tbuckley/cabot-search huggingface dataset:
Detection of mild cognitive impairment in middle-aged and older adults with obstructive sleep apnoea
Authors: Katia Gagnon, Andrée-Ann Baril, Jacques Montplaisir, Julie Carrier, Sirin Chami, Serge Gauthier, Chantal Lafond, Jean-François Gagnon, Nadia Gosselin
Journal: European Respiratory Journal (2018)

Obstructive sleep apnoea increases the risk for mild cognitive impairment and dementia. The present study aimed to characterise the ability of two cognitive screening tests, the Mini-Mental State Examination and the Montreal Cognitive Assessment, to detect mild cognitive impairment in adults aged 55–85 years with and without obstructive sleep apnoea. We included 42 subjects with mild and 67 subjects with moderate-to-severe obstructive sleep apnoea. We compared them to 22 control subjects. Mild cognitive impairment was diagnosed by a comprehensive neuropsychological assessment. We used receiver operating characteristic curves to assess the ability of the two screening tests to detect mild cognitive impairment. The two screening tests showed similar discriminative ability in control subjects. However, among the mild and the moderate-to-severe obstructive sleep apnoea groups, the Mini-Mental State Examination was not able to correctly identify subjects with mild cognitive impairment. The Montreal Cognitive Assessment's discriminant ability was acceptable in both sleep apnoea groups and was comparable to what was observed in controls. The Mini-Mental State Examination should not be used to screen for cognitive impairment in patients with obstructive sleep apnoea. The Montreal Cognitive Assessment could be used in clinical settings. However, clinicians should refer patients for neuropsychological assessment when neurodegenerative processes are suspected.
Prospective serial sequencing of CTC/cfDNA and NK cell activity in patients undergoing multimodality treatment for triple negative breast cancer.
Authors: Hanna Irie, Paul H. Schmidt, Elisa R. Port, Yayoi Kinoshita, Alan Soto, Kereeti Pisapati, Ronald Couri, Olivia Kolodka, Hanane Arib, Robert P. Sebra, Michael J. Donovan
Journal: Journal of Clinical Oncology (2018)

e24108 Background: Patients with early stage triple negative breast cancer (TNBC) are treated with multimodality therapy (chemotherapy, surgery, radiation). Cell-free DNA (cfDNA) and circulating tumor cell DNA (CTC DNA) sequencing offers less invasive approaches for response, resistance, and predicting residual disease. For utility of cf/CTC DNA sequencing, we prospectively collected cfDNA/CTC from patients undergoing treatment for early stage TNBC. We also evaluated immune response with NK cell activity during treatment and follow-up. Methods: Twenty-two patients, stage I-III TNBC, serial cf/CTC DNA samples: pre-treatment, post-neoadjuvant chemotherapy, and post-surgery. Collections every 6 months and to 5 years following active treatment. cf/CTC DNA isolated using Cynvenio’s Liquid Biopsy platform and sequenced with Oncomine panels. NK cell activity was assessed utilizing Cynvenio’s NK Vue assay. Clinical response to neoadjuvant chemotherapy was recorded. Results: 27% (6/22) patients with one baseline pre-treatment pathogenic mutation in cfDNA/CTC DNA. Three of 6 patients completed active treatment with no evidence of disease, and no known mutations. Interestingly, five patients (22%) without detectable pathogenic mutations at pre-treatment, had mutations post-neoadjuvant chemotherapy or post-surgery, regardless of response to neoadjuvant chemotherapy. 54% (6/11) with detectable mutations in any collection had multiple concurrent mutations. The most frequent mutations were: ARID1A (27%); PIK3CA (18%) and PALB2 (18%). Finally 31.8% (7/22) patients had low ( < 100) NK cell activity at baseline. Conclusions: cf/CTC DNA pathogenic mutations were identified in 27% of patients before active treatment. Patients with detectable pathogenic mutations following neoadjuvant chemotherapy or surgery, but not at baseline, may signify emergent treatment resistant disease. Finally, a significant percentage of patients had reduced NK cell activity at diagnosis suggesting a compromised immune system. Additional subjects are necessary to confirm original observations.
