tbuckley/cabot-search huggingface dataset:
Association of elevated serumfree light chains with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis
Authors: Alyssa I. Clay-Gilmour, Abdul R. Rishi, Lynn R. Goldin, Alexandra J. Greenberg-Worisek, Sara J. Achenbach, Kari G. Rabe, Matthew J. Maurer, Neil E. Kay, Tait D. Shanafelt, Timothy G. Call, J. Brice Weinberg, Nicola J. Camp, James R. Cerhan, Jose Leis, Aaron Norman, David L. Murray, S. Vincent Rajkumar, Neil E. Caporaso, Ola Landgren, Mary L. McMaster, Susan L. Slager, Celine M. Vachon
Journal: Blood Cancer Journal (2019)

Abstract Chronic lymphocytic leukemia (CLL) and its precursor, monoclonal B-cell lymphocytosis (MBL), are heritable. Serumfree light-chain (sFLC) measures are a prognostic factor for CLL, but their role in susceptibility to CLL is not clear. We investigated differences between sFLC measurements in pre-treatment serum from five groups to inform the association of sFLC with familial and sporadic CLL: (1) familial CLL ( n = 154), (2) sporadic CLL ( n = 302), (3) familial MBL ( n = 87), (4) unaffected first-degree relatives from CLL/MBL families ( n = 263), and (5) reference population ( n = 15,396). The percent of individuals having elevated monoclonal and polyclonal sFLCs was compared using age-stratified and age- and sex-adjusted logistic regression models. In age groups &gt;50 years, monoclonal sFLC elevations were increased in sporadic and familial CLL cases compared to the reference population ( p ’s &lt; 0.05). However, there were no statistically significant differences in sFLC monoclonal or polyclonal elevations between familial and sporadic CLL cases ( p ’s &gt; 0.05). Unaffected relatives and MBL cases from CLL/MBL families, ages &gt;60 years, showed elevated monoclonal sFLC, compared to the reference population ( p ’s &lt; 0.05). This is the first study to demonstrate monoclonal sFLC elevations in CLL cases compared to controls. Monoclonal sFLC levels may provide additional risk information in relatives of CLL probands.
IL-29 promoted obesity-induced inflammation and insulin resistance
Authors: Tian-Yu Lin, Chiao-Juno Chiu, Chen-Hsiang Kuan, Fang-Hsu Chen, Yin-Chen Shen, Chih-Hsing Wu, Yu-Hsiang Hsu
Journal: Cellular and Molecular Immunology (2019)

Abstract Adipocyte-macrophage crosstalk plays a critical role to regulate adipose tissue microenvironment and cause chronic inflammation in the pathogenesis of obesity. Interleukin-29 (IL-29), a member of type 3 interferon family, plays a role in host defenses against microbes, however, little is known about its role in metabolic disorders. We explored the function of IL-29 in the pathogenesis of obesity-induced inflammation and insulin resistance. We found that serum IL-29 level was significantly higher in obese patients. IL-29 upregulated IL-1β, IL-8, and monocyte chemoattractant protein-1 (MCP-1) expression and decreased glucose uptake and insulin sensitivity in human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes through reducing glucose transporter 4 (GLUT4) and AKT signals. In addition, IL-29 promoted monocyte/macrophage migration. Inhibition of IL-29 could reduce inflammatory cytokine production in macrophage-adipocyte coculture system, which mimic an obese microenvironment. In vivo, IL-29 reduced insulin sensitivity and increased the number of peritoneal macrophages in high-fat diet (HFD)-induced obese mice. IL-29 increased M1/M2 macrophage ratio and enhanced MCP-1 expression in adipose tissues of HFD mice. Therefore, we have identified a critical role of IL-29 in obesity-induced inflammation and insulin resistance, and we conclude that IL-29 may be a novel candidate target for treating obesity and insulin resistance in patients with metabolic disorders.
Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo
Authors: Jonathan Hasselmann, Morgan A. Coburn, Whitney England, Dario X. Figueroa Velez, Sepideh Kiani Shabestari, Christina H. Tu, Amanda McQuade, Mahshad Kolahdouzan, Karla Echeverria, Christel Claes, Taylor Nakayama, Ricardo Azevedo, Nicole G. Coufal, Claudia Z. Han, Brian J. Cummings, Hayk Davtyan, Christopher K. Glass, Luke M. Healy, Sunil P. Gandhi, Robert C. Spitale, Mathew Blurton-Jones
Journal: Neuron (2019)
Feasibility and challenges of a biopsy-driven and biomarker discovery clinical trial in metastatic colorectal cancer to identify signatures of clinical resistance.
Authors: Zuanel Diaz
Journal: Journal of Clinical Oncology (2012)

