In evaluating the importance of early aggressive treatment of rheumatoid arthritis (RA), we often look at prognostic factors for severe disease, such as seropositivity, elevated inflammatory markers, and erosions. Eberhard and colleagues looked at the relationship between damage as seen on radiography (including erosions and joint space narrowing) and pain and disability in early RA using an inception cohort with <12 months of symptoms. Over 200 patients in Sweden were followed for 5 years with clinical, laboratory, and radiographic evaluations. Of interest, pain was associated with female sex, tender joint count, and inflammatory markers at various time points but not with radiographic damage. This may reflect that pain is related to current inflammation rather than past joint damage or that pain is related to other factors, such as central sensitization. Radiographic damage was, however, associated with disability and thus remains an important target and outcome measure for assessing treatment effectiveness.

Leon and colleagues also looked at early RA but instead, at the category of difficult-to-treat RA (D2T RA), meaning persistent RA symptoms after a trial of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs. In order to gain better insight in preventing D2T RA, the authors examined its association with potentially modifiable risk factors early in the course of disease. Of the over 600 patients followed in this inception cohort, only about 6% were classified as having D2T RA. The study found that patients who had D2T RA tended to be younger, with a higher tender joint count, higher pain scores, and a higher initial level of disability. The Disease Activity Score (DAS28) itself was higher in patients with D2T RA, but the difference did not reach statistical significance. The small number of patients (35) in the D2T RA group may have affected the findings as well as their wider applicability. However, it is interesting to consider whether the associations may also reflect the impact of noninflammatory factors, as in the previous study, on the classification of D2T RA.

Park and colleagues evaluated the difference in clinical outcomes in postmenopausal patients with RA who underwent menopause at younger than 45 years or 45 years or older. Among over 2800 patients in Korea, those who underwent early menopause were more likely to be seronegative and have high disease activity and worse patient-reported outcome scores in fatigue, sleep, and health-related quality of life despite comparable treatments and prevalence of erosions. The authors suggest this may be related to lower cumulative estrogen exposure; whether this correlates to inflammatory cytokine signatures is not yet known. However, as with the prior studies, central sensitization and noninflammatory pain may also contribute and should be considered in interpreting response to therapy.

Finally, addressing the potential risk for cancer in patients with RA before or during treatment with immunosuppressive medications, Miyata and colleagues reported a study that screened nearly 2200 patients who underwent CT (from neck to pelvis) and compared them with those who underwent routine screening with physical exam plus radiography. The study found that CT screening enhanced cancer detection, with a large number of cancers detected at an earlier stage with CT screening compared with routine screening. The overall number of cancers detected was low (33), and thus routine screening with neck-to-pelvis CT for all patients with RA may not be a cost-effective practice. However, it bears further examination for potentially higher-risk populations or specific cancers.

In evaluating the importance of early aggressive treatment of rheumatoid arthritis (RA), we often look at prognostic factors for severe disease, such as seropositivity, elevated inflammatory markers, and erosions. Eberhard and colleagues looked at the relationship between damage as seen on radiography (including erosions and joint space narrowing) and pain and disability in early RA using an inception cohort with <12 months of symptoms. Over 200 patients in Sweden were followed for 5 years with clinical, laboratory, and radiographic evaluations. Of interest, pain was associated with female sex, tender joint count, and inflammatory markers at various time points but not with radiographic damage. This may reflect that pain is related to current inflammation rather than past joint damage or that pain is related to other factors, such as central sensitization. Radiographic damage was, however, associated with disability and thus remains an important target and outcome measure for assessing treatment effectiveness.

Leon and colleagues also looked at early RA but instead, at the category of difficult-to-treat RA (D2T RA), meaning persistent RA symptoms after a trial of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs. In order to gain better insight in preventing D2T RA, the authors examined its association with potentially modifiable risk factors early in the course of disease. Of the over 600 patients followed in this inception cohort, only about 6% were classified as having D2T RA. The study found that patients who had D2T RA tended to be younger, with a higher tender joint count, higher pain scores, and a higher initial level of disability. The Disease Activity Score (DAS28) itself was higher in patients with D2T RA, but the difference did not reach statistical significance. The small number of patients (35) in the D2T RA group may have affected the findings as well as their wider applicability. However, it is interesting to consider whether the associations may also reflect the impact of noninflammatory factors, as in the previous study, on the classification of D2T RA.

Park and colleagues evaluated the difference in clinical outcomes in postmenopausal patients with RA who underwent menopause at younger than 45 years or 45 years or older. Among over 2800 patients in Korea, those who underwent early menopause were more likely to be seronegative and have high disease activity and worse patient-reported outcome scores in fatigue, sleep, and health-related quality of life despite comparable treatments and prevalence of erosions. The authors suggest this may be related to lower cumulative estrogen exposure; whether this correlates to inflammatory cytokine signatures is not yet known. However, as with the prior studies, central sensitization and noninflammatory pain may also contribute and should be considered in interpreting response to therapy.

Finally, addressing the potential risk for cancer in patients with RA before or during treatment with immunosuppressive medications, Miyata and colleagues reported a study that screened nearly 2200 patients who underwent CT (from neck to pelvis) and compared them with those who underwent routine screening with physical exam plus radiography. The study found that CT screening enhanced cancer detection, with a large number of cancers detected at an earlier stage with CT screening compared with routine screening. The overall number of cancers detected was low (33), and thus routine screening with neck-to-pelvis CT for all patients with RA may not be a cost-effective practice. However, it bears further examination for potentially higher-risk populations or specific cancers.

In evaluating the importance of early aggressive treatment of rheumatoid arthritis (RA), we often look at prognostic factors for severe disease, such as seropositivity, elevated inflammatory markers, and erosions. Eberhard and colleagues looked at the relationship between damage as seen on radiography (including erosions and joint space narrowing) and pain and disability in early RA using an inception cohort with <12 months of symptoms. Over 200 patients in Sweden were followed for 5 years with clinical, laboratory, and radiographic evaluations. Of interest, pain was associated with female sex, tender joint count, and inflammatory markers at various time points but not with radiographic damage. This may reflect that pain is related to current inflammation rather than past joint damage or that pain is related to other factors, such as central sensitization. Radiographic damage was, however, associated with disability and thus remains an important target and outcome measure for assessing treatment effectiveness.

Leon and colleagues also looked at early RA but instead, at the category of difficult-to-treat RA (D2T RA), meaning persistent RA symptoms after a trial of at least two biologic or targeted synthetic disease-modifying antirheumatic drugs. In order to gain better insight in preventing D2T RA, the authors examined its association with potentially modifiable risk factors early in the course of disease. Of the over 600 patients followed in this inception cohort, only about 6% were classified as having D2T RA. The study found that patients who had D2T RA tended to be younger, with a higher tender joint count, higher pain scores, and a higher initial level of disability. The Disease Activity Score (DAS28) itself was higher in patients with D2T RA, but the difference did not reach statistical significance. The small number of patients (35) in the D2T RA group may have affected the findings as well as their wider applicability. However, it is interesting to consider whether the associations may also reflect the impact of noninflammatory factors, as in the previous study, on the classification of D2T RA.

Park and colleagues evaluated the difference in clinical outcomes in postmenopausal patients with RA who underwent menopause at younger than 45 years or 45 years or older. Among over 2800 patients in Korea, those who underwent early menopause were more likely to be seronegative and have high disease activity and worse patient-reported outcome scores in fatigue, sleep, and health-related quality of life despite comparable treatments and prevalence of erosions. The authors suggest this may be related to lower cumulative estrogen exposure; whether this correlates to inflammatory cytokine signatures is not yet known. However, as with the prior studies, central sensitization and noninflammatory pain may also contribute and should be considered in interpreting response to therapy.

Finally, addressing the potential risk for cancer in patients with RA before or during treatment with immunosuppressive medications, Miyata and colleagues reported a study that screened nearly 2200 patients who underwent CT (from neck to pelvis) and compared them with those who underwent routine screening with physical exam plus radiography. The study found that CT screening enhanced cancer detection, with a large number of cancers detected at an earlier stage with CT screening compared with routine screening. The overall number of cancers detected was low (33), and thus routine screening with neck-to-pelvis CT for all patients with RA may not be a cost-effective practice. However, it bears further examination for potentially higher-risk populations or specific cancers.

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that is clinically heterogeneous, ranging from indolent to aggressive in nature. As with other subtypes of NHL, the treatment landscape is rapidly evolving.

Chemoimmunotherapy remains the standard first-line therapy for younger, fit patients. Although multiple induction regimens are used in this setting, it is typical to use a cytarabine-containing approach. Recently, the long-term analysis of the MCL Younger trial continued to demonstrate improved outcomes with this strategy.¹ This phase 3 study included 497 patients aged ≥ 18 to < 66 years with previously untreated MCL who were randomly assigned to R-CHOP (cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine; n = 249) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; n = 248). After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer time to treatment failure (hazard ratio [HR] 0.59; P = .038) and overall survival (Mantle Cell Lymphoma International Prognostic Index + Ki-67–adjusted HR 0.60; P = .0066).

Following chemoimmunotherapy, treatment for this patient population typically consists of consolidation with autologous stem cell transplantation (ASCT) and maintenance rituximab.² Recently, the role of ASCT has been called into question.³ Preliminary data from the phase 3 TRIANGLE study demonstrated improvement in outcomes when the Bruton tyrosine kinase (BTK) inhibitor ibrutinib was added to chemoimmunotherapy, regardless of whether patients received ASCT.⁴ Additional studies evaluating the role of transplantation, particularly among patients who are minimal residual disease negative after chemoimmunotherapy, are ongoing (NCT03267433).

Options continue to expand in the relapsed/refractory setting. The chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (brexu-cel), was approved by the US Food and Drug Administration for relapsed/refractory MCL on the basis of the results of the ZUMA-2 study.⁵ Recently, a multicenter, retrospective study demonstrated promising efficacy in the real world as well (Wang et al). This study was performed across 16 medical centers and included 189 patients with relapsed/refractory MCL who underwent leukapheresis for commercial manufacturing of brexu-cel, of which 168 received brexu-cel infusion. Of all patients receiving leukapheresis, 149 (79%) would not have met the eligibility criteria for ZUMA-2. At a median follow-up of 14.3 months after infusion, the best overall and complete response rates were 90% and 82%, respectively. The 6- and 12-month progression-free survival (PFS) rates were 69% (95% CI 61%-75%) and 59% (95% CI 51%-66%), respectively. This approach, however, was associated with significant toxicity, with a nonrelapse mortality rate of 9.1% at 1 year, primarily because of infections. The grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 8% and 32%, respectively. Despite risks, this study confirms the role of CAR T-cell therapy for patients with relapsed/refractory MCL.

Other options in the relapsed setting include BTK and anti-apoptotic protein B-cell lymphoma (BCL-2) inhibitors. Although venetoclax, a BCL-2 inhibitor, has demonstrated activity in MCL in early-phase clinical trials, the role of this drug in clinical practice remains unclear.^6,7 A recent multicenter, retrospective study evaluated the use of venetoclax in 81 adult patients with relapsed/refractory MCL, most of whom were heavily pretreated (median of three prior treatments) and had high-risk features, including high Ki-67 and TP53 alterations, who received venetoclax without (n = 50) or with (n = 31) other agents (Sawalha et al). In this study, venetoclax resulted in a good overall response rate (ORR) but short PFS. At a median follow-up of 16.4 months, patients had a median PFS and overall survival of 3.7 months (95% CI 2.3-5.6) and 12.5 months (95% CI 6.2-28.2), respectively, and an ORR of 40%. Studies of venetoclax in earlier lines of therapy and in combination with other agents are ongoing. There may also be a role for this treatment as a bridge to more definitive therapies, including CAR T-cell therapy or allogeneic stem cell transplantation. Other studies that are evaluating the role of bispecific antibodies and antibody drug conjugates are also underway, suggesting the potential for additional options in this patient population.

Additional References

1.         Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023;41:479-484. doi: 10.1200/JCO.22.01780

2.         Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260. doi: 10.1056/NEJMoa1701769

3.         Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. 2023;41:541-554. doi: 10.1200/JCO.21.02698

4.         Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle Trial by the European MCL Network. Blood. 2022;140(Suppl 1):1-3. doi: 10.1182/blood-2022-163018

5.         Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347

6.         Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-833. doi: 10.1200/JCO.2016.70.4320

7.         Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-1223. doi: 10.1056/NEJMoa1715519

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that is clinically heterogeneous, ranging from indolent to aggressive in nature. As with other subtypes of NHL, the treatment landscape is rapidly evolving.

Chemoimmunotherapy remains the standard first-line therapy for younger, fit patients. Although multiple induction regimens are used in this setting, it is typical to use a cytarabine-containing approach. Recently, the long-term analysis of the MCL Younger trial continued to demonstrate improved outcomes with this strategy.¹ This phase 3 study included 497 patients aged ≥ 18 to < 66 years with previously untreated MCL who were randomly assigned to R-CHOP (cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine; n = 249) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; n = 248). After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer time to treatment failure (hazard ratio [HR] 0.59; P = .038) and overall survival (Mantle Cell Lymphoma International Prognostic Index + Ki-67–adjusted HR 0.60; P = .0066).

Following chemoimmunotherapy, treatment for this patient population typically consists of consolidation with autologous stem cell transplantation (ASCT) and maintenance rituximab.² Recently, the role of ASCT has been called into question.³ Preliminary data from the phase 3 TRIANGLE study demonstrated improvement in outcomes when the Bruton tyrosine kinase (BTK) inhibitor ibrutinib was added to chemoimmunotherapy, regardless of whether patients received ASCT.⁴ Additional studies evaluating the role of transplantation, particularly among patients who are minimal residual disease negative after chemoimmunotherapy, are ongoing (NCT03267433).

Options continue to expand in the relapsed/refractory setting. The chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (brexu-cel), was approved by the US Food and Drug Administration for relapsed/refractory MCL on the basis of the results of the ZUMA-2 study.⁵ Recently, a multicenter, retrospective study demonstrated promising efficacy in the real world as well (Wang et al). This study was performed across 16 medical centers and included 189 patients with relapsed/refractory MCL who underwent leukapheresis for commercial manufacturing of brexu-cel, of which 168 received brexu-cel infusion. Of all patients receiving leukapheresis, 149 (79%) would not have met the eligibility criteria for ZUMA-2. At a median follow-up of 14.3 months after infusion, the best overall and complete response rates were 90% and 82%, respectively. The 6- and 12-month progression-free survival (PFS) rates were 69% (95% CI 61%-75%) and 59% (95% CI 51%-66%), respectively. This approach, however, was associated with significant toxicity, with a nonrelapse mortality rate of 9.1% at 1 year, primarily because of infections. The grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 8% and 32%, respectively. Despite risks, this study confirms the role of CAR T-cell therapy for patients with relapsed/refractory MCL.

Other options in the relapsed setting include BTK and anti-apoptotic protein B-cell lymphoma (BCL-2) inhibitors. Although venetoclax, a BCL-2 inhibitor, has demonstrated activity in MCL in early-phase clinical trials, the role of this drug in clinical practice remains unclear.^6,7 A recent multicenter, retrospective study evaluated the use of venetoclax in 81 adult patients with relapsed/refractory MCL, most of whom were heavily pretreated (median of three prior treatments) and had high-risk features, including high Ki-67 and TP53 alterations, who received venetoclax without (n = 50) or with (n = 31) other agents (Sawalha et al). In this study, venetoclax resulted in a good overall response rate (ORR) but short PFS. At a median follow-up of 16.4 months, patients had a median PFS and overall survival of 3.7 months (95% CI 2.3-5.6) and 12.5 months (95% CI 6.2-28.2), respectively, and an ORR of 40%. Studies of venetoclax in earlier lines of therapy and in combination with other agents are ongoing. There may also be a role for this treatment as a bridge to more definitive therapies, including CAR T-cell therapy or allogeneic stem cell transplantation. Other studies that are evaluating the role of bispecific antibodies and antibody drug conjugates are also underway, suggesting the potential for additional options in this patient population.

Additional References

1.         Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023;41:479-484. doi: 10.1200/JCO.22.01780

2.         Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260. doi: 10.1056/NEJMoa1701769

3.         Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. 2023;41:541-554. doi: 10.1200/JCO.21.02698

4.         Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle Trial by the European MCL Network. Blood. 2022;140(Suppl 1):1-3. doi: 10.1182/blood-2022-163018

5.         Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347

6.         Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-833. doi: 10.1200/JCO.2016.70.4320

7.         Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-1223. doi: 10.1056/NEJMoa1715519

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma (NHL) that is clinically heterogeneous, ranging from indolent to aggressive in nature. As with other subtypes of NHL, the treatment landscape is rapidly evolving.

