of MGUS cases referred for specialty consultation. Areas of uncertainty that require further attention include: 1) skeletal surveys in patients with scant monoclonal protein, 2) routine promotion of DEXA and 3) targeted vitamin D supplementation practices among MGUS patients.
Non-visit electronic consultations (NVCs) are an important component of care for VA patients requiring sub-specialty consultation but not requiring urgent face to face evaluation. Here we specifically analyzed referrals for monoclonal gammopathy of undetermined significance (MGUS), since this is a diagnosis that requires ongoing surveillance once identified. It is an ideal model to study utilization and effectiveness of NVCs over time.
We identified 615 electronic hematology consultation encounters from 1/1/11-12/31/11 at our institution. Of these, 37 (6%) were consults for MGUS. Patient records were evaluated up to 5 years following the original consultation. We found that 16% (6/37) of MGUS patients subsequently had a face to face evaluation. 4 of these were due to onset of malignancy (3 multiple myeloma and 1 non-Hodgkin lymphoma). Over the 5 year study period, 51% (19/37) have been one-time consults while 32% (12/37) have utilized multiple NVCs. Typical recommendations at our institution for MGUS include yearly SPEP, serum free light chain assessment, and a baseline skeletal survey. Bone marrow biopsy is not routinely recommended for low-risk patients. Surveillance and re-consultation by a specialist is at the discretion of the referring provider.
22 of 37 MGUS patients had a documented skeletal survey. Of the 15 without evaluation, 7 had M-protein values that were only positive by immunofixation, while 4 were IgM cases. We do not routinely promote DEXA, though 14% of MGUS patients also had a DEXA (for any reason). In addition, the majority of MGUS patients (28/37) were found to have documented 25-OH vitamin D levels. Among these, only 4 had a mean vitamin D level that would be considered deficient (under 20 ng/mL).
Overall, we describe a cohort of MGUS patients initially identified via electronic consultation at our institution. With an average study follow-up of only 4-5 years, we identified 4 cases of malignancy (10.8% of MGUS NVCs), demonstrating the importance of careful evaluation of MGUS cases referred for specialty consultation. Areas of uncertainty that require further attention include: 1) skeletal surveys in patients with scant monoclonal protein, 2) routine promotion of DEXA and 3) targeted vitamin D supplementation practices among MGUS patients.
CT-Guided Bone Marrow Aspiration and Biopsy Is a Safe and Feasible Option to Decompress Busy Hematology/Oncology Clinics
Purpose: To disseminate information regarding the Louis Stokes Cleveland VAMC process for CT guided bone marrow aspiration and biopsies (BMAB).
Relevant Background/Problem: With timely access to quality care at the forefront of many VA-based initiatives we sought to decrease wait times for new patients with hematology concerns. Upon review of clinic utilization we recognized that many established patients requiring BMAB were scheduled into a new patient slot to allow enough time for the procedure. At the same time, our colleagues in Interventional Radiology (IR) approached us regarding the feasibility of performing BMAB using CT guidance.
Methods: We performed a retrospective review of all BMAB done between September 2014 and August 2015 before the IR guided procedure was offered to determine number of procedures performed. We then examined those cases performed from September 2015 to June 2016 after rollout of IR guided BMAB to determine numbers of cases, location of procedure (IR versus Hematology/Oncology), operator (IR versus staff versus fellow), and complications.
Data Analysis: From September 2014 to August 2015, 211 BMAB were performed, averaging 17 per month. From September 2015 to June 2016, 207 BMAB were performed with an average of 20 per month. During the latter time period, 50% of BMAB were performed using IR guidance with the other 50% performed by either Hematology/Oncology staff or fellows. There were no complications reported regardless of location and operator. Exposure to radiation dose was extremely low.
Results: IR guided BMAB is a safe and feasible option for patients and Hematology/Oncology providers.
Implications: IR guided BMAB can be one option to decompress already overbooked Hematology/Oncology clinics and to provide quicker access to care for patients with newly diagnosed hematologic and oncologic conditions.
Purpose: To disseminate information regarding the Louis Stokes Cleveland VAMC process for CT guided bone marrow aspiration and biopsies (BMAB).
Relevant Background/Problem: With timely access to quality care at the forefront of many VA-based initiatives we sought to decrease wait times for new patients with hematology concerns. Upon review of clinic utilization we recognized that many established patients requiring BMAB were scheduled into a new patient slot to allow enough time for the procedure. At the same time, our colleagues in Interventional Radiology (IR) approached us regarding the feasibility of performing BMAB using CT guidance.
Methods: We performed a retrospective review of all BMAB done between September 2014 and August 2015 before the IR guided procedure was offered to determine number of procedures performed. We then examined those cases performed from September 2015 to June 2016 after rollout of IR guided BMAB to determine numbers of cases, location of procedure (IR versus Hematology/Oncology), operator (IR versus staff versus fellow), and complications.
Data Analysis: From September 2014 to August 2015, 211 BMAB were performed, averaging 17 per month. From September 2015 to June 2016, 207 BMAB were performed with an average of 20 per month. During the latter time period, 50% of BMAB were performed using IR guidance with the other 50% performed by either Hematology/Oncology staff or fellows. There were no complications reported regardless of location and operator. Exposure to radiation dose was extremely low.
Results: IR guided BMAB is a safe and feasible option for patients and Hematology/Oncology providers.
Implications: IR guided BMAB can be one option to decompress already overbooked Hematology/Oncology clinics and to provide quicker access to care for patients with newly diagnosed hematologic and oncologic conditions.
Purpose: To disseminate information regarding the Louis Stokes Cleveland VAMC process for CT guided bone marrow aspiration and biopsies (BMAB).
Relevant Background/Problem: With timely access to quality care at the forefront of many VA-based initiatives we sought to decrease wait times for new patients with hematology concerns. Upon review of clinic utilization we recognized that many established patients requiring BMAB were scheduled into a new patient slot to allow enough time for the procedure. At the same time, our colleagues in Interventional Radiology (IR) approached us regarding the feasibility of performing BMAB using CT guidance.
Methods: We performed a retrospective review of all BMAB done between September 2014 and August 2015 before the IR guided procedure was offered to determine number of procedures performed. We then examined those cases performed from September 2015 to June 2016 after rollout of IR guided BMAB to determine numbers of cases, location of procedure (IR versus Hematology/Oncology), operator (IR versus staff versus fellow), and complications.
Data Analysis: From September 2014 to August 2015, 211 BMAB were performed, averaging 17 per month. From September 2015 to June 2016, 207 BMAB were performed with an average of 20 per month. During the latter time period, 50% of BMAB were performed using IR guidance with the other 50% performed by either Hematology/Oncology staff or fellows. There were no complications reported regardless of location and operator. Exposure to radiation dose was extremely low.
Results: IR guided BMAB is a safe and feasible option for patients and Hematology/Oncology providers.
Implications: IR guided BMAB can be one option to decompress already overbooked Hematology/Oncology clinics and to provide quicker access to care for patients with newly diagnosed hematologic and oncologic conditions.
Double-Expressor Lymphoma (DEL) in Veterans at DC VAMC
Purpose: To identify DEL amongst veteran patients with diffuse large B cell lymphoma (DLBCL) and its outcome.