e14108 Background: Biopsy-driven clinical trials are essential to develop personalized therapeutics, since many critical questions are best addressed in the tumor tissue being treated. In the metastatic setting, intrinsic resistance occurs even with the most advanced therapeutic agents, and even in responders, acquired resistance is inevitable. We have designed a prospective study to identify biomarkers of clinical resistance to standard first-line therapy (FOLFOX, XELOX or FOLFIRI in combination with bevacizumab in patients with metastatic CRC (NCT00984048). Methods: Eligible patients have confirmed metastatic CRC, measurable disease, and consent to three needle-core biopsies (NCBs) of a non-resectable liver metastasis before treatment and at resistance. This study is approved at several Quebec hospitals, demonstrating that Research Ethics Boards recognize the value of biopsy-driven studies without therapeutic benefit. Results: Forty patients agreed to partake in this multi-center trial and to provide NCBs. Of these, 5% were non-neoplastic, and 5% had neuroendocrine origins. Using standard operating procedures developed for this trial, we were able to both preserve morphology and obtain high-quality genomic material. We demonstrate that this material is suitable for DNA analysis (array comparative genomic, methylation profiling) and RNA analysis (gene expression profiling, splicing isoforms variants and micro RNA profiling). In parallel, we have generated resistant CRC cell lines resistant to the combination therapy to further study biomarkers of resistance. Challenges in obtaining a biopsy at time of progression include death, patient refusal, heterogeneity of tumors, metastasis at a different organ site, and time constraints for re-biopsy. No significant adverse events were reported related to the biopsy procedure. Conclusions: We conclude that obtaining serial liver NCBs are challenging, but safe and feasible in metastatic CRC patients with unresectable liver disease. This study will provide insight on the relevance of metastatic tissue in assessing signatures of clinical resistance.
Differences in patterns of care and outcomes of elderly versus younger metastatic pancreatic cancer (mPC) patients.
Authors: Namrata Vijayvergia, Efrat Dotan, Karthik Devarajan, Kamel Hatahet, Farah Rahman, Steven J. Cohen
Journal: Journal of Clinical Oncology (2013)

9546 Background: Despite a median age at diagnosis of 72, elderly pancreatic cancer patients (pts) are poorly represented in clinical trials. We thus compared patterns of care and outcomes of mPC pts ≤ and &gt; 65 yrs of age. Methods: We retrospectively analyzed medical charts of 277 mPC pts treated at an academic center between 2000 and 2009. Age groups ≤ 65 yrs and &gt;65 yrs were compared with respect to gender, comorbidities, performance status (PS), tobacco/alcohol use, primary site, stage, histological grade, metastatic sites, treatment modalities, type and number of chemotherapeutic agents received, and survival after diagnosis of mPC (OS). Log-rank tests and Cox proportional hazards models were used to analyze survival endpoints and Fisher’s exact test to compare categorical variables. Results: 155 pts ≤65 yrs with median age of 58 and 122 pts &gt;65 yrs with median age of 73.5 were evaluated. The groups were well balanced with respect to sex (majority male), PS (majority ≤1), stage (majority 3, 4), and primary site (majority head). Cardiovascular (CV) disease was more prevalent among older pts (OR 1.7, p=0.04). Older pts were less likely to receive any chemotherapy for mPC (79% vs 92%; OR 0.33, p&lt; 0.001) and if treated were less likely to receive more than one agent (34% vs 52%; OR 0.48, p=0.003). Median OS was shorter in older pts (5m vs 6m, p=0.01). OS was longer with higher number of agents received (RR: 0.57 for young, 0.51 for old; p&lt; 0.001). CV and renal disease negatively impacted OS only in younger pts. The presence of lung metastases was associated with longer survival (10m vs 6m (p=0.01)) and liver metastases with decreased survival (5m vs 8m (p&lt;0.01)) only among younger pts. Conclusions: Elderly mPC pts have shorter OS, are less likely to receive chemotherapy, and if treated receive fewer agents compared to younger pts. These differences cannot be explained solely by PS or disease characteristics and warrant further study.
Salvage high-dose chemotherapy for primary mediastinal nonseminomatous germ cell tumors: Single institute experience.
Authors: John WT Walker, Scott A. North, Naveen S. Basappa, Peter M. Venner
Journal: Journal of Clinical Oncology (2013)