Chemoimmunotherapy remains the standard first-line therapy for younger, fit patients. Although multiple induction regimens are used in this setting, it is typical to use a cytarabine-containing approach. Recently, the long-term analysis of the MCL Younger trial continued to demonstrate improved outcomes with this strategy.¹ This phase 3 study included 497 patients aged ≥ 18 to < 66 years with previously untreated MCL who were randomly assigned to R-CHOP (cyclophosphamide, doxorubicin, prednisone, rituximab, and vincristine; n = 249) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin; n = 248). After a median follow-up of 10.6 years, the R-DHAP vs R-CHOP arm continued to have a significantly longer time to treatment failure (hazard ratio [HR] 0.59; P = .038) and overall survival (Mantle Cell Lymphoma International Prognostic Index + Ki-67–adjusted HR 0.60; P = .0066).

Following chemoimmunotherapy, treatment for this patient population typically consists of consolidation with autologous stem cell transplantation (ASCT) and maintenance rituximab.² Recently, the role of ASCT has been called into question.³ Preliminary data from the phase 3 TRIANGLE study demonstrated improvement in outcomes when the Bruton tyrosine kinase (BTK) inhibitor ibrutinib was added to chemoimmunotherapy, regardless of whether patients received ASCT.⁴ Additional studies evaluating the role of transplantation, particularly among patients who are minimal residual disease negative after chemoimmunotherapy, are ongoing (NCT03267433).

Options continue to expand in the relapsed/refractory setting. The chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (brexu-cel), was approved by the US Food and Drug Administration for relapsed/refractory MCL on the basis of the results of the ZUMA-2 study.⁵ Recently, a multicenter, retrospective study demonstrated promising efficacy in the real world as well (Wang et al). This study was performed across 16 medical centers and included 189 patients with relapsed/refractory MCL who underwent leukapheresis for commercial manufacturing of brexu-cel, of which 168 received brexu-cel infusion. Of all patients receiving leukapheresis, 149 (79%) would not have met the eligibility criteria for ZUMA-2. At a median follow-up of 14.3 months after infusion, the best overall and complete response rates were 90% and 82%, respectively. The 6- and 12-month progression-free survival (PFS) rates were 69% (95% CI 61%-75%) and 59% (95% CI 51%-66%), respectively. This approach, however, was associated with significant toxicity, with a nonrelapse mortality rate of 9.1% at 1 year, primarily because of infections. The grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 8% and 32%, respectively. Despite risks, this study confirms the role of CAR T-cell therapy for patients with relapsed/refractory MCL.

Other options in the relapsed setting include BTK and anti-apoptotic protein B-cell lymphoma (BCL-2) inhibitors. Although venetoclax, a BCL-2 inhibitor, has demonstrated activity in MCL in early-phase clinical trials, the role of this drug in clinical practice remains unclear.^6,7 A recent multicenter, retrospective study evaluated the use of venetoclax in 81 adult patients with relapsed/refractory MCL, most of whom were heavily pretreated (median of three prior treatments) and had high-risk features, including high Ki-67 and TP53 alterations, who received venetoclax without (n = 50) or with (n = 31) other agents (Sawalha et al). In this study, venetoclax resulted in a good overall response rate (ORR) but short PFS. At a median follow-up of 16.4 months, patients had a median PFS and overall survival of 3.7 months (95% CI 2.3-5.6) and 12.5 months (95% CI 6.2-28.2), respectively, and an ORR of 40%. Studies of venetoclax in earlier lines of therapy and in combination with other agents are ongoing. There may also be a role for this treatment as a bridge to more definitive therapies, including CAR T-cell therapy or allogeneic stem cell transplantation. Other studies that are evaluating the role of bispecific antibodies and antibody drug conjugates are also underway, suggesting the potential for additional options in this patient population.

Additional References

1.         Hermine O, Jiang L, Walewski J, et al. High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: Long-term follow-up of the randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023;41:479-484. doi: 10.1200/JCO.22.01780

2.         Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260. doi: 10.1056/NEJMoa1701769

3.         Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: Results from large real-world cohorts. J Clin Oncol. 2023;41:541-554. doi: 10.1200/JCO.21.02698

4.         Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: Results from the randomized Triangle Trial by the European MCL Network. Blood. 2022;140(Suppl 1):1-3. doi: 10.1182/blood-2022-163018

5.         Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi: 10.1056/NEJMoa1914347

6.         Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35:826-833. doi: 10.1200/JCO.2016.70.4320

7.         Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-1223. doi: 10.1056/NEJMoa1715519

For as long as I can remember, psychiatrists have talked about what the appropriate boundaries are for self-disclosure about personal issues with patients. There is obviously no exact answer as to what is acceptable to disclose; this depends on the doctor, the patient, the “brand” of psychotherapy, the patient’s issues, the nature of what is being disclosed, and maybe the alignment of the stars on that particular day. “Stutz,” the Netflix documentary that Oscar-nominated actor/director Jonah Hill has made about his psychiatrist, Phil Stutz, MD, adds a whole new chapter to the discussion.

“Okay, entertain me,” Dr. Stutz says as his patient takes a seat. The therapeutic relationship and the paradigm Dr. Stutz has created to help his patients has been healing for Jonah Hill. The very serious and intimate dialogue that follows unfolds with moments of humor, warmth, and open affection. Hill candidly tells us why he is making this documentary – to share what he has learned and to honor his therapist – but we don’t know why Dr. Stutz has agreed to the endeavor and we’re left to our own inferences.

Dr. Stutz is the coauthor, with Barry Michels, of a best-selling self-help book, “The Tools: 5 Tools to Help You Find Courage, Creativity, and Willpower – and Inspire You to Live Life in Forward Motion.” He talks about his restlessness with the psychodynamic method during his training as a resident in New York – he wanted to offer his patients more immediate relief and a supervisor told him, “Don’t you dare!”

In the film, he talks about giving patients hope and direction. And Hill makes the comment, “In traditional therapy, you’re paying this person and you save all your problems for them, and they just listen, and your friends – who are idiots – give you advice, unsolicited, and you want your friends just to listen, and you want your therapist to give you advice!” Dr. Stutz gives advice and he is like no other therapist Jonah has ever had.

The premise of the film is that we are watching a single therapy session and Dr. Stutz will discuss the use of his tools and techniques that Hill has found helpful. Jonah is the interviewer, and when the doctor suggests it would be helpful if Jonah talked about his life, the patient/director rebuffs him; this documentary is about the psychiatrist.

Early in the film an alarm goes off, Dr. Stutz does not hear it, and Jonah has to remind him that it’s time for him to take his pills. The psychiatrist has Parkinson’s disease and how it has affected him becomes one focal point for the film. We later learn that he lost a younger brother as a child (something Hill did not know before they started filming) and grew up in the shadow of that loss. His extroverted father made it clear that medicine was the only acceptable career path for his son, and his introverted and depressed mother spent her days proclaiming that all men were as awful as her own abusive father.

About a third of the way through the film, the focus shifts. Jonah suddenly confesses that he is feeling stuck with regard to the movie, that he is troubled by the fact that he has not been able to share his distress with Dr. Stutz during their real-life, unfilmed therapy sessions, and the viewers learn that the single-session concept was disingenuous – they have been filming this documentary for two years, against a green screen and not in an office, always wearing the same clothes, and Jonah pulls off a wig that he wears to disguise the fact that he changed his hairstyle months earlier.

It’s a bit unnerving as they throw the wig around, and Jonah agrees to be more open about the issues he has struggled with. He acknowledges that this has been difficult, and he says, “I just keep asking myself, like, was this a f***ing horrible idea for a patient to make a movie about his therapist?” From my perspective as a psychiatrist-viewer, it’s a good question to ask!

Dr. Stutz reassures Jonah that it is okay to be vulnerable. “Failure, weakness, vulnerability – it’s like a connector, it connects you to the rest of the world.” A super-sized cardboard cutout of an obese 14-year-old Jonah now joins the room, and we learn that he continues to struggle with his self-image. Things get more real.

Peppered throughout the film, there are lessons from Dr. Stutz about his “tools,” constructs he uses to help people restructure their worlds and take action to move forward. One such construct he calls “the maze,” which occurs when one person in an interpersonal relationship is waiting for fairness and becomes preoccupied with feeling injured.

Jonah inquires about Dr. Stutz’s romantic life and the therapist replies with a transparency that overrides our usual professional boundaries. We all learn that Dr. Stutz is not in a relationship, he’s never been married, but there is a woman he has had some involvement with on and off for 40 years. Jonah’s line of questioning rivals that of any therapist. “How do you think it affects you, having your mom hate men and you being a man?” Dr. Stutz admits that he can never feel safe with women. “Did you ever override that wall you built with your mom and get close to a woman?” When Jonah professes, “I don’t feel anything but love for you and I just want you to be happy,” my own feeling was that the tables had turned too far, that the therapist’s failed romantic life risked being a burden to the patient.

Still, there is something about the relationship between the two men that is touching and beautiful. Dr. Stutz as a therapist is charismatic, caring, self-assured, and optimistic, and he radiates hope and certainty. He mixes an intense intimacy with humor in a way that is both authentic and entertaining. The interspersed jokes break the intensity, but they don’t diminish his wisdom and the healing he imparts.

Dr. Stutz is a psychiatrist, and his strength is clearly as a psychotherapist, yet there is not a single mention of psychotropic medications – there is a banter about recreational drugs and medications for Parkinson’s disease. If Hill is taking medication for depression or anxiety, and if prescribing is part of Dr. Stutz’s arsenal, the viewer is not made aware of this.

Dr. Stutz eschews the slow, detached, and “neutral” pace of psychodynamic therapy and the whole concept of the therapist as a blank wall for the transference to play out on, but here the transference screams: Jonah loves him, he respect and honors him, he wants him to be happy, and he is afraid of losing him.

“Stutz” is a movie about a larger-than-life psychiatrist, one whose warmth and inspiration are healing. I imagine his tools are helpful, but his personality is what carries the load. If a viewer has not had experience with psychiatry, and this film inspires him to begin therapy, there may be a good deal of disappointment. In this case, the patient is a successful actor, and one might wonder if that, together with the entire years-long project of filming, has altered the relationship well beyond the usual therapeutic hour.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore.

For as long as I can remember, psychiatrists have talked about what the appropriate boundaries are for self-disclosure about personal issues with patients. There is obviously no exact answer as to what is acceptable to disclose; this depends on the doctor, the patient, the “brand” of psychotherapy, the patient’s issues, the nature of what is being disclosed, and maybe the alignment of the stars on that particular day. “Stutz,” the Netflix documentary that Oscar-nominated actor/director Jonah Hill has made about his psychiatrist, Phil Stutz, MD, adds a whole new chapter to the discussion.

“Okay, entertain me,” Dr. Stutz says as his patient takes a seat. The therapeutic relationship and the paradigm Dr. Stutz has created to help his patients has been healing for Jonah Hill. The very serious and intimate dialogue that follows unfolds with moments of humor, warmth, and open affection. Hill candidly tells us why he is making this documentary – to share what he has learned and to honor his therapist – but we don’t know why Dr. Stutz has agreed to the endeavor and we’re left to our own inferences.

Dr. Stutz is the coauthor, with Barry Michels, of a best-selling self-help book, “The Tools: 5 Tools to Help You Find Courage, Creativity, and Willpower – and Inspire You to Live Life in Forward Motion.” He talks about his restlessness with the psychodynamic method during his training as a resident in New York – he wanted to offer his patients more immediate relief and a supervisor told him, “Don’t you dare!”

In the film, he talks about giving patients hope and direction. And Hill makes the comment, “In traditional therapy, you’re paying this person and you save all your problems for them, and they just listen, and your friends – who are idiots – give you advice, unsolicited, and you want your friends just to listen, and you want your therapist to give you advice!” Dr. Stutz gives advice and he is like no other therapist Jonah has ever had.

The premise of the film is that we are watching a single therapy session and Dr. Stutz will discuss the use of his tools and techniques that Hill has found helpful. Jonah is the interviewer, and when the doctor suggests it would be helpful if Jonah talked about his life, the patient/director rebuffs him; this documentary is about the psychiatrist.

Early in the film an alarm goes off, Dr. Stutz does not hear it, and Jonah has to remind him that it’s time for him to take his pills. The psychiatrist has Parkinson’s disease and how it has affected him becomes one focal point for the film. We later learn that he lost a younger brother as a child (something Hill did not know before they started filming) and grew up in the shadow of that loss. His extroverted father made it clear that medicine was the only acceptable career path for his son, and his introverted and depressed mother spent her days proclaiming that all men were as awful as her own abusive father.

About a third of the way through the film, the focus shifts. Jonah suddenly confesses that he is feeling stuck with regard to the movie, that he is troubled by the fact that he has not been able to share his distress with Dr. Stutz during their real-life, unfilmed therapy sessions, and the viewers learn that the single-session concept was disingenuous – they have been filming this documentary for two years, against a green screen and not in an office, always wearing the same clothes, and Jonah pulls off a wig that he wears to disguise the fact that he changed his hairstyle months earlier.

It’s a bit unnerving as they throw the wig around, and Jonah agrees to be more open about the issues he has struggled with. He acknowledges that this has been difficult, and he says, “I just keep asking myself, like, was this a f***ing horrible idea for a patient to make a movie about his therapist?” From my perspective as a psychiatrist-viewer, it’s a good question to ask!

Dr. Stutz reassures Jonah that it is okay to be vulnerable. “Failure, weakness, vulnerability – it’s like a connector, it connects you to the rest of the world.” A super-sized cardboard cutout of an obese 14-year-old Jonah now joins the room, and we learn that he continues to struggle with his self-image. Things get more real.

Peppered throughout the film, there are lessons from Dr. Stutz about his “tools,” constructs he uses to help people restructure their worlds and take action to move forward. One such construct he calls “the maze,” which occurs when one person in an interpersonal relationship is waiting for fairness and becomes preoccupied with feeling injured.

Jonah inquires about Dr. Stutz’s romantic life and the therapist replies with a transparency that overrides our usual professional boundaries. We all learn that Dr. Stutz is not in a relationship, he’s never been married, but there is a woman he has had some involvement with on and off for 40 years. Jonah’s line of questioning rivals that of any therapist. “How do you think it affects you, having your mom hate men and you being a man?” Dr. Stutz admits that he can never feel safe with women. “Did you ever override that wall you built with your mom and get close to a woman?” When Jonah professes, “I don’t feel anything but love for you and I just want you to be happy,” my own feeling was that the tables had turned too far, that the therapist’s failed romantic life risked being a burden to the patient.

Still, there is something about the relationship between the two men that is touching and beautiful. Dr. Stutz as a therapist is charismatic, caring, self-assured, and optimistic, and he radiates hope and certainty. He mixes an intense intimacy with humor in a way that is both authentic and entertaining. The interspersed jokes break the intensity, but they don’t diminish his wisdom and the healing he imparts.

Dr. Stutz is a psychiatrist, and his strength is clearly as a psychotherapist, yet there is not a single mention of psychotropic medications – there is a banter about recreational drugs and medications for Parkinson’s disease. If Hill is taking medication for depression or anxiety, and if prescribing is part of Dr. Stutz’s arsenal, the viewer is not made aware of this.

Dr. Stutz eschews the slow, detached, and “neutral” pace of psychodynamic therapy and the whole concept of the therapist as a blank wall for the transference to play out on, but here the transference screams: Jonah loves him, he respect and honors him, he wants him to be happy, and he is afraid of losing him.

“Stutz” is a movie about a larger-than-life psychiatrist, one whose warmth and inspiration are healing. I imagine his tools are helpful, but his personality is what carries the load. If a viewer has not had experience with psychiatry, and this film inspires him to begin therapy, there may be a good deal of disappointment. In this case, the patient is a successful actor, and one might wonder if that, together with the entire years-long project of filming, has altered the relationship well beyond the usual therapeutic hour.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore.

For as long as I can remember, psychiatrists have talked about what the appropriate boundaries are for self-disclosure about personal issues with patients. There is obviously no exact answer as to what is acceptable to disclose; this depends on the doctor, the patient, the “brand” of psychotherapy, the patient’s issues, the nature of what is being disclosed, and maybe the alignment of the stars on that particular day. “Stutz,” the Netflix documentary that Oscar-nominated actor/director Jonah Hill has made about his psychiatrist, Phil Stutz, MD, adds a whole new chapter to the discussion.