Background: Molecular profile determines prognosis in DLBCL. Activated B-cell (ABC), a subtype of DLBCL, is associated with poor outcome compared to germinal center Bcell (GCB). Poor response to standard chemotherapy is seen with double-hit lymphomas as detected by FISH (5% -10% of DLBCL) and DELs that express both MYC and BCL-2 as detected by immunohistochemistry (IHC) (cutoffs—30% MYC, 40% BCL-2), with a median overall survival of <12 months.
Methods: Sixty-nine DLBCL patients diagnosed at DC VAMC from 1/1996-4/2016 were identified utilizing cancer registry. IHC stains were reviewed for CD3, CD10, CD20, BCL-2, BCL-6, C-MYC, MUM-1, MIB1, and p53. DLBCL were sub-classified as GCB and ABC based on CD10, BCL6 and MUM1 stains. Demographic data, diagnosis, treatment and outcome in terms of relapse and death are analyzed and will be presented at the meeting.
Results: Of the 69 DLBCL cases, only 37 met inclusion criteria; 32 were excluded due to unavailable blocks (20, mostly sent to outside institutions), tissue exhaustion with incomplete IHC data (6), T-cell rich B cell lymphoma (5) and pending (1). 20 cases are GCB and 17 ABC. All cases are CD20 positive with high mib1. MYC is positive in 17 cases (46%) and 15 of them double positive for BCL-2 (40%).
Implications/Future Directions: DLBCL veterans at the DC VAMC have a high percentage of double expressors when compared to the literature. It will be important to examine clinical data, treatment, and outcome to develop better treatment guidelines for double-expressor DLBCL. Future studies are in plan to compare double hit lymphomas to double expressors.
Purpose: To identify DEL amongst veteran patients with diffuse large B cell lymphoma (DLBCL) and its outcome.
Background: Molecular profile determines prognosis in DLBCL. Activated B-cell (ABC), a subtype of DLBCL, is associated with poor outcome compared to germinal center Bcell (GCB). Poor response to standard chemotherapy is seen with double-hit lymphomas as detected by FISH (5% -10% of DLBCL) and DELs that express both MYC and BCL-2 as detected by immunohistochemistry (IHC) (cutoffs—30% MYC, 40% BCL-2), with a median overall survival of <12 months.
Methods: Sixty-nine DLBCL patients diagnosed at DC VAMC from 1/1996-4/2016 were identified utilizing cancer registry. IHC stains were reviewed for CD3, CD10, CD20, BCL-2, BCL-6, C-MYC, MUM-1, MIB1, and p53. DLBCL were sub-classified as GCB and ABC based on CD10, BCL6 and MUM1 stains. Demographic data, diagnosis, treatment and outcome in terms of relapse and death are analyzed and will be presented at the meeting.
Results: Of the 69 DLBCL cases, only 37 met inclusion criteria; 32 were excluded due to unavailable blocks (20, mostly sent to outside institutions), tissue exhaustion with incomplete IHC data (6), T-cell rich B cell lymphoma (5) and pending (1). 20 cases are GCB and 17 ABC. All cases are CD20 positive with high mib1. MYC is positive in 17 cases (46%) and 15 of them double positive for BCL-2 (40%).
Implications/Future Directions: DLBCL veterans at the DC VAMC have a high percentage of double expressors when compared to the literature. It will be important to examine clinical data, treatment, and outcome to develop better treatment guidelines for double-expressor DLBCL. Future studies are in plan to compare double hit lymphomas to double expressors.
Purpose: To identify DEL amongst veteran patients with diffuse large B cell lymphoma (DLBCL) and its outcome.
Background: Molecular profile determines prognosis in DLBCL. Activated B-cell (ABC), a subtype of DLBCL, is associated with poor outcome compared to germinal center Bcell (GCB). Poor response to standard chemotherapy is seen with double-hit lymphomas as detected by FISH (5% -10% of DLBCL) and DELs that express both MYC and BCL-2 as detected by immunohistochemistry (IHC) (cutoffs—30% MYC, 40% BCL-2), with a median overall survival of <12 months.
Methods: Sixty-nine DLBCL patients diagnosed at DC VAMC from 1/1996-4/2016 were identified utilizing cancer registry. IHC stains were reviewed for CD3, CD10, CD20, BCL-2, BCL-6, C-MYC, MUM-1, MIB1, and p53. DLBCL were sub-classified as GCB and ABC based on CD10, BCL6 and MUM1 stains. Demographic data, diagnosis, treatment and outcome in terms of relapse and death are analyzed and will be presented at the meeting.
Results: Of the 69 DLBCL cases, only 37 met inclusion criteria; 32 were excluded due to unavailable blocks (20, mostly sent to outside institutions), tissue exhaustion with incomplete IHC data (6), T-cell rich B cell lymphoma (5) and pending (1). 20 cases are GCB and 17 ABC. All cases are CD20 positive with high mib1. MYC is positive in 17 cases (46%) and 15 of them double positive for BCL-2 (40%).
Implications/Future Directions: DLBCL veterans at the DC VAMC have a high percentage of double expressors when compared to the literature. It will be important to examine clinical data, treatment, and outcome to develop better treatment guidelines for double-expressor DLBCL. Future studies are in plan to compare double hit lymphomas to double expressors.
Demographic and Clinical Characteristics of Patients With Polycythemia Vera (PV) in the U.S. Veterans Population
Introduction: PV is associated with an increased risk of thrombosis, which contributes to morbidity and mortality of patients. Limited data exist on patients with PV among the Veterans Health Administration (VHA) population. The objective of this study is to describe the demographic and clinical characteristics of patients with PV in the VHA population.
Methods: A retrospective, observational analysis was conducted using longitudinal data from the VHA database. The analysis included adult patients who had ≥ 2 claims for PV (ICD-9 238.4) ≥ 30 days apart between 01/01/2007 and 12/31/2009 and ≥ 12 months of continuous enrollment before the first PV claim (index date). Patients were followed from the index date until the earliest date of death, disenrollment, or end of study (9/30/2012). Demographics and comorbid conditions during the pre-index period, and cytoreductive treatments, select laboratory values, thrombotic event (TE) rate, and mortality rate during the follow-up period are reported.
Results: The analysis included 7718 patients with PV; most patients were ≥ 60 years of age (70.7%), male (97.9%), and white (63.9%). The 3 most common comorbid conditions reported during the pre-index period were hypertension (71.7%), dyslipidemia (54.2%), and diabetes (24.0%). Additionally, 8.8% had arterial thrombosis, 4.5% had venous thrombosis, and 8.7% had bleeding. During the follow-up period (median 4.8 years), 23.2% of patients received cytoreductive pharmacotherapy (86.7% hydroxyurea), 32.8% had phlebotomy, and 53.0% had neither cytoreductive therapy nor phlebotomy. 86.4% and 63.3% of patients were using antihypertensive agents and anti-lipid medications, respectively. 86.7% of patients had ≥ 2 elevated HCT levels (≥ 45%) and 37.3% had ≥ 2 elevated WBC counts ( ≥ 11*109/L). 22.9% of patients had ≥ 1 TE (16.5% arterial thrombosis and 8.78% venous thrombosis). The TE rate was 60.5 per 1,000 patient years. Deaths due to any cause were reported for 23.0% of patients during follow-up.