Assessment of the genomic stability and molecular landscape of patient-derived xenograft (PDX) models from NCI’s Patient-Derived Models Repository (PDMR).
Authors: Bishwajit Das, Yvonne A Evrard, Li Chen, Rajesh Patidar, Corinne Camalier, Vivekananda Datta, Palmer Fliss, Michelle M Gottholm-Ahalt, Erin Cantu, Gloryvee Rivera, Suzanne Borgel, John Carter, Margaret R Defreytas, Malorie Morris, Dianne Newton, Marianne Radzyminski, Melinda G. Hollingshead, Chris Alan Karlovich, Paul M. Williams, James H. Doroshow
Journal: Journal of Clinical Oncology (2018)

12023 Background: Patient-derived xenografts (PDXs) are a powerful tool for cancer translational research. However, it is unclear if early passage PDXs faithfully recapitulate the molecular profiles of the corresponding patient tumors. The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (PDMR; www.pdmr.cancer.gov) of PDXs with clinical annotation and comprehensive genomic data. We used this data set, which represents 13 broad categories of tumor types, to conduct an in-depth investigation of the genomic stability of PDXs with early passaging. Methods: Tumors (biopsy or resection), including some from metastatic sites, were used to establish 211 PDX models from 206 patients. Whole Exome Sequencing and RNA-Seq were performed on 2-9 mice per model. Passages represented include the original clinical sample, P0, P1, P2, and less frequently > P2. Results: By several metrics, genomic profiles of a large majority of PDMR models were stable with early passaging: (1) transcriptome profiles of mice from different passages in a model were found to always cluster together; (2) 75% of PDXs maintained similar copy number alteration profiles compared with the original clinical sample, with no significant differences between passages; (3) the allele frequency (AF) of clinically relevant mutations remained consistent across passages, with only 20% of models having > 15% AF range from the median. Moreover, genomic features of PDMR models were broadly comparable to those in large public patient data sets. For example, melanoma models had the highest tumor mutation burden and a 55% prevalence of BRAF V600X; 11% of colon adenocarcinoma models were MSI-H, with APC (65%), TP53 (59%) and KRAS (53%) being most frequently altered. Conclusions: In this large and histologically diverse PDMR data set, PDXs exhibited genomic stability with early passaging. The molecular landscape of PDMR models is faithfully comparable to large public patient data sets. As the PDMR collection expands additional in-depth analyses will be performed. The PDMR thus represents a valuable resource for researchers interested in pre-clinical drug or other studies.
UNC13D G863D as a genetic predisposition factor of lymphoma and a founder mutation in Chinese.