e15503 Background: Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) bear a worse prognosis than stage-matched testicular primaries, with a five year survival rate of 50%. In contrast to relapsed testicular NSGCT, retrospective analyses have not shown benefit to high-dose chemotherapy and autologous stem-cell transplant (HDCT/ ASCT) in PMNSGCT patients. Since publication of these studies, advancements in treatment regimens and supportive care have occurred, with emerging evidence suggesting HDCT/ASCT may benefit patients with PMNSGCT - both as first-line sequential treatment after standard-dose chemotherapy and at relapse. Objectives: Review the experience of patients presenting with PMNSGCT to a regional referral cancer center as a quality control assessment. Assess the benefit of salvage HDCT/ASCT to relapsed PMNSGCT patients. Methods: Patients presenting with PMNSGCT from 1980-2010 were abstracted from a Provincial cancer registry and records were retrospectively reviewed. Data includes patient demographics, cancer treatments and outcomes. Results: Fourteen male patients (median age 29; range: 17-54 years) with PMNSGCT were identified. Seven of 13 (54%) patients remain continuously disease-free with 1 patient lost to follow-up. Mean duration of follow-up in these patients is 57 (34-100) months. Three patients died having received ≤ 1 cycle of chemotherapy; exclusion of these patients results in a treatment failure rate of 30%. Six of the 7 cancer-free patients required salvage surgery. Three patients received tandem HDCT/ASCT (carboplatin 550 mg/m 2 and etoposide 150 mg/m 2 daily for 4 days) at subsequent relapse despite second-line chemotherapy. Two remain disease-free at 45 and 74 months respectively, while the third patient died of their disease 14 months post-transplant. Conclusions: Our experience with PMNSGCT is generally consistent with published outcomes in that ≈50% of patients are cured. However, in this series 2/3 heavily pretreated patients were salvaged with HDCT/ASCT, refuting the published historical experience. This study is limited by its small sample size, but provides impetus to re-examine HDCT/ASCT for high-risk patients.
Neutrophil toxicity and primary prophylaxis in diffuse large B cell lymphoma treated with R-CHOP
Authors: N. Naqi, J. Khatak
Journal: Journal of Clinical Oncology (2009)

e19548 Background: Three weekly R-CHOP therapy is regarded as standard treatment in advanced stage Diffuse Large B Cell Lymphoma (DLBCL) patients with low to intermediate-risk International prognostic index (IPI). This regimen is associated with intermediate risk (10–20%) of febrile neutropenia. Primary prophylaxis with colony-stimulating factor (CSFs) is therefore not recommended except in the presence of high risk factors as defined in the National Comprehensive Cancer Center Network guidelines for use of myeloid growth factors v.1.2008. It is however well realized that a significant number of good risk patients will still develop significant neutrophil toxicity. Methods: This observational study was conducted at Oncology department Combined Military Hospital, Rawalpindi, on fifty good risk patients of advanced stage DLBCL, treated with R-CHOP regimen without primary CSFs prophylaxis. NCI Common Toxicity Criteria version 3.0 was used for grading toxicity and significant neutrophil toxicity was defined as Grade 4 neutropenia between day 7 and 10 post therapy, febrile neutropenia and Grade 2 or more neutrophil toxicity persisting on day 1 of next cycle. Good risk patients were recruited by the following exclusion criteria: WHO Performance status scale 4, concurrent immunosuppressive drug therapy, abnormal hepatic or renal functions and inadequate hematological values. Results: 10(20%) patients, developed significant neutrophil toxicity. In this group 7(70%) had grade 4 neutropenia and 3(30%) patients developed febrile neutropenia. 8(80%) of these patients developing significant toxicity had WHO Performance scale ≥ 2. 2(20%) patients developing Grade 4 toxicity between days 7 and 10 post therapy had good performance status (0 or 1) and toxicity resolved by next cycle without getting complicated to febrile neutropenia. Conclusions: Performance status in terms of scale has not been defined in the high risk factors for developing febrile neutropenia in the NCCN guidelines on myeloid growth factors use. We observed that DLBCL patients with WHO performance status scale ≥ 2 treated with R-CHOP therapy at 3 weekly intervals are at greatest risk for developing significant neutrophil toxicity and febrile neutropenia. No significant financial relationships to disclose.
Association of Personalized Blood Pressure Targets With Hemorrhagic Transformation and Functional Outcome After Endovascular Stroke Therapy
Authors: Nils H. Petersen, Andrew Silverman, Anson Wang, Sumita Strander, Sreeja Kodali, Charles Matouk, Kevin N. Sheth
Journal: JAMA Neurology (2019)