“Okay, entertain me,” Dr. Stutz says as his patient takes a seat. The therapeutic relationship and the paradigm Dr. Stutz has created to help his patients has been healing for Jonah Hill. The very serious and intimate dialogue that follows unfolds with moments of humor, warmth, and open affection. Hill candidly tells us why he is making this documentary – to share what he has learned and to honor his therapist – but we don’t know why Dr. Stutz has agreed to the endeavor and we’re left to our own inferences.

Dr. Stutz is the coauthor, with Barry Michels, of a best-selling self-help book, “The Tools: 5 Tools to Help You Find Courage, Creativity, and Willpower – and Inspire You to Live Life in Forward Motion.” He talks about his restlessness with the psychodynamic method during his training as a resident in New York – he wanted to offer his patients more immediate relief and a supervisor told him, “Don’t you dare!”

In the film, he talks about giving patients hope and direction. And Hill makes the comment, “In traditional therapy, you’re paying this person and you save all your problems for them, and they just listen, and your friends – who are idiots – give you advice, unsolicited, and you want your friends just to listen, and you want your therapist to give you advice!” Dr. Stutz gives advice and he is like no other therapist Jonah has ever had.

The premise of the film is that we are watching a single therapy session and Dr. Stutz will discuss the use of his tools and techniques that Hill has found helpful. Jonah is the interviewer, and when the doctor suggests it would be helpful if Jonah talked about his life, the patient/director rebuffs him; this documentary is about the psychiatrist.

Early in the film an alarm goes off, Dr. Stutz does not hear it, and Jonah has to remind him that it’s time for him to take his pills. The psychiatrist has Parkinson’s disease and how it has affected him becomes one focal point for the film. We later learn that he lost a younger brother as a child (something Hill did not know before they started filming) and grew up in the shadow of that loss. His extroverted father made it clear that medicine was the only acceptable career path for his son, and his introverted and depressed mother spent her days proclaiming that all men were as awful as her own abusive father.

About a third of the way through the film, the focus shifts. Jonah suddenly confesses that he is feeling stuck with regard to the movie, that he is troubled by the fact that he has not been able to share his distress with Dr. Stutz during their real-life, unfilmed therapy sessions, and the viewers learn that the single-session concept was disingenuous – they have been filming this documentary for two years, against a green screen and not in an office, always wearing the same clothes, and Jonah pulls off a wig that he wears to disguise the fact that he changed his hairstyle months earlier.

It’s a bit unnerving as they throw the wig around, and Jonah agrees to be more open about the issues he has struggled with. He acknowledges that this has been difficult, and he says, “I just keep asking myself, like, was this a f***ing horrible idea for a patient to make a movie about his therapist?” From my perspective as a psychiatrist-viewer, it’s a good question to ask!

Dr. Stutz reassures Jonah that it is okay to be vulnerable. “Failure, weakness, vulnerability – it’s like a connector, it connects you to the rest of the world.” A super-sized cardboard cutout of an obese 14-year-old Jonah now joins the room, and we learn that he continues to struggle with his self-image. Things get more real.

Peppered throughout the film, there are lessons from Dr. Stutz about his “tools,” constructs he uses to help people restructure their worlds and take action to move forward. One such construct he calls “the maze,” which occurs when one person in an interpersonal relationship is waiting for fairness and becomes preoccupied with feeling injured.

Jonah inquires about Dr. Stutz’s romantic life and the therapist replies with a transparency that overrides our usual professional boundaries. We all learn that Dr. Stutz is not in a relationship, he’s never been married, but there is a woman he has had some involvement with on and off for 40 years. Jonah’s line of questioning rivals that of any therapist. “How do you think it affects you, having your mom hate men and you being a man?” Dr. Stutz admits that he can never feel safe with women. “Did you ever override that wall you built with your mom and get close to a woman?” When Jonah professes, “I don’t feel anything but love for you and I just want you to be happy,” my own feeling was that the tables had turned too far, that the therapist’s failed romantic life risked being a burden to the patient.

Still, there is something about the relationship between the two men that is touching and beautiful. Dr. Stutz as a therapist is charismatic, caring, self-assured, and optimistic, and he radiates hope and certainty. He mixes an intense intimacy with humor in a way that is both authentic and entertaining. The interspersed jokes break the intensity, but they don’t diminish his wisdom and the healing he imparts.

Dr. Stutz is a psychiatrist, and his strength is clearly as a psychotherapist, yet there is not a single mention of psychotropic medications – there is a banter about recreational drugs and medications for Parkinson’s disease. If Hill is taking medication for depression or anxiety, and if prescribing is part of Dr. Stutz’s arsenal, the viewer is not made aware of this.

Dr. Stutz eschews the slow, detached, and “neutral” pace of psychodynamic therapy and the whole concept of the therapist as a blank wall for the transference to play out on, but here the transference screams: Jonah loves him, he respect and honors him, he wants him to be happy, and he is afraid of losing him.

“Stutz” is a movie about a larger-than-life psychiatrist, one whose warmth and inspiration are healing. I imagine his tools are helpful, but his personality is what carries the load. If a viewer has not had experience with psychiatry, and this film inspires him to begin therapy, there may be a good deal of disappointment. In this case, the patient is a successful actor, and one might wonder if that, together with the entire years-long project of filming, has altered the relationship well beyond the usual therapeutic hour.

Dr. Miller is a coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016). She has a private practice and is an assistant professor of psychiatry and behavioral sciences at Johns Hopkins University in Baltimore.

Borderline ovarian tumors (BOTs) are estimated to comprise 10%-15% of all epithelial tumors of the ovary. They are characterized by their behavior, which falls somewhere between benign ovarian masses and frank carcinomas. They have cytologic characteristics suggesting malignancy, such as higher cellular proliferation and more variable nuclear atypia, but, unlike carcinomas, they lack destructive stromal invasion. For decades after their recognition by the International Federation of Gynecology and Obstetrics in 1971, these tumors were classified as being of low malignant potential (and subsequently referred to as LMP tumors of the ovary). Beginning with the 2014 World Health Organization classification, the recommended terminology is now borderline tumor of the ovary.

The primary treatment for BOTs is surgery. With a mean age at diagnosis in the fifth decade, many patients with BOTs desire ovarian preservation to maintain fertility and/or prevent surgical menopause. This raises multiple questions regarding the use of fertility-sparing surgery for BOTs: What types of procedures are safe and should be offered? For those patients who undergo fertility-sparing surgery initially, is additional surgery indicated after completion of childbearing or at an age closer to natural menopause? What should this completion surgery include?

Ovarian-sparing surgery

The diagnosis of a BOT is frequently only confirmed after the decision for ovarian conservation has been made. What should be considered before electing to proceed with ovarian cystectomy instead of unilateral salpingo-oophorectomy (USO)?

Is the risk of recurrence higher with cystectomy versus oophorectomy?

Yes. The risk of recurrence of BOT appears to be higher after cystectomy than it is after oophorectomy. There is a large range reported in the literature, with the risk of recurrence after cystectomy described as between 12% and 58%. Most studies report recurrences between 25% and 35% of patients who undergo cystectomy. In contrast, the risk of recurrence after USO is often reported to be approximately 10%. Higher risk of recurrence after cystectomy is speculated to be due to leaving some BOT at the time of initial surgery.

Multiple meta-analyses have found an increased risk of recurrence after cystectomy. The risk of recurrence after unilateral cystectomy was 19.4%, compared with 9.1% after USO, in 2,145 patients included in a 2017 meta-analysis.¹ Similarly, a 2021 meta-analysis found a significantly higher rate of BOT recurrence in patients who underwent unilateral or bilateral cystectomy compared with USO (odds ratio, 2.02; 95% confidence interval, 1.59-2.57).²
 

Does the higher recurrence risk translate into a difference in long-term outcomes?

No. Despite an increased risk of recurrence after cystectomy, ovarian-sparing surgery does not appear to alter patients’ survival. The pooled mortality estimate was 1.6% for those undergoing fertility-sparing surgery (95% CI, 0.011-0.023), compared with 2.0% for those undergoing radical surgery (95% CI, 0.014-0.029), in a 2015 meta-analysis of over 5,100 patients. The analysis included studies in which patients underwent unilateral cystectomy, bilateral cystectomy, USO, or USO plus contralateral cystectomy. The low mortality rate did not allow for comparison between the different types of fertility-sparing surgeries.³

Do we accept a higher risk of recurrence with ovarian sparing surgery to improve fertility?

Data are mixed. When we examine studies describing fertility rates after conservative surgery, there are significant limitations to interpreting the data available. Some studies do not differentiate among patients who underwent fertility-sparing surgery, or between those who had cystectomy versus USO. Other studies do not report the number of patients who tried to achieve pregnancy after surgery. Conception rates are reported to be as high as 88.2%, which was in 116 patients who were able to be reached after fertility-sparing surgery (retained at least one ovary). Of the 51 patients who tried to conceive, 45 were successful.⁴

Multiple studies and meta-analyses have shown no difference in postoperative pregnancy rates when comparing oophorectomy to cystectomy. For instance, in a 2021 meta-analysis, there was no significant difference noted in pregnancy rates between patients who underwent USO versus cystectomy (OR, 0.92; 95% CI, 0.60-1.42).

There are some data that support improved postoperative pregnancy rates in more conservative surgery, especially in the setting of bilateral BOT. In a small study of 32 patients who had laparoscopic staging for bilateral BOTs, patients were randomized to unilateral oophorectomy plus contralateral cystectomy or to bilateral cystectomy, which was referred to as ultraconservative surgery. The time to first recurrence was shorter in the ultraconservative group (although this lost significance when regression analysis was performed), but the time to first live birth was shorter and the relative chance of having a baby was higher in the bilateral cystectomy group.⁵

Ovarian-sparing procedures should be offered to patients in the setting of BOT. With ovarian-sparing surgery, it is important to counsel patients about the increased risk of recurrence and need for long-term follow-up. Pregnancy rates are generally good after fertility-sparing surgery. Surgery to conserve both ovaries does not seem to improve pregnancy rates in the setting of unilateral BOTs.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Jiao X et al. Int J Gynecol Cancer. 2017 Nov;27(9):1833-41.

2. Wang P and Fang L. World J Surg Oncol. 2021 Apr 21;19(1):132.

3. Vasconcelos I and de Sousa Mendes M. Eur J Cancer. 2015 Mar;51(5):620-31.

4. Song T et al. Int J Gynecol Cancer. 2011 May;21(4):640-6.

5. Palomba S et al. Hum Reprod. 2010 Aug;25(8):1966-72.

Borderline ovarian tumors (BOTs) are estimated to comprise 10%-15% of all epithelial tumors of the ovary. They are characterized by their behavior, which falls somewhere between benign ovarian masses and frank carcinomas. They have cytologic characteristics suggesting malignancy, such as higher cellular proliferation and more variable nuclear atypia, but, unlike carcinomas, they lack destructive stromal invasion. For decades after their recognition by the International Federation of Gynecology and Obstetrics in 1971, these tumors were classified as being of low malignant potential (and subsequently referred to as LMP tumors of the ovary). Beginning with the 2014 World Health Organization classification, the recommended terminology is now borderline tumor of the ovary.

The primary treatment for BOTs is surgery. With a mean age at diagnosis in the fifth decade, many patients with BOTs desire ovarian preservation to maintain fertility and/or prevent surgical menopause. This raises multiple questions regarding the use of fertility-sparing surgery for BOTs: What types of procedures are safe and should be offered? For those patients who undergo fertility-sparing surgery initially, is additional surgery indicated after completion of childbearing or at an age closer to natural menopause? What should this completion surgery include?

Ovarian-sparing surgery

The diagnosis of a BOT is frequently only confirmed after the decision for ovarian conservation has been made. What should be considered before electing to proceed with ovarian cystectomy instead of unilateral salpingo-oophorectomy (USO)?

Is the risk of recurrence higher with cystectomy versus oophorectomy?

Yes. The risk of recurrence of BOT appears to be higher after cystectomy than it is after oophorectomy. There is a large range reported in the literature, with the risk of recurrence after cystectomy described as between 12% and 58%. Most studies report recurrences between 25% and 35% of patients who undergo cystectomy. In contrast, the risk of recurrence after USO is often reported to be approximately 10%. Higher risk of recurrence after cystectomy is speculated to be due to leaving some BOT at the time of initial surgery.

Multiple meta-analyses have found an increased risk of recurrence after cystectomy. The risk of recurrence after unilateral cystectomy was 19.4%, compared with 9.1% after USO, in 2,145 patients included in a 2017 meta-analysis.¹ Similarly, a 2021 meta-analysis found a significantly higher rate of BOT recurrence in patients who underwent unilateral or bilateral cystectomy compared with USO (odds ratio, 2.02; 95% confidence interval, 1.59-2.57).²
 

Does the higher recurrence risk translate into a difference in long-term outcomes?

No. Despite an increased risk of recurrence after cystectomy, ovarian-sparing surgery does not appear to alter patients’ survival. The pooled mortality estimate was 1.6% for those undergoing fertility-sparing surgery (95% CI, 0.011-0.023), compared with 2.0% for those undergoing radical surgery (95% CI, 0.014-0.029), in a 2015 meta-analysis of over 5,100 patients. The analysis included studies in which patients underwent unilateral cystectomy, bilateral cystectomy, USO, or USO plus contralateral cystectomy. The low mortality rate did not allow for comparison between the different types of fertility-sparing surgeries.³

Do we accept a higher risk of recurrence with ovarian sparing surgery to improve fertility?

Data are mixed. When we examine studies describing fertility rates after conservative surgery, there are significant limitations to interpreting the data available. Some studies do not differentiate among patients who underwent fertility-sparing surgery, or between those who had cystectomy versus USO. Other studies do not report the number of patients who tried to achieve pregnancy after surgery. Conception rates are reported to be as high as 88.2%, which was in 116 patients who were able to be reached after fertility-sparing surgery (retained at least one ovary). Of the 51 patients who tried to conceive, 45 were successful.⁴

Multiple studies and meta-analyses have shown no difference in postoperative pregnancy rates when comparing oophorectomy to cystectomy. For instance, in a 2021 meta-analysis, there was no significant difference noted in pregnancy rates between patients who underwent USO versus cystectomy (OR, 0.92; 95% CI, 0.60-1.42).

There are some data that support improved postoperative pregnancy rates in more conservative surgery, especially in the setting of bilateral BOT. In a small study of 32 patients who had laparoscopic staging for bilateral BOTs, patients were randomized to unilateral oophorectomy plus contralateral cystectomy or to bilateral cystectomy, which was referred to as ultraconservative surgery. The time to first recurrence was shorter in the ultraconservative group (although this lost significance when regression analysis was performed), but the time to first live birth was shorter and the relative chance of having a baby was higher in the bilateral cystectomy group.⁵

Ovarian-sparing procedures should be offered to patients in the setting of BOT. With ovarian-sparing surgery, it is important to counsel patients about the increased risk of recurrence and need for long-term follow-up. Pregnancy rates are generally good after fertility-sparing surgery. Surgery to conserve both ovaries does not seem to improve pregnancy rates in the setting of unilateral BOTs.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Jiao X et al. Int J Gynecol Cancer. 2017 Nov;27(9):1833-41.

2. Wang P and Fang L. World J Surg Oncol. 2021 Apr 21;19(1):132.

3. Vasconcelos I and de Sousa Mendes M. Eur J Cancer. 2015 Mar;51(5):620-31.

4. Song T et al. Int J Gynecol Cancer. 2011 May;21(4):640-6.

5. Palomba S et al. Hum Reprod. 2010 Aug;25(8):1966-72.

Borderline ovarian tumors (BOTs) are estimated to comprise 10%-15% of all epithelial tumors of the ovary. They are characterized by their behavior, which falls somewhere between benign ovarian masses and frank carcinomas. They have cytologic characteristics suggesting malignancy, such as higher cellular proliferation and more variable nuclear atypia, but, unlike carcinomas, they lack destructive stromal invasion. For decades after their recognition by the International Federation of Gynecology and Obstetrics in 1971, these tumors were classified as being of low malignant potential (and subsequently referred to as LMP tumors of the ovary). Beginning with the 2014 World Health Organization classification, the recommended terminology is now borderline tumor of the ovary.

