tbuckley/cabot-search huggingface dataset:
Incidence and prediction of checkpoint inhibitor immune-related nephrotoxicity.
Authors: Jonathan D Sorah, Tracy L. Rose, Roshni Radhakrishna, Vimal Derebail, Matthew I. Milowsky
Journal: Journal of Clinical Oncology (2020)

91 Background: Immune checkpoint inhibitors (ICIs), through inhibition of self-tolerance, have the potential to cause immune-related adverse events that can affect any organ, including the kidneys. Our study aimed to better characterize the incidence of and predictive characteristics for immune-related nephrotoxicity. Methods: All patients at the University of North Carolina (UNC) who received ICIs between April 2014 and December 2018 for any malignancy were identified. Patients on dialysis or those who received concurrent platinum-based chemotherapy were excluded. Any patient who subsequently had a clinically significant acute kidney injury (AKI), defined as a doubling or more of baseline creatinine, was included for analysis. A retrospective chart review was performed to determine the cause of AKI. Any uncertain cases were reviewed by two nephrologists for expert consensus (R.R. and V.D.). Results: 1766 patients received an ICI during the study period. 123 (7%) patients had AKI within one year of the first ICI dose. 14 were due to immune-related nephrotoxicity (11% of patients with AKI and 0.8% of all ICI patients). Pre-existing autoimmune disease was more likely in patients with immune-related nephrotoxicity than in those with non-immune AKI (14% vs 3%, p = 0.04). Similarly, concurrent or prior other immune-related adverse events were more common in patients with immune-related AKI (57% vs 6%, p = 0.01). Patients with immune-related AKI were more likely to see a nephrologist (57% vs 23%, p = 0.007) and had a more profound increase in creatinine from baseline (median 2.6 vs 1.6, p = 0.02). Age, sex, urinalysis findings, and primary tumor type were not associated with increased risk. Conclusions: The true incidence of ICI related nephrotoxicity is difficult to ascertain due to the many confounders that contribute to AKI in this population. Severe immune-related nephrotoxicity is rare, but patients with preexisting autoimmune disease or history of immune-related adverse events are at increased risk.
Can immunologically hot lung cancer be distinguished from cold tumor by peripheral blood?
Authors: Satoshi Muto, Hayato Mine, Hironori Takagi, Masayuki Watanabe, Yuki Ozaki, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Yutaka Shio, Hiroyuki Suzuki
Journal: Journal of Clinical Oncology (2020)

48 Background: Depending on the number of tumor infiltrating lymphocytes, immunological cold to hot conditions vary. There are several clinical trials of administering immune checkpoint inhibitors as perioperative adjuvant therapy. Immune checkpoint inhibitors are generally effective in immunologically hot conditions. However, biopsy specimens are not enough to determine the amount of tumor infiltrating lymphocytes. Therefore, we focused on effector T lymphocytes in peripheral blood, and tried to understand the tumor microenvironment by looking at peripheral blood. Methods: Twenty-four patients with lung cancer who underwent surgery at Fukushima Medical University Hospital from December 2018 to June 2019 were able to separate and collect tumor infiltrating lymphocytes by magnetic cell sorting. Flow cytometry was used to analyze infiltrating lymphocytes and preoperative peripheral blood lymphocytes. Those not expressing CD62L, a marker of Naïve T lymphocytes, were designated as effector T lymphocytes. Results: In the group with a high proportion of cytotoxic T lymphocytes in tumor infiltrating lymphocytes, the proportion of CD62L-negative effector CD4 T lymphocytes in peripheral blood was high (p &lt; 0.05). The percentage of lymphocytes in peripheral blood was also high (p &lt; 0.05). Furthermore, tumor infiltrating lymphocytes had a high proportion of effector CD4 T lymphocytes (p &lt; 0.05). There was a similar trend in the proportion of CD8 T lymphocytes, but there was no statistically significant difference. Conclusions: These results showed that immunologically hot cases could be identified by measuring effector CD4 T lymphocytes in peripheral blood. In the future, we will continue to verify the results and examine antigen specificity of these T lymphocytes.
Using bioinformatic tools to examine similarities between human PDL-1 protein and common tobacco (Nicotiana tabacum).
Authors: Elie G. Dib, Nicholas Hill, Jessica Wollard, Ji Woon Yoo, Joe E. Dib, Anutosh Ganguly, Clifford Cho
Journal: Journal of Clinical Oncology (2020)

