tbuckley/cabot-search huggingface dataset:
ATRT-35. SMARCB1-DEFICIENT TUMORS ACTIVATE BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES AND ARE SUSCEPTIBLE TO CHECKPOINT BLOCKADE AND TLR3 ACTIVATION
Authors: Amaury Leruste, Pamela Caudana, Arnault Tauziede-Espariat, Zhi-Yan Han, Rodrigo N Ramos, Jovan Nikolic, Jimena Tosello, Solene Brohard, Mamy Andrianteranagna, Céline Chauvin, Julien Masliah-Planchon, Christine Sedlick, Aurore Coulomb, Louise Galmiche-Rolland, Dominique Ranchere, Philippe Benaroch, Joshua J Waterfall, Olivier Delattre, Eliane Piaggio, Franck Bourdeaut
Journal: Neuro-Oncology (2018)

In order to evaluate the immune infiltrate of AT/RT, we conducted a combined immunohistochemical, multiparametric flow cytometry and transcriptomic analysis of a series of 49 human AT/RT. This revealed substantial heterogeneity, with some subgroups of AT/RT showing a prominent immune infiltrate. In details, our analyses indicated that: i) myeloid cells were the most abundant immune population, including both microglial cells and non-resident pro-tumoral M2-polarized macrophages, ii) tumor-infiltrating lymphocytes consisted in equal proportions of CD4+ and CD8+ T cells with few regulatory T cells, and iii) immune modulatory molecules PD-L1 and TIM-3 were expressed at high levels. Intratumoral cytolytic activity of CD8+ T cells highly correlated with both interferon gamma and alpha signatures, confirming the involvement of both adaptive and innate immune cells in the anti-tumor response. A genetically engineered mouse model of AT/RT recently established in our laboratory recapitulates many of these traits, including important infiltration by both lymphoid and myeloid cells sharing similar phenotypic characteristics. Using this model, we showed that blockade of the PD-1/PD-L1 pathway significantly impaired tumor growth and induced memory against a second engraftment, confirming an anti-tumoral T cell memory response. Combination with TIM-3 blockade showed synergistic effects. Additionally, targeting the myeloid infiltrate by TLR3 activation with poly(I:C) induced a potent anti-tumor effect which, combined with PD-1 blockade, led to complete tumor regression in over 85% of treated mice. In conclusion, we demonstrate that immune infiltration is a recurrent property of AT/RT and that immunotherapy, particularly combination regimens, have promising therapeutic potential.
2018 Consensus statement on exercise therapy and physical interventions (orthoses, taping and manual therapy) to treat patellofemoral pain: recommendations from the 5th International Patellofemoral Pain Research Retreat, Gold Coast, Australia, 2017
Authors: Natalie J Collins, Christian J Barton, Marienke van Middelkoop, Michael J Callaghan, Michael Skovdal Rathleff, Bill T Vicenzino, Irene S Davis, Christopher M Powers, Erin M Macri, Harvi F Hart, Danilo de Oliveira Silva, Kay M Crossley
Journal: British Journal of Sports Medicine (2018)

Patellofemoral pain affects a large proportion of the population, from adolescents to older adults, and carries a substantial personal and societal burden. An international group of scientists and clinicians meets biennially at the International Patellofemoral Research Retreat to share research findings related to patellofemoral pain conditions and develop consensus statements using best practice methods. This consensus statement, from the 5th International Patellofemoral Research Retreat held in Australia in July 2017, focuses on exercise therapy and physical interventions (eg, orthoses, taping and manual therapy) for patellofemoral pain. Literature searches were conducted to identify new systematic reviews and randomised controlled trials (RCTs) published since the 2016 Consensus Statement. The methodological quality of included systematic reviews and RCTs was graded using AMSTAR and PEDro, respectively. Evidence-based statements were developed from included papers and presented to a panel of 41 patellofemoral pain experts for consensus discussion and voting. Recommendations from the expert panel support the use of exercise therapy (especially the combination of hip-focused and knee-focused exercises), combined interventions and foot orthoses to improve pain and/or function in people with patellofemoral pain. The use of patellofemoral, knee or lumbar mobilisations in isolation, or electrophysical agents, is not recommended. There is uncertainty regarding the use of patellar taping/bracing, acupuncture/dry needling, manual soft tissue techniques, blood flow restriction training and gait retraining in patients with patellofemoral pain. In 2017, we launched the International Patellofemoral Research Network (www.ipfrn.org) to consolidate and grow our patellofemoral research community, facilitate collaboration and disseminate patellofemoral pain knowledge to clinicians and the general public. The 6th International Patellofemoral Research Retreat will be held in Milwaukee, Wisconsin, USA, in October 2019.
MicroRNA-125b Interacts with Foxp3 to Induce Autophagy in Thyroid Cancer
Authors: Shanshan Wang, Juekun Wu, Jianwei Ren, Alexander C. Vlantis, Ming-yue Li, Shirley Y.W. Liu, Enders K.W. Ng, Amy B.W. Chan, Ding-Cun Luo, Zhimin Liu, Wei Guo, Lingbin Xue, Siu Kwan Ng, C. Andrew van Hasselt, Michael C.F. Tong, George G. Chen
Journal: Molecular Therapy (2018)

