Unconventional mechanism of action and resistance to rapalogs in renal cancer.

mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTORS2035T mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.

You Can Change a Girl's Life Today: The Truth About Periods and Endometriosis.

While endometriosis, a condition where tissue growing outside the uterus causes pain and infertility, is generally widespread among teenage girls and women, it is often misdiagnosed leading to a delay in treatment while the symptoms and damage from the disease increase. This article uses a case study to illustrate the signs and symptoms of endometriosis in a teenage girl, while also discussing many factors surrounding the issue such as the incidence, disease burden, medical research and women, reasons for diagnostic delay, and the current recommended treatments. School nurses are in the unique position to identify young girls and adolescents who are presenting with painful periods or other symptoms possibly associated with endometriosis and can become advocates for the next generation of patients.

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade.

Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutations, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. Bap1-deficient tumors were of high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells.Significance: Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that Bap1 and Pbrm1 loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. Cancer Discov; 7(8); 900-17. ©2017 AACR.See related commentary by Leung and Kim, p. 802This article is highlighted in the In This Issue feature, p. 783.

Application of a standardized screening protocol for diagnosis of invasive mold infections in children with hematologic malignancies.

PURPOSE: This study describes a standardized screening protocol for diagnosis of invasive mold infections in pediatric oncology patients with neutropenia and prolonged or recurrent fever. METHODS: A retrospective chart review was performed of children receiving intensive chemotherapy for hematologic malignancies who developed invasive mold infections from 2004 to 2011. Characteristics and outcomes were compared before and after implementation of the screening protocol in November 2006. The screen includes direct nasal endoscopy performed at the bedside by an otorhinolaryngologist, noncontrast computed tomography (CT) of the chest, and abdominal ultrasound in patients with neutropenia and prolonged or recurrent fever. RESULTS: Fifty patients had proven, probable, or possible invasive mold infections. Before routine use of direct nasal endoscopy, invasive nasosinal disease was detected in 5 of 19 patients (26 %) and all had a compatible clinical presentation. Thirteen of 31 patients (42 %) in the post-screen group had nasosinal disease, and fever was the only sign for 8 patients (62 %). Twenty-four patients with nasosinal disease had a sinus CT, and radiologic findings of bony erosion or peri-sinus invasion were never detected. Eight of 19 patients in the pre-screen group died from mold infection (42.1 %) versus 4 of 31 (12.9 %) in the post-screen group (p = 0.04). CONCLUSIONS: A screening protocol including direct nasal endoscopy, noncontrast chest CT, and abdominal ultrasound was effective in detecting invasive mold infections in at-risk patients. Nasosinal involvement often occurs before specific symptoms develop, and sinus CTs are insensitive and nonspecific. Bedside nasal endoscopy precludes radiation exposure associated with sinus CT and was associated with decrease in mold-related mortality, likely due to earlier diagnosis and initiation of appropriate antifungal therapy.

Immune thrombocytopenia and alopecia areata: spontaneous occurrence and resolution in the same patient.

Alopecia areata (AA) and immune thrombocytopenia (ITP) are autoimmune conditions occasionally encountered by pediatricians, but their simultaneous occurrence is rare. We describe here a 7-year-old female who acutely developed both AA and ITP. Within 3 months both conditions resolved spontaneously, suggesting a pathophysiologic relationship.