tbuckley/cabot-search huggingface dataset:
Hyperprogressive disease during nivolumab chemotherapy in metastatic gastric cancer: Multicenter retrospective study in Japan.
Authors: Takeshi Suzuki, Masahiko Aoki, Hiromichi Shirasu, Naoki Takahashi, Rie Nakatsuka, Takayuki Ando, Yosuke Kito, Yoshiyuki Yamamoto, Kentaro Kawakami, Toshihiko Matsumoto, Keitaro Shimozaki, Michitaka Nagase, Toshifumi Yamaguchi, Yuji Negoro, Takao Tamura, Yusuke Amanuma, Taito Esaki, Yuji Miura, Kengo Nagashima, Narikazu Boku
Journal: Journal of Clinical Oncology (2020)

377 Background: Nivolumab has demonstrated a survival benefit for advanced gastric cancer (AGC). However, hyperprogressive disease (HPD) has been reported in various cancers. Methods: The subjects of this retrospective study were AGC patients with measurable disease who received nivolumab, and their tumors were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. Tumor growth rates (TGR) during nivolumab were compared to those during prior therapy as reported (Champiat S, 2017). HPD was defined as an increase in TGR &gt; 2-fold. Results: 218 patients were identified as the subjects. While 33 (15.1%) partial response (PR) were achieved, 130 patients (59.6%) showed progression disease (PD), 38 of whom were classified as HPD (17.4%) and 2 patients showed pseudo progression (1.0%). The median progression-free survival (PFS) was 1.9 months (95% CI: 1.9–2.4) and the median overall survival (OS) was 8.5 months (95% CI: 7.1–9.6) in all patients. While patients with PD showed shorter prognosis compared with non-PD patients (median PFS: 1.5 months vs 6.4 months, hazard ratio; 6.0 [95% CI: 4.3–8.4]; p &lt; 0.0001; median OS: 4.7 months vs not reached, hazard ratio; 4.1 [95% CI: 2.8–6.3]; p &lt; 0.0001), there were no differences either in PFS or OS between patients with HPD and those with PD other than HPD (median PFS: 1.5 months vs 1.6 months, hazard ratio; 1.3 [95% CI: 0.9–2.0]; p = 0.1194; median OS: 5.0 months vs 4.6 months, hazard ratio; 1.0 [95% CI: 0.6–1.5]; p = 0.8695). Histological type, liver metastases, carbohydrate antigen 19-9 (CA19-9) level were associated with HPD. Conclusions: HPD was observed 17.4% in AGC patients treated with nivolumab. There were no differences either in PFS or OS between patients with HPD and those with PD other than HPD. Clinicopathological characteristics might be a predict factor for HPD.
The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: A multicenter retrospective analysis.
Authors: Suganija Lakkunarajah, Daniel Adam Breadner, Hanbo Zhang, Jennifer L. Spratlin, Karen E. Mulder, Sharlene Gill, Aaron Sha, Shirin Abadi, Shiying Kong, Winson Y. Cheung, Jonathan M. Loree, Stephen Welch
Journal: Journal of Clinical Oncology (2020)

248 Background: Colorectal cancer remains the second leading cause of cancer death in developed countries. The benefit of using fluorouracil-based chemotherapy with oxaliplatin, such as FOLFOX (fluorouracil (5-FU), leucovorin, oxaliplatin) and CAPOX (capecitabine and oxaliplatin) is well established. The optimal dose intensity (DI) under which overall survival (OS) is inferior is not established. Methods: Patients (pts) treated with adjuvant chemotherapy between 2006 and 2011 for resected stage III colon cancer (CC) from four academic cancer centres in Canada were retrospectively analysed. Patients that received CAPOX and FOLFOX were examined for the relationship between DI and OS. Results: A total of 625 pts with resected high risk stage II or stage III CC that received adjuvant chemotherapy were analysed. The median age was 63. Pts with T4 and N2 disease comprised 35.4% and 29.9% of pts, respectively. Median follow-up was 3.2 years. There was available survival data for 319 pts. The median oxaliplatin DI was 70%. The frequency of pts reaching an oxaliplatin DI of &gt; 80% was 43%, while 76.6% of pts had a dose intensity of &gt; 80% for their FU component. An oxaliplatin DI of &gt; 80% was associated with a significant improvement in survival, HR = 0.42 (95%CI 0.21 – 0.81, p &lt; 0.01). Achieving a DI of &gt; 80% for capecitabine or 5-FU did not improve OS. Other factors associated with inferior OS included T4 (HR = 3.5, p = 0.03) and N2 (HR = 5.27, p = 0.0005) subgroups. The improvement in OS was not significant when restricting the analysis to pts with non-T4 and non-N2 disease (n = 144), HR = 0.16 (0.02 – 1.26; p = 0.08). Conclusions: Oxaliplatin DI of &gt; 80% is associated with improved OS in patients receiving chemotherapy for high risk stage II and stage III CC.
Artificial neural network identifies nonsteroidal anti‐inflammatory drugs exacerbated respiratory disease (N‐ERD) cohort
Authors: Katarzyna Ewa Tyrak, Kinga Pajdzik, Ewa Konduracka, Adam Ćmiel, Bogdan Jakieła, Natalia Celejewska‐Wójcik, Gabriela Trąd, Adrianna Kot, Anna Urbańska, Ewa Zabiegło, Radosław Kacorzyk, Izabela Kupryś‐Lipińska, Krzysztof Oleś, Piotr Kuna, Marek Sanak, Lucyna Mastalerz
Journal: Allergy (2020)