Authors: Hongxing Liu, Xue Chen, Yang Zhang, Fang Wang, Wen Teng, Yuehui Lin, Xiangping Han, Yuanli Xu, Chunrong Tong
Journal: Journal of Clinical Oncology (2016)

e19015 Background: Some lymphoma patients may harbor mutations in PRF1, UNC13D, STX11, STXBP2 or SH2D1A, which cause function defects of cytotoxic lymphocytes. Data of the association between genetic defects and the development of lymphoma in Chinese patients is limited to date. Methods: 90 lymphoma patients were analyzed for UNC13D, PRF1, STXBP2, STX11, SH2D1A, and XIAP. 210 healthy donors were used as controls. Genetic polymorphism information in dbSNP, 1000 Genomes Project and ExAC were referenced to obtain the frequencies of variants in large populations. Results: Germline mutations were observed in 24 patients (26.67%). 16 patients carried mutations in UNC13D, including 12 heterozygotes, 1 homozygote and 3 compound heterozygotes. 7 patients had PRF1 mutations, including 4 heterozygotes, 1 homozygote and 2 compound heterozygotes. 1 patient carried STX11 monoallelic mutation. 60 controls were sequenced for these 6 genes with the same methods and 5 harbored monoallelic mutations. UNC13D c.2588G > A/p.G863D was the most common mutation, which was detected in 9 patients (10.00%), including 1 homozygous and 8 heterozygous. Data in the 1000 Genomes Project showed the c.2588A allele existed predominantly in Chinese (0.83%), rarely in Japanese and Bengali. Other populations did not carry this variant. Data in the ExAC also showed the c.2588A allele mainly existed in East Asians (0.43%), seldom in other populations. Considering the high allele frequency of this mutation in our patients and the distinctly different allele frequencies among diverse populations, genotyping of the c.2588 allele was performed in 210 controls and heterozygous c.2588G > A was observed in 4 of them. Combined with data in the 1000 Genomes Project, we obtained a control cohort of 511 individuals, 9 of them harbored c.2588A allele in a heterozygous state. Chi-Square test showed the frequency of c.2588A in patients was significantly superior to that in controls. Conclusions: Impaired cytotoxic machinery may represent a predisposing factor for the development of lymphoma. Chinese lymphoma patients show a distinct mutation spectrum that UNC13D is the most frequently mutated gene. In addition, UNC13D G863D mutation might be a founder mutation in Chinese.
Neurologic immune related adverse events (irAEs) in patients treated with immune checkpoint blockade.
Authors: Bianca Santomasso, Aya Haggiagi, Rachna Malani, Colleen Anne Maher, Jenessa N. Holder, Yelena Shames, Jessica Wilcox, Jessica Flynn, Samuel Briggs, Katherine Panageas, Margaret K. Callahan
Journal: Journal of Clinical Oncology (2018)

3084 Background: Neurologic irAEs are uncommon but potentially fatal toxicities of immune checkpoint blockade (ICB). Their incidence, clinical and pathologic features, and association with therapy received are poorly understood. Methods: An IRB approved retrospective study was conducted to identify neurologic irAEs of all patients (pts) treated with ICB (anti-CTLA4, anti-PD1, anti-PDL1 monotherapy or in combination) from January 2010 to August 2017 at our institution. Clinical, radiologic, and pathologic features of neurotoxicity were collected. We excluded pts with primary CNS tumors or neurologic symptoms that were attributable to their CNS disease. Results: Of 4,864 pts who received anti-CTLA4, anti-PD1, or anti-PDL1 either as monotherapy or in combination, neurologic irAEs developed in 81 (1.67%; 95% CI, 1.34% to 2.06%). Clinical, radiographic, and radiologic features of neurotoxicity were diverse. Time to onset ranged from 3 days to 17 months with a median of 2 doses (1 to 20) received. The incidence was higher with combination therapy versus monotherapy (36 of 1,448 [2.49%] v 45 of 3416 [1.32%]; P = 0.0047), and there was no significant difference in incidence among patients age ≤ 65 at time of treatment versus patients age > 65 (41 of 2,705 [1.90%] v 40 of 2,159 [1.85%]; P = 0.3692). Of pts who experienced neurotoxicity, 60% (49 of 81) were hospitalized, 5 (10%) in the ICU. Fifty nine percent (48 of 81) had a concurrent non-neurologic irAEs. Sixty nine percent (56 of 81) had grade 1-2 neurologic events and 77% (63 of 81) improved/resolved with drug holding/immunosuppression. Eight patients worsened clinically or died during the course of neurotoxicity treatment. Conclusions: Neurologic irAEs have variable clinical presentation and are more common when anti-CTLA-4 or anti-PD1/PD-L1 mAbs are combined with each other or with other checkpoint inhibitors. Incidence is similar among pts of advanced age and younger pts. Most events improve/resolve with drug holding/immunosuppression, but pts may require hospitalization and experience worsening despite immunosuppression. This underscores the need for earlier identification, as patient outcomes may improve with earlier treatment.
Increased hypercalcemia trend.