70 Background: Human CD274 receptor, known as programmed cell death 1 ligand 1 (RefSeq NP_054862.1), is an inhibitory ligand for Programmed cell death protein 1 (PD1). We aimed in this bioinformatic experiment to identify a homologous PDL-1 protein in plants. Methods: We chose to use tBLASTn because it compares a protein query sequence against a nucleotide sequence database dynamically translated in all six reading frames (both strands). We chose the EST database and restricted our search to plants (Viridiplantae). Results: Using the FASTA sequence of PDL-1 protein, the tBLASTn of the CD274 protein produced a single hit to Nicotiana tabacum (Common tobacco) cDNA, accession number FG181602.1 with E value of 2e-13 and score of 75.9. We translated the FASTA FG181602.1 through ExPASy and after inspecting the results of the 6 open reading frames (ORFs) in comparison with the matching homologous plant protein obtained through tBLASTn above, we found this “novel” protein which we named "PDL1LI". It has the following amino acid sequence: MHAVRRHRGEMHKVALLHNSFLIISILGSYADDFRVMVPTRRLTAARGHSVVLGCEFSPHFGPNPDLSSLVLTWQRQEDSRVVHSFYYERDQLAKQSSAYRNRTALFVTELSKGNASVRIENVGVTDAGRYLCTVSTNQGTNKAELQLDYGAFYTEPRLTINVNSSDVLLQYETEGFPAPVVIWKGEDGENLTDRMKTSVQSNEEMGLYYIKSSYTAPNTPLSLTFTLENHLLHQYLQRPVSYTGGQNSCFYQFIAPVVVS Gor4 shows that our novel PDL1LI protein is 181 amino acids long with 36% alpha helix, 18% extended strand and 46% random coil sequence. According to BLASTp, this protein contains an immunoglobulin domain found in the Ig superfamily in the first half of the protein, and specific domain hits to the Ig_HHLA2, V-set, and IGv domains, with e-values of 1.37e-28, 2.23e-08, and 1.73e-06. Conclusions: Of all the plants, we found a single homology for our original protein PDL1 only in Nicotiana tabacum. We named this novel protein PDL1LI. Tobacco has been implicated in the etiology of several cancers including lung cancer, bladder cancer, head and neck cancers, etc. A wet lab experiment is underway to isolate our novel protein PDL1LI and to study its properties including any possible inhibitory actions on T cells. If confirmed, then we would have elucidated a new carcinogenic mechanism of tobacco.
CheckMate 459: Health-related quality of life (HRQoL) in a randomized, multicenter phase III study of nivolumab (NIVO) versus sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: Julien Edeline, Thomas Yau, Joong-Won Park, Masatoshi Kudo, Kwang-Hyub Han, Philippe Mathurin, Philippe Merle, Richard S. Finn, Tobias Müller, Fiona Taylor, Mike Greenwood, Damir Begic, Marina Tschaika, Christine Yip, Emma Pranschke, Kim Cocks, Gwilym Thompson, Steven I Blum, Tami Wisniewski, Bruno Sangro
Journal: Journal of Clinical Oncology (2020)

483 Background: SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to help improve or maintain HRQoL. This phase 3 study compared HRQoL of NIVO vs SOR as 1L therapy in pts with aHCC as an exploratory endpoint. Methods: FACT-Hep was administered cycle 1, day 1 and every other cycle. The effect of NIVO vs SOR on HRQoL using FACT-Hep was assessed via repeated measures mixed models (MMRM). Kaplan–Meier curves and Cox proportional-hazards models determined between-treatment differences in time to first and time until definitive deterioration (TTD/TUDD) based on prespecified thresholds for minimally important differences. The GP5 item from FACT-Hep was used to assess the burden associated with treatment side effects. Results: 743 pts with aHCC were randomized to NIVO (n = 371) or SOR (n = 372). Median OS was 16.4 mo for NIVO, 14.7 mo for SOR (HR 0.85 [95% CI 0.72–1.02]; P = 0.0752). ORR was 15% for NIVO, 7% for SOR (OR 2.41 [95% CI 1.48–3.92]). HRQoL scores were completed at baseline by 94.6% and 92.5% of participants, respectively, and were similar (FACT-Hep total: NIVO 140.7 [SD 21.5] and SOR 140. 6 [SD 19.1]. Questionnaire compliance rates exceeded 70% at most visits. MMRM analyses yielded clinically meaningful and statistically significant least squares means differences favoring NIVO on FACT-Hep total (10.1 [95% CI 7.3–13.0]), physical well-being (PWB; 2.0 [95% CI 1.4–2.6]), and functional well-being (FWB; 2.5 [95% CI 1.7–3.2]) scores. No sub-scales favored sorafenib. TTD was significantly delayed in NIVO for FACT-Hep total (HR 0.62 [95% CI 0.51–0.74]), PWB (HR 0.62 [95% CI 0.52–0.74]), FWB (HR 0.73 [95% CI 0.61–0.88]), and hepatobiliary cancer subscale (HR 0.57 [95% CI 0.48–0.69]). TUDD results were consistent with TTD. A greater proportion of NIVO pts did not experience increased burden of side effects (50%–67.7%) compared with SOR (26.8%–45%) based on the GP5 item. Conclusions: These patient-reported findings demonstrate that pts taking NIVO had superior HRQoL and reduced side effect burden, further supporting clinical data showing a treatment benefit for 1L NIVO in aHCC. Clinical trial information: NCT02576509.
Effect of neoadjuvant immunotherapy and targeted therapies on surgical resection in patients with solid tumors: A systematic review and meta-analysis.
Authors: Pablo Emilio Serrano Aybar, Kasia Tywonek, Noor Faisal, Sandra Lee, Ali Alfayyadh, Connor O'Neill, Marylrose Gundayao, Leyo Ruo, Sameer Parpia, Brandon M. Meyers
Journal: Journal of Clinical Oncology (2020)

