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Renal calyceal rupture (RCR) is a rare phenomenon most commonly caused by increased renal pelvic pressure from ureteral obstruction. This can occur in the setting of acute obstruction such as with kidney stones and is not commonly seen as a consequence of malignancy due to the chronic nature of obstruction. In this case, we describe a patient with newly diagnosed cervical cancer presenting with thigh pain who was found to have a urinoma from RCR caused by malignant obstruction. We discuss the workup of a pelvic mass presenting as flank pain, as well as the role of history and physical exam when reviewing imaging. We also review the management of RCR in the setting of malignant obstruction. Lastly we highlight the alterations to cervical cancer treatment due to the presence of the infected urinoma. [ABSTRACT FROM AUTHOR]

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm which typically originates from liver, lung, or bone. Due to the low incidence of disease, the most effective treatment is not easily studied and much of the information known about EHE has been learned through case reports and case series. In this case, we will present an uncommon form of primary soft tissue EHE with local recurrence, bone metastasis, and lymphangitic spread to the lungs leading to respiratory failure. Imaging of the chest was atypical for EHE with intraseptal thickening and hilar lymphadenopathy. Respiratory failure was progressive despite aggressive multimodal treatment. This case highlights an unusually aggressive recurrence and metastasis of primary soft tissue EHE with atypical pulmonary imaging findings. [ABSTRACT FROM AUTHOR]

• PARP inhibitors are extremely effective treatment for patients with BRCA mutated ovarian cancer. • PARP inhibitors may cause clinical and financial toxicity without clinical benefit for patients with HRP ovarian cancer. • A "PARPi for all" strategy ignores critical lessons learned from the success of precision medicine. [ABSTRACT FROM AUTHOR]

Background: More than 80% of patients with advanced cancer develop weight loss. Because preclinical data suggest poly (ADP-ribose) polymerase (PARP) inhibitors can treat this weight loss, this study was undertaken to explore the PARP inhibitor veliparib for this indication. Objective: The current study was undertaken to analyze prospectively gathered data on weight in cancer patients on PARP inhibitors. Design/Setting: The current study relied on a previously published, prospectively conducted phase 1 single institution trial that combined veliparib and topotecan (NCT01012817) as antineoplastic therapy for advanced cancer patients. Serial weight data and, when available and clinically relevant, computerized tomography scans were also examined. Measurements: The primary endpoint was 10% or greater weight gain from trial enrollment. Results: Nearly all 60 patients lost weight over time. Only one patient manifested a 10% or greater gain in weight. However, review of computerized tomography L3 images showed this weight gain was a manifestation of ascites. Four other patients gained 5% of their baseline weight. However, findings in two patients with available radiographs showed no evidence of muscle augmentation. Conclusions: The addition of the PARP inhibitor veliparib to chemotherapy does not appear to result in notable weight gain or in weight maintenance in patients with advanced cancer. Interventions other than PARP inhibitors should be considered for the palliation/treatment of cancer-associated weight loss. [ABSTRACT FROM AUTHOR]

Anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta-analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti-CTLA-4 or anti-PD-1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression-free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76-0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59-0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76-0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune-related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65-9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti-PD-1 treatment compared to anti-CTLA-4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti-PD-1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and anti-apoptotic signaling in various lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are typically partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing a variety of lymphoid malignancies. OSI-027, but not rapamycin, inhibited phosphorylation of Akt at Ser473, a direct target of mTORC2, in multiple lymphoid lines. In further contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended upon transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Consistent with these results, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, upregulated Puma, and induced regressions in Jeko xenografts, derived from a patient with mantle cell lymphoma. Collectively, these studies not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Studies in tissue culture cell lines have indicated that silencing of the mitotic regulator CHFR is associated with increased paclitaxel sensitivity. More recently, it has been suggested that a UBC13-DNMT1-CHFR pathway also modulates sensitivity of ovarian cancer to paclitaxel in the clinic. Here we have credentialed an anti-CHFR monoclonal antibody for immunohistochemistry and directly examined the association of CHFR expression with outcome of paclitaxel-containing ovarian cancer therapy. While CHFR levels were higher in high grade, high stage ovarian cancer, after correction for stage and debulking status there was no association between CHFR levels and progression-free survival in high grade serous ovarian cancer treated with surgery followed by platinum/taxane therapy. Moreover, there was no association between CHFR expression and response of patient-derived ovarian cancer xenografts treated with paclitaxel monotherapy. These studies indicate that CHFR varies among ovarian cancers but is unlikely to be an independent biomarker for poor response to taxanes. The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer. [ABSTRACT FROM AUTHOR]

