Dulabh Monga

Platelet-derived growth factor receptor-α: a novel therapeutic target in human hepatocellular cancer

Hepatocellular cancer (HCC) is a disease of poor prognosis. Identifying novel molecular aberrations might present opportunities to identify new therapeutic targets. Due to the similarities between the processes of development and cancer, we used early developing livers to identify genes that might play a primary role in HCC. Platelet-derived growth factor receptor-α (PDGFRα) was identified from microarray using early developing mouse livers. Expression of PDGFRα and its upstream effectors, PDGF-AA and PDGF-CC, were examined in HCC tissues (n = 43) by Western blot, real-time PCR, and immunohistochemistry. Finally, effect of anti-PDGFRα antibody (mAb 3G3, ImClone Systems, Inc.) was examined on human hepatoma cells. A high expression of PDGFRα was observed during early liver development. HCCs (17 of 21) revealed cytoplasmic PDGFRα and activated PDGFRα (phospho-Tyr754) by immunohistochemistry. Additional HCCs (14 of 22) showed elevated PDGFRα levels when compared with the adjacent normal livers by Western blots. Of these 14 patients, 3 showed increased PDGFRα gene expression, 3 showed elevated PDGF-AA, and 4 had higher PDGF-CC levels in the tumors compared with adjacent livers. Multiple hepatoma cell lines, when treated with mAb 3G3, showed significant decreases in cell proliferation and survival (P < 0.05). In conclusion, ∼70% of HCC tissues had elevated PDGFRα levels due to diverse mechanisms. PDGFRα inhibition in hepatoma cells led to diminution of tumor cell survival and proliferation and thus might be of therapeutic significance. [Mol Cancer Ther 2007;6(7):1932–41]

Surgical Adjuvant Therapy for Colorectal Cancer: Current Approaches and Future Directions

Colon cancer is the fourth most common cancer worldwide. The role of systemic adjuvant chemotherapy in colorectal cancer patients with lymph node involvement has been established in a large number of clinical trials. However, its role in stage II colorectal cancer is less well established. 5-Fluorouracil has been the mainstay of therapy for the last four decades. With the development of novel chemotherapy and biological agents, we have entered into a new era for the treatment of colorectal cancer. The combination of adjuvant 5-fluorouracil, leucovorin, and oxaliplatin has been shown to significantly improve disease-free survival and is now considered the standard of care for completely resected colon cancer in healthy patients. For rectal cancer patients with locally advanced tumors, neoadjuvant chemoradiation followed by adjuvant chemotherapy after surgery is the mainstay of treatment. The availability of oral chemotherapy agents has helped with the ease of administration and avoidance of indwelling catheters. A number of national clinical trials are under way to determine the role of targeted agents in combination with chemotherapy. The goal is to develop a regimen that would improve survival without excessive toxicity while maintaining quality of life. Patients should be encouraged to participate in clinical trials whenever feasible. Despite the advances, many patients will develop recurrent disease. It is of utmost importance to develop molecular markers that could predict which patients are at high risk for disease recurrence. Clinical trials are under way to address this issue. Thus, it will be advantageous to be able to tailor therapy individually, according to the risk of recurrence.

Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors

OBJECTIVES We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. PATIENTS AND METHODS Patients with 1-4 hepatic lesions and tumor diameter ≤9 cm received SBRT at 46.8Gy ± 3.7 in 4-6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. RESULTS Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9-64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions ≤4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. CONCLUSION In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates.

Management of Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs): A Review

PURPOSE Neuroendocrine tumors (NETs) are heterogeneous tumors that arise from the neuroendocrine cells of the digestive tract and other organs, such as the lung, ovary, and thyroid glands. They can be well differentiated or poorly differentiated, and management of these tumors differs for each histologic subtype. We have performed a review of NETs and focused on management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEPNETs) and carcinoid syndrome. METHODS A PubMed search was performed to obtain articles on the management of well-differentiated NETs. Using the key words neuroendocrine tumors, carcinoid, pNET, octreotide, somatostatin analogues, and radiolabeled therapy, we reviewed Phase II and III trials that were published over the past 30 years. We also reviewed guidelines from the European Neuroendocrine Tumor Society, North America Neuroendocrine Tumor Society, and National Comprehensive Cancer Network in our search. FINDINGS NETs are usually slow-growing tumors that remain asymptomatic for a long duration and can be either nonfunctioning or functioning. Surgical resection is recommended for locoregional disease, impending obstruction, symptom control, and advanced disease. Nonsurgical treatment options include somatostatin analogues (SSAs), multikinase inhibitors, targeted therapy, chemotherapy, and radiolabeled SSAs. Carcinoid syndrome is mainly treated with SSAs. IMPLICATIONS Although GEPNETs are slow-growing tumors, most patients are diagnosed with metastatic disease, and therefore it is important that the management of each patient be discussed in a multidisciplinary setting to optimize the treatment strategy. Patients should be considered for clinical trials and refractory cases referred to a specialty center.

Niraparib – A promising drug with hematological toxicity

Ovarian cancer is the second most common and the most lethal gynecological malignancy in the western world. Unfortunately, there are lack of methods for early screening and diagnosis of the disease. Because of this, most of the cases are diagnosed at an advanced stage and have poor prognosis. The standard treatment of ovarian cancer is maximal cytoreductive surgical debulking followed by platinum-based chemotherapy. There are new molecular agents available for maintenance therapy of ovarian cancer including anti-angiogenic therapies, poly adenosine diphosphate ribose polymerase inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. Niraparib is a poly adenosine diphosphate ribose polymerase inhibitor that has shown to be clinically effective as maintenance therapy in patients with platinum sensitive, recurrent ovarian cancer. Studies have shown the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of presence or absence of BRCA gene mutations or homologous recombination deficiency status. Studies have shown that treatment-emergent Grade 3 or Grade 4 hematological events were observed in patients receiving niraparib including thrombocytopenia (33.8%), anemia (25.3%) and neutropenia (19.6%). Most of the hematological laboratory abnormalities occurred within the first three treatment cycles. After dose adjustment, the incidence of hematological abnormalities was infrequent beyond cycle 3. We are reporting two cases of Grade III/IV neutropenia and thrombocytopenia in patients treated with niraparib in our institution. Unfortunately, one of the patients succumbed to septic shock secondary to right lower lobe pneumonia while severely neutropenic. The second patient’s blood counts improved after discontinuing the medication and with supportive transfusions during the hospitalization.

Primary renal carcinoid tumour with lung metastasis misdiagnosed as renal cell carcinoma

A 58-year-old man with a history of metastatic renal cell carcinoma (RCC) diagnosed 10 years prior, status post right nephrectomy, presented for evaluation of pulmonary nodules. A year after the nephrectomy, he had undergone cutaneous metastasectomy in the right flank area, and a further 2 years later he had had his second cutaneous metastasectomy in the right chest wall. Both cutaneous pathologies had, at the time, shown metastatic neoplasm with histological features compatible with those of the previous renal tumour. He was treated with sorafenib. 3 years later he developed asymptomatic pulmonary nodules, which gradually doubled in size over the next 2.5 years. He underwent bronchoscopy and left lower lobe biopsy. Pathology revealed a metastatic renal carcinoid/neuroendocrine tumour. Second review of the previous renal neoplasm and the cutaneous metastatic pathology showed trabecular architecture, consistent with carcinoid, but mimicking the long parallel arrays that have been described in some cases of papillary RCC.