e16656 Background: Neoadjuvant immunotherapy with anti-programmed cell death protein-1 (PD-1) or anti-programmed cell death ligand-1 (PD-L1) and tyrosine kinase inhibitor (TKI) therapy is currently being used to treat certain solid tumours prior to surgery. Neoadjuvant therapy may cause delays to resection potentially losing a window of opportunity. We explored the pooled proportion of patients with solid tumours receiving neoadjuvant therapy who completed planned surgical resection. Methods: Medline, CENTRAL and Embase databases were searched for single arm or randomized controlled trials studying neoadjuvant PD-1/PD-L1 immunotherapy or TKI therapy. Random-effects model was used to estimate the pooled proportion of patients undergoing planned resection, and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Results: From 368 relevant articles, eleven studies with a total of 382 patients receiving neoadjuvant PD-1 immunotherapy (n = 234) or neoadjuvant TKI therapy (n = 148) were analyzed. The types of tumours included hepatocellular carcinoma (1 study), renal cell carcinoma (8 studies), bladder carcinoma (1 study) or non-small cell lung cancer (1 study). The pooled proportion of patients who completed planned surgery after neoadjuvant therapy was 95% (95% CI 0.92 to 0.99). The overall partial response rate prior to surgery was 12% (95% CI 0.07 to 0.16) in the PD-1 therapy group and 46% (95% CI -0.12 to 1.03) in the TKI group. The pooled serious adverse events rate was 17% (95% CI 0.02 to 0.32) in the PD-1 therapy group and 29% (95% CI -0.10 to 0.68) in the TKI group. For all patients receiving neoadjuvant therapy, the pooled median overall survival was 23.41 months (95% CI 16.21 to 30.62) and median progression free survival was 7.46 months (95% CI 4.41 to 10.51). Conclusions: Neoadjuvant PD-1 or TKI therapy prior to surgery for solid tumours is safe, does not delay surgical resection and can result in a partial radiological response prior to surgery.
China coronavirus: Hong Kong health staff strike to demand border closure as city records first death
Authors: Jane Parry
Journal: BMJ (2020)

Hong Kong has reported its first death related to the novel coronavirus 2019-nCoV, only the second fatality reported outside mainland China, as healthcare workers in the city started unprecedented industrial action to put pressure on the government to close the border and avert an escalation in the number of infections.

The 39 year old man, who had an underlying health condition, had travelled to Wuhan on 21 January. In late January, after his return to Hong Kong, he developed fever and myalgia. The Hong Kong Hospital Authority announced that he had died on 3 February. The news coincided with the second day of industrial action by members of the Hospital Authority Employees’ Alliance, a new labour union representing around 9000 of the 67 000 staff employed by the Hospital Authority, the statutory body that manages all of Hong Kong’s government hospitals.