To date, there has been no reliable in vitro test to either diagnose or differentiate nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD). The aim of the present study was to develop and validate an artificial neural network (ANN) for the prediction of N-ERD in patients with asthma.This study used a prospective database of patients with N-ERD (n = 121) and aspirin-tolerant (n = 82) who underwent aspirin challenge from May 2014 to May 2018. Eighteen parameters, including clinical characteristics, inflammatory phenotypes based on sputum cells, as well as eicosanoid levels in induced sputum supernatant (ISS) and urine were extracted for the ANN.The validation sensitivity of ANN was 94.12% (80.32%-99.28%), specificity was 73.08% (52.21%-88.43%), and accuracy was 85.00% (77.43%-92.90%) for the prediction of N-ERD. The area under the receiver operating curve was 0.83 (0.71-0.90).The designed ANN model seems to have powerful prediction capabilities to provide diagnosis of N-ERD. Although it cannot replace the gold-standard aspirin challenge test, the implementation of the ANN might provide an added value for identification of patients with N-ERD. External validation in a large cohort is needed to confirm our results.
Impact of Sapien 3 Balloon-Expandable Versus Evolut R Self-Expandable Transcatheter Aortic Valve Implantation in Patients With Aortic Stenosis
Authors: Pierre Deharo, Arnaud Bisson, Julien Herbert, Thibaud Lacour, Christophe Saint Etienne, Leslie Grammatico-Guillon, Alizée Porto, Frederic Collart, Thierry Bourguignon, Thomas Cuisset, Laurent Fauchier
Journal: Circulation (2019)

Background: Two competing transcatheter aortic valve replacement (TAVR) technologies are currently available. Head-to-head comparisons of the relative performances of these 2 devices have been published. However, long-term clinical outcome evaluation remains limited by the number of patients analyzed, in particular, for recent-generation devices. Methods: Based on the French administrative hospital-discharge database, the study collected information for all consecutive patients treated with a TAVR device commercialized in France between 2014 and 2018. Propensity score matching was used for the analysis of outcomes during follow-up. The objective of this study was to analyze the outcomes of TAVR according to Sapien 3 balloon-expandable (BE) versus Evolut R self-expanding TAVR technology at a nationwide level in France. Results: A total of 31 113 patients treated with either Sapien 3 BE or Evolut R self-expanding TAVR were found in the database. After matching on baseline characteristics, 20 918 patients were analyzed (10 459 in each group with BE or self-expanding valves). During follow-up (mean [SD], 358 [384]; median [interquartile range], 232 [10–599] days), BE TAVR was associated with a lower yearly incidence of all-cause death (relative risk, 0.88; corrected P =0.005), cardiovascular death (relative risk, 0.82; corrected P =0.002), and rehospitalization for heart failure (relative risk, 0.84; corrected P &lt;0.0001). BE TAVR was also associated with lower rates of pacemaker implantation after the procedure (relative risk, 0.72; corrected P &lt;0.0001). Conclusions: On the basis of the largest cohort available, we observed that Sapien 3 BE valves were associated with lower rates of all-cause death, cardiovascular death, rehospitalization for heart failure, and pacemaker implantation after a TAVR procedure.
Regulatory T Cells and Human Disease
Authors: Shimon Sakaguchi, Norihisa Mikami, James B. Wing, Atsushi Tanaka, Kenji Ichiyama, Naganari Ohkura
Journal: Annual Review of Immunology (2020)

Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a functionally distinct T cell subpopulation actively engaged in the maintenance of immunological self-tolerance and homeostasis. Recent studies have facilitated our understanding of the cellular and molecular basis of their generation, function, phenotypic and functional stability, and adaptability. It is under investigation in humans how functional or numerical Treg anomalies, whether genetically determined or environmentally induced, contribute to immunological diseases such as autoimmune diseases. Also being addressed is how Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. This review discusses our current understanding of Treg immunobiology in normal and disease states, with a perspective on the realization of Treg-targeting therapies in the clinic.
Intensity-modulated proton therapy using dose-painting pencil beam scanning for high-risk hepatocellular carcinoma.
Authors: Stephanie K. Schaub, Stephen R. Bowen, Matthew J. Nyflot, Smith Apisarnthanarax
Journal: Journal of Clinical Oncology (2020)

558 Background: High rates of local control are achievable with hypofractionated proton therapy with passive techniques for hepatocellular carcinoma (HCC), but may have limitations when tumors are adjacent to organs-at-risk (OARs), which may result in tumor underdosage and lead to inferior local control. We present the first reported series of HCC patients treated with pencil beam scanning (PBS) intensity-modulated proton therapy (IMPT) using a simultaneous-integrated boost and protection (SIB/SIP) technique to escalate tumor dose while protecting adjacent OARs. Methods: Twenty-five HCC patients were treated between 2015-2019 with a 15-fraction regimen using IMPT SIB/SIP. SIB/SIP dose levels generally ranged from 36.0-67.5 GyRBE to minimize dose to OARs at their respective dose-limiting thresholds (e.g. luminal gastrointestinal organs, chest wall). Radiation-induced liver disease (RILD) was defined by a Child-Pugh (CP) score increase of 2 or greater and/or any RTOG grade 3 enzyme elevation. Other toxicities were graded by CTCAEv5.0. Overall survival (OS), progression-free survival (PFS), and local control were calculated using the Kaplan-Meier method. Results: Patients most commonly had BCLC stage B or C disease (84%) and CP-A (80%) and ALBI grade 2 (60%) liver function. Median gross tumor volume (GTV) size and volume were 12.3 cm (range 2.17-20.57) and 461 cc (range 4.68-2439), and 32% had gross vascular invasion. Median mean and minimum dose delivered to the gross tumor volume (GTV) was 64.0 GyRBE (EQD2 76.1, BED 91.3, range 54.3-69.6) and 45.1 GyRBE (EQD2 48.9, BED 58.7, range 33.4-67.7), respectively. Median mean dose to liver minus GTV was 15.0 GyRBE (range, 8.2-19.6). 1-year OS, PFS, and local control were 66%, 32%, and 84%, respectively. No isolated local failures occurred. Two patients experienced RILD with no RILD-related deaths. Two grade 3 non-GI toxicities occurred: 1 rib fracture and 1 pneumonitis. No acute or late GI grade ≥2 occurred. Conclusions: In our series of HCC patients with large tumors near OARs, IMPT SIB/SIP allows for tumor dose escalation while sparing of OARs and results in favorable local control and acceptable toxicities.
Abstract 16436: Effect of Mediterranean Diet With Varying Amounts of Lean Beef on Measures of Arterial Stiffness and Central Blood Pressure
Authors: Jennifer Fleming, Penny Kris-Etherton, Kristina Petersen, David Baer
Journal: Circulation (2018)

The Mediterranean dietary pattern has gained widespread popularity because of an impressive evidence base showing beneficial effects on human health. This has led to research investigating the role...
Induction oxaliplatin capecitabine followed by switch to carboplatin-paclitaxel based RT versus continuing oxaliplatin capecitabine RT in operable esophageal adenocarcinoma: Survival analysis of the randomized phase II neoscope trial.
Authors: Somnath Mukherjee, Chris Hurt, Catrin Cox, Ganesh Radhakrishna, Sarah Gwynne, Andrew Rea Bateman, Simon Gollins, Maria A. Hawkins, Jo Canham, Heike I. Grabsch, Stephen Falk, Ricky A. Sharma, Ruby Ray, Rajarshi Roy, Wendy Wade, Rhydian Maggs, David joseph sebag-Montefiore, Tim Maughan, Gareth Owen Griffiths, Tom David Lewis Crosby
Journal: Journal of Clinical Oncology (2020)