Conclusion: The TE burden is significant among patients with PV in the VHA population. A large proportion of patients had elevated blood values, which may indicate uncontrolled PV, and may predispose patients to greater risk of clinical complications and consequences of PV.
Introduction: PV is associated with an increased risk of thrombosis, which contributes to morbidity and mortality of patients. Limited data exist on patients with PV among the Veterans Health Administration (VHA) population. The objective of this study is to describe the demographic and clinical characteristics of patients with PV in the VHA population.
Methods: A retrospective, observational analysis was conducted using longitudinal data from the VHA database. The analysis included adult patients who had ≥ 2 claims for PV (ICD-9 238.4) ≥ 30 days apart between 01/01/2007 and 12/31/2009 and ≥ 12 months of continuous enrollment before the first PV claim (index date). Patients were followed from the index date until the earliest date of death, disenrollment, or end of study (9/30/2012). Demographics and comorbid conditions during the pre-index period, and cytoreductive treatments, select laboratory values, thrombotic event (TE) rate, and mortality rate during the follow-up period are reported.
Results: The analysis included 7718 patients with PV; most patients were ≥ 60 years of age (70.7%), male (97.9%), and white (63.9%). The 3 most common comorbid conditions reported during the pre-index period were hypertension (71.7%), dyslipidemia (54.2%), and diabetes (24.0%). Additionally, 8.8% had arterial thrombosis, 4.5% had venous thrombosis, and 8.7% had bleeding. During the follow-up period (median 4.8 years), 23.2% of patients received cytoreductive pharmacotherapy (86.7% hydroxyurea), 32.8% had phlebotomy, and 53.0% had neither cytoreductive therapy nor phlebotomy. 86.4% and 63.3% of patients were using antihypertensive agents and anti-lipid medications, respectively. 86.7% of patients had ≥ 2 elevated HCT levels (≥ 45%) and 37.3% had ≥ 2 elevated WBC counts ( ≥ 11*109/L). 22.9% of patients had ≥ 1 TE (16.5% arterial thrombosis and 8.78% venous thrombosis). The TE rate was 60.5 per 1,000 patient years. Deaths due to any cause were reported for 23.0% of patients during follow-up.
Conclusion: The TE burden is significant among patients with PV in the VHA population. A large proportion of patients had elevated blood values, which may indicate uncontrolled PV, and may predispose patients to greater risk of clinical complications and consequences of PV.
Introduction: PV is associated with an increased risk of thrombosis, which contributes to morbidity and mortality of patients. Limited data exist on patients with PV among the Veterans Health Administration (VHA) population. The objective of this study is to describe the demographic and clinical characteristics of patients with PV in the VHA population.
Methods: A retrospective, observational analysis was conducted using longitudinal data from the VHA database. The analysis included adult patients who had ≥ 2 claims for PV (ICD-9 238.4) ≥ 30 days apart between 01/01/2007 and 12/31/2009 and ≥ 12 months of continuous enrollment before the first PV claim (index date). Patients were followed from the index date until the earliest date of death, disenrollment, or end of study (9/30/2012). Demographics and comorbid conditions during the pre-index period, and cytoreductive treatments, select laboratory values, thrombotic event (TE) rate, and mortality rate during the follow-up period are reported.
Results: The analysis included 7718 patients with PV; most patients were ≥ 60 years of age (70.7%), male (97.9%), and white (63.9%). The 3 most common comorbid conditions reported during the pre-index period were hypertension (71.7%), dyslipidemia (54.2%), and diabetes (24.0%). Additionally, 8.8% had arterial thrombosis, 4.5% had venous thrombosis, and 8.7% had bleeding. During the follow-up period (median 4.8 years), 23.2% of patients received cytoreductive pharmacotherapy (86.7% hydroxyurea), 32.8% had phlebotomy, and 53.0% had neither cytoreductive therapy nor phlebotomy. 86.4% and 63.3% of patients were using antihypertensive agents and anti-lipid medications, respectively. 86.7% of patients had ≥ 2 elevated HCT levels (≥ 45%) and 37.3% had ≥ 2 elevated WBC counts ( ≥ 11*109/L). 22.9% of patients had ≥ 1 TE (16.5% arterial thrombosis and 8.78% venous thrombosis). The TE rate was 60.5 per 1,000 patient years. Deaths due to any cause were reported for 23.0% of patients during follow-up.
Conclusion: The TE burden is significant among patients with PV in the VHA population. A large proportion of patients had elevated blood values, which may indicate uncontrolled PV, and may predispose patients to greater risk of clinical complications and consequences of PV.
Implementing a New Protocol for Heparin Anticoagulation
Purpose: Intravenous unfractionated heparin (UFH) remains an important anticoagulation (AC) agent, particularly in the inpatient setting. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. Given that several biologic factors can influence the aPTT, independent of the effects of UFH, institutions have transitioned to monitoring heparin with anti-Xa levels. Clinical data show that conversion from aPTT to anti-Xa monitoring may offer a smoother dose-response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments.
Background/Problem: The Cleveland VA Medical Center (CVAMC) provides annual care to over 105,000 veterans. It was recently designated as a center for implantation of left ventricular assist devices (LVADs.) As part of the AC monitoring for these patients, a hematologist introduced the use of anti-Xa assay as the test of choice to monitor heparin. Favorable results in this patient cohort prompted consideration for a hospital-wide change in heparin monitoring and a new heparin dosing protocol.
Methods: A multidisciplinary group assembled in November 2015 and developed a low-intensity and high-intensity heparin protocol with anti-Xa as the test to monitor heparin. Laboratory staffing was increased to accommodate phlebotomy rounds. Alaris IV pumps were re-programmed. Physicians developed a specific order set. Nurses designed an AC nurse’s note, and pharmacists devised safe-guard strategies when dose changes are made. Clinical Nurse Specialists developed an educational program for all 228 inpatient registered nurses which will be completed on July 3rd. All stakeholders are expected to meet and confirm their readiness to fully implement the new protocol.
Data Analysis: Anti-Xa equipment was purchased and validation tests were completed. In LVAD patients, therapeutic levels within 24 hours were noted in 86% of the cases.
Results: Hospital-wide implementation of the new heparin protocol is projected for August 1, 2016.
Implications: Presently, there are only 9 VAMCs using the anti-Xa assay to manage heparin anticoagulation. The CVAMC has developed a comprehensive implementation process that consists of new order sets, templates, training programs, and tools for common references. A poster at the AVAHO meeting will illustrate the process and provide postimplementation updates.
Purpose: Intravenous unfractionated heparin (UFH) remains an important anticoagulation (AC) agent, particularly in the inpatient setting. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. Given that several biologic factors can influence the aPTT, independent of the effects of UFH, institutions have transitioned to monitoring heparin with anti-Xa levels. Clinical data show that conversion from aPTT to anti-Xa monitoring may offer a smoother dose-response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments.
Background/Problem: The Cleveland VA Medical Center (CVAMC) provides annual care to over 105,000 veterans. It was recently designated as a center for implantation of left ventricular assist devices (LVADs.) As part of the AC monitoring for these patients, a hematologist introduced the use of anti-Xa assay as the test of choice to monitor heparin. Favorable results in this patient cohort prompted consideration for a hospital-wide change in heparin monitoring and a new heparin dosing protocol.
