tbuckley/cabot-search huggingface dataset:
Hand-foot skin reaction (HFSR) and overall survival (OS) in the phase 3 RESORCE trial of regorafenib for treatment of hepatocellular carcinoma (HCC) progressing on sorafenib.
Authors: Jordi Bruix, Philippe Merle, Alessandro Granito, Yi-Hsiang Huang, Gyorgy Bodoky, Osamu Yokosuka, Olivier Rosmorduc, Valeriy Vladimirovich Breder, René Gerolami, Gianluca Masi, Paul J. Ross, Shukui Qin, Tianqiang Song, Jean-Pierre Bronowicki, Isabelle Ollivier-Hourmand, Masatoshi Kudo, Lei Xu, Annette Baumhauer, Gerold Meinhardt, Guohong Han
Journal: Journal of Clinical Oncology (2018)

412 Background: Skin toxicity is a known adverse effect of multikinase inhibitors, and was shown to be a predictor of OS in patients (pts) with HCC treated with sorafenib (Reig M, 2014). In the RESORCE trial, regorafenib improved OS versus placebo in pts with HCC progressing on sorafenib (HR 0.62, 95% CI 0.50, 0.78; Bruix J, 2017). This retrospective analysis explored whether HFSR with regorafenib was associated with OS in RESORCE. Methods: Pts in RESORCE who were randomized to regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS (95% CI) were calculated using the Kaplan–Meier method. Pts who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of 379 pts randomized, 374 received at least one dose of regorafenib. Of the treated pts, 53% (n = 199) had HFSR of any grade and 13% (n = 47) had grade 3 HFSR. Among pts with HFSR at any time during the study, 77% (n = 153) had the first HFSR event (any grade) during Cycle 1. Subgroups of pts with and without HFSR at any time had some imbalances in baseline characteristics (Table). OS was improved in pts who had HFSR at any time versus those who did not (Table). Pts who had a HFSR event during Cycle 1 also had improved OS versus those who did not (median OS 13.2 vs 8.5 months; HR 0.66, 95% CI 0.51, 0.86). Conclusions: In this post-hoc exploratory analysis, HFSR with regorafenib was associated with improved OS, as was previously shown for sorafenib. The potential confounding influence of baseline factors requires further investigation. Clinical trial information: NCT01774344. [Table: see text]
Heat Shock Factor 1 Epigenetically Stimulates Glutaminase-1-Dependent mTOR Activation to Promote Colorectal Carcinogenesis
Authors: Jiaqiu Li, Ping Song, Tingting Jiang, Dongjun Dai, Hanying Wang, Jie Sun, Liyuan Zhu, Wenxia Xu, Lifeng Feng, Vivian Y. Shin, Helen Morrison, Xian Wang, Hongchuan Jin
Journal: Molecular Therapy (2018)
Detection of human parvovirus B19 infection in the thymus of patients with thymic hyperplasia-associated myasthenia gravis
Authors: L. Gong, Y. Li, X. Li, Q. Tu, X. Mou, S. Wang, Y. Wan, Q. Lu, J. Wang, W. Zhang, S. Zhu, X. Han, L. Yao, J. Zhang, G. Huang, W. Zhang
Journal: Clinical Microbiology and Infection (2018)
FDA Approval Summary: Niraparib for the Maintenance Treatment of Patients with Recurrent Ovarian Cancer in Response to Platinum-Based Chemotherapy
Authors: Gwynn Ison, Lynn J. Howie, Laleh Amiri-Kordestani, Lijun Zhang, Shenghui Tang, Rajeshwari Sridhara, Vadryn Pierre, Rosane Charlab, Anuradha Ramamoorthy, Pengfei Song, Fang Li, Jingyu Yu, Wimolnut Manheng, Todd R. Palmby, Soma Ghosh, Hisani N. Horne, Eunice Y. Lee, Reena Philip, Kaushalkumar Dave, Xiao Hong Chen, Sharon L. Kelly, Kumar G. Janoria, Anamitro Banerjee, Okponanabofa Eradiri, Jeannette Dinin, Kirsten B. Goldberg, William F. Pierce, Amna Ibrahim, Paul G. Kluetz, Gideon M. Blumenthal, Julia A. Beaver, Richard Pazdur
Journal: Clinical Cancer Research (2018)

