Rlip Depletion Suppresses Growth of Breast Cancer.

RLIP76 (RAL-binding protein-1, Rlip) is a stress-protective mercapturic-acid-pathway transporter protein that also plays a key role in regulating clathrin-dependent endocytosis as a Ral effector. Targeted inhibition or depletion of Rlip causes regression of xenografts of many cancers and is capable of abrogating tumor formation in p53-null mice. This is associated with the reversion of the abnormal methylomic profile of p53-null mice to wild-type. In a query of The Cancer Genome Atlas (TCGA) databases, we found that Rlip expression was associated with poor survival and with significant differences in the frequencies of PIK3CA mutation, MYC amplification, and CDKN2A/B deletion, which were the most commonly mutated, amplified, and deleted genes, respectively, among TCGA breast cancer patients. We conducted the present study to further examine the effects of Rlip inhibition and to evaluate the in vitro and in vivo efficacy in breast cancer. Using immunogold electron microscopy, we found that plasma-membrane Rlip was accessible to cell-surface antibodies in the MCF7 (ER+) breast cancer cell line. Rlip depletion resulted in decreased survival of MCF7 and MDA-MB-231 cells and increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity and DNA laddering, indicating apoptotic cell death. Additionally, in vitro knockdown of Rlip inhibited EGF endocytosis and WNT/MAPK signaling. Xenograft studies in nude mice showed regression of breast cancer via antisense-mediated depletion of Rlip mRNA as well as by anti-Rlip antibody. Finally, knockdown of Rlip by antisense locked nucleic acid oligonucleotides increased markers for apoptotic signaling and decreased markers for proliferation, angiogenesis, and cell cycling in MCF7 and MDA-MB-231luc xenografts. Our findings validate Rlip as an attractive target in breast cancer.

Gastric Cancer: Recent Molecular Classification Advances, Racial Disparity, and Management Implications.

Gastric adenocarcinoma remains an aggressive and poorly understood malignancy with a heterogeneous presentation and tumor biology. The current histologic and anatomic classification has been ineffective in guiding therapy, with only marginal improvement in outcome over time. Furthermore, the variation in presentation and disease among racial and ethnic groups amplifies the complexity of this cancer. An understanding of the clinical and molecular variability is important for effective treatment. Recent advances in molecular biology have better defined gastric cancer subtypes. We systematically review recent literature on the molecular classification of gastric adenocarcinoma and the associated management implications, with an emphasis on Hispanic and Native American populations.

The diagnostic utility of Merkel cell polyomavirus immunohistochemistry in a fine needle aspirate of metastatic Merkel cell carcinoma of unknown primary to the pancreas.

Merkel cell carcinoma (MCC) is an aggressive skin tumor with a high tendency for metastases. We report a case of MCC initially presenting as axillary and pancreatic metastases. A 33-year-old HIV-positive Hispanic male presented with a history of a rapidly growing axillary mass. A needle core biopsy demonstrated an epithelioid neoplasm composed of small to medium-sized cells with high nuclear-cytoplasmic ratio, nuclear molding, and frequent mitotic figures. A subsequent PET scan revealed a 1.5 cm FDG avid mass in the pancreas. Endoscopic ultrasound-guided FNA of the pancreatic mass showed neoplastic cells with similar morphology to those of the axillary mass. The tumor cells were positive with pancytokeratin AE1/AE3, CK20, CD56, synatophysin, chromogranin, and Merkel cell polyomavirus (MCPyV). This case of MCC most likely originated from a resolved primary skin lesion drained by the involved axillary lymph node with subsequent metastases to the pancreas and distant lymph nodes.

Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. OBJECTIVE: To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). DESIGN, SETTING, AND PARTICIPANTS: This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. INTERVENTIONS: Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. RESULTS: A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. CONCLUSIONS AND RELEVANCE: Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02045446.

Leiomyosarcoma of the Inferior Vena Cava in an HIV-Positive Adult Patient: A Case Report and Review of the Literature.