Methods: A multidisciplinary group assembled in November 2015 and developed a low-intensity and high-intensity heparin protocol with anti-Xa as the test to monitor heparin. Laboratory staffing was increased to accommodate phlebotomy rounds. Alaris IV pumps were re-programmed. Physicians developed a specific order set. Nurses designed an AC nurse’s note, and pharmacists devised safe-guard strategies when dose changes are made. Clinical Nurse Specialists developed an educational program for all 228 inpatient registered nurses which will be completed on July 3rd. All stakeholders are expected to meet and confirm their readiness to fully implement the new protocol.
Data Analysis: Anti-Xa equipment was purchased and validation tests were completed. In LVAD patients, therapeutic levels within 24 hours were noted in 86% of the cases.
Results: Hospital-wide implementation of the new heparin protocol is projected for August 1, 2016.
Implications: Presently, there are only 9 VAMCs using the anti-Xa assay to manage heparin anticoagulation. The CVAMC has developed a comprehensive implementation process that consists of new order sets, templates, training programs, and tools for common references. A poster at the AVAHO meeting will illustrate the process and provide postimplementation updates.
Purpose: Intravenous unfractionated heparin (UFH) remains an important anticoagulation (AC) agent, particularly in the inpatient setting. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. Given that several biologic factors can influence the aPTT, independent of the effects of UFH, institutions have transitioned to monitoring heparin with anti-Xa levels. Clinical data show that conversion from aPTT to anti-Xa monitoring may offer a smoother dose-response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments.
Background/Problem: The Cleveland VA Medical Center (CVAMC) provides annual care to over 105,000 veterans. It was recently designated as a center for implantation of left ventricular assist devices (LVADs.) As part of the AC monitoring for these patients, a hematologist introduced the use of anti-Xa assay as the test of choice to monitor heparin. Favorable results in this patient cohort prompted consideration for a hospital-wide change in heparin monitoring and a new heparin dosing protocol.
Methods: A multidisciplinary group assembled in November 2015 and developed a low-intensity and high-intensity heparin protocol with anti-Xa as the test to monitor heparin. Laboratory staffing was increased to accommodate phlebotomy rounds. Alaris IV pumps were re-programmed. Physicians developed a specific order set. Nurses designed an AC nurse’s note, and pharmacists devised safe-guard strategies when dose changes are made. Clinical Nurse Specialists developed an educational program for all 228 inpatient registered nurses which will be completed on July 3rd. All stakeholders are expected to meet and confirm their readiness to fully implement the new protocol.
Data Analysis: Anti-Xa equipment was purchased and validation tests were completed. In LVAD patients, therapeutic levels within 24 hours were noted in 86% of the cases.
Results: Hospital-wide implementation of the new heparin protocol is projected for August 1, 2016.
Implications: Presently, there are only 9 VAMCs using the anti-Xa assay to manage heparin anticoagulation. The CVAMC has developed a comprehensive implementation process that consists of new order sets, templates, training programs, and tools for common references. A poster at the AVAHO meeting will illustrate the process and provide postimplementation updates.
Influence of Tyrosine Kinase Inhibitors on Renal Function and Current Monitoring Procedures at the Cincinnati Veterans Affairs Medical Center
Purpose: Patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) are treated with tyrosine kinase inhibitors (TKI), namely, imatinib, nilotinib, and dasatinib. Recent studies suggest that TKI therapy may be linked to the development of an acute kidney injury (AKI) and chronic kidney disease (CKD). This review evaluates current monitoring procedures at the Cincinnati VAMC.
Methods: A retrospective chart review using the electronic medical record was used to identify patients receiving TKI therapy ≥ 1 year with a diagnosis of CML or GIST. Demographics collected include: age, gender, baseline and subsequent serum creatinine, comorbid conditions possibly confounding kidney dysfunction, and receipt of nephrotoxic agents. The average change in renal function for the duration of treatment as well as per year of therapy with TKI and average number of days between lab draws were calculated.
Results: Forty-two patients were identified with active prescriptions for a TKI between January 1, 2005 and December 31, 2014. Twenty-four patients were included, of which 22 did not receive a basic metabolic panel at the recommended interval based on VA PBM Guidance. The average time between lab draws was 114 days. Fifteen patients incurred an acute kidney injury. The average change in serum creatinine for the duration of treatment was a +0.29 mg/dL. Five patients were identified that met manufacturer renal dosing criteria. Of these patients, 2 had an appropriately adjusted dose. Two patients developed CKD during the treatment period who did not have CKD at baseline.
Conclusion: Current monitoring of renal function at the Cincinnati VAMC is not in compliance with VA PBM recommendations for patients receiving TKI therapy. However, they are in line with manufacturer recommendations. While a large portion of patients developed an AKI with therapy, direct causation cannot be established as several of these patients received nephrotoxic agents in the immediately preceding 7 days of the elevated serum creatinine value. The increase in serum creatinine does not appear to be sustained, as the average change in serum creatinine for the duration of therapy was not large. Thus, quarterly monitoring of renal function appears to be appropriate in this population.
Purpose: Patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) are treated with tyrosine kinase inhibitors (TKI), namely, imatinib, nilotinib, and dasatinib. Recent studies suggest that TKI therapy may be linked to the development of an acute kidney injury (AKI) and chronic kidney disease (CKD). This review evaluates current monitoring procedures at the Cincinnati VAMC.
Methods: A retrospective chart review using the electronic medical record was used to identify patients receiving TKI therapy ≥ 1 year with a diagnosis of CML or GIST. Demographics collected include: age, gender, baseline and subsequent serum creatinine, comorbid conditions possibly confounding kidney dysfunction, and receipt of nephrotoxic agents. The average change in renal function for the duration of treatment as well as per year of therapy with TKI and average number of days between lab draws were calculated.
Results: Forty-two patients were identified with active prescriptions for a TKI between January 1, 2005 and December 31, 2014. Twenty-four patients were included, of which 22 did not receive a basic metabolic panel at the recommended interval based on VA PBM Guidance. The average time between lab draws was 114 days. Fifteen patients incurred an acute kidney injury. The average change in serum creatinine for the duration of treatment was a +0.29 mg/dL. Five patients were identified that met manufacturer renal dosing criteria. Of these patients, 2 had an appropriately adjusted dose. Two patients developed CKD during the treatment period who did not have CKD at baseline.
Conclusion: Current monitoring of renal function at the Cincinnati VAMC is not in compliance with VA PBM recommendations for patients receiving TKI therapy. However, they are in line with manufacturer recommendations. While a large portion of patients developed an AKI with therapy, direct causation cannot be established as several of these patients received nephrotoxic agents in the immediately preceding 7 days of the elevated serum creatinine value. The increase in serum creatinine does not appear to be sustained, as the average change in serum creatinine for the duration of therapy was not large. Thus, quarterly monitoring of renal function appears to be appropriate in this population.
Purpose: Patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST) are treated with tyrosine kinase inhibitors (TKI), namely, imatinib, nilotinib, and dasatinib. Recent studies suggest that TKI therapy may be linked to the development of an acute kidney injury (AKI) and chronic kidney disease (CKD). This review evaluates current monitoring procedures at the Cincinnati VAMC.
