Breast implant-associated EBV-positive diffuse large B-cell lymphoma: Two case reports and literature review.

Lymphomas associated with breast implants are mostly of the T-cell type. They are predominantly anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) characterized by CD30 positivity universally. Whilst the majority of primary breast lymphomas occurring in the absence of breast implants are of B-cell origin, there are few cases of implant-associated B-cell lymphomas reported to date in the literature, a subset of which are diffuse large B-cell lymphoma (DLBCL). Given the rarity of this entity, we describe two cases of breast implant-associated DLBCL. Both patients developed Epstein-Barr Virus (EBV)-positive large cell lymphoma of B-cell origin confined to the implant capsule with no evidence of systemic lymphoma. Considering the association with EBV, the activated B-cell phenotype and the presumed chronic inflammatory environment associated with the implant capsule, these might represent forms of DLBCL associated with chronic inflammation (DLBCL-CI) or fibrin-associated DLBCL (FA-DLBCL). Treatment included implant removal with total capsulectomy, and for one of the cases adjuvant systemic chemotherapy. Recognizing this rare type of breast implant-associated B-cell lymphoma could improve our understanding of this entity and hence develop appropriate management strategies.

Evaluating the Indirect Costs of Care Associated with Salvage Chemotherapy for Relapsed and Refractory Aggressive-Histology Lymphoma: A Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial.

We conducted an analysis of indirect costs alongside the LY.12 randomized trial in patients with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL). Lost productivity data for Canadian patients and caregivers in the trial were collected at baseline and with each chemotherapy cycle pre-transplant, using an adapted Lost Productivity questionnaire. Mean per patient indirect costs were CAD 2999 for patients in the GDP arm and CAD 3400 in the DHAP arm. A substantial majority was not working or had to reduce their workload during this treatment time. Salvage chemotherapy for R/R aggressive NHL is associated with significant indirect costs to patients and their caregivers.

A phase I study of romidepsin, gemcitabine, dexamethasone and cisplatin combination therapy in the treatment of peripheral T-cell and diffuse large B-cell lymphoma; the Canadian cancer trials group LY.15 study†.

We investigated GDP (gemcitabine, 1000 mg/m2 IV d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 IV d1) combined with romidepsin on days 1 and 8 every 21 days to a maximum of six cycles in a standard 3 + 3, phase I dose escalation trial for patients with relapsed/refractory peripheral T-cell (PTCL) or diffuse large B-cell (DLBCL) lymphoma (NCT01846390). After treating four patients, gemcitabine and romidepsin were given on days 1 and 15 every 28 days. On the 21-day schedule at 6 mg/m2 romidepsin, there were three dose-limiting toxicities (DLTs) among four patients. On the 28-day schedule, there were no DLTs at the 6, 8, or 10 mg/m2 dose. At 12 mg/m2, there were four observed grade 3 DLTs among six evaluable patients. Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 if given on a day 1, 15 every 28 days schedule.

Eosinophils in the skin-a red herring masking lymphoma: a case series.

Eosinophilia, both peripheral and in cutaneous tissue, is not a typical finding in mycosis fungoides; in fact, when faced with a lymphoeosinophilic infiltrate, mycosis fungoides is often not part of initial differential considerations. However, eosinophilia has been described in certain subtypes of mycosis fungoides, namely, in folliculotropic mycosis fungoides. We describe three challenging cases of folliculotropic mycosis fungoides presenting with varied clinical morphologies and a dense lymphoeosinophilic infiltrate and/or severe hypereosinophilia that obscured the final diagnosis for years. Only after treatment of the eosinophilia were the underlying atypical lymphocytes more apparent on histology and a correct diagnosis made. Thus, when characteristic features of mycosis fungoides are subtle, eosinophils can act as a red herring in terms of clinico-pathologic correlation and may prevent early and accurate diagnosis of mycosis fungoides. We suggest that further studies are needed to evaluate whether treatments to reduce eosinophilia, once other causes have been excluded, may help clear the confounding reactive inflammatory infiltrate and facilitate the diagnosis of mycosis fungoides.

Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90 Y ibritumomab tiuxetan in a phase II study.

Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5-year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio-immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio-immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow-up of 48 months (range 3-84 months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

Core Competencies or a Competent Core? A Scoping Review and Realist Synthesis of Invasive Bedside Procedural Skills Training in Internal Medicine.

PURPOSE: Invasive bedside procedures are core competencies for internal medicine, yet no formal training guidelines exist. The authors conducted a scoping review and realist synthesis to characterize current training for lumbar puncture, arthrocentesis, paracentesis, thoracentesis, and central venous catheterization. They aimed to collate how educators justify using specific interventions, establish which interventions have the best evidence, and offer directions for future research and training. METHOD: The authors systematically searched Medline, Embase, the Cochrane Library, and ERIC through April 2015. Studies were screened in three phases; all reviews were performed independently and in duplicate. The authors extracted information on learner and patient demographics, study design and methodological quality, and details of training interventions and measured outcomes. A three-step realist synthesis was performed to synthesize findings on each study's context, mechanism, and outcome, and to identify a foundational training model. RESULTS: From an initial 6,671 studies, 149 studies were further reduced to 67 (45%) reporting sufficient information for realist synthesis. Analysis yielded four types of procedural skills training interventions. There was relative consistency across contexts and significant differences in mechanisms and outcomes across the four intervention types. The medical procedural service was identified as an adaptable foundational training model. CONCLUSIONS: The observed heterogeneity in procedural skills training implies that programs are not consistently developing residents who are competent in core procedures. The findings suggest that researchers in education and quality improvement will need to collaborate to design training that develops a "competent core" of proceduralists using simulation and clinical rotations.