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17-0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066-71. ©2018 AACRSee related commentary by Konstantinopoulos and Matulonis, p. 4062.
Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study
Authors: Carlo Gambacorti‐Passerini, Sergey Orlov, Li Zhang, Fadi Braiteh, Huiqiang Huang, Taito Esaki, Keizo Horibe, Jin‐Seok Ahn, Joseph T. Beck, William Jeffrey Edenfield, Yuankai Shi, Matthew Taylor, Kenji Tamura, Brian A. Van Tine, Shang‐Ju Wu, Jolanda Paolini, Paulina Selaru, Tae Min Kim
Journal: American Journal of Hematology (2018)

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK-positive or ROS1-positive advanced non-small-cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large-cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single-arm, open-label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK-positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty-four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28-77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30-93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2-36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2-year progression-free survival of 63% and 67%, respectively. The most common treatment-related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK-positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long-term treatment.
151P Maintenance therapy using tyrosine kinase inhibitor (erlotinib) or pemetrexed in metastatic/locally advanced in EGFR mutation-negative lung cancer: Comparison of results
Authors: K. Gupta, A. Joshi, V. Noronha, S.K. Parthiban, V. Patil, A. Janu, R. Kaushal, K. Prabhash
Journal: Journal of Thoracic Oncology (2018)
The Plausibility of Obesity Paradox in Cancer—Point
Authors: Yikyung Park, Lindsay L. Peterson, Graham A. Colditz
Journal: Cancer Research (2018)

In contrast to the convincing evidence that obesity (measured by body mass index, BMI) increases the risk of many different types of cancer, there is an ambiguity in the role of obesity in survival among cancer patients. Some studies suggested that higher BMI decreased mortality risk in cancer patients, a phenomenon called the obesity paradox. The spurious positive association between BMI and cancer survival is likely to be explained by several methodologic limitations including confounding, reverse causation, and collider stratification bias. Also, the inadequacy of BMI as a measure of body fatness in cancer patients commonly experiencing changes in body weight and body composition may have resulted in the paradox. Other factors contributing to the divergent results in literature are significant heterogeneity in study design and method (e.g., study population, follow-up length); time of BMI assessment (pre-, peri-, or post-diagnosis); and lack of consideration for variability in the strength and directions of associations by age, sex, race/ethnicity, and cancer subtype. Robust but practical methods to accurately assess body fatness and body compositions and weight trajectories in cancer survivors are needed to advance this emerging field and to develop weight guidelines to improve both the length and the quality of cancer survival. Cancer Res; 78(8); 1898-903. ©2018 AACR.
Medulloblastoma: From Molecular Subgroups to Molecular Targeted Therapies
Authors: Jun Wang, Alexandra Garancher, Vijay Ramaswamy, Robert J. Wechsler-Reya
Journal: Annual Review of Neuroscience (2018)

Brain tumors are the leading cause of cancer-related death in children, and medulloblastoma (MB) is the most common malignant pediatric brain tumor. Advances in surgery, radiation, and chemotherapy have improved the survival of MB patients. But despite these advances, 25–30% of patients still die from the disease, and survivors suffer severe long-term side effects from the aggressive therapies they receive. Although MB is often considered a single disease, molecular profiling has revealed a significant degree of heterogeneity, and there is a growing consensus that MB consists of multiple subgroups with distinct driver mutations, cells of origin, and prognosis. Here, we review recent progress in MB research, with a focus on the genes and pathways that drive tumorigenesis, the animal models that have been developed to study tumor biology, and the advances in conventional and targeted therapy.
Embolization of Struts from an Inferior Vena Cava Filter
Authors: Laura D Flannery, Noam Shabani
Journal: New England Journal of Medicine (2018)

A 28-year-old woman who had had deep venous thrombosis and pulmonary embolus 10 years earlier presented with flank pain and was found to have multiple struts from an inferior vena cava filter that had embolized to the abdomen and right ventricle.
Perspectives from the community setting: A retrospective chart review of nivolumab for previously treated non-small cell lung cancer.
Authors: Brian Richard Nhan, Swati Kulkarni
Journal: Journal of Clinical Oncology (2017)