The primary treatment for BOTs is surgery. With a mean age at diagnosis in the fifth decade, many patients with BOTs desire ovarian preservation to maintain fertility and/or prevent surgical menopause. This raises multiple questions regarding the use of fertility-sparing surgery for BOTs: What types of procedures are safe and should be offered? For those patients who undergo fertility-sparing surgery initially, is additional surgery indicated after completion of childbearing or at an age closer to natural menopause? What should this completion surgery include?

Ovarian-sparing surgery

The diagnosis of a BOT is frequently only confirmed after the decision for ovarian conservation has been made. What should be considered before electing to proceed with ovarian cystectomy instead of unilateral salpingo-oophorectomy (USO)?

Is the risk of recurrence higher with cystectomy versus oophorectomy?

Yes. The risk of recurrence of BOT appears to be higher after cystectomy than it is after oophorectomy. There is a large range reported in the literature, with the risk of recurrence after cystectomy described as between 12% and 58%. Most studies report recurrences between 25% and 35% of patients who undergo cystectomy. In contrast, the risk of recurrence after USO is often reported to be approximately 10%. Higher risk of recurrence after cystectomy is speculated to be due to leaving some BOT at the time of initial surgery.

Multiple meta-analyses have found an increased risk of recurrence after cystectomy. The risk of recurrence after unilateral cystectomy was 19.4%, compared with 9.1% after USO, in 2,145 patients included in a 2017 meta-analysis.¹ Similarly, a 2021 meta-analysis found a significantly higher rate of BOT recurrence in patients who underwent unilateral or bilateral cystectomy compared with USO (odds ratio, 2.02; 95% confidence interval, 1.59-2.57).²
 

Does the higher recurrence risk translate into a difference in long-term outcomes?

No. Despite an increased risk of recurrence after cystectomy, ovarian-sparing surgery does not appear to alter patients’ survival. The pooled mortality estimate was 1.6% for those undergoing fertility-sparing surgery (95% CI, 0.011-0.023), compared with 2.0% for those undergoing radical surgery (95% CI, 0.014-0.029), in a 2015 meta-analysis of over 5,100 patients. The analysis included studies in which patients underwent unilateral cystectomy, bilateral cystectomy, USO, or USO plus contralateral cystectomy. The low mortality rate did not allow for comparison between the different types of fertility-sparing surgeries.³

Do we accept a higher risk of recurrence with ovarian sparing surgery to improve fertility?

Data are mixed. When we examine studies describing fertility rates after conservative surgery, there are significant limitations to interpreting the data available. Some studies do not differentiate among patients who underwent fertility-sparing surgery, or between those who had cystectomy versus USO. Other studies do not report the number of patients who tried to achieve pregnancy after surgery. Conception rates are reported to be as high as 88.2%, which was in 116 patients who were able to be reached after fertility-sparing surgery (retained at least one ovary). Of the 51 patients who tried to conceive, 45 were successful.⁴

Multiple studies and meta-analyses have shown no difference in postoperative pregnancy rates when comparing oophorectomy to cystectomy. For instance, in a 2021 meta-analysis, there was no significant difference noted in pregnancy rates between patients who underwent USO versus cystectomy (OR, 0.92; 95% CI, 0.60-1.42).

There are some data that support improved postoperative pregnancy rates in more conservative surgery, especially in the setting of bilateral BOT. In a small study of 32 patients who had laparoscopic staging for bilateral BOTs, patients were randomized to unilateral oophorectomy plus contralateral cystectomy or to bilateral cystectomy, which was referred to as ultraconservative surgery. The time to first recurrence was shorter in the ultraconservative group (although this lost significance when regression analysis was performed), but the time to first live birth was shorter and the relative chance of having a baby was higher in the bilateral cystectomy group.⁵

Ovarian-sparing procedures should be offered to patients in the setting of BOT. With ovarian-sparing surgery, it is important to counsel patients about the increased risk of recurrence and need for long-term follow-up. Pregnancy rates are generally good after fertility-sparing surgery. Surgery to conserve both ovaries does not seem to improve pregnancy rates in the setting of unilateral BOTs.

Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Jiao X et al. Int J Gynecol Cancer. 2017 Nov;27(9):1833-41.

2. Wang P and Fang L. World J Surg Oncol. 2021 Apr 21;19(1):132.

3. Vasconcelos I and de Sousa Mendes M. Eur J Cancer. 2015 Mar;51(5):620-31.

4. Song T et al. Int J Gynecol Cancer. 2011 May;21(4):640-6.

5. Palomba S et al. Hum Reprod. 2010 Aug;25(8):1966-72.

The Food and Drug Administration has approved over-the-counter sales of the overdose reversal agent Narcan (naloxone, Emergent BioSolutions). Greater access to the drug should mean more lives saved. However, it’s unclear how much the nasal spray will cost and whether pharmacies will stock the product openly on shelves. 

Currently, major pharmacy chains such as CVS and Walgreens make naloxone available without prescription, but consumers have to ask a pharmacist to dispense the drug.

“The major question is what is it going to cost,” Brian Hurley, MD, MBA, president-elect of the American Society of Addiction Medicine, said in an interview. “In order for people to access it they have to be able to afford it.”

“We won’t accomplish much if people can’t afford to buy Narcan,” said Chuck Ingoglia, president and CEO of the National Council for Mental Wellbeing, in a statement. Still, he applauded the FDA.

“No single approach will end overdose deaths but making Narcan easy to obtain and widely available likely will save countless lives annually,” he said.

“The timeline for availability and price of this OTC product is determined by the manufacturer,” the FDA said in a statement.

Commissioner Robert M. Califf, MD, called for the drug’s manufacturer to “make accessibility to the product a priority by making it available as soon as possible and at an affordable price.”

Emergent BioSolutions did not comment on cost. It said in a statement that the spray “will be available on U.S. shelves and at online retailers by the late summer,” after it has adapted Narcan for direct-to-consumer use, including more consumer-oriented packaging.

Naloxone’s cost varies, depending on geographic location and whether it is generic. According to GoodRX, a box containing two doses of generic naloxone costs $31-$100, depending on location and coupon availability.

A two-dose box of Narcan costs $135-$140. Emergent reported a 14% decline in naloxone sales in 2022 – to $373.7 million – blaming it in part on the introduction of generic formulations.

Dr. Hurley said he expects those who purchase Narcan at a drug store will primarily already be shopping there. It may or may not be those who most often experience overdose, such as people leaving incarceration or experiencing homelessness.

Having Narcan available over-the-counter “is an important supplement but it doesn’t replace the existing array of naloxone distribution programs,” Dr. Hurley said.

The FDA has encouraged naloxone manufacturers to seek OTC approval for the medication since at least 2019, when it designed a model label for a theoretical OTC product.

In November, the agency said it had determined that some naloxone products had the potential to be safe and effective for OTC use and again urged drugmakers to seek such an approval.

Emergent BioSolutions was the first to pursue OTC approval, but another manufacturer – the nonprofit Harm Reduction Therapeutics – is awaiting approval of its application to sell its spray directly to consumers.

Scott Gottlieb, MD, who was the FDA commissioner from 2017 to 2019, said in a tweet that more work needed to be done.

“This regulatory move should be followed by a strong push by elected officials to support wider deployment of Narcan, getting more doses into the hands of at risk households and frontline workers,” he tweeted.

Mr. Ingoglia said that “Narcan represents a second chance. By giving people a second chance, we also give them an opportunity to enter treatment if they so choose. You can’t recover if you’re dead, and we shouldn’t turn our backs on those who may choose a pathway to recovery that includes treatment.”
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved over-the-counter sales of the overdose reversal agent Narcan (naloxone, Emergent BioSolutions). Greater access to the drug should mean more lives saved. However, it’s unclear how much the nasal spray will cost and whether pharmacies will stock the product openly on shelves. 

Currently, major pharmacy chains such as CVS and Walgreens make naloxone available without prescription, but consumers have to ask a pharmacist to dispense the drug.

“The major question is what is it going to cost,” Brian Hurley, MD, MBA, president-elect of the American Society of Addiction Medicine, said in an interview. “In order for people to access it they have to be able to afford it.”

“We won’t accomplish much if people can’t afford to buy Narcan,” said Chuck Ingoglia, president and CEO of the National Council for Mental Wellbeing, in a statement. Still, he applauded the FDA.

“No single approach will end overdose deaths but making Narcan easy to obtain and widely available likely will save countless lives annually,” he said.

“The timeline for availability and price of this OTC product is determined by the manufacturer,” the FDA said in a statement.

Commissioner Robert M. Califf, MD, called for the drug’s manufacturer to “make accessibility to the product a priority by making it available as soon as possible and at an affordable price.”

Emergent BioSolutions did not comment on cost. It said in a statement that the spray “will be available on U.S. shelves and at online retailers by the late summer,” after it has adapted Narcan for direct-to-consumer use, including more consumer-oriented packaging.

Naloxone’s cost varies, depending on geographic location and whether it is generic. According to GoodRX, a box containing two doses of generic naloxone costs $31-$100, depending on location and coupon availability.

A two-dose box of Narcan costs $135-$140. Emergent reported a 14% decline in naloxone sales in 2022 – to $373.7 million – blaming it in part on the introduction of generic formulations.

Dr. Hurley said he expects those who purchase Narcan at a drug store will primarily already be shopping there. It may or may not be those who most often experience overdose, such as people leaving incarceration or experiencing homelessness.

Having Narcan available over-the-counter “is an important supplement but it doesn’t replace the existing array of naloxone distribution programs,” Dr. Hurley said.

The FDA has encouraged naloxone manufacturers to seek OTC approval for the medication since at least 2019, when it designed a model label for a theoretical OTC product.

In November, the agency said it had determined that some naloxone products had the potential to be safe and effective for OTC use and again urged drugmakers to seek such an approval.

Emergent BioSolutions was the first to pursue OTC approval, but another manufacturer – the nonprofit Harm Reduction Therapeutics – is awaiting approval of its application to sell its spray directly to consumers.

Scott Gottlieb, MD, who was the FDA commissioner from 2017 to 2019, said in a tweet that more work needed to be done.

“This regulatory move should be followed by a strong push by elected officials to support wider deployment of Narcan, getting more doses into the hands of at risk households and frontline workers,” he tweeted.

Mr. Ingoglia said that “Narcan represents a second chance. By giving people a second chance, we also give them an opportunity to enter treatment if they so choose. You can’t recover if you’re dead, and we shouldn’t turn our backs on those who may choose a pathway to recovery that includes treatment.”
 

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved over-the-counter sales of the overdose reversal agent Narcan (naloxone, Emergent BioSolutions). Greater access to the drug should mean more lives saved. However, it’s unclear how much the nasal spray will cost and whether pharmacies will stock the product openly on shelves. 

Currently, major pharmacy chains such as CVS and Walgreens make naloxone available without prescription, but consumers have to ask a pharmacist to dispense the drug.

“The major question is what is it going to cost,” Brian Hurley, MD, MBA, president-elect of the American Society of Addiction Medicine, said in an interview. “In order for people to access it they have to be able to afford it.”

“We won’t accomplish much if people can’t afford to buy Narcan,” said Chuck Ingoglia, president and CEO of the National Council for Mental Wellbeing, in a statement. Still, he applauded the FDA.

“No single approach will end overdose deaths but making Narcan easy to obtain and widely available likely will save countless lives annually,” he said.

“The timeline for availability and price of this OTC product is determined by the manufacturer,” the FDA said in a statement.

Commissioner Robert M. Califf, MD, called for the drug’s manufacturer to “make accessibility to the product a priority by making it available as soon as possible and at an affordable price.”

Emergent BioSolutions did not comment on cost. It said in a statement that the spray “will be available on U.S. shelves and at online retailers by the late summer,” after it has adapted Narcan for direct-to-consumer use, including more consumer-oriented packaging.

Naloxone’s cost varies, depending on geographic location and whether it is generic. According to GoodRX, a box containing two doses of generic naloxone costs $31-$100, depending on location and coupon availability.

A two-dose box of Narcan costs $135-$140. Emergent reported a 14% decline in naloxone sales in 2022 – to $373.7 million – blaming it in part on the introduction of generic formulations.

Dr. Hurley said he expects those who purchase Narcan at a drug store will primarily already be shopping there. It may or may not be those who most often experience overdose, such as people leaving incarceration or experiencing homelessness.

Having Narcan available over-the-counter “is an important supplement but it doesn’t replace the existing array of naloxone distribution programs,” Dr. Hurley said.

The FDA has encouraged naloxone manufacturers to seek OTC approval for the medication since at least 2019, when it designed a model label for a theoretical OTC product.

In November, the agency said it had determined that some naloxone products had the potential to be safe and effective for OTC use and again urged drugmakers to seek such an approval.

Emergent BioSolutions was the first to pursue OTC approval, but another manufacturer – the nonprofit Harm Reduction Therapeutics – is awaiting approval of its application to sell its spray directly to consumers.

Scott Gottlieb, MD, who was the FDA commissioner from 2017 to 2019, said in a tweet that more work needed to be done.

“This regulatory move should be followed by a strong push by elected officials to support wider deployment of Narcan, getting more doses into the hands of at risk households and frontline workers,” he tweeted.

Mr. Ingoglia said that “Narcan represents a second chance. By giving people a second chance, we also give them an opportunity to enter treatment if they so choose. You can’t recover if you’re dead, and we shouldn’t turn our backs on those who may choose a pathway to recovery that includes treatment.”
 

A version of this article first appeared on Medscape.com.

BOSTON – Women with breast cancer who have several tumors in one breast do not necessarily need to have a mastectomy, as new data show a low risk of recurrence at 5 years when they are treated with breast-conserving therapy and radiation.

“[The study] proves the oncologic safety of breast conservation in women with two or three sites of disease, making this a very reasonable option for (previously reluctant) surgeons to present to patients,” first author Kari Rosenkranz, MD, an associate professor at Dartmouth Health in Norwich, Vt., said in an interview.

The findings were presented here at the International Conference on Surgical Cancer Care (SSO 2023), and were published online in the Journal of Clinical Oncology.

Commenting on the study, Hiram S. Cody III, MD, an attending surgeon and professor of surgery at Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, in New York, said the findings provide valuable new evidence on the issue.

“This is an important study confirming that breast conservation is feasible and safe for women with multiple ipsilateral breast cancers, with excellent results comparable to those for women with unifocal (single site) disease,” he said in an interview.

Although there have been as many as seven previous randomized trials that have shown identical outcomes in survival and local control of disease with breast-conserving therapy versus mastectomy, all those studies excluded patients with more than one site of disease.

At present, many surgeons and guidelines continue to recommend mastectomy for women with multiple-site tumors, based on older data that showed higher recurrence rates.

That is why the new study is so important, Dr. Cody explained. “Here, we see in a prospective trial that breast-conserving therapy is feasible for those with more than one site of disease as well, with high survival and very low rates of local recurrence,” he emphasized.

Dr. Cody noted that “the ideal candidate would be a woman with relatively small tumor size and a breast large enough that the multiple excisions could be performed with a good cosmetic result.”

“We have followed this approach for some time and hope that with the publication of these results more surgeons will recommend this approach for suitable patients,” he said.

The new results were also highlighted in a press release from Mayo Clinic highlighting the Journal of Clinical Oncology publication. Lead author of the article, surgical oncologist Judy Boughey, MD, from the Mayo Clinic in Rochester, Minn., commented: “I am excited about these findings because it will empower patients and the multidisciplinary care teams caring for patients to be thinking about this option for women who may want to preserve their breast.”

This study showed the rate of cancer local recurrence was 3.1%, she noted. This is an excellent outcome and is similar to the local recurrence rate for patients with a single tumor in a breast who had breast-conserving therapy, Dr. Boughey said.

Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, she added.


 

Study details

This study, known as the ACOSOG (Alliance) Z11102 trial, was a phase 2 trial conducted in 204 patients enrolled between 2012 and 2016 who had two or three sites of biopsy-proven breast cancer (each site less rhan 5 cm in size, with cN0 or cN1 disease).

These patients were a median age of 61 years, and 83.5% were ER-positive/HER2-negative, 11.5% were HER2-positive, 5.0% were ER-negative/HER2-negative, and 77.5% were node-negative.

All patients were treated with breast conservation surgery, including lumpectomy resected to negative margins, followed by whole breast radiation with a cavity boost to all lumpectomy beds.

With a median follow-up of 66.4 months, six patients developed local recurrence, with five of the recurrences occurring in the ipsilateral breast and one in the chest wall.