Methods: A retrospective chart review using the electronic medical record was used to identify patients receiving TKI therapy ≥ 1 year with a diagnosis of CML or GIST. Demographics collected include: age, gender, baseline and subsequent serum creatinine, comorbid conditions possibly confounding kidney dysfunction, and receipt of nephrotoxic agents. The average change in renal function for the duration of treatment as well as per year of therapy with TKI and average number of days between lab draws were calculated.
Results: Forty-two patients were identified with active prescriptions for a TKI between January 1, 2005 and December 31, 2014. Twenty-four patients were included, of which 22 did not receive a basic metabolic panel at the recommended interval based on VA PBM Guidance. The average time between lab draws was 114 days. Fifteen patients incurred an acute kidney injury. The average change in serum creatinine for the duration of treatment was a +0.29 mg/dL. Five patients were identified that met manufacturer renal dosing criteria. Of these patients, 2 had an appropriately adjusted dose. Two patients developed CKD during the treatment period who did not have CKD at baseline.
Conclusion: Current monitoring of renal function at the Cincinnati VAMC is not in compliance with VA PBM recommendations for patients receiving TKI therapy. However, they are in line with manufacturer recommendations. While a large portion of patients developed an AKI with therapy, direct causation cannot be established as several of these patients received nephrotoxic agents in the immediately preceding 7 days of the elevated serum creatinine value. The increase in serum creatinine does not appear to be sustained, as the average change in serum creatinine for the duration of therapy was not large. Thus, quarterly monitoring of renal function appears to be appropriate in this population.
Can Serum Free Light Chains Be Used for the Early Diagnosis of Monoclonal Immunoglobulin-Secreting B-Cell and Plasma-Cell Diseases? (FULL)
Patients who are undergoing multiple myeloma screening with serum protein electrophoresis and immunofixation, especially those with renal failure, also should receive serum free light chain testing to increase specificity and reduce false-negatives.
Multiple myeloma (MM) is a devastating disease with an estimated 26,850 new cases in 2015 according to Surveillance, Epidemiology, and End Results data and no definitive chemotherapeutic cure.1 In 97% of cases, MM is defined by monoclonal hypergammaglobulinemia, in which a malignant plasma cell clone secretes a monoclonal globulin; the remaining cases are nonsecretors.2 Each pathologically produced clonal globulin contains 2 heavy chains attached by disulfide linkage and 2 light chains. Unchecked plasma cell production is what later causes the symptoms of renal failure, bone destruction, and anemia.
The rate of MM is disproportionately high in the veteran population, and the VA health care system provides care for many of these patients. The higher rate is likely secondary to the predominantly male population, which has higher MM rates, and has been linked to Agent Orange exposure in Vietnam. As MM is not easy to diagnose, any algorithm or testing method would be of great benefit to this population.
The gold standard for MM detection remains serum protein electrophoresis (SPEP) with immunofixation (IFE), but other detection methods have been emerging. The method of serum free light chain (SFLC) assay has become more readily available, and its incorporation into diagnostic guidelines has become more apparent but is not universal.3
In the case series reported in this article, SPEP/IFE and SFLC assays were used to test 207 patients from the VA New York Harbor Healthcare System (VANYHHS). All these patients had a clinical context for MM testing.
Methods
In this retrospective study, the authors reviewed the charts of VANYHHS patients who were being treated for conditions that prompted SPEP/IFE and λ and κ SFLC analysis between December 2013 and March 2014. The study was exempt from institutional review board approval.
The SPEP/IFE analysis was performed with an automated electrophoresis machine (Sebia Electrophoresis), and the SFLC analysis was performed with an automated SFLC assay (Freelite). Sensitivity, specificity, and positive and negative predictive values were calculated using SPEP/IFE as the gold standard and SFLC κ-to-λ ratio asthe test method. Patients with a positive κ-to-λ ratio but negative SPEP were considered false-positives. These patients’ SFLC analyses were further analyzed in an effort to evaluate use of the κ-to-λ ratio as an early tumor marker.
The κ reference range used was 3.3 to 19.4 mg/L, and the λ reference range used was 5.7 to 26.3 mg/L.4 The traditional reference range for the κ-to-λ ratio is 0.26 to 1.65.5
Results
Of the 207 patients in this study, 205 were men. Mean age was 69 years (range, 28-97 years). Mean serum urea nitrogen level was 8.75 mmol/L (range, 2.86-38.21 mmol/L), and mean creatinine level was 140.59 μmol/L (range, 44.21-1503.14 μmol/L). Mean κ was 49.82 mg/L (range, 4.6-700.96 mg/L), and mean λ was 54.27 mg/L (range, 3-1,750 mg/L). Table 1 compares the SPEP and SFLC data. Sensitivity was 67%, specificity was 85%, positive predictive value was 58%, and negative predictive value was 89%. Concordance of the 2 methods was 80%. The false-positive group was followed up 16 months later to check for diagnosis of disease. Two of the 24 patients in this quadrant were later diagnosed with MM (Table 1). 
One of the patients with MM was an 82-year-old African American man with a history of hypertension, diabetes, and prostate cancer (Gleason 4 + 4 = 8/10). He presented to VANYHHS after a fall in which he sustained a pathologic fracture of the left acromion. Recurrent prostate cancer was initially suspected, and nuclear bone scintigraphy revealed increased uptake in the left shoulder and the posterior ninth rib. Results of computed tomography-guided biopsy showed the rib lesion packed with plasma cells and consistent with MM. Immunohistochemical analysis was positive for CD138 and κ in the malignant plasma cells. Initial SPEP performed before the biopsy showed an acute phase reaction with hypogammaglobulinemia, and SPEP after the biopsy showed an increased α-2 band but no monoclonal gammaglobulinopathy. The initial κ of 42.18 mg/L (κ-to-λ ratio, 4.01) was up to 67.53 mg/L 4 months later.
The other patient with MM was a 91-year-old man who had coronary artery disease after undergoing coronary artery bypass grafting in 1993, sick sinus syndrome after pacemaker implantation, hypertension, and anemia. He initially presented to the geriatrics clinic with polyneuropathy, which prompted SPEP and SFLC analysis. SPEP results showed a normal electrophoretic pattern, but κ increased to 47.52 mg/L (κ-to-λ ratio, 2.63). The decision was made to monitor the patient in the hematology clinic. Subsequent κ chain analysis revealed an increase to 59.50 mg/L. A repeat SPEP, performed 1 year after the first SPEP, revealed monoclonal immunoglobulin A on IFE.
Of the 24 patients with false-positive results, 16 had moderate-to-severe kidney disease (stage IIIa-IV).6All patients in this quadrant were men; their mean age was 75 years, and their mean creatinine level was 182.15 μmol/L. Further laboratory data are listed in Table 2. 
The patient whose biopsy results led to an MM diagnosis and the patient whose IFE led to a gammopathy diagnosis both maintained a glomerular filtration rate within normal limits. The Figure shows the κ-to-λ ratios of this quadrant logarithmically. 
Discussion
Use of SFLC analysis as a supplement to serum and urine protein electrophoresis has been investigated and accepted in the recent literature.3,4,7,8 Use of light chains as a method of earlier or alternative detection has not been proved. In the present study of 207 patients, comparisons showed that more traditional MM detection methods and SFLC analysis are largely concordant. The 2 patients with MM and negative electrophoretic patterns provided a clear indication of the potential benefit of SFLC analysis in the diagnosis of secretory and nonsecretory myeloma.