What do I do? Developing a competency inventory for postgraduate (residency) program directors.

BACKGROUND: Few new Residency Program Directors (PD) are formally trained for the demands and responsibilities of the leadership aspect of their role. Currently, there are no comprehensive frameworks that describe specific leadership competencies that can inform PD self-reflection or faculty development. METHODS: The authors developed a Postgraduate Program Director Competency Inventory (PPDCI) in order to frame the performance of PDs for a multisource feedback (MSF) program. The development of the PPDCI occurred in five phases which involved: development of an initial inventory, implementation of a key informant survey of national opinion leaders, execution of a validity survey with postgraduate education leaders and committee members and implementation of a further refined inventory with 17 PD and 147 raters as part of a pilot MSF program. OUTCOMES: Five distinct domains of leadership competence were identified which included: Communication and relationship management, leadership, professionalism and self-management, environmental engagement, and management skills and knowledge. The content validity of the PPDCI was endorsed by 85% of the key informants. The validity survey indicated strong endorsement of the PPDCI domains and recognition of its utility for both orientation of new PD as well as a frame for self-assessment. The pilot MSF program yielded a further refined and reduced inventory of 26 items of competence as well as recommendations for its utility. CONCLUSIONS: Use of this leadership inventory has the potential to ensure effective leadership of postgraduate programs.

Alemtuzumab and CHOP Chemotherapy for the Treatment of Aggressive Histology Peripheral T Cell Lymphomas: A Multi-Center Phase I Study.

BACKGROUND: Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way. PATIENTS AND METHODS: Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured. RESULTS: Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lymphopenia at baseline was common and T cell recovery was significantly delayed. CONCLUSION: With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels.

Gemcitabine/dexamethasone/cisplatin vs cytarabine/dexamethasone/cisplatin for relapsed or refractory aggressive-histology lymphoma: cost-utility analysis of NCIC CTG LY.12.

BACKGROUND: The NCIC CTG LY.12 study showed that gemcitabine, dexamethasone, and cisplatin (GDP) were noninferior to dexamethasone, cytarabine, and cisplatin (DHAP) in patients with relapsed or refractory aggressive histology lymphoma prior to autologous stem cell transplantation. We conducted an economic evaluation from the perspective of the Canadian public healthcare system based on trial data. METHODS: The primary outcome was an incremental cost utility analysis comparing costs and benefits associated with GDP vs DHAP. Resource utilization data were collected from 519 Canadian patients in the trial. Costs were presented in 2012 Canadian dollars and disaggregated to highlight the major cost drivers of care. Benefit was measured as quality-adjusted life-years (QALYs) based on utilities translated from prospectively collected quality-of-life data. All statistical tests were two-sided. RESULTS: The mean overall costs of treatment per patient in the GDP and DHAP arms were $19 961 (95% confidence interval (CI) = $17 286 to $24 565) and $34 425 (95% CI = $31 901 to $39 520), respectively, with an incremental difference in direct medical costs of $14 464 per patient in favor of GDP (P < .001). The predominant cost driver for both treatment arms was related to hospitalizations. The mean discounted quality-adjusted overall survival with GDP was 0.161 QALYs and 0.152 QALYs for DHAP (difference = 0.01 QALYs, P = .146). In probabilistic sensitivity analysis, GDP was associated with both cost savings and improved quality-adjusted outcomes compared with DHAP in 92.6% of cost-pair simulations. CONCLUSIONS: GDP was associated with both lower costs and similar quality-adjusted outcomes compared with DHAP in patients with relapsed or refractory lymphoma. Considering both costs and outcomes, GDP was the dominant therapy.

Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12.

PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P < .001) and need for hospitalization (P < .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

A systematic review of the effects of resident duty hour restrictions in surgery: impact on resident wellness, training, and patient outcomes.