For the primary endpoint, the six recurrences represented an estimated cumulative incidence of local recurrence of 3.1% (95% CI, 1.3-6.4), well below the cutoff of 8% that was determined to be the acceptable 5-year local recurrence rate based on historic recurrence rates for unifocal disease, Dr. Rosenkranz explained.

There were no cases of synchronous local and distant recurrences, six contralateral breast cancers, and three new primary nonbreast cancers. Eight patients died, including one related to breast cancer.

There were no significant associations between risk of local recurrence and factors including patient age, number of sites of preoperative biopsy-proven breast cancer, HER2 status, and pathologic T and N category.

In terms of secondary endpoints, 14 patients (7.1%) converted to mastectomy because of positive margins, while 67.6% achieved margin-negative excision in a single operation.

Regarding cosmesis, 70.6% of patients reported good or excellent cosmetic outcomes at 2 years.

In terms of adherence, the whole breast radiation therapy protocol was feasible in most patients.

Of note, among patients without a breast preoperative MRI, the 5-year rate of local recurrence was significantly higher, at 22.6% (n = 14) at 5 years, compared with 1.7% among the 180 patients who did have a preoperative MRI (P = .002). However, Dr. Rosenkranz said these differences should be interpreted with caution.

“We may look at these data and think we should consider preoperative breast MRI in patients who do have known multiple ipsilateral breast cancer, although I think this cohort was certainly much too small to draw definitive conclusions, and this was not a planned secondary endpoint of the trial,” she said during her presentation.
 

Most prefer breast conservation, when possible

Overall, the findings are important considering the array of known benefits of breast conservation over mastectomy, Dr. Rosenkranz concluded.

“The reason this is so important is that we know that patients who undergo breast conservation report improved quality of life, self-esteem, and body image, and therefore it’s incumbent on us as surgeons to expand the indications for breast conservation where we can,” she told the audience.

Speaking with this news organization, she added that the decision-making around breast conservation versus mastectomy can be complicated, and some women do opt for mastectomy because of a variety of factors; therefore, “tailoring therapy to the individual goals and priorities in addition to the disease characteristics is critical.”

That said, she added that “the majority of patients who are eligible for breast conservation do prefer this option.”

Dr. Rosenkranz and Dr. Cody have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

BOSTON – Women with breast cancer who have several tumors in one breast do not necessarily need to have a mastectomy, as new data show a low risk of recurrence at 5 years when they are treated with breast-conserving therapy and radiation.

“[The study] proves the oncologic safety of breast conservation in women with two or three sites of disease, making this a very reasonable option for (previously reluctant) surgeons to present to patients,” first author Kari Rosenkranz, MD, an associate professor at Dartmouth Health in Norwich, Vt., said in an interview.

The findings were presented here at the International Conference on Surgical Cancer Care (SSO 2023), and were published online in the Journal of Clinical Oncology.

Commenting on the study, Hiram S. Cody III, MD, an attending surgeon and professor of surgery at Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, in New York, said the findings provide valuable new evidence on the issue.

“This is an important study confirming that breast conservation is feasible and safe for women with multiple ipsilateral breast cancers, with excellent results comparable to those for women with unifocal (single site) disease,” he said in an interview.

Although there have been as many as seven previous randomized trials that have shown identical outcomes in survival and local control of disease with breast-conserving therapy versus mastectomy, all those studies excluded patients with more than one site of disease.

At present, many surgeons and guidelines continue to recommend mastectomy for women with multiple-site tumors, based on older data that showed higher recurrence rates.

That is why the new study is so important, Dr. Cody explained. “Here, we see in a prospective trial that breast-conserving therapy is feasible for those with more than one site of disease as well, with high survival and very low rates of local recurrence,” he emphasized.

Dr. Cody noted that “the ideal candidate would be a woman with relatively small tumor size and a breast large enough that the multiple excisions could be performed with a good cosmetic result.”

“We have followed this approach for some time and hope that with the publication of these results more surgeons will recommend this approach for suitable patients,” he said.

The new results were also highlighted in a press release from Mayo Clinic highlighting the Journal of Clinical Oncology publication. Lead author of the article, surgical oncologist Judy Boughey, MD, from the Mayo Clinic in Rochester, Minn., commented: “I am excited about these findings because it will empower patients and the multidisciplinary care teams caring for patients to be thinking about this option for women who may want to preserve their breast.”

This study showed the rate of cancer local recurrence was 3.1%, she noted. This is an excellent outcome and is similar to the local recurrence rate for patients with a single tumor in a breast who had breast-conserving therapy, Dr. Boughey said.

Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, she added.


 

Study details

This study, known as the ACOSOG (Alliance) Z11102 trial, was a phase 2 trial conducted in 204 patients enrolled between 2012 and 2016 who had two or three sites of biopsy-proven breast cancer (each site less rhan 5 cm in size, with cN0 or cN1 disease).

These patients were a median age of 61 years, and 83.5% were ER-positive/HER2-negative, 11.5% were HER2-positive, 5.0% were ER-negative/HER2-negative, and 77.5% were node-negative.

All patients were treated with breast conservation surgery, including lumpectomy resected to negative margins, followed by whole breast radiation with a cavity boost to all lumpectomy beds.

With a median follow-up of 66.4 months, six patients developed local recurrence, with five of the recurrences occurring in the ipsilateral breast and one in the chest wall.

For the primary endpoint, the six recurrences represented an estimated cumulative incidence of local recurrence of 3.1% (95% CI, 1.3-6.4), well below the cutoff of 8% that was determined to be the acceptable 5-year local recurrence rate based on historic recurrence rates for unifocal disease, Dr. Rosenkranz explained.

There were no cases of synchronous local and distant recurrences, six contralateral breast cancers, and three new primary nonbreast cancers. Eight patients died, including one related to breast cancer.

There were no significant associations between risk of local recurrence and factors including patient age, number of sites of preoperative biopsy-proven breast cancer, HER2 status, and pathologic T and N category.

In terms of secondary endpoints, 14 patients (7.1%) converted to mastectomy because of positive margins, while 67.6% achieved margin-negative excision in a single operation.

Regarding cosmesis, 70.6% of patients reported good or excellent cosmetic outcomes at 2 years.

In terms of adherence, the whole breast radiation therapy protocol was feasible in most patients.

Of note, among patients without a breast preoperative MRI, the 5-year rate of local recurrence was significantly higher, at 22.6% (n = 14) at 5 years, compared with 1.7% among the 180 patients who did have a preoperative MRI (P = .002). However, Dr. Rosenkranz said these differences should be interpreted with caution.

“We may look at these data and think we should consider preoperative breast MRI in patients who do have known multiple ipsilateral breast cancer, although I think this cohort was certainly much too small to draw definitive conclusions, and this was not a planned secondary endpoint of the trial,” she said during her presentation.
 

Most prefer breast conservation, when possible

Overall, the findings are important considering the array of known benefits of breast conservation over mastectomy, Dr. Rosenkranz concluded.

“The reason this is so important is that we know that patients who undergo breast conservation report improved quality of life, self-esteem, and body image, and therefore it’s incumbent on us as surgeons to expand the indications for breast conservation where we can,” she told the audience.

Speaking with this news organization, she added that the decision-making around breast conservation versus mastectomy can be complicated, and some women do opt for mastectomy because of a variety of factors; therefore, “tailoring therapy to the individual goals and priorities in addition to the disease characteristics is critical.”

That said, she added that “the majority of patients who are eligible for breast conservation do prefer this option.”

Dr. Rosenkranz and Dr. Cody have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

BOSTON – Women with breast cancer who have several tumors in one breast do not necessarily need to have a mastectomy, as new data show a low risk of recurrence at 5 years when they are treated with breast-conserving therapy and radiation.

“[The study] proves the oncologic safety of breast conservation in women with two or three sites of disease, making this a very reasonable option for (previously reluctant) surgeons to present to patients,” first author Kari Rosenkranz, MD, an associate professor at Dartmouth Health in Norwich, Vt., said in an interview.

The findings were presented here at the International Conference on Surgical Cancer Care (SSO 2023), and were published online in the Journal of Clinical Oncology.

Commenting on the study, Hiram S. Cody III, MD, an attending surgeon and professor of surgery at Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, in New York, said the findings provide valuable new evidence on the issue.

“This is an important study confirming that breast conservation is feasible and safe for women with multiple ipsilateral breast cancers, with excellent results comparable to those for women with unifocal (single site) disease,” he said in an interview.

Although there have been as many as seven previous randomized trials that have shown identical outcomes in survival and local control of disease with breast-conserving therapy versus mastectomy, all those studies excluded patients with more than one site of disease.

At present, many surgeons and guidelines continue to recommend mastectomy for women with multiple-site tumors, based on older data that showed higher recurrence rates.

That is why the new study is so important, Dr. Cody explained. “Here, we see in a prospective trial that breast-conserving therapy is feasible for those with more than one site of disease as well, with high survival and very low rates of local recurrence,” he emphasized.

Dr. Cody noted that “the ideal candidate would be a woman with relatively small tumor size and a breast large enough that the multiple excisions could be performed with a good cosmetic result.”

“We have followed this approach for some time and hope that with the publication of these results more surgeons will recommend this approach for suitable patients,” he said.

The new results were also highlighted in a press release from Mayo Clinic highlighting the Journal of Clinical Oncology publication. Lead author of the article, surgical oncologist Judy Boughey, MD, from the Mayo Clinic in Rochester, Minn., commented: “I am excited about these findings because it will empower patients and the multidisciplinary care teams caring for patients to be thinking about this option for women who may want to preserve their breast.”

This study showed the rate of cancer local recurrence was 3.1%, she noted. This is an excellent outcome and is similar to the local recurrence rate for patients with a single tumor in a breast who had breast-conserving therapy, Dr. Boughey said.

Historically, women with multiple tumors in one breast have been advised to have a mastectomy. Now, patients can be offered a less invasive option with faster recovery, resulting in better patient satisfaction and cosmetic outcomes, she added.


 

Study details

This study, known as the ACOSOG (Alliance) Z11102 trial, was a phase 2 trial conducted in 204 patients enrolled between 2012 and 2016 who had two or three sites of biopsy-proven breast cancer (each site less rhan 5 cm in size, with cN0 or cN1 disease).

These patients were a median age of 61 years, and 83.5% were ER-positive/HER2-negative, 11.5% were HER2-positive, 5.0% were ER-negative/HER2-negative, and 77.5% were node-negative.

All patients were treated with breast conservation surgery, including lumpectomy resected to negative margins, followed by whole breast radiation with a cavity boost to all lumpectomy beds.

With a median follow-up of 66.4 months, six patients developed local recurrence, with five of the recurrences occurring in the ipsilateral breast and one in the chest wall.

For the primary endpoint, the six recurrences represented an estimated cumulative incidence of local recurrence of 3.1% (95% CI, 1.3-6.4), well below the cutoff of 8% that was determined to be the acceptable 5-year local recurrence rate based on historic recurrence rates for unifocal disease, Dr. Rosenkranz explained.

There were no cases of synchronous local and distant recurrences, six contralateral breast cancers, and three new primary nonbreast cancers. Eight patients died, including one related to breast cancer.

There were no significant associations between risk of local recurrence and factors including patient age, number of sites of preoperative biopsy-proven breast cancer, HER2 status, and pathologic T and N category.

In terms of secondary endpoints, 14 patients (7.1%) converted to mastectomy because of positive margins, while 67.6% achieved margin-negative excision in a single operation.

Regarding cosmesis, 70.6% of patients reported good or excellent cosmetic outcomes at 2 years.

In terms of adherence, the whole breast radiation therapy protocol was feasible in most patients.

Of note, among patients without a breast preoperative MRI, the 5-year rate of local recurrence was significantly higher, at 22.6% (n = 14) at 5 years, compared with 1.7% among the 180 patients who did have a preoperative MRI (P = .002). However, Dr. Rosenkranz said these differences should be interpreted with caution.

“We may look at these data and think we should consider preoperative breast MRI in patients who do have known multiple ipsilateral breast cancer, although I think this cohort was certainly much too small to draw definitive conclusions, and this was not a planned secondary endpoint of the trial,” she said during her presentation.
 

Most prefer breast conservation, when possible

Overall, the findings are important considering the array of known benefits of breast conservation over mastectomy, Dr. Rosenkranz concluded.

“The reason this is so important is that we know that patients who undergo breast conservation report improved quality of life, self-esteem, and body image, and therefore it’s incumbent on us as surgeons to expand the indications for breast conservation where we can,” she told the audience.

Speaking with this news organization, she added that the decision-making around breast conservation versus mastectomy can be complicated, and some women do opt for mastectomy because of a variety of factors; therefore, “tailoring therapy to the individual goals and priorities in addition to the disease characteristics is critical.”

That said, she added that “the majority of patients who are eligible for breast conservation do prefer this option.”

Dr. Rosenkranz and Dr. Cody have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

HAMBURG, GERMANY – Around 86 billion nerve cells in our brain work together in complex dynamic networks to control almost every sensorimotor and cognitive process. However, the way in which the information is processed in the different regions of the brain is still unclear. There are already some promising approaches to specifically influence the dynamics of neuronal networks to treat neurological and psychiatric diseases.

One of the main topics at the Congress for Clinical Neuroscience of the German Society for Clinical Neurophysiology and Functional Neuroimaging (DGKN), recently held in Hamburg, Germany, was the dynamics of cerebral networks in sensorimotor and cognitive processes, as well as disruptions to network dynamics in neurological and psychiatric diseases.

“We will be unable to develop innovative therapies for widespread neurological and psychiatric diseases until we understand neuronal functions on every level of complexity,” Andreas K. Engel, PhD, director of the Institute for Neurophysiology and Pathophysiology at the University Hospital of Hamburg-Eppendorf, president of the DGKN, and congress president, said during an online press conference.
 

Characterizing states of consciousness

For more than 30 years, it has been known that neuronal signals in the brain are dynamically coupled. Despite intensive research, the functional significance of this coupling on information processing is still largely unknown.

Neuroimaging methods such as electroencephalography (EEG), magnetoencephalography (MEG), structural and functional magnetic resonance imaging (MRI), and electrophysiological examinations were used. Model calculations of the data suggest that dynamic couplings of signals in the cortex play a crucial role in memory performance, thinking processes, and developing perception, among other things.

It has already been shown that the network dynamics of neuronal signals could possibly characterize states of consciousness. Neuronal signals and coupling patterns differ significantly between healthy individuals in a waking state and those who are asleep, under general anesthetic, or in a vegetative state. In Dr. Engel’s view, it may be possible in the future for machine learning algorithms to be used to classify states of consciousness.
 

Changes in brain activity as a biomarker?

The differences in the dynamics of neuronal signals between healthy individuals and patients with psychiatric diseases such as schizophrenia appear much more important for clinical practice. “The characteristic changes in brain activity in the primary auditory cortex could be considered a potential biomarker and used to predict the clinical course of psychiatric diseases, such as psychoses,” reported Dr. Engel.

The gamma-band activity in the auditory cortex could be a potential marker for schizophrenia. According to MEG examinations, the values are decreased both in people at increased risk of psychosis and experiencing first symptoms compared with controls.
 

Activation or inhibition of cerebral networks as new therapeutic approaches

New therapeutic approaches based on the activation or inhibition of cerebral networks are currently areas of intensive research. Close interdisciplinary collaboration between basic science researchers and clinicians is necessary, stressed Dr. Engel. The use of noninvasive brain stimulation is already within reach for the neurorehabilitation of stroke patients. “I am optimistic that in a few years brain stimulation will be established as an integral element of stroke therapy,” said Christian Grefkes-Hermann, MD, PhD, director of the department of neurology at University Hospital of Frankfurt and first vice president of the DGKN.

Despite great advances in acute stroke therapy, many patients must endure permanent deficits in their everyday life, he said. According to Dr. Grefkes-Hermann, rehabilitation procedures often have a dissatisfactory effect, and results greatly vary. He hopes that in the future it may be possible to personalize therapy by using network patterns, thereby improving results.

The aim is to reorganize areas of the brain in which the network activity has been disrupted following a stroke using targeted transcranial magnetic stimulation (TMS). “The most important factor for functional recovery after a stroke is neuronal reorganization,” said Dr. Grefkes-Hermann. With the new methods of neurorehabilitation, network-connectivity disruptions, which are associated with motor function deficits, are first visualized using functional MRI (fMRI).