In 2014, Kim and colleagues compared 2 SFLC assays (Freelite, N Latex) to each other and to SPEP in a 120-patient population.9 The Freelite results in their study correlated closely with VA population findings (κ-to-λ ratio sensitivity and specificity: 72.2% and 93.6%, respectively). N Latex, the newer SFLC assay, had lower sensitivity (64.6%) and higher specificity (100%). With application of the extended reference range (0.37-3.1) proposed by Hutchison and colleagues for use in patients with renal failure, SFLC becomes a more statistically powerful tool.5
The patients who tested false-positive had higher mean creatinine levels, and 16 had renal insufficiency. The 2 false-positive patients were later found to have clinical myeloma and were within the normal range of renal function. Of the 16 patients with an abnormal κ-to-λ ratio and renal failure, 15 would be within the revised normal reference range, leaving 9 false-positives, 2 of whom eventually were found to have disease. With the application of the extended light chain range (as per Hutchison) for those patients with renal failure, 15 of the original 24 false-positives became true-negatives. Two of the false-positives become true-positives after they were subsequently diagnosed. Therefore, SFLC analysis detected disease in 22% of the revised false-positives when SPEP could not.
Table 2 lists the revised data after follow-up and renal failure correction. The strongest aspect of SFLC analysis remains its 95% specificity; its 69% sensitivity remains relatively constant. The test’s positive predictive value is 84%, and its negative predictive value is 90%. In veteran and other at-risk populations, SFLC analysis proves to be a very powerful tool on its own.
Conclusion
Both patient cases described in this article demonstrate the usefulness of SFLC analysis as an adjunct to SPEP. The authors propose SFLC testing for all patients who are undergoing MM screening with SPEP/IFE. In patients with renal failure, the expanded reference range seems to reduce erroneous false-positive results. Patients who have abnormal ratios should be followed up in clinic with repeat MM testing. It seems clear that, at the very least, SFLC analysis is a necessary adjunct to SPEP testing. However, SFLC stands on its own merit as well.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
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1. National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program. SEER website. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed July 11, 2016.
2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
3. Dimopoulos M, Kyle R, Fermand JP, et al; International Myeloma Workshop Consensus Panel 3. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117(18):4701-4705.
4. Katzmann JA, Clark RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem. 2002;48(9):1437-1444.
5. Hutchison CA, Plant T, Drayson M, et al. Serum free light chain measurement
aids the diagnosis of myeloma in patients with severe renal failure.
BMC Nephrol. 2008;9:11.
6. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease
Epidemiology Collaboration). A new equation to estimate glomerular filtration
rate. Ann Intern Med. 2009;150(9):604-612.
7. McTaggart MP, Lindsay J, Kearney EM. Replacing urine protein electrophoresis
with serum free light chain analysis as a first-line test for detecting plasma
cell disorders offers increased diagnostic accuracy and potential health benefit
to patients. Am J Clin Pathol. 2013;140(6):890-897.
8. Abadie JM, Bankson DD. Assessment of serum free light chain assays for
plasma cell disorder screening in a Veterans Affairs population. Ann Clin Lab
Sci. 2006;36(2):157-162.
9. Kim HS, Kim HS, Shin KS, et al. Clinical comparisons of two free light chain
assays to immunofixation electrophoresis for detecting monoclonal gammopathy.
Biomed Res Int. 2014;2014:647238.
Note: Page numbers differ between the print issue and digital edition.
Patients who are undergoing multiple myeloma screening with serum protein electrophoresis and immunofixation, especially those with renal failure, also should receive serum free light chain testing to increase specificity and reduce false-negatives.
Multiple myeloma (MM) is a devastating disease with an estimated 26,850 new cases in 2015 according to Surveillance, Epidemiology, and End Results data and no definitive chemotherapeutic cure.1 In 97% of cases, MM is defined by monoclonal hypergammaglobulinemia, in which a malignant plasma cell clone secretes a monoclonal globulin; the remaining cases are nonsecretors.2 Each pathologically produced clonal globulin contains 2 heavy chains attached by disulfide linkage and 2 light chains. Unchecked plasma cell production is what later causes the symptoms of renal failure, bone destruction, and anemia.
The rate of MM is disproportionately high in the veteran population, and the VA health care system provides care for many of these patients. The higher rate is likely secondary to the predominantly male population, which has higher MM rates, and has been linked to Agent Orange exposure in Vietnam. As MM is not easy to diagnose, any algorithm or testing method would be of great benefit to this population.
The gold standard for MM detection remains serum protein electrophoresis (SPEP) with immunofixation (IFE), but other detection methods have been emerging. The method of serum free light chain (SFLC) assay has become more readily available, and its incorporation into diagnostic guidelines has become more apparent but is not universal.3
In the case series reported in this article, SPEP/IFE and SFLC assays were used to test 207 patients from the VA New York Harbor Healthcare System (VANYHHS). All these patients had a clinical context for MM testing.
Methods
In this retrospective study, the authors reviewed the charts of VANYHHS patients who were being treated for conditions that prompted SPEP/IFE and λ and κ SFLC analysis between December 2013 and March 2014. The study was exempt from institutional review board approval.
The SPEP/IFE analysis was performed with an automated electrophoresis machine (Sebia Electrophoresis), and the SFLC analysis was performed with an automated SFLC assay (Freelite). Sensitivity, specificity, and positive and negative predictive values were calculated using SPEP/IFE as the gold standard and SFLC κ-to-λ ratio asthe test method. Patients with a positive κ-to-λ ratio but negative SPEP were considered false-positives. These patients’ SFLC analyses were further analyzed in an effort to evaluate use of the κ-to-λ ratio as an early tumor marker.
The κ reference range used was 3.3 to 19.4 mg/L, and the λ reference range used was 5.7 to 26.3 mg/L.4 The traditional reference range for the κ-to-λ ratio is 0.26 to 1.65.5
Results
Of the 207 patients in this study, 205 were men. Mean age was 69 years (range, 28-97 years). Mean serum urea nitrogen level was 8.75 mmol/L (range, 2.86-38.21 mmol/L), and mean creatinine level was 140.59 μmol/L (range, 44.21-1503.14 μmol/L). Mean κ was 49.82 mg/L (range, 4.6-700.96 mg/L), and mean λ was 54.27 mg/L (range, 3-1,750 mg/L). Table 1 compares the SPEP and SFLC data. Sensitivity was 67%, specificity was 85%, positive predictive value was 58%, and negative predictive value was 89%. Concordance of the 2 methods was 80%. The false-positive group was followed up 16 months later to check for diagnosis of disease. Two of the 24 patients in this quadrant were later diagnosed with MM (Table 1).
One of the patients with MM was an 82-year-old African American man with a history of hypertension, diabetes, and prostate cancer (Gleason 4 + 4 = 8/10). He presented to VANYHHS after a fall in which he sustained a pathologic fracture of the left acromion. Recurrent prostate cancer was initially suspected, and nuclear bone scintigraphy revealed increased uptake in the left shoulder and the posterior ninth rib. Results of computed tomography-guided biopsy showed the rib lesion packed with plasma cells and consistent with MM. Immunohistochemical analysis was positive for CD138 and κ in the malignant plasma cells. Initial SPEP performed before the biopsy showed an acute phase reaction with hypogammaglobulinemia, and SPEP after the biopsy showed an increased α-2 band but no monoclonal gammaglobulinopathy. The initial κ of 42.18 mg/L (κ-to-λ ratio, 4.01) was up to 67.53 mg/L 4 months later.