BACKGROUND Leiomyosarcoma is the most common primary malignancy of the inferior vena cava (IVC), and represents approximately 10% of primary retroperitoneal sarcomas. Leiomyosarcoma presents with non-specific symptoms, including abdominal pain or back pain. There is an increased incidence in immunosuppressed individuals. CASE REPORT An unusual presentation of IVC leiomyosarcoma is reported in a 46-year-old female patient infected with human immunodeficiency virus (HIV) who was on highly active antiretroviral therapy (HAART) and who had a normal CD4 count of 934, who presented with back pain. Magnetic resonance imaging (MRI) of the lumbar spine showed a mass of the IVC. Initial computed tomography (CT)-guided biopsy of the IVC mass was non-diagnostic. An IVC filter was inserted, and the patient was discharged home, but 20 days later, she returned to the hospital with worsening right flank pain. Laboratory tests showed acute renal failure, and a repeat CT scan showed IVC thrombus extending 5 cm superiorly. When compared with the previous CT, there was an extension of thrombus into both renal veins. Histopathology of a transjugular needle core biopsy showed a moderately differentiated leiomyosarcoma. The patient was transferred to a multidisciplinary sarcoma center for surgical resection, chemotherapy, and radiation therapy. CONCLUSIONS This report is of a rare case of IVC leiomyosarcoma in a middle-aged HIV-positive woman with a normal CD4 count. Leiomyosarcoma of the IVC is extremely rare, is often detected when advanced, and has a poor prognosis. This case report describes the clinical, imaging, surgical and histopathological findings of leiomyosarcoma of the IVC.

Hepatitis B Reactivation After Ifosfamide Therapy for Retroperitoneal Sarcoma.

BACKGROUND: Patients receiving cancer treatment are at risk for hepatitis B virus (HBV) reactivation. Ifosfamide is an alkylating agent and is considered to be one of the important drugs for the treatment of metastatic sarcoma. No association of ifosfamide and HBV reactivation has been reported so far. CASE REPORT: We report a case of a 61-year-old Asian man with metastatic retroperitoneal liposarcoma who was HBcAb positive and was treated with ifosfamide and dacarbazine, developed HBV reactivation secondary to ifosfamide requiring treatment with tenofovir. To the best of our knowledge, this is the first report describing HBV reactivation in a patient with positive HBcAb who was treated with ifosfamide. CONCLUSIONS: We recommend close surveillance of possible HBV reactivation while employing ifosfamide chemotherapy.

Liver Metastases in Prostate Carcinoma Represent a Relatively Aggressive Subtype Refractory to Hormonal Therapy and Short-Duration Response to Docetaxel Monotherapy.

BACKGROUND: We report a single institution's experience from a small series of patients suggesting that liver metastasis in metastatic castration-refractory prostate cancer (mCRPC) represents a relatively aggressive subtype that is refractory to hormonal manipulation treatment, including luteinizing hormone-releasing hormone agonist (LA) and abiraterone (Ab) therapy, although docetaxel is briefly effective. METHODS: Between 2007 and 2013, six patients with prostate cancer with liver metastases were analyzed. Biochemical response was defined as > 50% decrease in prostate-specific antigen (PSA) value. RESULTS: Two patients who presented with liver metastases died in less than 3 months after LA therapy. Two out of three patients (one died while receiving chemotherapy) received Ab after chemotherapy did not show any response and died while on therapy. One patient who presented with lung metastases initially received LA therapy and progressed on it with liver metastases in < 6 months. Thus, five of six patients did not respond to hormone therapy including LA and Ab. Three patients who received docetaxel after LA therapy had more than 50% objective PSA response with a mean survival of 4 months. CONCLUSIONS: No literature addresses the response to hormone treatment in hepatic metastasis in prostate carcinoma. This small series suggests that liver metastases in prostate carcinoma represent a relatively aggressive subset against which hormonal therapy, including the LA and Ab, appears to be ineffective. Although our patients responded to docetaxel chemotherapy, their responses were of short duration. A further clinical trial involving more patients will be necessary to substantiate our findings.