86 Background: Lung cancer is among the most commonly diagnosed cancers in Canada and is the leading cause of cancer deaths. Non-small cell lung cancer (NSCLC) is one of the most common types representing 85-90% of cases. Compared to other cancers, the five-year survival rate for lung cancer in Canada is among the lowest at 17%. Nivolumab has been in use in the setting of progression of previously treated NSCLC at the Windsor Regional Cancer Center since June 2015. This retrospective chart review abstracts data from 26 patients at WRCC with NSCLC who were treated with nivolumab. Methods: A retrospective chart review of 26 patients treated with nivolumab in the setting of progressive NSCLC. Results: 26 patients were reviewed (1 stage 2a, 2 stage 3a, 3 stage 3b, 20 stage 4 with 12 M1b and 8 M1a). Grade 1-2 side effects were documented in 4 patients treated with monitoring and no discontinuation or dose modification of nivolumab. A grade 3 side effect was documented in 1 patient leading to discontinuation of treatment. 3 living patients discontinued treatment due to progression. 6 patients died while on treatment secondary to disease progression. The remaining patients are on nivolumab with no side effects documented. Conclusions: As the use of immuno-oncology agents use expand in community clinics, opportunities arise from community data to further learn which patients benefit from these treatments, what side effects can occur and how to manage them, and how response to treatment may look. Out of the 26 patients receiving nivolumab, 5 patients had documented side effects resulting in discontinuation of treatment in 1 patient. Overall nivolumab has been well tolerated in patients with NSCLC in this community setting.
Correlation of T-cell infiltration and clonality with PD-L1 expression in soft tissue sarcomas.
Authors: Seth Pollack, Qianchuan He, Jennifer Yearley, Ryan O Emerson, Marissa Vignali, Yuzheng Zhang, Mary Redman, Elizabeth Trice Loggers, Lee D. Cranmer, Venu Gopal Pillarisetty, Robert Ricciotti, Benjamin L Hoch, Erin Murphy, Terrill K McClanahan, Wendy Blumenschein, Steven Matthew Townson, Sharon Benzeno, Stanley R. Riddell, Robin Lewis Jones
Journal: Journal of Clinical Oncology (2017)

23 Background: The success of immunotherapy has raised new issues regarding the selection of patients, design of combination strategies, and sequencing of various regimens. Sarcomas have poor outcomes in the metastatic setting but may be amenable to immune therapies. However, we currently have limited knowledge of the immunologic profiles of different soft tissue sarcoma (STS) subtypes. Methods: We identified patients with the relatively common STS subtypes: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS) and liposarcoma. Formalin fixed paraffin embedded (FFPE) tumor samples from 81 patients underwent gene expression analysis, immunohistochemistry for PD-1 and PD-L1, and sequencing of the T cell receptor Vβ region. Differences in liposarcoma subsets were also evaluated. Results: UPS and LMS had high expression levels of genes related to antigen presentation and T cell infiltration. UPS had higher levels of PD-L1 (p ≤ 0.001) and PD-1 (p ≤ 0.05) on IHC. UPS also had the highest T cell infiltration based on TCR sequencing, significantly more than SS, which had the lowest (p ≤ 0.05). UPS and LMS both had higher clonality compared with SS and liposarcoma (p ≤ 0.05). A model adjusted for STS histologic subtype found that for all sarcoma T cell infiltration and clonality were highly correlated with PD-1 and PD-L1 staining levels (p ≤ 0.01). Conclusions: In a model adjusted for sarcoma histologic subtypes, T cell infiltration and clonality were highly correlated with PD-1 and PD-L1 expression, consistent with the emerging view of tumor immunity that highly inflamed tumors acquire inhibitory ligands to evade tumor-specific T cells. UPS, which is a more highly mutated STS subtype, provokes a strong immune response evidenced by multiple inflammatory features suggesting that it may be well-suited to checkpoint inhibitor based approaches. SS and liposarcoma subsets are less highly mutated but do express immunogenic self-antigens therefore strategies to improve antigen presentation and T cell infiltration may be valuable for allowing immunotherapeutic success in these tumor types.
Notch Pathway Activation Targets Leukemic Stem Cells in Chronic-Phase Chronic Myeloid Leukemia (CP-CML)
Authors: Gillian A. Horne, Heather Morrison, Victoria Campbell, Ross Kinstrie, Jennifer Cassels, Alan Hair, David Vetrie, Helen Wheadon, Tessa L. Holyoake, Mhairi Copland
Journal: Blood (2016)
The MEF2 transcriptional target DMPK induces loss of sarcomere structure and cardiomyopathy
Authors: Amin Damanafshan, Ies Elzenaar, Benoit Samson-Couterie, Ingeborg van der Made, Meriem Bourajjaj, Maarten M van den Hoogenhof, Henk A van Veen, Daisy I Picavet, Abdelaziz Beqqali, Elisabeth Ehler, Leon J De Windt, Yigal M Pinto, Ralph J van Oort
Journal: Cardiovascular Research (2018)

