Srinath Sundararajan

Anti-PD-1 and PD-L1 therapy for bladder cancer: what is on the horizon?

Oncologic therapeutics has evolved enormously as we entered the 21st century. Unfortunately, the treatment of advanced urothelial cancer has remained unchanged over the last two decades despite a better understanding of the genetic alterations in bladder cancer. Pathways such as the PI3K/AKT3/mTOR and FGFR have been implicated in urothelial bladder cancer. However, targeted therapies have not shown proven benefit yet and are still considered investigational. Recently, researchers have been successful in manipulating the systemic immune response to mount antitumor effects in melanoma, lung cancer and lymphoma. Historically, intravesical Bacillus Calmette-Guérin immunotherapy has been highly active in nonmuscle invasive bladder cancer. Early data suggest that immune checkpoint inhibitors will soon prove to be another cornerstone in the treatment armamentarium of advanced bladder cancer.

Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab

ABSTRACT Background: To identify the optimal sequencing and timing of immunotherapy (IT) and stereotactic radiosurgery (SRS) for melanoma brain metastases (MBMs). Methods: The elapsed days between IT and SRS were correlated with local control (LC), regional brain control (RBC), time to CNS progression (TTPCNS), overall survival (OS), and radiation necrosis (RN). Logistic regression and Cox proportional models were used for statistical analysis. Results: Twenty-five patients with 58 MBMs underwent SRS and IT. Median follow-up was 22.7 mo (3.1–77.9 mo). A median of 2 SRS treatments of 21 Gy (range 16–24 Gy) and 4 cycles of Ipilimumab were delivered. SRS was delivered Before, After or Concurrently with IT in 9, 5, and 11 patients, respectively; 8/25 received SRS ≤30 d of IT and 17/25 were >30 d of IT. Median OS was 35.8 mo, 1- and 2-y OS was 83% and 64%, respectively, and LC was 94.8%. By timing, RBC and TTPCNS were significantly improved when SRS was delivered ≤30 d of IT (75% vs 23.5%, p = 0.03 and median not reached vs 5.7 mo, p = 0.02, respectively). By groups, Concurrent delivery improved TTPCNS (p = 0.04). The rate of RN was 20.7% (12/58 lesions) and RN was associated with improved OS (HR 0.21, p = 0.01). Conclusions: High OS was found for MBM treated with SRS and IT compared to historical reports. A significant association for improved RBC and TTPCNS was found when SRS was delivered concurrently and within 30 d of IT. Occurrence of RN was higher than SRS alone series but significantly associated with improved OS.

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.

Molecular and Genomic Profiling to Identify Actionable Targets in Chromophobe Renal Cell Cancer

Metastatic chromophobe renal cell cancer (chRCC) is a rare subtype of RCC with no standard treatment. We performed molecular profiling of 12 chRCC cases to identify alterations predictive of response to therapy. Tests included immunohistochemistry assays, fluorescence in situ hybridization, and next-generation sequencing. Analysis identified c-KIT overexpression in 6/9 (67%) samples analyzed, and loss of protein expression of RRM1 and MGMT in 11/12 (92%) and of PTEN in 7/12 samples (58%). Mutations of TP53, PTEN, APC, and VHL genes were identified. In summary, molecular profiling of chRCC identified alterations in genes and protein expression that might provide a mechanistic rationale for off-label use of approved therapies in advanced chRCC, and could guide the design of molecularly targeted clinical trials. PATIENT SUMMARY: In this study, we evaluated samples of a rare type of kidney cancer (chromophobe type) and identified potential genetic markers that could be used to individualize treatment and possibly improve treatment outcomes.

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.

Poorly Differentiated Neuroendocrine Tumor of the Rectum Coexistent with Giant Rectal Villous Adenoma Presenting as McKittrick-Wheelock Syndrome

McKittrick-Wheelock Syndrome is a rare disorder, noted for electrolyte and fluid depletion caused by secretory colorectal adenomas and carcinomas. We report here the first reported case of a 55-year-old man with a large rectal villous adenoma coexistent with a poorly differentiated neuroendocrine tumor of rectum presenting with McKittrick-Wheelock Syndrome. Palliative chemotherapy resulted in complete resolution of symptoms and improved quality of life.

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

COMPARISON OF DRUG COATED BALLOONS AND DRUG ELUTING STENTS IN IN-STENT RESTENOSIS: A META ANALYSIS

The aim of this meta-analysis was to compare the clinical and angiographic variables in patients with in-stent restenosis (ISR) treated with either drug-coated balloon (DCB) or with a drug eluting stent (DES). A systematic literature search was performed in PubMed and EMBASE database for trials

A Rare Case of Primary Anterior Mediastinal Yolk Sac Tumor in an Elderly Adult Male

Mediastinal germ cell tumors are extragonadal germ cell tumors (EGGCTs) commonly seen in children and young adults. They are more common in men. Clinically they are classified as teratomas, seminomas, and nonseminomatous germ cell tumors. Primary mediastinal yolk sac neoplasm is an extremely rare tumor. We present here a very rare case of primary yolk sac tumor of the anterior mediastinum in a 73-year-old male. Mediastinal germ cell tumors have a worse prognosis than gonadal germ cell tumors. Chemotherapy followed by adjuvant surgery improves overall response in EGGCTs. However, comorbidities can render treatment with chemotherapy and surgery challenging in elderly patients.

Mixed Germ Cell Testicular Cancer with Left Ventricular Metastasis Presenting with Embolic Stroke and Small Bowel Tumor Seeding

Testicular germ cell tumors (GCTs) metastasize in a very predictable fashion involving the retroperitoneal nodes first followed by hematogenous spread to distant organs like lungs, liver, and brain. Metastasis to heart is an extremely rare entity for GCT and fewer than 20 cases have been reported in the literature so far. We have summarized here a unique case of nonseminomatous germ cell tumor (NSGCT) with intracardiac metastasis resulting in systemic macroembolization to liver, spleen, brain, bowel and musculoskeletal tissues. This led to multiple adverse sequelae including ischemic stroke and bowel perforation.