The other patient with MM was a 91-year-old man who had coronary artery disease after undergoing coronary artery bypass grafting in 1993, sick sinus syndrome after pacemaker implantation, hypertension, and anemia. He initially presented to the geriatrics clinic with polyneuropathy, which prompted SPEP and SFLC analysis. SPEP results showed a normal electrophoretic pattern, but κ increased to 47.52 mg/L (κ-to-λ ratio, 2.63). The decision was made to monitor the patient in the hematology clinic. Subsequent κ chain analysis revealed an increase to 59.50 mg/L. A repeat SPEP, performed 1 year after the first SPEP, revealed monoclonal immunoglobulin A on IFE.
Of the 24 patients with false-positive results, 16 had moderate-to-severe kidney disease (stage IIIa-IV).6All patients in this quadrant were men; their mean age was 75 years, and their mean creatinine level was 182.15 μmol/L. Further laboratory data are listed in Table 2.
The patient whose biopsy results led to an MM diagnosis and the patient whose IFE led to a gammopathy diagnosis both maintained a glomerular filtration rate within normal limits. The Figure shows the κ-to-λ ratios of this quadrant logarithmically.
Discussion
Use of SFLC analysis as a supplement to serum and urine protein electrophoresis has been investigated and accepted in the recent literature.3,4,7,8 Use of light chains as a method of earlier or alternative detection has not been proved. In the present study of 207 patients, comparisons showed that more traditional MM detection methods and SFLC analysis are largely concordant. The 2 patients with MM and negative electrophoretic patterns provided a clear indication of the potential benefit of SFLC analysis in the diagnosis of secretory and nonsecretory myeloma.
In 2014, Kim and colleagues compared 2 SFLC assays (Freelite, N Latex) to each other and to SPEP in a 120-patient population.9 The Freelite results in their study correlated closely with VA population findings (κ-to-λ ratio sensitivity and specificity: 72.2% and 93.6%, respectively). N Latex, the newer SFLC assay, had lower sensitivity (64.6%) and higher specificity (100%). With application of the extended reference range (0.37-3.1) proposed by Hutchison and colleagues for use in patients with renal failure, SFLC becomes a more statistically powerful tool.5
The patients who tested false-positive had higher mean creatinine levels, and 16 had renal insufficiency. The 2 false-positive patients were later found to have clinical myeloma and were within the normal range of renal function. Of the 16 patients with an abnormal κ-to-λ ratio and renal failure, 15 would be within the revised normal reference range, leaving 9 false-positives, 2 of whom eventually were found to have disease. With the application of the extended light chain range (as per Hutchison) for those patients with renal failure, 15 of the original 24 false-positives became true-negatives. Two of the false-positives become true-positives after they were subsequently diagnosed. Therefore, SFLC analysis detected disease in 22% of the revised false-positives when SPEP could not.
Table 2 lists the revised data after follow-up and renal failure correction. The strongest aspect of SFLC analysis remains its 95% specificity; its 69% sensitivity remains relatively constant. The test’s positive predictive value is 84%, and its negative predictive value is 90%. In veteran and other at-risk populations, SFLC analysis proves to be a very powerful tool on its own.
Conclusion
Both patient cases described in this article demonstrate the usefulness of SFLC analysis as an adjunct to SPEP. The authors propose SFLC testing for all patients who are undergoing MM screening with SPEP/IFE. In patients with renal failure, the expanded reference range seems to reduce erroneous false-positive results. Patients who have abnormal ratios should be followed up in clinic with repeat MM testing. It seems clear that, at the very least, SFLC analysis is a necessary adjunct to SPEP testing. However, SFLC stands on its own merit as well.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
Patients who are undergoing multiple myeloma screening with serum protein electrophoresis and immunofixation, especially those with renal failure, also should receive serum free light chain testing to increase specificity and reduce false-negatives.
Multiple myeloma (MM) is a devastating disease with an estimated 26,850 new cases in 2015 according to Surveillance, Epidemiology, and End Results data and no definitive chemotherapeutic cure.1 In 97% of cases, MM is defined by monoclonal hypergammaglobulinemia, in which a malignant plasma cell clone secretes a monoclonal globulin; the remaining cases are nonsecretors.2 Each pathologically produced clonal globulin contains 2 heavy chains attached by disulfide linkage and 2 light chains. Unchecked plasma cell production is what later causes the symptoms of renal failure, bone destruction, and anemia.
The rate of MM is disproportionately high in the veteran population, and the VA health care system provides care for many of these patients. The higher rate is likely secondary to the predominantly male population, which has higher MM rates, and has been linked to Agent Orange exposure in Vietnam. As MM is not easy to diagnose, any algorithm or testing method would be of great benefit to this population.
The gold standard for MM detection remains serum protein electrophoresis (SPEP) with immunofixation (IFE), but other detection methods have been emerging. The method of serum free light chain (SFLC) assay has become more readily available, and its incorporation into diagnostic guidelines has become more apparent but is not universal.3
In the case series reported in this article, SPEP/IFE and SFLC assays were used to test 207 patients from the VA New York Harbor Healthcare System (VANYHHS). All these patients had a clinical context for MM testing.
Methods
In this retrospective study, the authors reviewed the charts of VANYHHS patients who were being treated for conditions that prompted SPEP/IFE and λ and κ SFLC analysis between December 2013 and March 2014. The study was exempt from institutional review board approval.
The SPEP/IFE analysis was performed with an automated electrophoresis machine (Sebia Electrophoresis), and the SFLC analysis was performed with an automated SFLC assay (Freelite). Sensitivity, specificity, and positive and negative predictive values were calculated using SPEP/IFE as the gold standard and SFLC κ-to-λ ratio asthe test method. Patients with a positive κ-to-λ ratio but negative SPEP were considered false-positives. These patients’ SFLC analyses were further analyzed in an effort to evaluate use of the κ-to-λ ratio as an early tumor marker.
The κ reference range used was 3.3 to 19.4 mg/L, and the λ reference range used was 5.7 to 26.3 mg/L.4 The traditional reference range for the κ-to-λ ratio is 0.26 to 1.65.5
Results
Of the 207 patients in this study, 205 were men. Mean age was 69 years (range, 28-97 years). Mean serum urea nitrogen level was 8.75 mmol/L (range, 2.86-38.21 mmol/L), and mean creatinine level was 140.59 μmol/L (range, 44.21-1503.14 μmol/L). Mean κ was 49.82 mg/L (range, 4.6-700.96 mg/L), and mean λ was 54.27 mg/L (range, 3-1,750 mg/L). Table 1 compares the SPEP and SFLC data. Sensitivity was 67%, specificity was 85%, positive predictive value was 58%, and negative predictive value was 89%. Concordance of the 2 methods was 80%. The false-positive group was followed up 16 months later to check for diagnosis of disease. Two of the 24 patients in this quadrant were later diagnosed with MM (Table 1).