After a strike by 2700 non-essential staff on 2 February, the union pledged to escalate the strike if the government did not …
中枢神経系疾患:電位依存性カリウムチャネル遺伝子KCNH1の変異がテンプル・バライスター症候群およびてんかんを引き起こす
Authors: Simons Cas, Rash Lachlan D, Crawford Joanna, MA Linlin, Cristofori-Armstrong Ben, Miller David, RU Kelin, Baillie Gregory J, Grimmond Sean M, King Glenn F, Taft Ryan J, Alanay Yasemin, Jacquinet Adeline, Debray Francois-Guillaume, Verloes Alain, Shen Joseph, Yesil Goezde, Guler Serhat, Yuksel Adnan, Cleary John G, Mcgaughran Julie, Gabbett Michael T
Journal: Nature Genetics (2015)
PD-L1 profiling of circulating tumor cells for immune checkpoint inhibitor therapy in gastroesophageal cancers.
Authors: Pradip Devhare, Revati Patil, Dadasaheb B. Akolkar, Darshana Patil, Navin Srivastava, Pooja Fulmali, Shoeb Patel, Pradyumna Shejwalkar, Vineet Datta, Cynthe Sims, Ajay Srinivasan, Rajan Datar
Journal: Journal of Clinical Oncology (2020)

29 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Gastroesophageal cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been constrained by low CTC yields. We employed a novel approach for harvesting sufficient CTCs from Gastroesophageal cancers that permit PD-L1 profiling by Immunocytochemistry (ICC). Methods: 15 ml peripheral blood was collected from 106 patients among whom 20 were diagnosed with gastric adenocarcinomas (AD) and 86 with either esophageal AD or esophageal squamous cell carcinomas (SCC). CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induced apoptosis in non-malignant cells and conferred survival privilege on apoptosis-resistant CTCs, which were harvested and confirmed by immunostaining for EpCAM and pan-CK positivity. Deep ICC profiling of CTCs was performed with organ-specific markers as well as PD-L1:22c3 and PD-L1:28-8 clones. Results: Viable CTCs could be enriched and harvested in 103 out of 106 samples (97.2%) regardless of metastatic or treatment status. Deep ICC and PD-L1 profiling could be performed in all 103 samples (100%). PD-L1 expression was quantitatively assigned as ‘Low’, ‘Moderate’ or ‘High’. Among the 19 gastric ADs, 5 (26.3%) samples were positive for PD-L1:22c3 and 2 (10.5%) were positive for PD-L1:28-8; all gastric ADs were ‘Low’ for either PD-L1 subtype. Among the 84 esophageal carcinomas (AD+SCC), 32 samples (38.1%) were positive for PD-L1:22c3 (26 Low + 5 Moderate + 1 High) and 16 (19.1%) were positive for PD-L1:28-8 (11 Low + 5 Moderate). Conclusions: CTCs in Gastroesophageal cancers can be considered for evaluating PD-L1 expression in patients where ICI therapies are otherwise viable.
94P Comparison of A Novel, Label-Free, and Real-Time cell Based System (Xcelligence) With a Conventional Viability Assay (Xtt) to Determine the Anti-Proliferative Effect of At-101 in Human Breast Cancer Cells
Authors: B. Karaca, H. Atmaca, K. Asli, E. Bozkurt, B. Cakar, Z.G. Surmeli, P. Gursoy, B. Karabulut, S. Uzunoglu, C. Sezgin
Journal: Annals of Oncology (2012)
Myelin degeneration and diminished myelin renewal contribute to age-related deficits in memory
Authors: Fei Wang, Shu-Yu Ren, Jing-Fei Chen, Kun Liu, Rui-Xue Li, Zhi-Fang Li, Bo Hu, Jian-Qin Niu, Lan Xiao, Jonah R. Chan, Feng Mei
Journal: Nature Neuroscience (2020)
Use of <i>Ex</i> <i>Vivo</i> Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for <i>HER2</i> Mutant Non–Small Cell Lung Cancer
Authors: Elena Ivanova, Mari Kuraguchi, Man Xu, Andrew J. Portell, Luke Taus, Irmina Diala, Alshad S. Lalani, Jihyun Choi, Emily S. Chambers, Shuai Li, Shengwu Liu, Ting Chen, Thanh U. Barbie, Geoffrey R. Oxnard, Jacob J. Haworth, Kwok-Kin Wong, Suzanne E. Dahlberg, Amir A. Aref, David A. Barbie, Magda Bahcall, Cloud P. Paweletz, Pasi A. Jänne
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non–small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. Experimental Design: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2YVMA genetically engineered mouse model. Results: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. Conclusions: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.
Analysis of weight loss as a prognostic factor in patients (pts) with advanced gastric cancer from REGARD, RAINBOW and RAINFALL phase III studies.
Authors: Wasat Mansoor, Eric Roeland, Aafia Chaudhry, Ran Wei, Anindya Chatterjee, Holly Knoderer, Paolo Abada, Samuel J. Klempner
Journal: Journal of Clinical Oncology (2020)