This cohort study assesses the feasibility of determining personalized blood pressure targets as well as the association of deviating from these targets with radiographic and clinical outcomes.
Impact of age at diagnosis on survival of hormone-refractory prostate cancer (HRPC) patients
Authors: M. R. Humphreys, C. Ma, S. S. Sridhar
Journal: Journal of Clinical Oncology (2009)

e16050 Background: Conflicting data exist for age as a determinant of overall survival (OS) in pts with HRPC. We hypothesize that young (&lt;55) HRPC pts represent a more aggressive biological phenotype and therefore have a decreased OS. Methods: A retrospective chart review was conducted on 334 consective HRPC pts treated between 1995–2005. Summary statistics for demographic and clinical factors were generated, and Kaplan-Meier (KM) OS curves were created. Bivariate Cox Proportional-Hazards regression was used to test the association of age at diagnosis while adjusting for a covariate, with significant covariates entered into multivariate models. Results: Overall median survivals in the age stratified categories (&lt;55, ≥55–65, ≥65–75, ≥75) were 5.5, 6.9, 7.9, and 4.3 yrs, with 5 yr survivals 51.9%, 67.4%, 67.0%, and 34.9%, respectively. KM curves showed divergence with an overall significant log-rank test (p &lt; 0.0001). Compared to pts ≥65–75, the hazard ratios (HR) for HRPC pts &lt;55 and ≥75 were 1.40 (95% CI 0.90–2.60) and 2.52 (95% CI 1.67–3.82), respectively. However, following multivariate analysis HRs for HRPC pts &lt;55 and ≥75 were 1.60 (95% CI 0.98–2.62) and 1.25 (95% CI 0.71–2.20). Pts &lt;55 and ≥75 presented with advanced stage at diagnosis and progressed to bone metastasis earlier. Pts ≥75 had decreased performance status, more comorbidities, higher PSA at diagnosis, shorter duration of hormone sensitive disease, and were less likely to receive chemotherapy than pts &lt;75. The percentage of rapid PSA doubling times was highest in the &lt;55 cohort. In multivariate analysis with age as a categorical variate, ECOG 3–4 (HR 2.65), time from diagnosis to both HRPC (HR 0.78) and bone metastasis (HR 0.80), and duration of response to androgen ablation (HR 0.86) remained highly predictive. Conclusions: Age at diagnosis influences OS in HRPC with a bimodal survival curve. Pts &lt;55 and ≥75 present with more aggressive disease, translating into reduced median and 5 yr survivals. Other covariates, especially ECOG status, likely account for the decreased OS in the ≥75 cohort. Conversely, pts &lt;55 had an adjusted HR of 1.60 (p = 0.06). Our study supports a growing body evidence that suggests a poor prognosis in younger men; correlating these differences at the molecular level could lead to better targeted therapies. No significant financial relationships to disclose.
Tumor Microenvironment (TME) Regulation of Programmed Death-1 (PD1) Receptor and Its Ligands PDL1 and PDL2 in Chronic Lymphocytic Leukemia (CLL)
Authors: Fortunato Morabito, Sabrina Bossio, Claudio Tripodo, Anna Recchia, Laura De Stefano, Nadia Caruso, Angela Palummo, Francesca Storino, Massimo Gentile, Ernesto Vigna, Anna Maria Petrungaro, Iolanda Donatella Vincelli, Daniela Fenoglio, Gilberto Filaci, Franco Fais, Giuseppina Uccello, Alessandro Gulino, Roberto Vallone, Martina Manzoni, Antonino Neri, Giovanna Cutrona, Pierfrancesco Tassone, Manlio Ferrarini
Journal: Blood (2017)
Challenges When Conducting Complex Clinical Research
Authors: Dost Ongür
Journal: JAMA Psychiatry (2019)