Purpose of review: BRCA1 and BRCA2 mutation carriers can be at increased cardiovascular risk. The goal of this review is to provide information about factors associated with increased cardiovascular risk, methods to prevent cardiovascular toxicities, and recommended screening guidelines.Recent findings: BRCA1/2 mutation carriers who are diagnosed with cancer are often exposed to chemotherapy, chest radiotherapy, and/or HER2 directed therapies, all of which can be cardiotoxic. In addition, BRCA1/2 carriers often undergo prophylactic salpingoopherectomies, which may also increase cardiovascular risks.Summary: Understanding the potential for increased cardiovascular risk in individuals with a BRCA1 or BRCA2 mutation, as well as gold standard practices for prevention, detection, and treatment of cardiac concerns in this population, is important. [ABSTRACT FROM AUTHOR]

Replication stress and DNA damage activate the ATR-Chk1 checkpoint signaling pathway that licenses repair and cell survival processes. In this study, we examined the respective roles of the ATR and Chk1 kinases in ovarian cancer cells using genetic and pharmacologic inhibitors in combination with cisplatin, topotecan, gemcitabine, and the PARP inhibitor veliparib (ABT-888), four agents with clinical activity in ovarian cancer. RNA interference (RNAi)-mediated depletion or inhibition of ATR sensitized ovarian cancer cells to all four agents. In contrast, while cisplatin, topotecan, and gemcitabine each activated Chk1, RNAi-mediated depletion or inhibition of this kinase in cells sensitized them only to gemcitabine. Unexpectedly, we found that neither the ATR kinase inhibitor VE-821 nor the Chk1 inhibitor MK-8776 blocked ATR-mediated Chk1 phosphorylation or autophosphorylation, two commonly used readouts for inhibition of the ATR-Chk1 pathway. Instead, their ability to sensitize cells correlated with enhanced CDC25A levels. In addition, we also found that VE-821 could further sensitize BRCA1- depleted cells to cisplatin, topotecan, and veliparib beyond the potent sensitization already caused by their deficiency in homologous recombination. Taken together, our results established that ATR and Chk1 inhibitors differentially sensitize ovarian cancer cells to commonly used chemotherapy agents and that Chk1 phosphorylation status may not offer a reliable marker for inhibition of the ATR-Chk1 pathway. A key implication of our work is the clinical rationale it provides to evaluate ATR inhibitors in combination with PARP inhibitors in BRCA1/2-deficient cells. [ABSTRACT FROM AUTHOR]

The mammalian target of rapamycin (mTOR), a kinase that regulates proliferation and apoptosis, has been extensively evaluated as a therapeutic target in multiple malignancies. Rapamycin analogs, which partially inhibit mTOR complex 1 (mTORC1), exhibit immunosuppressive and limited antitumor activity, but sometimes activate survival pathways through feedback mechanisms involving mTORC2. Thus, attention has turned to agents targeting bothmTORcomplexes by binding themTORactive site. Herewe show that disruption of eithermTOR-containingcomplex is toxic to acutelymphocytic leukemia (ALL) cells and identify 2 previously unrecognized pathways leading to this cell death. Inhibition of mTORC1-mediated 4EBP1 phosphorylation leads to decreased expression of c-MYC and subsequent upregulation of the proapoptotic BCL2 family member PUMA, whereas inhibition of mTORC2 results in nuclear factor-κB–mediated expression of the Early Growth Response 1 (EGR1) gene, which encodes a transcription factor that binds and transactivates the proapoptotic BCL2L11 locus encoding BIM. Importantly, 1 or both pathways contribute to death of malignant lymphoid cells after treatment with dual mTORC1/mTORC2 inhibitors. Collectively, these observations not only provide new insight into the survival roles of mTOR in lymphoid malignancies, but also identify alterations that potentially modulate the action of mTOR dual inhibitors in ALL. [ABSTRACT FROM AUTHOR]