Thyroid cancer is rapidly increasing in incidence worldwide. Although most thyroid cancer can be cured with surgery, radioactive iodine, and/or chemotherapy, thyroid cancers still recur and may become chemoresistant. Autophagy is a complex self-degradative process that plays a dual role in cancer development and progression. In this study, we found that miR-125b was downregulated in tissue samples of thyroid cancer as well as in thyroid cancer cell lines, and the expression of Foxp3 was upregulated. Further, we demonstrated that miR-125b could directly act on Foxp3 by binding to its 3′ UTR and inhibit the expression of Foxp3. A negative relationship between miR-125b and Foxp3 was thus revealed. Overexpression of miR-125b markedly sensitized thyroid cancer cells to cisplatin treatment by inducing autophagy through an Atg7 pathway in vitro and in vivo. Taken together, our findings demonstrate a novel mechanism by which miR-125b has the potential to negatively regulate Foxp3 to promote autophagy and enhance the efficacy of cisplatin in thyroid cancer. miR-125 may be of therapeutic significance in thyroid cancer. Thyroid cancer is rapidly increasing in incidence worldwide. Although most thyroid cancer can be cured with surgery, radioactive iodine, and/or chemotherapy, thyroid cancers still recur and may become chemoresistant. Autophagy is a complex self-degradative process that plays a dual role in cancer development and progression. In this study, we found that miR-125b was downregulated in tissue samples of thyroid cancer as well as in thyroid cancer cell lines, and the expression of Foxp3 was upregulated. Further, we demonstrated that miR-125b could directly act on Foxp3 by binding to its 3′ UTR and inhibit the expression of Foxp3. A negative relationship between miR-125b and Foxp3 was thus revealed. Overexpression of miR-125b markedly sensitized thyroid cancer cells to cisplatin treatment by inducing autophagy through an Atg7 pathway in vitro and in vivo. Taken together, our findings demonstrate a novel mechanism by which miR-125b has the potential to negatively regulate Foxp3 to promote autophagy and enhance the efficacy of cisplatin in thyroid cancer. miR-125 may be of therapeutic significance in thyroid cancer.
MBRS-41. DIFFERENTIAL microRNA EXPRESSION IN THE MOLECULAR SUBGROUPS OF MEDULLOBLASTOMAS: ROLE IN TUMOR BIOLOGY AND CLINICAL CHARACTERISTICS
Authors: Satishkumar Singh, Harish Bharambe, Raikamal Paul, Kedar Yogi, Pooja Panwalkar, Rakesh Jalali, Epari Sridhar, Aliasgar Moiyadi, Tejpal Gupta, Girish Chinnaswamy, Neelam Shirsat
Journal: Neuro-Oncology (2018)

Over 250 medulloblastoma tumors tissues from an Indian cohort have been molecularly classified using the microRNA based real time RT-PCR assay and correlated with clinical characteristics. The Indian cohort continues to show three distinct features viz. higher incidence of the WNT tumors particularly in the adult patients, higher male:female (9:1) ratio of Group 4 tumors and their lower incidence in adults. At the functional level, we have studied the effect of expression of several miRNAs differentially expressed in the medulloblastoma subgroups. The miRNA encoding genes were expressed in multiple medulloblastoma cell lines using inducible lentiviral vectors. MiR-193a expression was found to inhibit anchorage-independent growth and tumorigenicity of medulloblastoma cell lines. MiR-224 expression was found to increase radiation sensitivity of both medulloblastoma and glioblastoma cells and was found to down-regulate Apoptosis Inhibitor 5 gene. MiR-148a expression was found to inhibit tumorigenic and invasion potential of multiple medulloblastoma cells lines by targeting NRP1. MiR-30a and miR-206 are downregulated in all medulloblastoma subgroups as compared to normal brain tissues. MiR-30a was found to inhibit autophagy by targeting Beclin1 in medulloblastoma cells while miR-206 targets OTX2. Studies on two microRNAs miR-592 and miR-204, differentially expressed in the Group 3/Group 4 medulloblastomas will be presented.
Recurrent Amplification of the Heterochromatin Protein 1 (HP1) Gene Family across Diptera
Authors: Quentin Helleu, Mia T Levine
Journal: Molecular Biology and Evolution (2018)