Authors: Zachary Michael Trisel, Stuthi Perimbeti, Daniel Kyung, Pamela A. Crilley, David Lane Topolsky, Michael Styler, Kristine Marie Ward
Journal: Journal of Clinical Oncology (2018)

e22117 Background: Hypercalcemia of malignancy (HCM) represents a complication of a variety of cancers. Bisphosphonates (BP) are routinely used to decrease skeletal related events in cases with osseous involvement. We hypothesized there would be a downtrend in HCM hospital admissions from 1999-2014 for breast (BC), lung (LC), renal (RC) cancers & multiple myeloma (MM) given the widespread use of BP. Methods: We analyzed data from the Healthcare Cost and Utilization Project’s National Inpatient Sample between 1999-2014 using ICD 9 codes for primary diagnosis of BC, LC, MM & RC and hypercalcemia as a secondary diagnosis. HCM % was evaluated. Chi-square testing determined significance. Hazard ratios (HR) of death during hospitalization related to HCM within 30 days were controlled for confounding factors like age, race, sex, income insurance status & comorbidities. Results: *w = weighted Conclusions: Hospital admissions remained relatively stable for the interval studied. HCM related to BC, LC & MM increased despite more aggressive BP use. RC did not show a significant change. Given the opposite trend in prevalence as expected, we believe this discrepancy is multifactorial. With advancements in therapies, patients live longer thus potentially increasing the prevalence of comorbidities such as HCM. Also, BP may be delaying the onset of HCM without decreasing incidence. PTHrP is less responsive to BP which could account for the increased frequency in BC & LC. With data becoming easily accessible and improved reporting during these 15 years studied, the incidence of HCM may have been under reported in the earlier years. HCM is an important metabolic disturbance with significant mortality in a variety of neoplasms that requires ongoing investigation for better preventive strategies. HCM Trends 1999 (%) 2014 (%) BC 0.52 1.91 N = 98,748 w* = 485,414 p = 0.0001 LC 2.57 4.05 N = 133,297 w = 656,021 p = 0.0001 MM 14.42 20.10 N = 56,295 w = 277,722 p = 0.0001 RC 1.41 1.49 N = 129,617 w = 638,856 p = 0.42 Admissions 1999 2014 BC N = 6,040 w: 29,917 N = 5,780 w: 28,900 LC N = 6,714 w: 33,147 N = 8,582 w: 42,910 MM N = 2,861 w: 14,176 N = 2,699 w: 13,495 RC N = 5,887 w: 29,061 N = 8,688 w: 43,440 Hospital Mortality HR 95%Cl P value BC 1.521 1.417-1.632 < 0.0001 LC 0.995 0.966 - 1.024 0.7202 MM 1.282 1.234 - 1.332 < 0.0001 RC 2.368 2.195 - 2.554 < 0.0001
Lutetium-177 PSMA617 theranostics in metastatic castrate-resistant prostate cancer (mCRPC): Interim results of a phase II trial.