The imaging or the EEG makes visible the area of the brain that may benefit most from neurostimulation. Subsequently, nerve cells in this region may be precisely stimulated with TMS. Because the healthy hemisphere of the brain is usually overactive after a stroke, there are simultaneous attempts to inhibit the contralesional motor cortex.

Initial results are hopeful. In the initial period after a stroke, TMS can be used in some patients to correct pathological connectivities and thereby improve motor deficits, reported Dr. Grefkes-Hermann. The fMRI pattern can also be used to predict recovery and intervention effects on an individual basis. A phase 3 trial is currently underway of 150 patients who have had a stroke and aims to study the efficacy of the new procedure.
 

Combined TMS and EEG

With the combination of TMS and the simultaneous measurement of EEG activity, a further development of fMRI connectivity analyses is currently being tested. Dr. Grefkes-Hermann believes that this procedure, which is more cost-effective, has higher temporal resolution, can be used directly at the bedside, and has more potential for personalized therapy planning in clinical practice.

The TMS-EEG procedure also makes it possible to predict the risk of post-stroke delirium, which affects around 30% of stroke patients and greatly worsens the outcome, underlined Ulf Ziemann, MD, medical director of the department of neurology at Tübingen (Germany) University Hospital. In a study of 33 patients with acute stroke, the onset of post-stroke delirium could be predicted with a high degree of accuracy by using the TMS-EEG procedure no later than 48 hours after the event.

Other promising, noninvasive methods for neuron activation mentioned by Dr. Ziemann include transcranial focused ultrasound stimulation (tFUS) with low intensity, which is being studied for chronic pain, dementia, epilepsy, traumatic brain injury, and depression, as well as transcranial pulse stimulation (TPS), which is also based on ultrasound. In a pilot study of 35 patients with Alzheimer’s disease, use of TPS within 3 months had positive effects on cognition. However, the study was not controlled and therefore further assessments are needed.
 

Custom deep brain stimulation

For deep brain stimulation (DBS), an established therapy for Parkinson’s disease and other movement disorders, the aim is individualized, symptom-related network stimulation, reported Andrea Kühn, MD, head of the movement disorders and neuromodulation section in the department of neurology at Charité University Hospital Berlin.

At the panregional collaborative research center ReTune, which has been supported for 4 years now by €10 million from the German Research Foundation (DFG), imaging and computer-assisted programming algorithms are being developed for DBS. They will greatly simplify the time-consuming standard procedure for the best possible setting of the stimulation parameters, which requires a hospital stay of several days.

A randomized crossover study of 35 patients with Parkinson’s disease proved the equivalence of the fast, algorithm-assisted DBS for the control of motor symptoms compared with standard procedures.

The new methods have the potential to considerably improve the outcome of patients with neurological and psychiatric diseases, according to scientists. However, the positive data must still be validated in further studies.
 

This article was translated from Medscape’s German edition. A version of this article appeared on Medscape.com.

HAMBURG, GERMANY – Around 86 billion nerve cells in our brain work together in complex dynamic networks to control almost every sensorimotor and cognitive process. However, the way in which the information is processed in the different regions of the brain is still unclear. There are already some promising approaches to specifically influence the dynamics of neuronal networks to treat neurological and psychiatric diseases.

One of the main topics at the Congress for Clinical Neuroscience of the German Society for Clinical Neurophysiology and Functional Neuroimaging (DGKN), recently held in Hamburg, Germany, was the dynamics of cerebral networks in sensorimotor and cognitive processes, as well as disruptions to network dynamics in neurological and psychiatric diseases.

“We will be unable to develop innovative therapies for widespread neurological and psychiatric diseases until we understand neuronal functions on every level of complexity,” Andreas K. Engel, PhD, director of the Institute for Neurophysiology and Pathophysiology at the University Hospital of Hamburg-Eppendorf, president of the DGKN, and congress president, said during an online press conference.
 

Characterizing states of consciousness

For more than 30 years, it has been known that neuronal signals in the brain are dynamically coupled. Despite intensive research, the functional significance of this coupling on information processing is still largely unknown.

Neuroimaging methods such as electroencephalography (EEG), magnetoencephalography (MEG), structural and functional magnetic resonance imaging (MRI), and electrophysiological examinations were used. Model calculations of the data suggest that dynamic couplings of signals in the cortex play a crucial role in memory performance, thinking processes, and developing perception, among other things.

It has already been shown that the network dynamics of neuronal signals could possibly characterize states of consciousness. Neuronal signals and coupling patterns differ significantly between healthy individuals in a waking state and those who are asleep, under general anesthetic, or in a vegetative state. In Dr. Engel’s view, it may be possible in the future for machine learning algorithms to be used to classify states of consciousness.
 

Changes in brain activity as a biomarker?

The differences in the dynamics of neuronal signals between healthy individuals and patients with psychiatric diseases such as schizophrenia appear much more important for clinical practice. “The characteristic changes in brain activity in the primary auditory cortex could be considered a potential biomarker and used to predict the clinical course of psychiatric diseases, such as psychoses,” reported Dr. Engel.

The gamma-band activity in the auditory cortex could be a potential marker for schizophrenia. According to MEG examinations, the values are decreased both in people at increased risk of psychosis and experiencing first symptoms compared with controls.
 

Activation or inhibition of cerebral networks as new therapeutic approaches

New therapeutic approaches based on the activation or inhibition of cerebral networks are currently areas of intensive research. Close interdisciplinary collaboration between basic science researchers and clinicians is necessary, stressed Dr. Engel. The use of noninvasive brain stimulation is already within reach for the neurorehabilitation of stroke patients. “I am optimistic that in a few years brain stimulation will be established as an integral element of stroke therapy,” said Christian Grefkes-Hermann, MD, PhD, director of the department of neurology at University Hospital of Frankfurt and first vice president of the DGKN.

Despite great advances in acute stroke therapy, many patients must endure permanent deficits in their everyday life, he said. According to Dr. Grefkes-Hermann, rehabilitation procedures often have a dissatisfactory effect, and results greatly vary. He hopes that in the future it may be possible to personalize therapy by using network patterns, thereby improving results.

The aim is to reorganize areas of the brain in which the network activity has been disrupted following a stroke using targeted transcranial magnetic stimulation (TMS). “The most important factor for functional recovery after a stroke is neuronal reorganization,” said Dr. Grefkes-Hermann. With the new methods of neurorehabilitation, network-connectivity disruptions, which are associated with motor function deficits, are first visualized using functional MRI (fMRI).

The imaging or the EEG makes visible the area of the brain that may benefit most from neurostimulation. Subsequently, nerve cells in this region may be precisely stimulated with TMS. Because the healthy hemisphere of the brain is usually overactive after a stroke, there are simultaneous attempts to inhibit the contralesional motor cortex.

Initial results are hopeful. In the initial period after a stroke, TMS can be used in some patients to correct pathological connectivities and thereby improve motor deficits, reported Dr. Grefkes-Hermann. The fMRI pattern can also be used to predict recovery and intervention effects on an individual basis. A phase 3 trial is currently underway of 150 patients who have had a stroke and aims to study the efficacy of the new procedure.
 

Combined TMS and EEG

With the combination of TMS and the simultaneous measurement of EEG activity, a further development of fMRI connectivity analyses is currently being tested. Dr. Grefkes-Hermann believes that this procedure, which is more cost-effective, has higher temporal resolution, can be used directly at the bedside, and has more potential for personalized therapy planning in clinical practice.

The TMS-EEG procedure also makes it possible to predict the risk of post-stroke delirium, which affects around 30% of stroke patients and greatly worsens the outcome, underlined Ulf Ziemann, MD, medical director of the department of neurology at Tübingen (Germany) University Hospital. In a study of 33 patients with acute stroke, the onset of post-stroke delirium could be predicted with a high degree of accuracy by using the TMS-EEG procedure no later than 48 hours after the event.

Other promising, noninvasive methods for neuron activation mentioned by Dr. Ziemann include transcranial focused ultrasound stimulation (tFUS) with low intensity, which is being studied for chronic pain, dementia, epilepsy, traumatic brain injury, and depression, as well as transcranial pulse stimulation (TPS), which is also based on ultrasound. In a pilot study of 35 patients with Alzheimer’s disease, use of TPS within 3 months had positive effects on cognition. However, the study was not controlled and therefore further assessments are needed.
 

Custom deep brain stimulation

For deep brain stimulation (DBS), an established therapy for Parkinson’s disease and other movement disorders, the aim is individualized, symptom-related network stimulation, reported Andrea Kühn, MD, head of the movement disorders and neuromodulation section in the department of neurology at Charité University Hospital Berlin.

At the panregional collaborative research center ReTune, which has been supported for 4 years now by €10 million from the German Research Foundation (DFG), imaging and computer-assisted programming algorithms are being developed for DBS. They will greatly simplify the time-consuming standard procedure for the best possible setting of the stimulation parameters, which requires a hospital stay of several days.

A randomized crossover study of 35 patients with Parkinson’s disease proved the equivalence of the fast, algorithm-assisted DBS for the control of motor symptoms compared with standard procedures.

The new methods have the potential to considerably improve the outcome of patients with neurological and psychiatric diseases, according to scientists. However, the positive data must still be validated in further studies.
 

This article was translated from Medscape’s German edition. A version of this article appeared on Medscape.com.

HAMBURG, GERMANY – Around 86 billion nerve cells in our brain work together in complex dynamic networks to control almost every sensorimotor and cognitive process. However, the way in which the information is processed in the different regions of the brain is still unclear. There are already some promising approaches to specifically influence the dynamics of neuronal networks to treat neurological and psychiatric diseases.

One of the main topics at the Congress for Clinical Neuroscience of the German Society for Clinical Neurophysiology and Functional Neuroimaging (DGKN), recently held in Hamburg, Germany, was the dynamics of cerebral networks in sensorimotor and cognitive processes, as well as disruptions to network dynamics in neurological and psychiatric diseases.

“We will be unable to develop innovative therapies for widespread neurological and psychiatric diseases until we understand neuronal functions on every level of complexity,” Andreas K. Engel, PhD, director of the Institute for Neurophysiology and Pathophysiology at the University Hospital of Hamburg-Eppendorf, president of the DGKN, and congress president, said during an online press conference.
 

Characterizing states of consciousness

For more than 30 years, it has been known that neuronal signals in the brain are dynamically coupled. Despite intensive research, the functional significance of this coupling on information processing is still largely unknown.

Neuroimaging methods such as electroencephalography (EEG), magnetoencephalography (MEG), structural and functional magnetic resonance imaging (MRI), and electrophysiological examinations were used. Model calculations of the data suggest that dynamic couplings of signals in the cortex play a crucial role in memory performance, thinking processes, and developing perception, among other things.

It has already been shown that the network dynamics of neuronal signals could possibly characterize states of consciousness. Neuronal signals and coupling patterns differ significantly between healthy individuals in a waking state and those who are asleep, under general anesthetic, or in a vegetative state. In Dr. Engel’s view, it may be possible in the future for machine learning algorithms to be used to classify states of consciousness.
 

Changes in brain activity as a biomarker?

The differences in the dynamics of neuronal signals between healthy individuals and patients with psychiatric diseases such as schizophrenia appear much more important for clinical practice. “The characteristic changes in brain activity in the primary auditory cortex could be considered a potential biomarker and used to predict the clinical course of psychiatric diseases, such as psychoses,” reported Dr. Engel.

The gamma-band activity in the auditory cortex could be a potential marker for schizophrenia. According to MEG examinations, the values are decreased both in people at increased risk of psychosis and experiencing first symptoms compared with controls.
 

Activation or inhibition of cerebral networks as new therapeutic approaches

New therapeutic approaches based on the activation or inhibition of cerebral networks are currently areas of intensive research. Close interdisciplinary collaboration between basic science researchers and clinicians is necessary, stressed Dr. Engel. The use of noninvasive brain stimulation is already within reach for the neurorehabilitation of stroke patients. “I am optimistic that in a few years brain stimulation will be established as an integral element of stroke therapy,” said Christian Grefkes-Hermann, MD, PhD, director of the department of neurology at University Hospital of Frankfurt and first vice president of the DGKN.

Despite great advances in acute stroke therapy, many patients must endure permanent deficits in their everyday life, he said. According to Dr. Grefkes-Hermann, rehabilitation procedures often have a dissatisfactory effect, and results greatly vary. He hopes that in the future it may be possible to personalize therapy by using network patterns, thereby improving results.

The aim is to reorganize areas of the brain in which the network activity has been disrupted following a stroke using targeted transcranial magnetic stimulation (TMS). “The most important factor for functional recovery after a stroke is neuronal reorganization,” said Dr. Grefkes-Hermann. With the new methods of neurorehabilitation, network-connectivity disruptions, which are associated with motor function deficits, are first visualized using functional MRI (fMRI).

The imaging or the EEG makes visible the area of the brain that may benefit most from neurostimulation. Subsequently, nerve cells in this region may be precisely stimulated with TMS. Because the healthy hemisphere of the brain is usually overactive after a stroke, there are simultaneous attempts to inhibit the contralesional motor cortex.

Initial results are hopeful. In the initial period after a stroke, TMS can be used in some patients to correct pathological connectivities and thereby improve motor deficits, reported Dr. Grefkes-Hermann. The fMRI pattern can also be used to predict recovery and intervention effects on an individual basis. A phase 3 trial is currently underway of 150 patients who have had a stroke and aims to study the efficacy of the new procedure.
 

Combined TMS and EEG

With the combination of TMS and the simultaneous measurement of EEG activity, a further development of fMRI connectivity analyses is currently being tested. Dr. Grefkes-Hermann believes that this procedure, which is more cost-effective, has higher temporal resolution, can be used directly at the bedside, and has more potential for personalized therapy planning in clinical practice.

The TMS-EEG procedure also makes it possible to predict the risk of post-stroke delirium, which affects around 30% of stroke patients and greatly worsens the outcome, underlined Ulf Ziemann, MD, medical director of the department of neurology at Tübingen (Germany) University Hospital. In a study of 33 patients with acute stroke, the onset of post-stroke delirium could be predicted with a high degree of accuracy by using the TMS-EEG procedure no later than 48 hours after the event.

Other promising, noninvasive methods for neuron activation mentioned by Dr. Ziemann include transcranial focused ultrasound stimulation (tFUS) with low intensity, which is being studied for chronic pain, dementia, epilepsy, traumatic brain injury, and depression, as well as transcranial pulse stimulation (TPS), which is also based on ultrasound. In a pilot study of 35 patients with Alzheimer’s disease, use of TPS within 3 months had positive effects on cognition. However, the study was not controlled and therefore further assessments are needed.
 

Custom deep brain stimulation

For deep brain stimulation (DBS), an established therapy for Parkinson’s disease and other movement disorders, the aim is individualized, symptom-related network stimulation, reported Andrea Kühn, MD, head of the movement disorders and neuromodulation section in the department of neurology at Charité University Hospital Berlin.

At the panregional collaborative research center ReTune, which has been supported for 4 years now by €10 million from the German Research Foundation (DFG), imaging and computer-assisted programming algorithms are being developed for DBS. They will greatly simplify the time-consuming standard procedure for the best possible setting of the stimulation parameters, which requires a hospital stay of several days.

A randomized crossover study of 35 patients with Parkinson’s disease proved the equivalence of the fast, algorithm-assisted DBS for the control of motor symptoms compared with standard procedures.

The new methods have the potential to considerably improve the outcome of patients with neurological and psychiatric diseases, according to scientists. However, the positive data must still be validated in further studies.
 

This article was translated from Medscape’s German edition. A version of this article appeared on Medscape.com.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become integral to the treatment of HR+/HER2- breast cancer. Approved in 2015 for use in the metastatic setting and most recently in the adjuvant setting, CDK4/6 inhibitors have revolutionized treatment in both endocrine-sensitive and endocrine-resistant settings and in pre- and postmenopausal women. 

But many questions remain regarding the optimal use of these medications in clinical practice. 

In this ReCAP, Dr Virginia Kaklamani from the University of Texas Health Sciences Center in San Antonio, Texas, and Dr Harold Burstein from Dana-Farber Cancer Institute, Boston, Massachusetts, begin their discussion by examining the potential role of adjuvant CDK4/6 inhibitor therapy in early, high-risk breast cancer.  

They discuss the three main studies that looked at the role of adjuvant CDK4/6 inhibitors, including the PALLAS and PENELOPE-B trials, in which palbociclib showed no benefit in invasive disease-free survival. In contrast, in the monarchE trial, abemaciclib showed a robust benefit in preventing recurrence, which was sustained after longer follow-up, as reported at the San Antonio Breast Cancer Symposium 2022. 