The heterochromatic genome compartment mediates strictly conserved cellular processes such as chromosome segregation, telomere integrity, and genome stability. Paradoxically, heterochromatic DNA sequence is wildly unconserved. Recent reports that many hybrid incompatibility genes encode heterochromatin proteins, together with the observation that interspecies hybrids suffer aberrant heterochromatin-dependent processes, suggest that heterochromatic DNA packaging requires species-specific innovations. Testing this model of coevolution between fast-evolving heterochromatic DNA and its packaging proteins begins with defining the latter. Here we describe many such candidates encoded by the Heterochromatin Protein 1 (HP1) gene family across Diptera, an insect Order that encompasses dramatic episodes of heterochromatic sequence turnover. Using BLAST, synteny analysis, and phylogenetic tree building across 64 Diptera genomes, we discovered a staggering 121 HP1 duplication events. In contrast, we observed virtually no gene duplication in gene families that share a common "chromodomain" with HP1s, including Polycomb and Su(var)3-9. The remarkably high number of Dipteran HP1 paralogs arises from distant clades undergoing convergent HP1 family amplifications. These independently derived, young HP1s span diverse ages, domain structures, and rates of molecular evolution, including episodes of positive selection. Moreover, independently derived HP1s exhibit convergent expression evolution. While ancient HP1 parent genes are transcribed ubiquitously, young HP1 paralogs are transcribed primarily in male germline tissue, a pattern typical of young genes. Pervasive gene youth, rapid evolution, and germline specialization implicate heterochromatin-encoded selfish elements driving recurrent HP1 gene family expansions. The 121 young genes offer valuable experimental traction for elucidating the germline processes shaped by Diptera's many dramatic episodes of heterochromatin turnover.
Comorbidities (CM) and potential impact in outcomes of advanced colorectal cancer patients (ACC) in Argentina: EVIREPRO real life program - Trial in progress
Authors: A. Schmilovich, F. Ramello, M. Malicki, N. Colombo Berra, S. Rojo, G. Davila, V. Binner, H. Barrionuevo, J. Capria, M. Poggio, R. Arca, D. Tabares, D. Vicente, D. Santillan, J. Burre, M. Vazquez
Journal: Annals of Oncology (2018)

Introduction: CM may influence systemic treatment decisions in cancer care and it could potentially impact outcomes of patients (pts) who receive it. We sought to determine whether CM impacts systemic treatment and survival in pts with ACC. Methods: Pts with diagnosis of ACC between 11/2015 through 1/2018 were selected from the EVIREPRO database. The program is planned to include pts since 11/2015 to 11/2020.It is an electronic private database of real life office medical practice in oncology, hematology and other chronic ill conditions where 275 physicians from all over the country and related with the medical care of those disease conditions are participating. EVIREPRO is conducted by the Investigar Foundation and is funded by Grupo Biotoscana. All participants signed a contract before participation and pt anonymity is warranted. Physicians complete surveys and questionnaires at inclusion, follow up and exit of the program. They include diagnostic procedures (laboratory, biologic markers, and image studies), clinical data (tumor stage and sided location, comorbidities, performance status, quality of life, treatment response and tolerability) and previous treatments (surgery, radiotherapy, chemotherapy, target therapy or palliative treatment). CM was categorized as no CM or with CM. Pts in the last subset are stratified according 1, 2 or 3 or more CM. A multivariate Cox proportional model will be used to estimate the association of CM with overall survival. As of 1/31/2018, 81/203 enrolled pts have ACC.
ATRT-18. VALIDATION OF PROTEASOME INHIBITION AS A THERAPEUTIC TARGET IN ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Andrew Morin, Caroline Soane, Angela Pierce, Irina Alimova, Michele Desmarais, Shadi Zahedi, Rajeev Vibhakar, Andrea Griesinger, Adam Green, Lindsey Hoffman, Jean Mulcahy Levy
Journal: Neuro-Oncology (2018)