348 Background: Maintaining weight (wt) and adequate nutrition during systemic treatment in advanced gastric cancer (G/GEJ) therapy remains a challenge. We investigated the impact of early wt-loss on survival in three phase 3 studies of ramucirumab (R); REGARD (RG), RAINBOW (RB), and RAINFALL (RF) in G/GEJ. Methods: ITT pts were categorized into 2 groups based on their body wt change from start to end of cycle 1 (C1; C = 28 days in RG, RB; C = 21 days in RF): wt-loss &lt; 3% vs ≥3%. Univariate Cox PH models were performed in each individual study to evaluate the effects of body wt change from the start to end of C1 on OS. A pooled meta-analysis stratified by study and a sensitivity analysis of the subgroup of responders was also performed. Results: A total of 311 (RG: 212 in R+BSC; 99 in Placebo (PB)+BSC), 591 (RB: 306 in the R+Paclitaxel (P); 285 PB+P), and 562 (RF: 279 in R+Cape/Cis (CC); 283 in PB+CC) pts with body wt data during C1 were evaluated. The number of pts with wt-loss of ≥3% and &lt; 3% are shown in Table. Pts with wt-loss &lt; 3% during C1 experienced longer OS compared to those with wt-loss ≥3%, irrespective of treatment arms across studies (Table). In pooled treatment arms within each study, the HR for wt-loss group ( &lt; 3% vs ≥3%) was 0.359 (95% CI = 0.254, 0.507), 0.632 (0.497, 0.804), 0.752 (0.608, 0.930) in RG, RB, RF, respectively. In the meta-analysis that combined the 3-studies, univariate Cox PH model stratified by study showed consistent effect of early wt-loss on OS regardless of treatment arm, HR ( &lt; 3% vs ≥3%) = 0.632 (0.546, 0.732). Conclusions: Analysis from three phase 3 studies demonstrates early wt-loss ≥3% during C1 is an important negative prognostic factor for survival in gastric/GEJ cancer. Prospective studies of the relationship of weight preserving nutritional interventions on OS are warranted. Clinical trial information: NCT00917384, NCT01170663, NCT02314117. [Table: see text]
Pancreatic adenosquamous carcinoma: Clinical associations, treatment, and outcomes.
Authors: Mindy L. Hartgers, William Bamlet, Rondell P. Graham, Amit Mahipal, Taofic Mounajjed, Sean P. Cleary, Robert R. McWilliams
Journal: Journal of Clinical Oncology (2020)

751 Background: Pancreatic adenosquamous carcinomas (PASC) are rare malignancies, with limited evidence regarding best treatment options. The Mayo Clinic Pancreatic Cancer SPORE Registry was utilized to compare/contrast outcomes for pancreatic cancers with a squamous component to pancreatic ductal adenocarcinoma (PDAC). Methods: Patients were identified from the SPORE Registry (2000-2019), were reviewed and confirmed by expert pathologists. Demographic and clinical information was ascertained from medical records and risk factor questionnaires. A case control study of patients with PASC vs PDAC was constructed. PASC patients were also followed for outcome and treatment records were extracted. Results: Of 2,584 total patients with pancreatic cancers, 45 cases of PASC and 2,438 with PDAC were identified. There were no differences in age (median 69 vs 67 years, p=0.42), sex (male 64.4vs 56.6%, p= 0.29), BMI (27.41 vs 27.78 kg/m2, P=0.50), or ever-smoking (61.0 vs 55.3%, P=0.47), with a borderline association with reported diabetes (17.8 vs 29.9%, p =0.08). Compared to PDAC, PASCs were more likely to involve the body/tail (48.9 vs 33.2%, p= 0.02) and had poorer overall survival, adjusted for age, gender, and stage (median 7.1 m vs 12.8m, HR 1.89, p=0.0004). Of 9 PASC pts treated with neoadjuvant intent, 4 were surgically resected, median survival was 7 months. Eleven pts underwent upfront surgery, with variable adjuvant treatments. Median OS post- surgery was 18m (range 7-51). Of 14 patients presenting with metastatic disease, median survival was 4.5 m (range 1-22). With regard to systemic chemotherapy, for neoadjuvant or metastatic disease median duration of treatment was 3 months (range 0.5-7m) for Gemcitabine + nab-paclitaxel (N=9) and also 3 months (range 2-6m) for FOLFIRINOX (N-13). Conclusions: The diagnosis of PASC carries an even poorer outcome than pancreatic adenocarcinoma. Tumors are more likely to arise in the distal pancreas, and patients may be less likely to report associated diabetes. Limited antitumor activity was noted with multi-agent chemotherapeutic regimens. Prospective trials will be needed to clarify choice of regimen in the future.