Authors: Shahneen Kaur Sandhu, John A Violet, Justin Ferdinandus, Sue-Ping Thang, Amir Iravani, Christina Guo, Grace Kong, Aravind Ravi Kumar, Timothy J. Akhurst, Alexis Beaulieu, Declan G. Murphy, Jennifer Mooi, Ben Tran, Guy C. Toner, Scott Williams, Rodney J Hicks, Michael Hofman
Journal: Journal of Clinical Oncology (2018)

5040 Background: Lutetium-177 (177Lu)-PSMA617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling tumor-targeted delivery of beta-radiation. We previously reported favourable activity and toxicity in 30 patients with mCRPC and now report updated safety and efficacy results including an additional 20 patient expansion cohort. Methods: In this phase II trial, 50 patients with PSMA-avid mCRPC who had progressed after conventional therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were 50% PSA response rate (PCWG2) and toxicity (CTCAE v4.3). Other endpoints were objective response rate (ORR), quality of life (EORTC QLQ-C30, BPI), PSA progression free survival (PFS) and overall survival (OS). Results: 50 patients (median age 71, range: 50-87) were eligible for treatment. 90% had progressed after abiraterone and/or enzalutamide, and 88% progressed after chemotherapy (84% post docetaxel and 48% following docetaxel and cabazitaxel). A median of 4 (range: 1-4) cycles and mean radioactivity of 7.5 GBq/cycle was administered. At this interim analysis (cut-off: 19 Jan 2018), the primary endpoint of PSA decline ≥ 50% was achieved in 31 of 50 patients (62%, 95% CI 47-75%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline ≥ 80%. Common toxicities included dry mouth (68%), fatigue (38%), nausea (48%) and pain flare (10%). These were all Grade 1-2, self-limiting or manageable. G3-4 hematological toxicities attributed as possibly related to LuPSMA included thrombocytopenia (10%), anemia (10%), and neutropenia (6%). Median PSA PFS was 7.0 months (95% CI 5.7-8.8) and median OS was 12.0 months (95% CI 10.0-18.7). Conclusions: This LuPSMA Phase II trial suggests high response rates and low toxicity in men with mCRPC who progressed after multiple conventional therapies. These compelling results have justified a randomized trial comparing LuPSMA to carbazitaxel (NCT03392428). Updated QOL, ORR, PSA-PFS and OS data will be presented. Clinical trial information: 12615000912583.
A comparison of three clinical factors as predictive markers for response to immunotherapy in non-small cell lung cancer.
Authors: Isabel Ruth Preeshagul, Kevin M. Sullivan, Doru Paul, Robert G. Maki, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2018)

e21158 Background: While prior studies demonstrated that pre-treatment Neutrophil Lymphocyte Ratio (NLR) < 5 and tobacco exposure predict benefit from checkpoint inhibition, presently, the only regulator-approved predictive biomarker is tumor-based PD-L1. Methods: 140 patients with non-small cell lung cancer were treated with ICI from July 2015 to November 2017. NLR and smoking history were recorded prior to starting ICI. A cut-off of 5 categorized NLR as high or low. Disease control (DC) was defined as objective response or stable disease per RECIST 1.1 after 3 months of therapy. PD-L1 expression (IHC Dako 22C3 PharmDx) was captured as high (≥50%), low (1-49%) and negative (0%); Positive PD-L1 is defined as PD-L1 expression > 0. We calculated the percentage of DC for each factor. We compared the sensitivity (SN), specificity (SP) and positive/negative predictive values (PPV and NPV) with those of PD-L1 in the subset of patients with PD-L1 data. Descriptive statistics were utilized to summarize the data. A chi-square test was used to compare proportions. Results: There were 140 patients in all, with PD-L1 data on 51 patients. 95/140 (67%) had DC. Comparative results for each parameter are tabulated in Table 1. Conclusion: There was no statistically significant difference between the groups in terms of sensitivity. NLR <5 had significantly higher PPV, SP and NPV compared to PD-L1. Smoking, on the other hand, had a significantly inferior NPV in this small group of patients, even though PPV was numerically greater when compared to PD-L1. These simple and easily available biomarkers, particularly NLR, should be evaluated further in large prospective studies. Table 1. Parameter (+) smoking (124) (-) Smoking (16) NLR <5 (93) NLR ≥5 (47) PD-L1 High (22) PD-L1 Low/- (29) PD-L1 + (35) PD-L1 - (16) DC (%) 83(67%) P = 0.52 12(75%) 80(86%) P < 0.0001 14(29%) 19(86%) P=0.52 23(79%) 28(80%) P=0.49 14(88%) SN 66% 86% 86% 80% P value vs PD-L1 high P = 0.007 P = 1 P value vs PD-L1 + P = 0.06 P = 0.31 SP 25% 70% 20% 13% P value vs PD-L1 high P = 0.47 P < 0.0001 P value vs PD-L1 + P = 0.06 P < 0.0001 PPV 87% 85% 45% 66% P value vs PD-L1 high P < 0.0001 P < 0.0001 P value vs. PD-L1 + P = 0.001 P = 0.001 NPV 8% 71% 70% 22% P value vs PDL-1 low/- P < 0.0001 P = 0.89 P value vs. PD-L1 - P < 0.008 P < 0.0001
Effects of neoadjuvant chemotherapy on immune microenvironment and clinical outcomes in locally advanced gastric cancer.
