Binod Dhakal

Resolving diagnostic uncertainty in initially poorly localizable fevers: a prospective study

Aims:  Prospective, observational data collection of fever patients with regard to aetiology and means of detecting it particularly noting the factors, which quickly helped resolve diagnostic uncertainty.

Allogeneic stem cell transplantation for multiple myeloma: is there a future?

Despite remarkable progress in survival with the availability of novel agents, an overwhelming majority of patients with multiple myeloma (MM) relapse and the curability of MM remains limited. Genetically defined high-risk MM represents a subgroup with an aggressive disease course despite novel agents. Allogeneic hematopoietic cell transplantation (allo-SCT) is a potentially curative option in MM that has several advantages including a tumor-free graft, and the potential for sustained immune-mediated disease control. However, historically high treatment-related mortality (TRM) and conflicting reports from prospective studies in the United States and European Union have limited the utilization of this modality. Meanwhile, newer preparative regimens, planned maintenance strategies and improvements in supportive care have led to a decline in TRM and better survival in recent years. The allo-SCT platform also provides additional options of immunotherapy at relapse including donor lymphocyte infusions, immunomodulatory drug maintenance and withdrawal of immune suppression. In this article, we provide an in-depth review of literature for allo-SCT and other immunotherapy options, as well as the authors’ approach to using allo-SCT in MM.

Morbidities of lung cancer surgery in obese patients

BACKGROUND Obesity is a risk factor for increased perioperative morbidity and mortality in surgical patients. There have been limited studies to correlate the morbidity of lung cancer resection with obesity. METHODS We performed a retrospective study of patients who underwent surgical resection for lung cancer at the Medical College of Wisconsin, Milwaukee, from 2006 to 2010. Data on patient demographics, weight, pathological findings, and hospital course were abstracted after appropriate institutional review board approval. Perioperative morbidity was defined as atrial fibrillation, heart failure, respiratory failure, pulmonary embolism, or any medical complications arising within 30 days after surgery. The Fisher exact test was used to test the association between body mass index (BMI) and perioperative morbidities. RESULTS Between 2006 and 2010, 320 lung resections were performed for lung cancer. The median age was 67 (interquartile range, 59-75) years, and 185 (57.8%) were females. A total of 121 (37.8%) of patients had a BMI lower than 25, and 199 (62.18%) patients had a BMI of 25 or higher. The 30-day mortality rate was 1.8% (n = 6) in the whole group; only 2 of these patients had a BMI of 25 or higher. Perioperative morbidity occurred in 28 (23.14%) of patients with a normal BMI and in 47 (23.61%) of patients with a BMI of 25 or higher (P = .54). Specific morbidities encountered by patients with normal versus BMI of 25 or higher were as follows: atrial fibrillation, 11 (9.09%) versus 24 (12.06%) (P = .46); pulmonary embolism, 1 (0.83%) versus 3 (1.51%) (P = 1.0); congestive heart failure, 2 (1.65%) versus 2 (1.01%) (P = .63); renal failure, 4 (3.3%) versus 2 (1.0%) (P = .29); respiratory failure, 12 (9.92%) versus 17 (8.54%) (P = .69); and acute respiratory distress syndrome, 2 (1.65%) versus 1 (0.50%) (P = .55). The median hospital stay was 5 days in the lower BMI group and 4 days in the BMI of 25 or higher group (P = .52). CONCLUSIONS Overweight and normal weight patients do not differ significantly in rates of perioperative morbidities, 30-day mortality, and length of stay. Our study indicates that potential curative surgical resections can be offered to even significantly overweight patients.

IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

BACKGROUND: Heparin‐induced thrombocytopenia (HIT) complicated by severe thrombocytopenia and thrombosis can pose significant treatment challenges. Use of alternative anticoagulants in this setting may increase bleeding risks, especially in patients who have a protracted disease course. Additional therapies are lacking in this severely affected patient population. METHODS: We describe three patients with HIT who had severe thromboembolism and prolonged thrombocytopenia refractory to standard treatment but who achieved an immediate and sustained response to IVIg therapy. The mechanism of action of IVIg was evaluated in these patients and in five additional patients with severe HIT. The impact of a common polymorphism (H/R 131) in the platelet IgG receptor Fc&ggr;RIIa on IVIg‐mediated inhibition of platelet activation was also examined. RESULTS: At levels attained in vivo, IVIg inhibits HIT antibody‐mediated platelet activation. The constant domain of IgG (Fc) but not the antigen‐binding portion (Fab) is required for this effect. Consistent with this finding, IVIg had no effect on HIT antibody binding in a solid‐phase HIT immunoassay (platelet factor 4 enzyme‐linked immunoassay). The H/R131 polymorphism in Fc&ggr;RIIa influences the susceptibility of platelets to IVIg treatment, with the HH131 genotype being most susceptible to IVIg‐mediated inhibition of antibody‐induced activation. However, at high doses of IVIg, activation of platelets of all Fc&ggr;RIIa genotypes was significantly inhibited. All three patients did well on long‐term anticoagulation therapy with direct oral anticoagulants. CONCLUSIONS: These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies.

Autologous Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction: A Systematic Review and Meta-analysis

Importance The role of high-dose therapy with melphalan followed by autologous stem cell transplant (HDT/ASCT) in patients with multiple myeloma continues to be debated in the context of novel agent induction. Objective To perform a systematic review, conventional meta-analysis, and network meta-analysis of all phase 3 randomized clinical trials (RCTs) evaluating the role of HDT/ASCT. Data Sources We performed a systematic literature search of Cochrane Central, MEDLINE, and Scopus from January 2000 through April 2017 and relevant annual meeting abstracts from January 2014 to December 2016. The following search terms were used: “myeloma” combined with “autologous,” “transplant,” “myeloablative,” or “stem cell.” Study Selection Phase 3 RCTs comparing HDT/ASCT with standard-dose therapy (SDT) using novel agents were assessed. Studies comparing single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone consolidation and tandem transplantation were included for network meta-analysis. Data Extraction And Synthesis For the random effects meta-analysis, we used hazard ratios (HRs) and corresponding 95% CIs. Main Outcomes and Measures The primary outcome was progression-free survival (PFS). Overall survival (OS), complete response, and treatment-related mortality were secondary outcomes. Results A total of 4 RCTs (2421 patients) for conventional meta-analysis and 5 RCTs (3171 patients) for network meta-analysis were selected. The combined odds for complete response were 1.27 (95% CI, 0.97-1.65; P = .07) with HDT/ASCT when compared with SDT. The combined HR for PFS was 0.55 (95% CI, 0.41-0.74; P < .001) and 0.76 for OS (95% CI, 0.42-1.36; P = .20) in favor of HDT. Meta-regression showed that longer follow-up was associated with superior PFS (HR/mo, 0.98; 95% CI, 0.96-0.99; P = .03) and OS (HR/mo, 0.90; 95% CI, 0.84-0.96; P = .002). For PFS, tandem HDT/ASCT had the most favorable HR (0.49; 95% CI, 0.37-0.65) followed by single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone (HR, 0.53; 95% CI, 0.37-0.76) and single HDT/ASCT alone (HR, 0.68; 95% CI, 0.53-0.87) compared with SDT. For OS, none of the HDT/ASCT-based approaches had a significant effect on survival. Treatment-related mortality with HDT/ASCT was minimal (<1%). Conclusions and Relevance The results of the conventional meta-analysis and network meta-analysis of all the phase 3 RCTs showed that HDT/ASCT was associated with superior PFS with minimal toxic effects compared with SDT. Both tandem HDT/ASCT and single HDT/ASCT with bortezomib, lenalidomide, and dexamethasone were superior to single HDT/ASCT alone and SDT for PFS, but OS was similar across the 4 approaches. Longer follow-up may better delineate any OS benefit; however, is likely to be affected by effective postrelapse therapy.

Marizomib for central nervous system-multiple myeloma

Marizomib, a natural marine product, is an irreversible proteasome inhibitor currently under investigation in relapsed‐refractory multiple myeloma (RRMM) and malignant glioma. Central nervous system‐multiple myeloma (CNS‐MM) is a rare manifestation of extra‐medullary disease with few therapeutic options, highlighting the unmet clinical need in these patients. Marizomib demonstrated encouraging activity in RRMM and has emerging clinical activity in glioma, making it a potential CNS‐MM therapeutic intervention. Herein, we present two patients with RRMM and CNS involvement who benefited from marizomib‐based therapy. These cases provide the first proof of principle for further exploring marizomib in CNS‐MM patients.

