High frequency of central nervous system involvement in transformed Waldenstrom macroglobulinemia

Histologicaltransformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a rare event in Waldenström macroglobulinemia (WM) and is associated with a poor prognosis.1-4 It confers an inferior outcome compared with WM patients without HT.2,3 Most transformed WM patients present with elevated serum lactate dehydrogenase (LDH) levels and extranodal disease.1 Among extranodal sites, the central nervous system (CNS) is one of the most frequently involved sites identified at diagnosis of transformed WM (ranging from 13% to 18%).1,3 However, the prognostic value of CNS involvement is unknown, and the rate of CNS involvement at relapse has not been previously reported in this setting.This work was supported by Cancer Research UK [C355/A26819], FC AECC, and AIRC under the “Accelerator Award Program” [EDITOR] to M.A. and R.G.-S

Therapeutic Emesis (Vamana) - Management of Ekakustha- A Case Study

50 years old male with well defined, slightly raised dry erythematous macules with silvery scales and typical extensor distribution diagnosed as ekkustha (psoriasis). As shodhan chikitsa is more effective patient is treated by giving sadhya snehan and madanphala vaman karma in which vitiated doshas are expelled through urdhvamarga. The patient vomited 6 times a total content of 3800ml against 2500ml of input. At the end of vaman, pitta is vomited. After an hour of vaman karma patient felt remarkable relief from itching, scaling and gradual reduction of erythema. The madanphala vaman karma (therapeutic emesis) is a safe Ayurveda .Panchakarma protocol to eliminate kapha accumulated either by pathological condition or dietetic mismanagement

Treating Multiple Myeloma in the Context of the Bone Marrow Microenvironment

The treatment landscape of multiple myeloma (MM) has evolved considerably with the FDA-approval of at least 15 drugs over the past two decades. Together with the use of autologous stem cell transplantation, these novel therapies have resulted in significant survival benefit for patients with MM. In particular, our improved understanding of the BM and immune microenvironment has led to the development of highly effective immunotherapies that have demonstrated unprecedented response rates even in the multiple refractory disease setting. However, MM remains challenging to treat especially in a high-risk setting. A key mediator of therapeutic resistance in MM is the bone marrow (BM) microenvironment; a deeper understanding is necessary to facilitate the development of therapies that target MM in the context of the BM milieu to elicit deeper and more durable responses with the ultimate goal of long-term control or a cure of MM. In this review, we discuss our current understanding of the role the BM microenvironment plays in MM pathogenesis, with a focus on its immunosuppressive nature. We also review FDA-approved immunotherapies currently in clinical use and highlight promising immunotherapeutic approaches on the horizon

A prognostic index predicting survival in transformed Waldenstrom macroglobulinemia

Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenstrom macroglobulinemia (WM) and is usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival of patients with transformed WM. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an endpoint. For external validation, a dataset of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum lactate dehydrogenase (2 points), platelet count <100x10(9)/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%; hazard ratio = 3.4) and high-risk (4 points, 17%; hazard ratio = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P<0.0001). This model appeared to be a better discriminant than either the International Prognostic Index or the revised International Prognostic Index. We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies

Experience with non-cremophor-based paclitaxel-gemcitabine regimen in advanced pancreatic cancer: Results from a single tertiary cancer centre

Background & objectives: Gemcitabine combined with non-cremophor-based paclitaxel is one of the standards of care in advanced inoperable pancreatic cancer. This study was undertaken to retrospectively evaluate real world non-trial outcomes with this combination. Methods: Patients with histologically proven advanced inoperable pancreatic adenocarcinoma (PDAC), treated with non-cremophor-based paclitaxel-gemcitabine combination (PG) (gemcitabine-nanoxel or gemcitabine-abraxane) between January 2012 and June 2015, were retrospectively analyzed. Response assessment was done every 8-12 wk with computed tomography scan and responses were measured as per the Response Evaluation Criteria in Solid Tumours 1.1 criteria where feasible. Toxicity was recorded as per the Common Terminology Criteria for Adverse Events (CTCAE) v4 criteria. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: A total of 78 patients with PDAC were treated with the combination. Of these, 83.3 per cent of patients had metastatic disease. The median number of chemotherapy cycles administered was three. The objective response rate for the whole group was 30.8 per cent. Grade III/IV toxicities were seen in 35.9 per cent of patients. Median PFS was 5.6 months and median OS was 11.6 months. Interpretation & conclusions: Non-cremophor-based paclitaxel in combination with gemcitabine appeared efficacious for advanced pancreatic cancers in routine clinical practice. Within the confines of a single-centre retrospective analysis, gemcitabine-nanoxel and gemcitabine-abraxane appeared to have similar efficacy and toxicity in advanced pancreatic cancers

Clinical practice and outcomes in advanced gastrointestinal stromal tumor: Experience from an Indian tertiary care center