Turning to the metastatic setting, the panelists discuss the varied side effect profiles of the three approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. They also discuss current research into the continuation of these agents beyond progression and whether sequencing of CDK4/6 inhibitors may provide benefit. 

--

Virginia Kaklamani, MD, Professor of Medicine, Division of Hematology/Oncology, University of Texas Health Sciences Center; Leader, Breast Oncology Program, University of Texas Health MD Anderson Cancer Center, San Antonio, Texas 

Virginia Kaklamani, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; Menarini; Pfizer; Novartis; Lilly; AstraZeneca; Genentech; Daichii; Seagen 

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become integral to the treatment of HR+/HER2- breast cancer. Approved in 2015 for use in the metastatic setting and most recently in the adjuvant setting, CDK4/6 inhibitors have revolutionized treatment in both endocrine-sensitive and endocrine-resistant settings and in pre- and postmenopausal women. 

But many questions remain regarding the optimal use of these medications in clinical practice. 

In this ReCAP, Dr Virginia Kaklamani from the University of Texas Health Sciences Center in San Antonio, Texas, and Dr Harold Burstein from Dana-Farber Cancer Institute, Boston, Massachusetts, begin their discussion by examining the potential role of adjuvant CDK4/6 inhibitor therapy in early, high-risk breast cancer.  

They discuss the three main studies that looked at the role of adjuvant CDK4/6 inhibitors, including the PALLAS and PENELOPE-B trials, in which palbociclib showed no benefit in invasive disease-free survival. In contrast, in the monarchE trial, abemaciclib showed a robust benefit in preventing recurrence, which was sustained after longer follow-up, as reported at the San Antonio Breast Cancer Symposium 2022. 

Turning to the metastatic setting, the panelists discuss the varied side effect profiles of the three approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. They also discuss current research into the continuation of these agents beyond progression and whether sequencing of CDK4/6 inhibitors may provide benefit. 

--

Virginia Kaklamani, MD, Professor of Medicine, Division of Hematology/Oncology, University of Texas Health Sciences Center; Leader, Breast Oncology Program, University of Texas Health MD Anderson Cancer Center, San Antonio, Texas 

Virginia Kaklamani, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; Menarini; Pfizer; Novartis; Lilly; AstraZeneca; Genentech; Daichii; Seagen 

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become integral to the treatment of HR+/HER2- breast cancer. Approved in 2015 for use in the metastatic setting and most recently in the adjuvant setting, CDK4/6 inhibitors have revolutionized treatment in both endocrine-sensitive and endocrine-resistant settings and in pre- and postmenopausal women. 

But many questions remain regarding the optimal use of these medications in clinical practice. 

In this ReCAP, Dr Virginia Kaklamani from the University of Texas Health Sciences Center in San Antonio, Texas, and Dr Harold Burstein from Dana-Farber Cancer Institute, Boston, Massachusetts, begin their discussion by examining the potential role of adjuvant CDK4/6 inhibitor therapy in early, high-risk breast cancer.  

They discuss the three main studies that looked at the role of adjuvant CDK4/6 inhibitors, including the PALLAS and PENELOPE-B trials, in which palbociclib showed no benefit in invasive disease-free survival. In contrast, in the monarchE trial, abemaciclib showed a robust benefit in preventing recurrence, which was sustained after longer follow-up, as reported at the San Antonio Breast Cancer Symposium 2022. 

Turning to the metastatic setting, the panelists discuss the varied side effect profiles of the three approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. They also discuss current research into the continuation of these agents beyond progression and whether sequencing of CDK4/6 inhibitors may provide benefit. 

--

Virginia Kaklamani, MD, Professor of Medicine, Division of Hematology/Oncology, University of Texas Health Sciences Center; Leader, Breast Oncology Program, University of Texas Health MD Anderson Cancer Center, San Antonio, Texas 

Virginia Kaklamani, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Gilead; Menarini; Pfizer; Novartis; Lilly; AstraZeneca; Genentech; Daichii; Seagen 

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

DENVER – Adding therapies such as acupuncture, electrophysical stimulation, or other interventions to standard exercise therapy does not appear to offer much benefit in pain relief or physical function for patients with knee osteoarthritis, according to a study presented at the OARSI 2023 World Congress. The findings were also published in the Cochrane Database of Systematic Reviews in October 2022.

“The results do not support the use of adjunctive therapies when we add them to exercise for pain, physical function, or quality of life, when compared against placebo, adjunctive therapy, and exercise,” Helen P. French, PhD, told attendees at the meeting sponsored by the Osteoarthritis Research Society International. The findings were similar for pain and physical function when comparing adjunctive therapies with exercise against exercise alone, said Dr. French, an associate professor in physiotherapy at the Royal College of Surgeons, Dublin, except that patients using adjunctive therapies reported feeling greater improvement in their global assessments.

Exercise is recommended as a core treatment for osteoarthritis, but some patients or clinicians may be interested in supplementing that therapy with acupuncture, heat therapy, electromagnetic fields, transcutaneous electrical nerve stimulation, braces/orthotics, and other interventions. Various Cochrane Reviews of the evidence exist for these interventions in treating chronic pain in general but not for their use as adjunctive therapies in addition to exercise for osteoarthritis pain.

Researchers therefore assessed the evidence for improvement in pain, physical function, and quality of life for two sets of comparisons: adjunctive therapies plus exercise versus exercise alone, and adjunctive therapies with exercise versus placebo adjunctive therapy with exercise. The review excluded studies looking at medications or supplements.

Pain was assessed with the Numeric Pain Rating Scale (NPRS, 0-10), with an improvement of at least 2 points (15% improvement) representing the minimum clinically important difference (MCID). Physical function was assessed with the Western Ontario and McMaster Universities Arthritis Index (WOMAC, 0-68), with 6 points (15%) considered the MCID, and quality of life was assessed with the SF-36 (0-100), with 6 points (12%) as the MCID.

The researchers identified trials on knee osteoarthritis that included an overall 6,508 participants with an average age ranging from 52 to 83 years. A total of 36 studies evaluated electrophysical agents. Another seven looked at manual therapies; four looked at acupuncture/dry needling or taping; three looked at psychological, dietary, or “whole body vibration” therapies; and two evaluated spa or peloid therapy. Only one trial evaluated foot insoles.

Nearly all the studies (98%) assessed pain, and most (87%) assessed physical function. Only about one in five (21%) assessed quality of life. The improvement in pain from adding adjunctive therapies to exercise, compared with placebo therapies plus exercise, was 0.77 points, or just under a 10% improvement, which fell short of the 15% MCID. Physical function improvement similarly fell short, with an average improvement of 5 points (12%).

In comparisons of exercise plus adjunctive therapies against exercise alone, the improvement from the additional interventions was even lower. Pain improvement was 0.41 points (7%), and physical function improvement was 2.8 points (9%). However, patients’ perceptions told a different story: 37% more patients who were using an adjunctive therapy reported feeling that the therapies were successful, compared with patients undergoing exercise therapy alone.

Adverse events were poorly reported in the trials, with only 10 trials reporting them at all, and the researchers found no significant difference in adverse events among the studies reporting them. The most common adverse events were increased pain in the joint with the osteoarthritis, pain elsewhere, or swelling and inflammation. It’s unclear, however, whether the pain, swelling, and inflammation were related to the interventions and how serious these effects might have been.

Michelle Hall, PhD, an associate professor in the department of physiotherapy at the University of Melbourne, comoderated the session with this presentation and found it interesting that more than one-third of patients perceived that they did better with the additional therapies even though improvement didn’t bear out in their pain or physical function assessments.

“But the other part of that was that the studies were of poor quality, so we can’t say with confidence, ‘Don’t do this therapy because it’s not going to work,’ ” Dr. Hall said in an interview. She said she personally would probably discourage patients from those therapies, “but I don’t think the evidence is there for everybody to do that,” she added.

Martin Van Der Esch, PhD, of Reade Centre of Rehabilitation and Rheumatology in Amsterdam, also comoderated the discussion and had more concerns about the use of adjunctive therapies in light of the study’s findings. He said in an interview that he tended to believe the patients’ overall self-reported improvement is likely a placebo effect, and he sees potential harm in that effect. If the pain is not truly decreasing as patients continue using those therapies, then the pain may become a more stable part of the nervous system, “so I think they need to do an intervention which really has evidence in reducing pain, an active approach that means exercising in the right way,” Dr. Van Der Esch said. If patients are undergoing therapy whose primary benefit is a placebo effect, “the pain will prolong and become more fixed in the nervous system,” shifting the patients toward greater risk of the pain becoming chronic, he said.

“I want to emphasize that we have an ethical role to our management, and it’s not ethical to give treatments which have no response and no pain relief except that the patient or the professional believes it will have an effect,” Dr. Van Der Esch said.

The research did not involve outside funding. Dr. French, Dr. Hall, and Dr. Van Der Esch reported having no relevant financial relationships.

DENVER – Adding therapies such as acupuncture, electrophysical stimulation, or other interventions to standard exercise therapy does not appear to offer much benefit in pain relief or physical function for patients with knee osteoarthritis, according to a study presented at the OARSI 2023 World Congress. The findings were also published in the Cochrane Database of Systematic Reviews in October 2022.

“The results do not support the use of adjunctive therapies when we add them to exercise for pain, physical function, or quality of life, when compared against placebo, adjunctive therapy, and exercise,” Helen P. French, PhD, told attendees at the meeting sponsored by the Osteoarthritis Research Society International. The findings were similar for pain and physical function when comparing adjunctive therapies with exercise against exercise alone, said Dr. French, an associate professor in physiotherapy at the Royal College of Surgeons, Dublin, except that patients using adjunctive therapies reported feeling greater improvement in their global assessments.

Exercise is recommended as a core treatment for osteoarthritis, but some patients or clinicians may be interested in supplementing that therapy with acupuncture, heat therapy, electromagnetic fields, transcutaneous electrical nerve stimulation, braces/orthotics, and other interventions. Various Cochrane Reviews of the evidence exist for these interventions in treating chronic pain in general but not for their use as adjunctive therapies in addition to exercise for osteoarthritis pain.

Researchers therefore assessed the evidence for improvement in pain, physical function, and quality of life for two sets of comparisons: adjunctive therapies plus exercise versus exercise alone, and adjunctive therapies with exercise versus placebo adjunctive therapy with exercise. The review excluded studies looking at medications or supplements.

Pain was assessed with the Numeric Pain Rating Scale (NPRS, 0-10), with an improvement of at least 2 points (15% improvement) representing the minimum clinically important difference (MCID). Physical function was assessed with the Western Ontario and McMaster Universities Arthritis Index (WOMAC, 0-68), with 6 points (15%) considered the MCID, and quality of life was assessed with the SF-36 (0-100), with 6 points (12%) as the MCID.

The researchers identified trials on knee osteoarthritis that included an overall 6,508 participants with an average age ranging from 52 to 83 years. A total of 36 studies evaluated electrophysical agents. Another seven looked at manual therapies; four looked at acupuncture/dry needling or taping; three looked at psychological, dietary, or “whole body vibration” therapies; and two evaluated spa or peloid therapy. Only one trial evaluated foot insoles.

Nearly all the studies (98%) assessed pain, and most (87%) assessed physical function. Only about one in five (21%) assessed quality of life. The improvement in pain from adding adjunctive therapies to exercise, compared with placebo therapies plus exercise, was 0.77 points, or just under a 10% improvement, which fell short of the 15% MCID. Physical function improvement similarly fell short, with an average improvement of 5 points (12%).

In comparisons of exercise plus adjunctive therapies against exercise alone, the improvement from the additional interventions was even lower. Pain improvement was 0.41 points (7%), and physical function improvement was 2.8 points (9%). However, patients’ perceptions told a different story: 37% more patients who were using an adjunctive therapy reported feeling that the therapies were successful, compared with patients undergoing exercise therapy alone.

Adverse events were poorly reported in the trials, with only 10 trials reporting them at all, and the researchers found no significant difference in adverse events among the studies reporting them. The most common adverse events were increased pain in the joint with the osteoarthritis, pain elsewhere, or swelling and inflammation. It’s unclear, however, whether the pain, swelling, and inflammation were related to the interventions and how serious these effects might have been.

Michelle Hall, PhD, an associate professor in the department of physiotherapy at the University of Melbourne, comoderated the session with this presentation and found it interesting that more than one-third of patients perceived that they did better with the additional therapies even though improvement didn’t bear out in their pain or physical function assessments.

“But the other part of that was that the studies were of poor quality, so we can’t say with confidence, ‘Don’t do this therapy because it’s not going to work,’ ” Dr. Hall said in an interview. She said she personally would probably discourage patients from those therapies, “but I don’t think the evidence is there for everybody to do that,” she added.

Martin Van Der Esch, PhD, of Reade Centre of Rehabilitation and Rheumatology in Amsterdam, also comoderated the discussion and had more concerns about the use of adjunctive therapies in light of the study’s findings. He said in an interview that he tended to believe the patients’ overall self-reported improvement is likely a placebo effect, and he sees potential harm in that effect. If the pain is not truly decreasing as patients continue using those therapies, then the pain may become a more stable part of the nervous system, “so I think they need to do an intervention which really has evidence in reducing pain, an active approach that means exercising in the right way,” Dr. Van Der Esch said. If patients are undergoing therapy whose primary benefit is a placebo effect, “the pain will prolong and become more fixed in the nervous system,” shifting the patients toward greater risk of the pain becoming chronic, he said.

“I want to emphasize that we have an ethical role to our management, and it’s not ethical to give treatments which have no response and no pain relief except that the patient or the professional believes it will have an effect,” Dr. Van Der Esch said.

The research did not involve outside funding. Dr. French, Dr. Hall, and Dr. Van Der Esch reported having no relevant financial relationships.

DENVER – Adding therapies such as acupuncture, electrophysical stimulation, or other interventions to standard exercise therapy does not appear to offer much benefit in pain relief or physical function for patients with knee osteoarthritis, according to a study presented at the OARSI 2023 World Congress. The findings were also published in the Cochrane Database of Systematic Reviews in October 2022.

“The results do not support the use of adjunctive therapies when we add them to exercise for pain, physical function, or quality of life, when compared against placebo, adjunctive therapy, and exercise,” Helen P. French, PhD, told attendees at the meeting sponsored by the Osteoarthritis Research Society International. The findings were similar for pain and physical function when comparing adjunctive therapies with exercise against exercise alone, said Dr. French, an associate professor in physiotherapy at the Royal College of Surgeons, Dublin, except that patients using adjunctive therapies reported feeling greater improvement in their global assessments.

Exercise is recommended as a core treatment for osteoarthritis, but some patients or clinicians may be interested in supplementing that therapy with acupuncture, heat therapy, electromagnetic fields, transcutaneous electrical nerve stimulation, braces/orthotics, and other interventions. Various Cochrane Reviews of the evidence exist for these interventions in treating chronic pain in general but not for their use as adjunctive therapies in addition to exercise for osteoarthritis pain.

Researchers therefore assessed the evidence for improvement in pain, physical function, and quality of life for two sets of comparisons: adjunctive therapies plus exercise versus exercise alone, and adjunctive therapies with exercise versus placebo adjunctive therapy with exercise. The review excluded studies looking at medications or supplements.

Pain was assessed with the Numeric Pain Rating Scale (NPRS, 0-10), with an improvement of at least 2 points (15% improvement) representing the minimum clinically important difference (MCID). Physical function was assessed with the Western Ontario and McMaster Universities Arthritis Index (WOMAC, 0-68), with 6 points (15%) considered the MCID, and quality of life was assessed with the SF-36 (0-100), with 6 points (12%) as the MCID.

The researchers identified trials on knee osteoarthritis that included an overall 6,508 participants with an average age ranging from 52 to 83 years. A total of 36 studies evaluated electrophysical agents. Another seven looked at manual therapies; four looked at acupuncture/dry needling or taping; three looked at psychological, dietary, or “whole body vibration” therapies; and two evaluated spa or peloid therapy. Only one trial evaluated foot insoles.

Nearly all the studies (98%) assessed pain, and most (87%) assessed physical function. Only about one in five (21%) assessed quality of life. The improvement in pain from adding adjunctive therapies to exercise, compared with placebo therapies plus exercise, was 0.77 points, or just under a 10% improvement, which fell short of the 15% MCID. Physical function improvement similarly fell short, with an average improvement of 5 points (12%).