Atypical Teratoid/Rhabdoid tumor (AT/RT), characterized by loss-of-function mutations in the SMARCB1 component of the SWI/SNF chromatin-remodeling complex, remains a difficult-to-treat tumor with a five-year overall survival rate of 15–45%. Proteasome inhibition (PI) has recently been opened as an avenue for cancer treatment with the FDA approval of bortezomib (BTZ) in 2003 and carfilzomib (CFZ) in 2012. We performed a drug screen using a panel of 119 FDA-approved drugs in three AT/RT cell lines, and found that both BTZ and CFZ are highly effective in vitro, producing some of the strongest growth-inhibition responses of the entire panel. We further found that these results are consistent through all three established cell lines and a freshly patient-derived tumor culture, and that the effective doses are clinically achievable. BTZ and CFZ are limited for treatment of CNS tumors due to poor blood brain barrier (BBB) penetrance. Marizomib (MRZ) is a newer proteasome inhibitor which has been shown to cross the BBB, and is already in clinical trials for adult high-grade glioma (NCT NCT02330562 and NCT02903069). Proteasome inhibition causes rapid AT/RT cell death in vitro, which may be moderately inhibited by the addition of the ROS scavenger N-acetyl cysteine, consistent with studies in leukemic and glioma contexts. MRZ has been shown to be effective in vivo in other tumor models, and confirmation of the in vivo efficacy of MRZ in an intracranial AT/RT model demonstrating the clinical applicability of PI at both low and high-burden tumor stages is ongoing.
CADM1 is a diagnostic marker in early-stage mycosis fungoides: Multicenter study of 58 cases
Authors: Akihiko Yuki, Satoru Shinkuma, Ryota Hayashi, Hiroki Fujikawa, Taisuke Kato, Erina Homma, Yohei Hamade, Osamu Onodera, Masao Matsuoka, Hiroshi Shimizu, Hiroaki Iwata, Riichiro Abe
Journal: Journal of the American Academy of Dermatology (2018)
SWRK-02. WHOLE PERSON CARE IN PEDIATRIC ONCOLOGY: INSIGHT FOR CHAPLAIN-PHYSICIAN COLLABORATION
Authors: Alex Lion, Jodi Skiles, Beth Watson, Daniel Young, Alexia Torke
Journal: Neuro-Oncology (2018)

High quality care of pediatric neuro-oncology patients requires a whole person approach. Attending to spiritual needs is a crucial aspect of this. Understanding what the chaplain does precedes appropriate utilization and integration of spiritual care into clinical practice. To our knowledge, this research represents the first explicit description of what the chaplain does in pediatric oncology. We conducted a qualitative analysis of chaplain chart notes on the pediatric oncology service of a large children’s hospital. We selected 30 patients for thematic analysis of chaplain notes. The selection included a representative sample of patients who varied as to these factors: age, tumor type, prognosis, and mortality. Thematic analysis was applied to all chaplain notes from these 30 patients to derive a code book. The data in the code book was further explored to look for overarching themes. From the 166 pediatric patients diagnosed with cancer in the study period, 112 had at least one chaplain note. From the 30 patients selected, 230 chaplain encounters were documented. Four major themes emerged: 1. A rich description of the psychosocial and spiritual dimensions of the patient and family; 2. Deep, empathic listening as both an assessment tool and intervention; 3. Both universal and age specific interventions; and 4. A longitudinal therapeutic relationship. The chaplains’ observations are an important contribution to high quality whole person care. More prospective research is needed to test integrated chaplain interventions in a neuro-oncology team setting.
Underwater endoscopic mucosal resection of a laterally spreading tumor overlying a previous endoscopic carbon tattoo
Authors: Jaime Rodrigues, Rolando Pinho, Mafalda Sousa, João Silva, Catarina Gomes, João Carvalho
Journal: Endoscopy (2018)

A 53-year-old man with no relevant past medical history was referred to our department for resection of a laterally spreading tumor (LST) on the descending colon, which had been tattooed previously.
The prognostic value of systemic inflammatory factors in patients with HER2-positive metastatic gastric cancer
Authors: N. Martínez-Lago, R. Lesta-Mellid, C. Reboredo Rendo, M. Reboredo-Lopez, L. Antón Aparicio
Journal: Annals of Oncology (2018)

