Abhijeet Kumar

Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance

&NA; Immunotherapy with checkpoint inhibitors targeting CTLA‐4 and/or PD‐1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy. Graphical abstract Figure. No caption available.

CNS Involvement in Pancreatic Adenocarcinoma: a Report of Eight Cases from the Johns Hopkins Hospital and Review of Literature

PurposeCNS metastasis of pancreatic cancer is extremely rare, although systemic metastasis is very common. We present eight such cases with various forms of nervous system involvement.MethodsData was gathered from chart review of 800 patients with pancreatic cancer treated between 2004 and 2012 of which eight patients are described with CNS metastases.ResultsThe median age of patients was 61.5 years and the median time to develop CNS metastasis was 29 months. Interestingly, two patients had no other sites of metastasis. The treatment modalities tried included resection followed by radiation, resection alone, or whole brain radiation.

Cardiovascular adverse effects of targeted antiangiogenic drugs: mechanisms and management

Anticancer treatment has evolved enormously over the last decade. Drugs targeting receptor tyrosine kinases, VEGFR and EGFR have changed the treatment landscape of certain cancers and have shifted the theme of anticancer therapy toward personalized care. However, these newer agents also come with unique side-effect profiles not seen with conventional chemotherapy including serious cardiovascular adverse effects. Hence, meticulous understanding of the adverse effects is crucial in maximizing clinical benefits and minimizing detrimental effects of these newer drugs. We have reviewed the cardiovascular adverse effects of anti-VEGF therapy in this article.

Phase 2 Open-Label Study of Bortezomib, Cladribine, and Rituximab in Advanced, Newly Diagnosed, and Relapsed/Refractory Mantle-Cell and Indolent Lymphomas

Background Mantle‐cell lymphoma (MCL) and indolent non‐Hodgkin lymphoma (iNHL) are incurable heterogeneous diseases characterized by relapse. There is a need for newer treatments in MCL and iNHL, especially in the relapsed/refractory (R/R) setting. We therefore investigated the novel combination of bortezomib (Velcade), cladribine, and rituximab (VCR) in front‐line and R/R settings in MCL and iNHL (NCT00980395). Patients and Methods Eligible patients included adults with biopsy‐proven CD20‐positive MCL and iNHL who met the criteria for treatment. Rituximab 375 mg/m2 intravenous (IV) day 1, cladribine 4 mg/m2 IV days 1 to 5, and bortezomib 1.3 mg/m2 IV days 1 and 4 were administered every 28 days for 6 cycles. Results Twenty‐four patients were enrolled onto the study with a median follow‐up of 38.5 months. Median age was 66.5 years, and 46% had MCL. The most common adverse events were hematologic, with febrile neutropenia in 3 patients. Neuropathy was noted in 17% of patients, of which 8% was grade 3 or above. The overall response rate was 92%. For the entire cohort, and for MCL patients, the median progression‐free survival and the median overall survival were not reached. The 2‐year progression‐free survival was 82% for the MCL group and 54% for the iNHL group; it was 80% for treatment‐naive patients and 57% for R/R patients. Conclusion VCR is effective in MCL and iNHL. Although hematologic toxicity can be an issue, this study demonstrates a high response rate to a novel combination and provides an alternative option in transplant‐ineligible R/R MCL and iNHL. Micro‐Abstract The combination of bortezomib, cladribine, and rituximab is novel and effective in mantle‐cell and indolent non‐Hodgkin lymphomas.

Donor-derived marginal zone lymphoma following reduced-intensity allogeneic peripheral blood stem cell transplant.

Post-transplant lympho-proliferative disorders (PTLD) pose significant therapeutic challenges accompanied by increase in morbidity and mortality. The timing and severity of PTLD is often variable; early identification and treatment is crucial in managing these patients. We are presenting the first known case of late onset donorderived marginal zone or mucosa-assisted lymphoid tissue (MALT) lymphoma as PTLD in a patient with acute myeloid leukemia (AML) treated with an allogeneic hematopoietic stem cell transplant. The World Health Organization does not consider indolent lymphomas as PTLD; however, there is a significant incidence of indolent lymphomas in posttransplant setting raising the question, if they need to be considered as PTLD. This disorder is more common in patients with solid organ transplant who are on longterm immunosuppression. PTLD is seen in about 1–3% in kidney transplants, 1–2.8% of liver transplants, 1–6.3% of heart transplants and 11–20% of small bowel, intestinal or multi-organ transplants.[1,2] PTLD is seen less commonly in patients who are hematopoietic stem cell transplant (HSCT) recipients (around 1%) and a majority of these cases are diagnosed in the first 1–5 months.[3] Our case is a 60-year-old female with past medical history of AML (M1 subtype, normal cytogenetics) who underwent a medically unrelated donor (MUD) peripheral blood stem cell transplant in her second remission in May 2003. Fludarabine with total body irradiation (TBI) was used for conditioning. Her post transplant course was complicated by acute skin graft versus host disease (GVHD) requiring high dose steroids. Later, the patient developed chronic GVHD of skin, eyes requiring longterm immunosuppression with steroids and mycophenolate. Steroids and mycophenolate were tapered and discontinued by February 2010. The patient resumed her job full time as an office manager for a multi-specialty physician practice. In April 2014, the patient underwent a colonoscopy for evaluation of unexplained hypochromic, microcytic anemia, which showed a three cm subepithelial non-obstructing cecal mass (Fig. 1A). Pathology revealed monomorphic B lymphocyte population staining positive for CD20, CD10 negative, BCL-2, IgD, PAX-5 and dim CD5 positivity (Fig. 1D) suggestive of an extra-nodal marginal zone lymphoma or mucosaassociated lymphoid tissue (MALT lymphoma). In situ hybridization (ISH) studies were negative for EBV encoded RNA and showed 94.5% of the cells analyzed to be XY type implying that the mass was a post transplant lymphoma of male donor origin (Fig. 1B). FISH for t(11;18) was negative. Bone marrow biopsy confirmed presence of MALT lymphoma. A staging positron emission tomography (PET) scan showed no other sites of disease. The cecal mass was noted to be intensively hyper metabolic with a standardized uptake value (SUV) of 15.5 (Fig. 1C). Patient received involved field radiation treatment to symptomatic cecal mass for 24Gy in 12 fractions. A follow up PET scan performed 6 months after radiation showed complete resolution of her cecal mass and a repeat bone marrow biopsy showed no evidence of lymphoma. PTLD after HSCT is mostly seen with in the first 3-5 months after engraftment and is extremely rare after 1 year.[4] The risk of PTLD after HSCT increases significantly in patients receiving anti thymocyte globulin; total body irradiation and T cell depleted stem cells.[2,3] PTLD in patients with solid organ transplantation is predominantly of recipient origin and tends to be more aggressive.[5] In contrast, PTLD seen in patients after HSCT is predominantly of donor origin, which is likely