The pathology of heart failure is characterized by poorly contracting and dilated ventricles. At the cellular level, this is associated with lengthening of individual cardiomyocytes and loss of sarcomeres. While it is known that the transcription factor myocyte enhancer factor-2 (MEF2) is involved in this cardiomyocyte remodelling, the underlying mechanism remains to be elucidated. Here, we aim to mechanistically link MEF2 target genes with loss of sarcomeres during cardiomyocyte remodelling.Neonatal rat cardiomyocytes overexpressing MEF2 elongated and lost their sarcomeric structure. We identified myotonic dystrophy protein kinase (DMPK) as direct MEF2 target gene involved in this process. Adenoviral overexpression of DMPK E, the isoform upregulated in heart failure, resulted in severe loss of sarcomeres in vitro, and transgenic mice overexpressing DMPK E displayed disruption of sarcomere structure and cardiomyopathy in vivo. Moreover, we found a decreased expression of sarcomeric genes following DMPK E gain-of-function. These genes are targets of the transcription factor serum response factor (SRF) and we found that DMPK E acts as inhibitor of SRF transcriptional activity.Our data indicate that MEF2-induced loss of sarcomeres is mediated by DMPK via a decrease in sarcomeric gene expression by interfering with SRF transcriptional activity. Together, these results demonstrate an unexpected role for DMPK as a direct mediator of adverse cardiomyocyte remodelling and heart failure.
Targeting Hif1a rescues cone degeneration and prevents subretinal neovascularization in a model of chronic hypoxia
Authors: Maya Barben, Christian Schori, Marijana Samardzija, Christian Grimm
Journal: Molecular Neurodegeneration (2018)