Introduction: Multiple studies have reported prognostic association of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLT) including patients with early and advanced gastric cancer. However, it is unknown the prognostic impact in patients with HER2-positive metastatic gastric cancer. Methods: We conducted an observational, retrospective, unicentric study of patients with metastatic HER2 positive gastric cancer treated at University Hospital of A Coruña (Spain). Demographic, clinic and pathological data were retrospectively collected and correlated with overall survival (OS) and progression free survival (PFS). Results: From 158 patients with metastatic gastric cancer treated between November 2010 to November 2017, we analyzed 18 HER2-positive cases. Clinicopathological characteristics: 100% intestinal histological tumor type, 44% low grade, 66.7% gastroesophageal junction location. With a median follow up of 39.6 months, median overall survival (OS) was 15.0 months and median first line progression free survival was 9.2 months. Neutrophil to lymphocyte ratio (HR 10.989; p = 0.007), and platelet to lymphocyte ratio (HR 6.329; p = 0.013) were independent prognostic factors for both OS and PFS. Patients with higher NLR (>3 vs. <3): had a significantly lower PFS 5.3 vs 16.8 (m) HR 4.444 (IC 95% 1.2-16.7) p = 0.017 and OS 8.4 vs 29.7 months (m) (HR 10.989; IC 95% 1.3-90.9, p = 0.007), while patients with lower PLR had a worse outcome (<200 vs. >200): with lower PFS 4.7 vs 16.8(m) HR 3.571 (IC 95% 1.1-13.0, p = 0.041) and OS 8.4 vs 27.3 (m) (HR 6.329; IC 95% 1.2-32.3, p = 0.013). Other prognostic factors were albumin (p = 0.097), histologic Grade (p = 0.099). Gender (p = 0.123), ECOG PS (p=.0637) or tumor location (p = 0.818), were not prognostic in this series. Conclusion: NLR and PLR are highly significant prognostic factors in patients with HER2-positive metastatic gastric. This is the first series in which a specific association between HER2 status and prognostic effect of NLR and PLR is described, suggesting a possible interaction between systemic inflammatory factors and the response to HER2 targeted therapy.
Biochemical and radiological inflammatory markers in oesophageal squamous cell carcinoma treated with radical chemoradiation
Authors: N. Khin, W. Peh, W. Tham, W. Lam, M. Wang, T. Siow, F. Lim, D. Tan, F. Chin, E. Chua, F. Wang, S. Ho, C. Yip
Journal: Annals of Oncology (2018)

Introduction: Inflammatory markers have been shown to be associated with poor prognosis in various solid tumours. We aimed to evaluate the role of biochemical and radiological inflammatory markers in oesophageal SCC treated with radical chemoradiation (CRT). Methods: We retrospectively evaluated 48 patients with primary oesophageal SCC who completed radical CRT in a single tertiary institution between 2006-2015. Baseline and post-CRT serum inflammatory markers (neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR)) and baseline 18F-FDG PET parameters (SUV max, SUV mean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG)) were derived and dichotomised using median values. Clinical parameters such as age and RT dose were obtained from medical notes. Univariate and multivariate overall survival (OS) analyses were performed using Cox regression model. Kaplan-Meier survival analysis was performed using dichotomised variables. A p-value Results: All patients (median age 65; 44 males) received radical radiotherapy (RT) with platinum-based chemotherapy. Total RT doses ranged between 41.4-70Gy. Sixteen patients had baseline PET scans available for analysis. Median follow-up was 21.5 months (range 3.0-113.8 months). Median OS for all patients was 21.2 months. Baseline PLR (HR 1.007, 95% CI 1.003-1.010, p < 0.001), post-CRT PLR (HR 1.002, 95% CI 1.001-1.003, p < 0.001) and RT dose (HR 0.938, 95% CI 0.892-0.986, p = 0.012) were significant univariate parameters. Patients with lower baseline (median OS 31.3 vs. 13.3 months, p = 0.007) and post-CRT PLRs (median OS 32.7 vs. 14.4 months, p = 0.001), and who received RT doses >50.4Gy (median OS 32.0 vs. 10.0 months, p < 0.001) had improved OS. An elevated post-CRT PLR (HR 1.002, 95% CI 1.001-1.003, p = 0.003) was associated with inferior OS in multivariate analysis. Age (HR 1.010, 95% CI 0.978-1.042, p = 0.556), NLR (baseline: HR 1.083, 95% CI 0.861-1.362, p = 0.495; post-CRT: HR 1.016, 95% CI 0.977-1.055, p = 0.432) and PET parameters (SUVmax: HR 1.051, 95% CI 0.967-1.144, p = 0.242; SUVmean: HR 1.213, 95% CI 0.977-1.508, p = 0.081; MTV: HR 1.003, 95% CI 0.987-1.019, p = 0.746; TLG: HR 1.000, 95% CI 0.999-1.002, p = 0.666) were not associated with OS. Conclusion: PLR, particularly in the post-CRT setting is a significant prognostic marker in oesophageal SCC but NLR and PET parameters are not associated with OS. Although the study is limited by the small sample size and retrospective bias, these results warrant larger confirmatory studies.
Normal on-treatment ALT during antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B
Authors: Grace Lai-Hung Wong, Henry Lik-Yuen Chan, Yee-Kit Tse, Terry Cheuk-Fung Yip, Kelvin Long-Yan Lam, Grace Chung-Yan Lui, Vincent Wai-Sun Wong
Journal: Journal of Hepatology (2018)