High-throughput simultaneous screen and counterscreen identifies homoharringtonine as synthetic lethal with von Hippel-Lindau loss in renal cell carcinoma

Renal cell carcinoma (RCC) accounts for 85% of primary renal neoplasms, and is rarely curable when metastatic. Approximately 70% of RCCs are clear-cell type (ccRCC), and in >80% the von Hippel-Lindau (VHL) gene is mutated or silenced. We developed a novel, high-content, screening strategy for the identification of small molecules that are synthetic lethal with genes mutated in cancer. In this strategy, the screen and counterscreen are conducted simultaneously by differentially labeling mutant and reconstituted isogenic tumor cell line pairs with different fluorochromes and using a highly sensitive high-throughput imaging-based platform. This approach minimizes confounding factors from sequential screening, and more accurately replicates the in vivo cancer setting where cancer cells are adjacent to normal cells. A screen of ~12,800 small molecules identified homoharringtonine (HHT), an FDA-approved drug for treating chronic myeloid leukemia, as a VHL-synthetic lethal agent in ccRCC. HHT induced apoptosis in VHL-mutant, but not VHL-reconstituted, ccRCC cells, and inhibited tumor growth in 30% of VHL-mutant patient-derived ccRCC tumorgraft lines tested. Building on a novel screening strategy and utilizing a validated RCC tumorgraft model recapitulating the genetics and drug responsiveness of human RCC, these studies identify HHT as a potential therapeutic agent for a subset of VHL-deficient ccRCCs.     

双相恶性子宫肿瘤:一例报道及文献复习(英文)

We present a rare case of a 50-year old lady who presented with pain abdomen and bleeding per vaginum of 3 months duration. Per vaginal examination revealed an exophytic growth arising from vault. Histopathological examination of the vault biopsy showed malignant neoplasm with features suggestive of carcinosarcoma of vault with immunohistochemistry showing stromal cells positive for CD10 and negative for SMA. Ki67 index was 40%-50%. She received external beam radiotherapy to pelvis 50.4 Gy/25 fractions but did not respond to the same. The lesion was not surgically resectable and hence referred to the division of medical oncology for chemotherapy. She was started on ifosphamide with cisplatin with growth factor support. It was planned to do a reassessment after 3 cycles of chemotherapy, but patient succumbed to the illness.     

Isolated Pupil-Involving Third Nerve Palsy as the First Presentation of Sarcoidosis

Neurosarcoidosis is seen in 5–15% of patients with systemic sarcoidosis. The most common cranial nerve presentations are optic neuropathy and facial nerve palsy. The authors present a case of sarcoidosis presenting with a pupil-involving third nerve palsy. The patient responded to corticosteroid therapy with resolution of investigations her cranial nerve palsy but progressed to develop cerebellar signs. This is the first documented case of a pupil-involving third nerve palsy occurring as the first presentation of neurosarcoidosis. Although typically a pupil-involving third nerve palsy necessitates urgent neuroimaging to rule out a posterior communicating artery aneurysm, it is important to recognise inflammatory causes in the differential diagnosis.     

Triple Leads Programmed to Perform as Longitudinal Guarded Cathodes in Spinal Cord Stimulation: A Modeling Study

Objective: In spinal cord stimulation, neurosurgeons increasingly tend to implant dual leads. Dual leads (longitudinal bipole/tripole) provide medio‐lateral control over the recruited dorsal column (DC) area by steering the injected cathodal currents. However, the DC recruited area is suboptimal when dual aligned leads straddling the midline programmed as longitudinal guarded cathodes (+−+) are used instead of a single lead placed over the spinal cord midline with the same configuration. As a potential improvement, an additional third lead between the two aligned leads is modeled to maximize the medio‐lateral extent of the DCs at the low‐thoracic vertebral region (T10‐T12). Methods and Materials: The University of Twente Spinal Cord Stimulation software (UT‐SCS) is used in this modeling study. Longitudinal guarded cathodes were modeled on the low‐thoracic vertebral region (T10‐T12) using percutaneous triple lead configurations. The central lead was modeled over the spinal cord midline and the two lateral leads were modeled at several transverse distances to the midline lead. Medio‐lateral field steering was performed with the midline lead and the second lead on each side to achieve constant anodal current ratios and variable anodal current ratios. Results: Reducing the transverse lead separation resulted in increasing the depths and widths of the recruited DC area. The triple lead configuration with the least transverse separation had the largest DC recruited area and usage range. The maximum DC recruited area (in terms of both depth and width) was always found to be larger under variable anodal current ratio than constant anodal current ratio conditions. Conclusions: Triple leads programmed to perform as longitudinal guarded cathodes provide more postoperative flexibility than single and dual leads in covering a larger width of the low‐thoracic DCs. The transverse separation between the leads is a major determinant of the area and distribution of paresthesia.