BACKGROUND: In 2003, the Accreditation Council for Graduate Medical Education (ACGME) mandated 80-hour resident duty limits. In 2011 the ACGME mandated 16-hour duty maximums for PGY1 (post graduate year) residents. The stated goals were to improve patient safety, resident well-being, and education. A systematic review and meta-analysis were performed to evaluate the impact of resident duty hours (RDH) on clinical and educational outcomes in surgery. METHODS: A systematic review (1980-2013) was executed on CINAHL, Cochrane Database, Embase, Medline, and Scopus. Quality of articles was assessed using the GRADE guidelines. Sixteen-hour shifts and night float systems were analyzed separately. Articles that examined mortality data were combined in a random-effects meta-analysis to evaluate the impact of RDH on patient mortality. RESULTS: A total of 135 articles met the inclusion criteria. Among these, 42% (N = 57) were considered moderate-high quality. There was no overall improvement in patient outcomes as a result of RDH; however, some studies suggest increased complication rates in high-acuity patients. There was no improvement in education related to RDH restrictions, and performance on certification examinations has declined in some specialties. Survey studies revealed a perception of worsened education and patient safety. There were improvements in resident wellness after the 80-hour workweek, but there was little improvement or negative effects on wellness after 16-hour duty maximums were implemented. CONCLUSIONS: Recent RDH changes are not consistently associated with improvements in resident well-being, and have negative impacts on patient outcomes and performance on certification examinations. Greater flexibility to accommodate resident training needs is required. Further erosion of training time should be considered with great caution.

Chemoimmunotherapy resistant follicular lymphoma: predictors of resistance, association with transformation and prognosis.

Follicular lymphoma (FL) is characterized by an initial response to treatment with inevitable relapse. We evaluated chemoimmunotherapy resistance (CIR resistance) including transformation. We identified patients who received rituximab combination therapy for symptomatic FL. CIR resistance was defined as disease progression during rituximab-based chemoimmunotherapy, rituximab maintenance or within 6 months of treatment completion. Our primary outcome was time to early progression (CIR resistance). Between July 2006 and April 2010, 132 patients met the inclusion criteria and 22 (16.7%) demonstrated CIR resistance with a median follow-up of 33 months. High-risk Follicular Lymphoma International Prognostic Index (FLIPI) score was predictive of CIR resistance (hazard ratio [HR] 2.43; 95% confidence interval [CI], 1.4-4.1; p = 0.001). Overall, eight patients (36.3%) transformed (biopsy-proven), with no transformation in the chemoimmunotherapy responder group. Median overall survival in the CIR resistant group was 47 months. Patients with CIR resistance had high rates of histologic transformation and shorter survival with poor response to next therapy.

Survival of patients with transformed lymphoma in the rituximab era.

In the pre-rituximab era, transformation of indolent B-cell lymphoma to diffuse large B-cell lymphoma (DLBCL) was associated with an extremely poor outcome and a median post-transformation survival ranging from 1 to 2 years. We evaluated the impact of rituximab-cyclophosphamide, adriamycin, vincristine, prednisone (R-CHOP) on the survival outcomes of transformed lymphoma compared with de novo DLBCL. Between 2002 and 2010, 317 DLBCL patients who were consecutively diagnosed and treated with R-CHOP were identified at our institution. Patients with transformed lymphoma were included if they had not previously received R-CHOP. Patient characteristics, treatment, and outcome data were retrospectively collected. Sixty patients (19 %) had transformed lymphoma of which 37 (62 %) had transformed from follicular lymphoma, 50 (83 %) were chemotherapy naïve, and 58 (96 %) were rituximab naïve at the time of treatment. With a median follow-up of 31.4 months, 231 patients achieved either complete response or complete response unconfirmed (73 %) with no significant difference between de novo DLBCL (n = 192, 75 %) and the transformed group (n = 39, 65 %) (P = 0.25). Six patients (15 %) relapsed in the transformed group at a median time to relapse of 29.3 months. The 2-year and 5-year overall survivals for all patients were 82 and 72 %, respectively. The overall and progression-free survivals for transformed lymphoma and de novo DLBCL were not statistically different (P = 0.45 and P = 0.38, respectively). With R-CHOP chemotherapy, the prognosis of transformed lymphoma in patients with minimal chemotherapy exposure for indolent disease is similar to that of de novo DLBCL.

Why resident duty hours regulations must address attending physicians' workload.

For much of the past decade, the duty hours debate has focused primarily on the intended and unintended effects of resident duty hours restrictions on resident well-being and fatigue, patient safety, discontinuity and handoffs, and opportunities for teaching. On the other hand, attending physicians' needs and perspectives generally have been ignored. The authors of this commentary discuss the report by Roshetsky and colleagues in this issue of Academic Medicine, which found that attending physicians reported a greater clinical workload since the implementation of the 2003 Accreditation Council for Graduate Medical Education resident duty hours regulations, and that this increase in attending physicians' workload appears to correlate with decreased time for teaching. However, attending physicians not having time to teach may be but the tip of the iceberg. Other potential implications include faculty members' decreased availability for direct supervision of residents, their reduced emphasis on resident assessment, and their burnout and dissatisfaction, which ultimately also negatively affect patient care. Therefore, deliberate efforts to address attending physicians' workload must receive greater attention if the duty hours movement is to achieve its ultimate goal of improving patient outcomes. In this commentary, the authors advocate that duty hours regulations require programs to seek creative solutions to address these issues, just as the 2011 regulations require programs to address patient handoff training.

Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature.

Central nervous system (CNS) prophylaxis for diffuse large B-cell lymphoma (DLBCL) is controversial with even less evidence in the era of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R-CHOP at a tertiary care centre over a 7-year period. CNS prophylaxis was recommended for 'higher risk' patients and consisted of intrathecal methotrexate and/or high-dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow-up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R-CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.