373 Background: Initial results of the NEOSCOPE trial comparing pre-operative CarPac vs OxCap based chemoradiotherapy (CRT) in patients with adenocarcinoma of the oesophagus or oesophagogastric junction showed comparable toxicity and improvement in pathological complete response (pCR) in favour of the CarPacRT. Here we report survival after a median follow-up of 40.7 months (95% CI: 45.1-53.6). Methods: NEOSCOPE was an open, randomised, ‘pick a winner’ phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m 2 day 1, 15, 29; capecitabine 625 mg/m 2 bd on days of RT) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m 2 day 1, 8, 15, 22, 29). RT dose was 45 Gy/25 fractions/5 weeks. Induction OxCap (2 cycles) was given prior to CRT. Surgery was performed 6–8 weeks after CRT.The primary endpoint was pCR, secondary endpoints were toxicity, PFS and OS. Results: Between Oct 2013 and Feb 2015, 85 patients were recruited from 17 UK centres. Median OS was not reached in the CarPacRT group and was 41.72 months (95% CI 19.58-.)in the OxCap group (HR 0.56[95% CI 0.29-1.07]; p=0.079). 3-year and 5-year OS rates were 74% (95% CI 58%-85%) and 54% (95% CI 34%-71%) (CarPacRT), and 52% (95% CI 35%-67%) and 39% (95% CI 21%-56%) (OxCapRT). Median PFS (not reached vs 35.3 months, HR=0.61 [95% CI 0.33-1.12]; p=0.111) and metastatic PFS (not reached vs 39.0 months, HR=0.61 [95% CI 0.32-1.14], p=0.118) both favoured the CarPacRT arm. Local recurrence rate was low (OxCapRT= 10%; CarPacRT= 7%). The OS benefit for CarPacRT was consistent across subgroups but not statistically significant. Conclusions: In this longer term analysis there was some evidence that induction OxCap followed by switch to CarPacRT was superior to continuing OxCapRT, with efficacy similar to that seen in other published studies such as ‘CROSS’ and ‘FLOT’. Taken together with the previously published pCR results CarPacRT rather than OxCapRT warrants inclusion in future trials. Funding: Cancer Research UK (C44694/A14614). Clinical trial information: NCT01843829.
A woman with nail changes
Authors: Yingyuan Yu, Yuling Shi
Journal: BMJ (2020)

A 64 year old woman presented with two weeks of redness, pain, swelling, and exudation of the periungual skin around all fingernails and toenails. Examination found she had complete destruction over the nailfolds, and the periungual skin was erythematous with blisters (fig 1).



Fig 1 
Damage over the nail folds of finger and toenails



She was treated for bacterial and fungal paronychia without any improvement, and the results of fungal microscopy and culture of periungual skin were negative.

Two weeks later, she developed cutaneous blisters/bullae on the trunk, which were thinly walled and relatively flaccid. The rest of the skin became fragile, and light stroking caused the epidermis to …
The effect of TGF-β on PD-L1 expression on PDAC TAMs.
Authors: Katarzyna Trebska-McGowan, Liza Makowski, Marcus A. Alvarez, Rita Kansal, S. Mazher Husain, Ajeeth K. Pingili, Evan Scott Glazer
Journal: Journal of Clinical Oncology (2020)

764 Background: Pancreatic Ductal Adenocarcinoma (PDAC) has less than a 10% five year survival and will become the second leading cause of US cancer mortality in the next decade. Immunotherapy, such as checkpoint inhibition against anti-Programmed death-ligand 1 (PD-L1) has not been successful in the treatment of PDAC patients. Both tumor associated macrophages (TAMs) and the TGF-β protein are ubiquitous in PDAC tumors. We hypothesize that TGF-β increases the overall number of TAMs and degree of PD-L1 expression of TAMs in PDAC. Methods: Our lab has a mouse pancreatic cancer cell line derived from a genetically engineered mouse model (KPC mice that spontaneously form PDAC tumors that are similar to human PDAC). We orthotopically implanted this cell line into the pancreas of immunocompetent C57BL/6 (B6) mice. In groups of 5 each, mice were treated with saline (control) or TGF-β. We investigated tumor burden, the number of TAMs (CD45 + , CD11b + F4/80 hi , Ly6C − , Ly6G −/lo ) in the tumors with flow cytometry and the percentage of TAMs expressing PD-L1 in the pancreas and metastatic lesions in the liver. Results: As a percent of leukocytes in the tumor, PDAC liver metastases had more TAMs compared to tumors in the pancreas (33 ± 5% vs 10 ± 4%, P = 0.001). Compared to controls, TGF-β treatment significantly increased the percent of PD-L1 expressing TAMs (32 ± 6 % vs 12 ± 5%, P = 0.013, see Figure) in the pancreas but no effect was evident on TAM density. In liver metastases, treatment with TGF-β decreased the overall TAM density (P = 0.039) but did not affect the number of PD-L1 positive TAMs. Conclusions: TGF-β plays pivotal role in the progression of PDAC and demonstrates context dependent activity. Our results suggest that an immunosuppressive effect mediated by PD-L1 expression on TAMs may be initiated by TGF-β. Future investigations will focus on understanding the role of the PDAC – TAM interaction to develop effective immune therapies for PDAC patients.
Evolution of the Autism-Associated Neuroligin-4 Gene Reveals Broad Erosion of Pseudoautosomal Regions in Rodents
Authors: Stephan Maxeiner, Fritz Benseler, Gabriela Krasteva-Christ, Nils Brose, Thomas C Südhof
Journal: Molecular Biology and Evolution (2020)