Presentation and management of post-allogeneic transplantation EBV-positive mucocutaneous ulcer.

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid neoplasms occurring as a result of immunosuppression following both solid organ and hematopoietic cell transplant (HCT). PTLD have a variety of presentations and only recently have been described to present as an isolated EBV-associated mucocutaneous ulceration (MCU). To our knowledge, only one case of PTLD manifesting as EBV+ MCU has been reported following HCT.1 Here we report a second case and provide diagnostic consideration and management recommendations.

Pemetrexed induced pneumonitis

Pemetrexed is an antifolate chemotherapy agent that is active in malignant mesothelioma and non-small cell lung cancer (NSCLC). Pneumonitis is a rare side effect of Pemetrexed. We report the case of 72-year-old female with metastatic poorly differentiated lung adenocarcinoma. She was placed on maintenance pemetrexed and developed gradual progressive dyspnea after first cycle of maintenance of pemextrexed. The computed tomography (CT) of the chest showed ground glass opacity in both lung fields. Transbronchial lung biopsy showed uniform interstitial widening by a cellular chronic infiltrate with areas of type II pneumocyte and exudation of pale eosinophilic edema fluid; features consistent with acute lung injury. Patient improved both clinically and radiological after stopping pemetrexed and starting prednisone. Although pemetrexed induced lung injury is relatively rare, with the increasing use of peme-trexed in first-line treatment and in maintenance therapy of non-small cell lung cancer, awareness of this potential adverse effects is important.

Autologous Hematopoietic Cell Transplantation in Patients With Multiple Myeloma: Effect of Age

Background In the novel and pre–novel agent era, high‐dose therapy, followed by autologous hematopoietic cell transplantation (AHCT), has been shown to prolong survival in patients with multiple myeloma (MM) in randomized trials. However, these trials only included patients aged ≤ 65 years. Given that the median age at diagnosis is 66 years, it is important to know the outcomes of AHCT in older patients. Similarly, definite outcomes of AHCT in very young patients (aged < 50 years) are also lacking because they represent a very small proportion of patients in clinical trials. Materials and Methods We analyzed a consecutive cohort of patients with MM receiving AHCT from 2000 to 2015 in 2 different age groups, older (> 70 years) and younger (≤ 50 years), and compared the outcomes. The primary objectives were to assess overall survival, progression‐free survival (PFS), and nonrelapse mortality in these 2 groups. Results Of the 191 patients, 86 were young (age ≤ 50 years) and 105 were old (age > 70 years). The younger patients had better performance status and a lower comorbidity index, and most of the older patients had received a melphalan dose of 140 to 180 mg/m2. The median follow‐up period for the young group was 33 months (range, 2‐164 months) compared with 22.5 months (range, 3‐133 months) in the old group (P = .02). The PFS rate at 1 year was 60% (95% confidence interval [CI], 46%‐72%) for the young group and 58% (95% CI, 45%‐69%) for the old group. The overall survival rate at 1 year was 92% (95% CI, 84%‐96%) for the young group and 85% (95% CI, 76%‐91%) for the old group. On multivariate analysis, age did not have any effect on survival (P = .82); however, the patients with high‐risk cytogenetics (hazard ratio [HR], 2.2; 95% CI, 1.06‐4.6; P = .04) had worse overall mortality. High‐risk cytogenetics (HR, 1.2; 95% CI, 1.1‐3.5; P = .004) and no disease response or progressive disease at transplantation (HR, 5.0; 95% CI, 1.8‐13.5; P = .02) were significantly associated with worse PFS. Conclusion Age should not be a limiting factor in considering the modality of AHCT. However, younger patients might also benefit from additional novel treatment approaches in the setting of clinical trials, given their similar outcomes with the older patients in our study. Micro‐Abstract Autologous hematopoietic cell transplantation has been shown to prolong survival in patients with multiple myeloma; however, adequate data are lacking for patients aged > 70 years and < 50 years. We retrospectively analyzed and compared the outcomes of patients between the 2 age groups (> 70 vs. ≤ 50 years). Our study showed comparable outcomes between these 2 age groups.

Recent advances in understanding multiple myeloma

There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both.