Background: Management of advanced Gastrointestinal stromal tumors (GIST) has been revolutionized with the use of Imatinib guided by mutation analysis. Data from India remains scarce. Materials and Methods: Patients with metastatic GIST who were treated at Department of Gastro-intestinal & Hepaticopancreaticobiliary Oncology Unit at Tata Memorial Hospital, Mumbai between December, 2004 and December 2015 were included in the analysis. Clinical and radiological data was retrieved from stored medical records and charts. Results: A total of 83 patients with metastatic GIST were available for analysis. Median age was 54 years with a 3:1 male predominance. Stomach was the most common site of primary with liver being the most common site of metastasis. c-Kit mutation analysis results were available for 44 patients with exon 11 mutant being the most common mutation. With a median follow up of 33 months, the 10 years estimated progression free and overall survival (OS) was 18% and 51% respectively. Overall response rate to first line imatinib was 37.6% and estimated 3 years OS to first line therapy was significantly better for Exon 11 mutated patients (p=0.016). 34 patients received second line therapy in the form of either sunitinib, pazopanib or increased dose imatinib with a clinical benefit rate of 73.5%. C-Kit mutated patients had a better median OS compared to non mutated patients. Conclusions: GIST diagnosed and treated in the Indian subcontinent appears to show improved outcomes. The importance of c-Kit mutation analysis in determining the prognosis and outcomes of patients with advanced GIST is emphasized

Dihydropyrimidine dehydrogenase mutation in neoadjuvant chemotherapy in head and neck cancers: Myth or reality?

Purpose: The docetaxel, 5-fluorouracil (5-FU), and cisplatin (TPF) regimen in India is associated with high percentages of Grade 3-4 toxicity. This analysis was planned to evaluate the incidence of dihydropyrimidine dehydrogenase (DPD) mutation in patients with severe gastrointestinal toxicity, to assess whether the mutation could be predicted by a set of clinical criteria and whether it has any impact on postneoadjuvant chemotherapy response. Methods: All consecutive patients who received TPF regimen in head and neck cancers between January 2015 and April 2015 were selected. Patients who had predefined set of toxicities in Cycle 1 were selected for DPD mutation testing. Depending on the results, C2 doses were modified. Postcompletion of two cycles, patients underwent radiological response assessment. Descriptive statistics has been performed. The normally distributed continuous variables were compared by unpaired Student′s t-test, whereas variables which were not normally distributed by Wilcoxon sum rank test. For noncontinuous variables, comparison was performed by Fisher′s exact test. Results: Out of 34 patients, who received TPF, 12 were selected for DPD testing, and 11 (32.4%, 95% confidence interval [95% CI]: 19.1-49.3%) had DPD mutation. The predictive accuracy of the criteria for the tested DPD mutations was 81.3% (95% CI: 62.1-100%). Of the 11 DPD mutation positive patients, except for one patient, all others received the second cycle of TPF. The dose adjustments done in 5-FU were 50% dose reduction in 9 patients and no dose reduction in one patient. The response rate in DPD mutated patients was 27.3% (3/11) and that in DPD nonmutated/nontested was 39.1% (9/23) (P = 0.70). Conclusion: In this small study, it seems that the incidence of DPD mutation is more common in Indian then it′s in the Caucasian population. Clinical toxicity criteria can accurately predict for DPD mutation. Postdose adjustments of 5-FU from C2 onward, TPF can safely be delivered in the majority of patients with DPD heterozygous mutations without decrement in efficacy

The immunome of mobilized peripheral blood stem cells is predictive of long-term outcomes and therapy-related myeloid neoplasms in patients with multiple myeloma undergoing autologous stem cell transplant

Abstract Upfront autologous stem cell transplant (ASCT) is the standard of care for newly diagnosed multiple myeloma (MM) patients. However, relapse is ubiquitous and therapy-related myeloid neoplasms (t-MN) post-ASCT are commonly associated with poor outcomes. We hypothesized that the enrichment of abnormal myeloid progenitors and immune effector cells (IEC) in the peripheral blood stem cells (PBSCs) is associated with a higher risk of relapse and/or development of t-MN. We performed a comprehensive myeloid and lymphoid immunophenotyping on PBSCs from 54 patients with MM who underwent ASCT. Median progression-free (PFS), myeloid neoplasm-free (MNFS), and overall survival (OS) from ASCT were 49.6 months (95% CI: 39.5-Not Reached), 59.7 months (95% CI: 55–74), and 75.6 months (95% CI: 62–105), respectively. Abnormal expression of CD7 and HLA-DR on the myeloid progenitor cells was associated with an inferior PFS, MNFS, and OS. Similarly, enrichment of terminally differentiated (CD27/CD28-, CD57/KLRG1+) and exhausted (TIGIT/PD-1+) T-cells, and inhibitory NK-T like (CD159a+/CD56+) T-cells was associated with inferior PFS, MNFS, and OS post-transplant. Our observation of abnormal myeloid and IEC phenotype being present even before ASCT and maintenance therapy suggests an early predisposition to t-MN and inferior outcomes for MM, and has the potential to guide sequencing of future treatment modalities