Degeneration of cone photoreceptors leads to loss of vision in patients suffering from age-related macular degeneration (AMD) and other cone dystrophies. Evidence, such as choroidal ischemia and decreased choroidal blood flow, implicates reduced tissue oxygenation in AMD pathology and suggests a role of the cellular response to hypoxia in disease onset and progression. Such a chronic hypoxic situation may promote several cellular responses including stabilization of hypoxia-inducible factors (HIFs). To investigate the consequence of a chronic activation of the molecular response to hypoxia in cones, von Hippel Lindau protein (VHL) was specifically ablated in cones of the all-cone R91W;Nrl -/- mouse. Retinal function and morphology was evaluated by ERG and light microscopy, while differential gene expression was tested by real-time PCR. Retinal vasculature was analyzed by immunostainings and fluorescein angiography. Two-way ANOVA with Šídák's multiple comparison test was performed for statistical analysis. Cone-specific ablation of Vhl resulted in stabilization and activation of hypoxia-inducible factor 1A (HIF1A) which led to increased expression of genes associated with hypoxia and retinal stress. Our data demonstrate severe cone degeneration and pathologic vessel growth, features that are central to AMD pathology. Subretinal neovascularization was accompanied by vascular leakage and infiltration of microglia cells. Interestingly, we observed increased expression of tissue inhibitor of metalloproteinase 3 (Timp3) during the aging process, a gene associated with AMD and Bruch's membrane integrity. Additional deletion of Hif1a protected cone cells, prevented pathological vessel growth and preserved vision. Our data provide evidence for a HIF1A-mediated mechanism leading to pathological vessel growth and cone degeneration in response to a chronic hypoxia-like situation. Consequently, our results identify HIF1A as a potential therapeutic target to rescue hypoxia-related vision loss in patients.
Metastatic uveal melanoma showing durable response to anti-CTLA-4 and anti-PD-1 combination therapy after experiencing progression on anti-PD-1 therapy alone
Authors: Muhammad Zubair Afzal, Rodwell Mabaera, Keisuke Shirai
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Uveal melanoma accounts for 85% of the ocular melanomas and has an increased risk of hematogenous spread, most commonly to the liver. After curative intent therapy like surgery and radiation, fifty percent of patients present with distant metastasis. Metastatic uveal melanoma (MUM) does not harbor typically targetable mutations, e.g., BRAF as in cutaneous melanoma. As a result, there is no proven therapy for MUM. Various chemotherapy and immunotherapy regimens have been tried and only partial response (PR) is the best that has been achieved in most of the cases. Here, we present a case of MUM treated with combination immune checkpoint therapy (ipilimumab and nivolumab) following the progression with single-agent nivolumab and demonstrating a durable response without recurrence more than 22 months from the last treatment. <h3>Case Presentation</h3> A 72-year-old Caucasian man presented with ciliary body melanoma of the left eye and underwent curative-intent enucleation but six months later developed diffuse hepatic metastases. He initially was treated with nivolumab 3 mg/kg every two weeks for four cycles but restaging scan showed a significant progression of the disease with increasing LDH. With the FDA approval for the combination of nivolumab 1mg/kg with Ipilimumab 3 mg/kg every three weeks for metastatic melanoma, this combination was given for four cycles with continuous rise in LDH to 993 unit/L (110-220 unit/L) until finishing cycle four of the treatment. Three weeks later, maintainence nivolumab 3mg/kg was initiated but two weeks later, he developed grade 4 liver toxicity&nbsp;with ALT 1565 unit/L (0-55 unit/L). A presumptive diagnosis of autoimmune hepatitis was made, nivolumab was stopped and oral prednisone 1mg/kg was started with quick resolution of elevated transaminases. Restaging abdominal MRI one month after the first and last dose of maintenance nivolumab showed PR and continuous shrinkage of the metastatic lesions with no hypermetabolic activity even on PET/CT. He is 22 months9 post-treatment and continues to do well without any evidence of active disease. <h3>Conclusion</h3> Although, limited response has been shown to single agent immune checkpoint inhibitors and chemotherapy, our patient showed durable response with anti-CTLA-4 and anti-PD-1 combination therapy in MUM.
A 58-Year-Old Man With a Macerated Rash of the Neck and Axilla
Authors: Christopher Haley, Uyen Ngoc Mui, Stephen K. Tyring
Journal: JAMA (2018)

An African American man presented with a 5-year history of a pruritic and painful rash of the right lateral area of the neck and right axilla that worsened in the summer and sometimes blistered. A sister had a similar rash. What would you do next?
Hiding in Plain Sight: Rediscovering the Importance of Noncoding RNA in Human Malignancy
Authors: Kyle P. Feeley, Mick D. Edmonds
Journal: Cancer Research (2018)

Abstract At the time of its construction in the 1950s, the central dogma of molecular biology was a useful model that represented the current state of knowledge for the flow of genetic information after a period of prolific scientific discovery. Unknowingly, it also biased many of our assumptions going forward. Whether intentional or not, genomic elements not fitting into this paradigm were deemed unimportant and emphasis on the study of protein-coding genes prevailed for decades. The phrase “Junk DNA,” first popularized in the 1960s, is still used with alarming frequency to describe the entirety of noncoding DNA. It has since become apparent that RNA molecules not coding for protein are vitally important in both normal development and human malignancy. Cancer researchers have been pioneers in determining noncoding RNA function and developing new technologies to study these molecules. In this review, we will discuss well known and newly emerging species of noncoding RNAs, their functions in cancer, and new technologies being utilized to understand their mechanisms of action in cancer. Cancer Res; 78(9); 2149–58. ©2018 AACR.