One of the patients with MM was an 82-year-old African American man with a history of hypertension, diabetes, and prostate cancer (Gleason 4 + 4 = 8/10). He presented to VANYHHS after a fall in which he sustained a pathologic fracture of the left acromion. Recurrent prostate cancer was initially suspected, and nuclear bone scintigraphy revealed increased uptake in the left shoulder and the posterior ninth rib. Results of computed tomography-guided biopsy showed the rib lesion packed with plasma cells and consistent with MM. Immunohistochemical analysis was positive for CD138 and κ in the malignant plasma cells. Initial SPEP performed before the biopsy showed an acute phase reaction with hypogammaglobulinemia, and SPEP after the biopsy showed an increased α-2 band but no monoclonal gammaglobulinopathy. The initial κ of 42.18 mg/L (κ-to-λ ratio, 4.01) was up to 67.53 mg/L 4 months later.
The other patient with MM was a 91-year-old man who had coronary artery disease after undergoing coronary artery bypass grafting in 1993, sick sinus syndrome after pacemaker implantation, hypertension, and anemia. He initially presented to the geriatrics clinic with polyneuropathy, which prompted SPEP and SFLC analysis. SPEP results showed a normal electrophoretic pattern, but κ increased to 47.52 mg/L (κ-to-λ ratio, 2.63). The decision was made to monitor the patient in the hematology clinic. Subsequent κ chain analysis revealed an increase to 59.50 mg/L. A repeat SPEP, performed 1 year after the first SPEP, revealed monoclonal immunoglobulin A on IFE.
Of the 24 patients with false-positive results, 16 had moderate-to-severe kidney disease (stage IIIa-IV).6All patients in this quadrant were men; their mean age was 75 years, and their mean creatinine level was 182.15 μmol/L. Further laboratory data are listed in Table 2.
The patient whose biopsy results led to an MM diagnosis and the patient whose IFE led to a gammopathy diagnosis both maintained a glomerular filtration rate within normal limits. The Figure shows the κ-to-λ ratios of this quadrant logarithmically.
Discussion
Use of SFLC analysis as a supplement to serum and urine protein electrophoresis has been investigated and accepted in the recent literature.3,4,7,8 Use of light chains as a method of earlier or alternative detection has not been proved. In the present study of 207 patients, comparisons showed that more traditional MM detection methods and SFLC analysis are largely concordant. The 2 patients with MM and negative electrophoretic patterns provided a clear indication of the potential benefit of SFLC analysis in the diagnosis of secretory and nonsecretory myeloma.
In 2014, Kim and colleagues compared 2 SFLC assays (Freelite, N Latex) to each other and to SPEP in a 120-patient population.9 The Freelite results in their study correlated closely with VA population findings (κ-to-λ ratio sensitivity and specificity: 72.2% and 93.6%, respectively). N Latex, the newer SFLC assay, had lower sensitivity (64.6%) and higher specificity (100%). With application of the extended reference range (0.37-3.1) proposed by Hutchison and colleagues for use in patients with renal failure, SFLC becomes a more statistically powerful tool.5
The patients who tested false-positive had higher mean creatinine levels, and 16 had renal insufficiency. The 2 false-positive patients were later found to have clinical myeloma and were within the normal range of renal function. Of the 16 patients with an abnormal κ-to-λ ratio and renal failure, 15 would be within the revised normal reference range, leaving 9 false-positives, 2 of whom eventually were found to have disease. With the application of the extended light chain range (as per Hutchison) for those patients with renal failure, 15 of the original 24 false-positives became true-negatives. Two of the false-positives become true-positives after they were subsequently diagnosed. Therefore, SFLC analysis detected disease in 22% of the revised false-positives when SPEP could not.
Table 2 lists the revised data after follow-up and renal failure correction. The strongest aspect of SFLC analysis remains its 95% specificity; its 69% sensitivity remains relatively constant. The test’s positive predictive value is 84%, and its negative predictive value is 90%. In veteran and other at-risk populations, SFLC analysis proves to be a very powerful tool on its own.
Conclusion
Both patient cases described in this article demonstrate the usefulness of SFLC analysis as an adjunct to SPEP. The authors propose SFLC testing for all patients who are undergoing MM screening with SPEP/IFE. In patients with renal failure, the expanded reference range seems to reduce erroneous false-positive results. Patients who have abnormal ratios should be followed up in clinic with repeat MM testing. It seems clear that, at the very least, SFLC analysis is a necessary adjunct to SPEP testing. However, SFLC stands on its own merit as well.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Click here to read the digital edition.
1. National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program. SEER website. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed July 11, 2016.
2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
3. Dimopoulos M, Kyle R, Fermand JP, et al; International Myeloma Workshop Consensus Panel 3. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117(18):4701-4705.
4. Katzmann JA, Clark RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem. 2002;48(9):1437-1444.
5. Hutchison CA, Plant T, Drayson M, et al. Serum free light chain measurement
aids the diagnosis of myeloma in patients with severe renal failure.
BMC Nephrol. 2008;9:11.
6. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease
Epidemiology Collaboration). A new equation to estimate glomerular filtration
rate. Ann Intern Med. 2009;150(9):604-612.
7. McTaggart MP, Lindsay J, Kearney EM. Replacing urine protein electrophoresis
with serum free light chain analysis as a first-line test for detecting plasma
cell disorders offers increased diagnostic accuracy and potential health benefit
to patients. Am J Clin Pathol. 2013;140(6):890-897.
8. Abadie JM, Bankson DD. Assessment of serum free light chain assays for
plasma cell disorder screening in a Veterans Affairs population. Ann Clin Lab
Sci. 2006;36(2):157-162.
9. Kim HS, Kim HS, Shin KS, et al. Clinical comparisons of two free light chain
assays to immunofixation electrophoresis for detecting monoclonal gammopathy.
Biomed Res Int. 2014;2014:647238.
Note: Page numbers differ between the print issue and digital edition.
1. National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) Program. SEER website. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed July 11, 2016.
2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
3. Dimopoulos M, Kyle R, Fermand JP, et al; International Myeloma Workshop Consensus Panel 3. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011;117(18):4701-4705.
4. Katzmann JA, Clark RJ, Abraham RS, et al. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem. 2002;48(9):1437-1444.
5. Hutchison CA, Plant T, Drayson M, et al. Serum free light chain measurement
aids the diagnosis of myeloma in patients with severe renal failure.
BMC Nephrol. 2008;9:11.
6. Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease
Epidemiology Collaboration). A new equation to estimate glomerular filtration
rate. Ann Intern Med. 2009;150(9):604-612.
7. McTaggart MP, Lindsay J, Kearney EM. Replacing urine protein electrophoresis
with serum free light chain analysis as a first-line test for detecting plasma
cell disorders offers increased diagnostic accuracy and potential health benefit
to patients. Am J Clin Pathol. 2013;140(6):890-897.
8. Abadie JM, Bankson DD. Assessment of serum free light chain assays for
plasma cell disorder screening in a Veterans Affairs population. Ann Clin Lab
Sci. 2006;36(2):157-162.
9. Kim HS, Kim HS, Shin KS, et al. Clinical comparisons of two free light chain
assays to immunofixation electrophoresis for detecting monoclonal gammopathy.
Biomed Res Int. 2014;2014:647238.
Note: Page numbers differ between the print issue and digital edition.