Authors: Yue Yu, Yi-Xin Zeng, Ai-Ping Zhou, Xiaopeng Ma, Yun Zhang, Zhirong Shen, Jianming Ying, Wen Zhang, Qiaofeng Zhong
Journal: Journal of Clinical Oncology (2018)

e24133 Background: It has been demonstrated that chemotherapy can modulate antitumor immunity in various types of tumors. However, the effect of neoadjuvant chemotherapy (NAC) on tumor microenvironment for patients with locally advanced gastric cancer (GC) still remains unclear. In this study, we aim to characterize the immunological changes after NAC and the clinical outcomes of these changes in GC. Methods: Paired tumor samples (pre-NAC biopsies and post- NAC surgical resections) of 59 patients with locally advanced GC were retrospectively identified and analyzed by multiplex immunohistochemistry with a panel including CD4, CD8, FOXP3, PD-1, PD-L1, and Tim-3. Samples were categorized as low (L) or high (H) expressors of each marker, and relationship between the expression level and clinical variables was further applied by survival analysis using log-rank test. Results: Following NAC, CD4, CD8, PD1, PD-L1 and Tim-3 expression are significantly increased, with a strong pairwise correlation (P < 0.001) between these markers. 33 (55.1%) patients received a platinum plus fluoropyrimidine chemotherapy and 26 patients (44.1%) received a taxane, platinum and fluoropyrimidine chemotherapy as NAC. Among the 26 patients, up-regulation of CD8, PDL1, and Tim-3 after NAC was found to be good prognostic factors of both progression free survival (PFS) and overall survival (OS) (Table 1). Further analysis is under investigation. Conclusions: NAC in locally advanced GC strongly impacts the tumor immunity. Elevated expression of CD8, PD-L1 and Tim-3 could be prognostic biomarkers for PFS and OS in patients received taxane, platinum and fluoropyrimidine chemotherapy. Our study provides evidence of the effect of NAC on tumor microenvironment and rationale for combination of checkpoint inhibitors and NAC in GC. Table 1. Correlation between expression of markers and survival Marker Group Median PFS (95% CI), Months P value Median OS (95% CI), Months P value CD8 H 35.4 (21.4-NA) 0.0047 44.6 (35.8-NA) 0.00021 L 13.3 (11.1-NA) 20.2 (14.3-NA) PD-L1 H 35.4 (21.4-NA) 0.0014 44.6 (35.8-NA) < 0.00010 L 13.7 (9.6-NA) 20.2 (14.3-NA) TIM-3 H 35.4 (21.4-NA) < 0.0010 44.6 (35.8-NA) 0.00021 L 12.9 (9.6-NA) 20.2 (14.3-NA)
Induction of Paracrine Signaling in Metastatic Melanoma Cells by PPARγ Agonist Rosiglitazone Activates Stromal Cells and Enhances Tumor Growth
Authors: Christine Pich, Patrick Meylan, Beatris Mastelic-Gavillet, Thanh Nhan Nguyen, Romain Loyon, Bao Khanh Trang, Hélène Moser, Catherine Moret, Christine Goepfert, Jürg Hafner, Mitchell P. Levesque, Pedro Romero, Camilla Jandus, Liliane Michalik
Journal: Cancer Research (2018)

Abstract In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious. Significance: These findings uncover a novel mechanism by which the thiazolidinedione compound rosiglitazone contributes to tumorigenesis, thus highlighting a potential risk associated with its use in patients with established tumors. Cancer Res; 78(22); 6447–61. ©2018 AACR.