In comparisons of exercise plus adjunctive therapies against exercise alone, the improvement from the additional interventions was even lower. Pain improvement was 0.41 points (7%), and physical function improvement was 2.8 points (9%). However, patients’ perceptions told a different story: 37% more patients who were using an adjunctive therapy reported feeling that the therapies were successful, compared with patients undergoing exercise therapy alone.

Adverse events were poorly reported in the trials, with only 10 trials reporting them at all, and the researchers found no significant difference in adverse events among the studies reporting them. The most common adverse events were increased pain in the joint with the osteoarthritis, pain elsewhere, or swelling and inflammation. It’s unclear, however, whether the pain, swelling, and inflammation were related to the interventions and how serious these effects might have been.

Michelle Hall, PhD, an associate professor in the department of physiotherapy at the University of Melbourne, comoderated the session with this presentation and found it interesting that more than one-third of patients perceived that they did better with the additional therapies even though improvement didn’t bear out in their pain or physical function assessments.

“But the other part of that was that the studies were of poor quality, so we can’t say with confidence, ‘Don’t do this therapy because it’s not going to work,’ ” Dr. Hall said in an interview. She said she personally would probably discourage patients from those therapies, “but I don’t think the evidence is there for everybody to do that,” she added.

Martin Van Der Esch, PhD, of Reade Centre of Rehabilitation and Rheumatology in Amsterdam, also comoderated the discussion and had more concerns about the use of adjunctive therapies in light of the study’s findings. He said in an interview that he tended to believe the patients’ overall self-reported improvement is likely a placebo effect, and he sees potential harm in that effect. If the pain is not truly decreasing as patients continue using those therapies, then the pain may become a more stable part of the nervous system, “so I think they need to do an intervention which really has evidence in reducing pain, an active approach that means exercising in the right way,” Dr. Van Der Esch said. If patients are undergoing therapy whose primary benefit is a placebo effect, “the pain will prolong and become more fixed in the nervous system,” shifting the patients toward greater risk of the pain becoming chronic, he said.

“I want to emphasize that we have an ethical role to our management, and it’s not ethical to give treatments which have no response and no pain relief except that the patient or the professional believes it will have an effect,” Dr. Van Der Esch said.

The research did not involve outside funding. Dr. French, Dr. Hall, and Dr. Van Der Esch reported having no relevant financial relationships.

Sudden cardiac arrest (SCA) due to commotio cordis occurs more frequently in non–sport-related settings than is commonly thought, resulting in lower rates of resuscitation and increased mortality, especially among young women, a new review suggests.

The condition is rare, caused by an often fatal arrhythmia secondary to a blunt, nonpenetrating impact over the precordium, without direct structural damage to the heart itself. Common causes in nonsport settings include assault, motor vehicle accidents (MVAs), and daily activities such as occupational accidents.

“We found a stark difference in mortality outcomes between non–sport-related commotio cordis compared to sport-related events,” at 88% vs. 66%, Han S. Lim, MBBS, PhD, of the University of Melbourne, and Austin Health, Heidelberg, Australia, told this news organization. “Rates of cardiopulmonary resuscitation (CPR) (27% vs. 97%) and defibrillation (17% vs. 81%) were considerably lower in the non–sport-related events.”

“Although still being male-predominant, of concern, we saw a higher proportion of females in non–sport-related commotio cordis due to assault, MVAs, and other activities,” he noted. Such events may occur “in secluded domestic settings, may not be witnessed, or may occur as intentional harm, whereby the witness could also be the perpetrator, reducing the likelihood of prompt diagnosis, CPR, and defibrillation administration.”

The study was published online in JACC: Clinical Electrophysiology.
 

Young women affected

Dr. Lim and colleagues searched the literature through 2021 for all cases of commotio cordis. Three hundred and thirty-four cases from among 53 citations were included in the analysis; of those, 121 (36%) occurred in non–sport-related settings, including assault (76%), MVAs (7%), and daily activities (16%). “Daily activities” comprised activities that were expected in a person’s day-to-day routine such as falls, play fighting (in children), and occupational accidents.

Non–sport-related cases primarily involved nonprojectile etiologies (95%), including bodily contact (79%), such as impacts from fists, feet, and knees; impacts with handlebars or steering wheels; and solid stick-like weapons and flat surfaces.

Sport-related cases involved a significantly higher proportion of projectiles (94% vs. 5%) and occurred across a range of sports, mostly at the competitive level (66%).

Both sport-related and non–sport-related commotio cordis affected a similar younger demographic (mean age, 19; mostly males). No statistically significant differences between the two groups were seen with regard to previous cardiac history or family history of cardiac disease, or in arrhythmias on electrocardiogram, biomarkers, or imaging findings.

However, in non–sport-related events, the proportion of females affected was significantly higher (13% vs. 2%), as was mortality (88% vs. 66%). Rates were lower for CPR (27% vs. 97%) and defibrillation use (17% vs. 81%), and resuscitation was more commonly delayed beyond 3 minutes (80% vs. 5%).

The finding that more than a third of reported cases were non–sport-related “is higher than previously reported, and included data from 15 different countries,” the authors noted.

Study limitations included the use of data only from published studies, inclusion of a case series limited to fatal cases, small sample sizes, and lack of consistent reporting of demographic data, mechanisms, investigation results, management, and outcomes.
 

Increased awareness ‘essential’

Dr. Lim and colleagues concluded that increased awareness of non–sport-related commotio cordis is “essential” for early recognition, resuscitation, and mortality reduction. 

Jim Cheung, MD, chair of the American College of Cardiology’s electrophysiology section, “completely agrees.” Greater awareness among the general population could reduce barriers to CPR and automated external defibrillator (AED) use, he said, which in turn, can lead to improved survival.

Furthermore, Dr. Cheung added, “This study underscores the importance of ensuring that non–cardiology-trained physicians such as emergency medicine physicians and trauma surgeons who might encounter patients with non–sports-related commotio cordis recognize the entity during the course of treatment.”

Because the review relied only on published cases, “it may not represent the true breadth of cases that are occurring in the real world,” he noted. “I suspect that cases that occur outside of sports-related activities, such as MVAs and assault, are more likely to be underreported and that the true proportion of non–sports-related commotio cordis may be significantly higher than 36%.” Increased reporting of cases as part of an international commotio cordis registry would help provide additional insights, he suggested.

“There is a common misperception that SCA only occurs among older patients and patients with known coronary artery disease or heart failure,” he said. “For us to move the needle on improving SCA survival, we will need to tackle the problem from multiple angles including increasing public awareness, training the public on CPR and AED use, and improving access to AEDs by addressing structural barriers.”

Dr. Cheung pointed to ongoing efforts by nonprofit, patient-driven organizations such as the SADS Foundation and Omar Carter Foundation, and professional societies such as the American College of Cardiology, the American Heart Association, and Heart Rhythm Society, to direct public awareness campaigns and legislative proposals to address this problem.

Similar efforts are underway among cardiac societies and SCA awareness groups in Australia, Dr. Lim said.

No funding or relevant financial relationships were disclosed.
 

A version of this article first appeared on Medscape.com.

Sudden cardiac arrest (SCA) due to commotio cordis occurs more frequently in non–sport-related settings than is commonly thought, resulting in lower rates of resuscitation and increased mortality, especially among young women, a new review suggests.

The condition is rare, caused by an often fatal arrhythmia secondary to a blunt, nonpenetrating impact over the precordium, without direct structural damage to the heart itself. Common causes in nonsport settings include assault, motor vehicle accidents (MVAs), and daily activities such as occupational accidents.

“We found a stark difference in mortality outcomes between non–sport-related commotio cordis compared to sport-related events,” at 88% vs. 66%, Han S. Lim, MBBS, PhD, of the University of Melbourne, and Austin Health, Heidelberg, Australia, told this news organization. “Rates of cardiopulmonary resuscitation (CPR) (27% vs. 97%) and defibrillation (17% vs. 81%) were considerably lower in the non–sport-related events.”

“Although still being male-predominant, of concern, we saw a higher proportion of females in non–sport-related commotio cordis due to assault, MVAs, and other activities,” he noted. Such events may occur “in secluded domestic settings, may not be witnessed, or may occur as intentional harm, whereby the witness could also be the perpetrator, reducing the likelihood of prompt diagnosis, CPR, and defibrillation administration.”

The study was published online in JACC: Clinical Electrophysiology.
 

Young women affected

Dr. Lim and colleagues searched the literature through 2021 for all cases of commotio cordis. Three hundred and thirty-four cases from among 53 citations were included in the analysis; of those, 121 (36%) occurred in non–sport-related settings, including assault (76%), MVAs (7%), and daily activities (16%). “Daily activities” comprised activities that were expected in a person’s day-to-day routine such as falls, play fighting (in children), and occupational accidents.

Non–sport-related cases primarily involved nonprojectile etiologies (95%), including bodily contact (79%), such as impacts from fists, feet, and knees; impacts with handlebars or steering wheels; and solid stick-like weapons and flat surfaces.

Sport-related cases involved a significantly higher proportion of projectiles (94% vs. 5%) and occurred across a range of sports, mostly at the competitive level (66%).

Both sport-related and non–sport-related commotio cordis affected a similar younger demographic (mean age, 19; mostly males). No statistically significant differences between the two groups were seen with regard to previous cardiac history or family history of cardiac disease, or in arrhythmias on electrocardiogram, biomarkers, or imaging findings.

However, in non–sport-related events, the proportion of females affected was significantly higher (13% vs. 2%), as was mortality (88% vs. 66%). Rates were lower for CPR (27% vs. 97%) and defibrillation use (17% vs. 81%), and resuscitation was more commonly delayed beyond 3 minutes (80% vs. 5%).

The finding that more than a third of reported cases were non–sport-related “is higher than previously reported, and included data from 15 different countries,” the authors noted.

Study limitations included the use of data only from published studies, inclusion of a case series limited to fatal cases, small sample sizes, and lack of consistent reporting of demographic data, mechanisms, investigation results, management, and outcomes.
 

Increased awareness ‘essential’

Dr. Lim and colleagues concluded that increased awareness of non–sport-related commotio cordis is “essential” for early recognition, resuscitation, and mortality reduction. 

Jim Cheung, MD, chair of the American College of Cardiology’s electrophysiology section, “completely agrees.” Greater awareness among the general population could reduce barriers to CPR and automated external defibrillator (AED) use, he said, which in turn, can lead to improved survival.

Furthermore, Dr. Cheung added, “This study underscores the importance of ensuring that non–cardiology-trained physicians such as emergency medicine physicians and trauma surgeons who might encounter patients with non–sports-related commotio cordis recognize the entity during the course of treatment.”

Because the review relied only on published cases, “it may not represent the true breadth of cases that are occurring in the real world,” he noted. “I suspect that cases that occur outside of sports-related activities, such as MVAs and assault, are more likely to be underreported and that the true proportion of non–sports-related commotio cordis may be significantly higher than 36%.” Increased reporting of cases as part of an international commotio cordis registry would help provide additional insights, he suggested.

“There is a common misperception that SCA only occurs among older patients and patients with known coronary artery disease or heart failure,” he said. “For us to move the needle on improving SCA survival, we will need to tackle the problem from multiple angles including increasing public awareness, training the public on CPR and AED use, and improving access to AEDs by addressing structural barriers.”

Dr. Cheung pointed to ongoing efforts by nonprofit, patient-driven organizations such as the SADS Foundation and Omar Carter Foundation, and professional societies such as the American College of Cardiology, the American Heart Association, and Heart Rhythm Society, to direct public awareness campaigns and legislative proposals to address this problem.

Similar efforts are underway among cardiac societies and SCA awareness groups in Australia, Dr. Lim said.

No funding or relevant financial relationships were disclosed.
 

A version of this article first appeared on Medscape.com.

Sudden cardiac arrest (SCA) due to commotio cordis occurs more frequently in non–sport-related settings than is commonly thought, resulting in lower rates of resuscitation and increased mortality, especially among young women, a new review suggests.

The condition is rare, caused by an often fatal arrhythmia secondary to a blunt, nonpenetrating impact over the precordium, without direct structural damage to the heart itself. Common causes in nonsport settings include assault, motor vehicle accidents (MVAs), and daily activities such as occupational accidents.

“We found a stark difference in mortality outcomes between non–sport-related commotio cordis compared to sport-related events,” at 88% vs. 66%, Han S. Lim, MBBS, PhD, of the University of Melbourne, and Austin Health, Heidelberg, Australia, told this news organization. “Rates of cardiopulmonary resuscitation (CPR) (27% vs. 97%) and defibrillation (17% vs. 81%) were considerably lower in the non–sport-related events.”

“Although still being male-predominant, of concern, we saw a higher proportion of females in non–sport-related commotio cordis due to assault, MVAs, and other activities,” he noted. Such events may occur “in secluded domestic settings, may not be witnessed, or may occur as intentional harm, whereby the witness could also be the perpetrator, reducing the likelihood of prompt diagnosis, CPR, and defibrillation administration.”

The study was published online in JACC: Clinical Electrophysiology.
 

Young women affected

Dr. Lim and colleagues searched the literature through 2021 for all cases of commotio cordis. Three hundred and thirty-four cases from among 53 citations were included in the analysis; of those, 121 (36%) occurred in non–sport-related settings, including assault (76%), MVAs (7%), and daily activities (16%). “Daily activities” comprised activities that were expected in a person’s day-to-day routine such as falls, play fighting (in children), and occupational accidents.

Non–sport-related cases primarily involved nonprojectile etiologies (95%), including bodily contact (79%), such as impacts from fists, feet, and knees; impacts with handlebars or steering wheels; and solid stick-like weapons and flat surfaces.

Sport-related cases involved a significantly higher proportion of projectiles (94% vs. 5%) and occurred across a range of sports, mostly at the competitive level (66%).

Both sport-related and non–sport-related commotio cordis affected a similar younger demographic (mean age, 19; mostly males). No statistically significant differences between the two groups were seen with regard to previous cardiac history or family history of cardiac disease, or in arrhythmias on electrocardiogram, biomarkers, or imaging findings.

However, in non–sport-related events, the proportion of females affected was significantly higher (13% vs. 2%), as was mortality (88% vs. 66%). Rates were lower for CPR (27% vs. 97%) and defibrillation use (17% vs. 81%), and resuscitation was more commonly delayed beyond 3 minutes (80% vs. 5%).

The finding that more than a third of reported cases were non–sport-related “is higher than previously reported, and included data from 15 different countries,” the authors noted.

Study limitations included the use of data only from published studies, inclusion of a case series limited to fatal cases, small sample sizes, and lack of consistent reporting of demographic data, mechanisms, investigation results, management, and outcomes.
 

Increased awareness ‘essential’

Dr. Lim and colleagues concluded that increased awareness of non–sport-related commotio cordis is “essential” for early recognition, resuscitation, and mortality reduction. 

Jim Cheung, MD, chair of the American College of Cardiology’s electrophysiology section, “completely agrees.” Greater awareness among the general population could reduce barriers to CPR and automated external defibrillator (AED) use, he said, which in turn, can lead to improved survival.

Furthermore, Dr. Cheung added, “This study underscores the importance of ensuring that non–cardiology-trained physicians such as emergency medicine physicians and trauma surgeons who might encounter patients with non–sports-related commotio cordis recognize the entity during the course of treatment.”

Because the review relied only on published cases, “it may not represent the true breadth of cases that are occurring in the real world,” he noted. “I suspect that cases that occur outside of sports-related activities, such as MVAs and assault, are more likely to be underreported and that the true proportion of non–sports-related commotio cordis may be significantly higher than 36%.” Increased reporting of cases as part of an international commotio cordis registry would help provide additional insights, he suggested.

“There is a common misperception that SCA only occurs among older patients and patients with known coronary artery disease or heart failure,” he said. “For us to move the needle on improving SCA survival, we will need to tackle the problem from multiple angles including increasing public awareness, training the public on CPR and AED use, and improving access to AEDs by addressing structural barriers.”

Dr. Cheung pointed to ongoing efforts by nonprofit, patient-driven organizations such as the SADS Foundation and Omar Carter Foundation, and professional societies such as the American College of Cardiology, the American Heart Association, and Heart Rhythm Society, to direct public awareness campaigns and legislative proposals to address this problem.

Similar efforts are underway among cardiac societies and SCA awareness groups in Australia, Dr. Lim said.

No funding or relevant financial relationships were disclosed.
 

A version of this article first appeared on Medscape.com.