Variants in genes encoding synaptic adhesion proteins of the neuroligin family, most notably neuroligin-4, are a significant cause of autism spectrum disorders in humans. Although human neuroligin-4 is encoded by two genes, NLGN4X and NLGN4Y, that are localized on the X-specific and male-specific regions of the two sex chromosomes, the chromosomal localization and full genomic sequence of the mouse Nlgn4 gene remain elusive. Here, we analyzed the neuroligin-4 genes of numerous rodent species by direct sequencing and bioinformatics, generated complete drafts of multiple rodent neuroligin-4 genes, and examined their evolution. Surprisingly, we find that the murine Nlgn4 gene is localized to the pseudoautosomal region (PAR) of the sex chromosomes, different from its human orthologs. We show that the sequence differences between various neuroligin-4 proteins are restricted to hotspots in which rodent neuroligin-4 proteins contain short repetitive sequence insertions compared with neuroligin-4 proteins from other species, whereas all other protein sequences are highly conserved. Evolutionarily, these sequence insertions initiate in the clade eumuroidea of the infraorder myomorpha and are additionally associated with dramatic changes in noncoding sequences and gene size. Importantly, these changes are not exclusively restricted to neuroligin-4 genes but reflect major evolutionary changes that substantially altered or even deleted genes from the PARs of both sex chromosomes. Our results show that despite the fact that the PAR in rodents and the neuroligin-4 genes within the rodent PAR underwent massive evolutionary changes, neuroligin-4 proteins maintained a highly conserved core structure, consistent with a substantial evolutionary pressure preserving its physiological function.
Patterns of disease, treatment, and outcomes of esophageal cancer arising within a previous radiation treatment field.
Authors: Lucy Xiaolu Ma, Peiran Sun, Osvaldo Espin-Garcia, Chihiro Suzuki, Di Maria Jiang, Charles Henry Lim, Kirsty Taylor, Bryan Anthony Chan, Hao-Wen Sim, Akina Natori, Eric Xueyu Chen, Geoffrey Liu, Jennifer J. Knox, Jonathan Yeung, Gail Elizabeth Darling, John Kim, Sangeetha Kalimuthu, Elena Elimova, Raymond Woo-Jun Jang
Journal: Journal of Clinical Oncology (2020)

328 Background: Esophageal cancer arising within a previous radiation treatment field (ECRF) is rare. The patterns of disease, treatment and outcomes in these patients (pts) have not been well characterized. Methods: A retrospective analysis was performed for pts treated for esophageal cancer at the Princess Margaret Cancer Centre from 2002-2016. Electronic medical records of all pts with a histologic diagnosis of esophageal cancer occurring within the field of previous radiotherapy were reviewed. The Kaplan-Meier method was used to calculate progression free survival (PFS) and overall survival (OS). Results: Of 31 ECRF pts identified, the most common prior cancer was head and neck (45%), median radiation (RT) dose 50Gy, median time to diagnosis of esophageal cancer 12 years. Features at diagnosis of ECRF included: median age 71 years, 58% male, 87% with performance status (PS) 0-1, 77% squamous cell carcinoma, 19% stage IV. Treatment intent was curative in 16 pts, palliative in 15 (Table). Reasons for palliative treatment were: 40% metastatic, 53% comorbidities/PS, 7% anatomic factors. Of resected pts, 36% had a pT1-2 tumour, 55% pN0, 69% R0. For curative pts, median PFS was 26.2 months (95%CI 10.9-34.4) with a 3 year PFS rate of 35% (95% CI 15-81). Median OS for curative pts was 26.4 months (95%CI 17.8-105.5) with a 3 year OS rate of 43% (95% CI 22-83). Most palliative pts were unable to have chemotherapy due to comorbidities and PS. Median OS for palliative pts was 9.5 months (95% CI 3.6-15.4). Conclusions: Most ECRF pts presented with earlier stage disease; however, more than a third of these could not have aggressive curative treatment due to comorbidities and/or PS. Most curative pts had surgery alone. Few palliative pts had chemotherapy, largely due to poor clinical status. Our data suggest that outcomes in both curative and palliative ECRF pts may be limited by the ability to tolerate standard of care treatments. [Table: see text]