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Risk and predictors of suicide in colorectal cancer patients: A SEER analysis.
Authors: Haider Samawi, Abdel Aziz Shaheen, Patricia Tang, Daniel Yick Chin Heng, Winson Y. Cheung, Michael M. Vickers
Journal: Journal of Clinical Oncology (2013)

9596 Background: Colorectal cancer (CRC) patients have a higher risk of suicide as compared with the general population. Due to differences in the sites/morbidity of recurrences as well as ostomy rates, we sought to evaluate the distribution and predictors of suicide among patients with colon and rectal cancer. Methods: A retrospective analysis was undertaken using the Surveillance, Epidemiology, and End Results (SEER) database from 1973-2009. Patients included were &gt;18yrs and had confirmed adenocarcinoma of the colon or rectum. Results: Included in this analysis were 187,996 rectal cancer and 443,368 colon cancer patients. Colon cancer patients were older (median age 71 vs. 67 yrs, p &lt;0.001) and included more females (51 vs. 43%, p &lt;0.001) as compared to rectal cancer patients. Suicide rates were similar (611 [0.14%] vs. 337 [0.18%], p &lt;0.001), as was the median time to suicide for colon vs. rectal cancer patients respectively (37 vs.32 months, p = 0.13). On univariate analysis, having rectal cancer was a predictor of suicide (HR 1.26; 95% CI: 1.10-1.43). However after adjustment for age, sex, race, marital, primary site surgery, stage and one primary, rectal cancer was not a predictor of suicide (HR 1.05; CI: 0.83- 1.33). In the combined CRC cohort, independent predictors of suicide included age &gt;70 (HR 1.55; CI: 1.23-1.94), male gender (HR 7.56; CI: 5.34-10.70), being single (HR 1.56; CI: 1.14- 2.13), distant metastases at diagnosis (HR 1.58; CI: 1.13- 2.21), and white race (HR 3.21; CI: 1.75- 5.88). Also, lack of resection of primary tumor was associated with increased risk of suicide (HR 2.83; CI: 1.97- 4.05). Among colon cancer cohort, older age, male gender, and white race as well as lack of primary resection were independent predictors of suicide. Similarly, the aforementioned predictors as well as metastatic disease on presentation were the independent predictors of suicide in the rectal cohort. Conclusions: The suicide risk in CRC patients is low (&lt; 0.2%) and no difference was found based on location of primary tumor. Gender, age, distant spread of disease, intact primary tumour and race are the main predictors of suicide among colorectal patients. Future studies and interventions are needed to target these high risk groups.
Study of tumor-infiltrating T-cell reactivity to metastatic gastrointestinal cancers.
Authors: Simon Turcotte, Alena Gros, John R Wunderlich, Katherine Hogan, Qiong J. Wang, Patricia Fetsch, Mark E. Dudley, Steven A. Rosenberg
Journal: Journal of Clinical Oncology (2012)

e14179 Background: A high density of tumor-infiltrating lymphocytes (TIL) found in gastrointestinal cancers has been associated with improved prognosis. Evidence supporting specific autologous tumor recognition by TIL remains sparse and limits the development of innovative immunotherapy approaches. Methods: Metastases from 15 GI cancer patients (13 colorectal, 1 gastric, 1 cholangiocarcinoma) processed into fragments and fresh tumor cell suspensions (FrTu) were used to grow TIL and cancer cell lines. TIL phenotype was assessed by flowcytometry and reactivity by coculture with available cryopreserved FrTu and cancer cell lines. Limiting dilution techniques were used to isolate reactive CD8+ TIL clones. T-cell receptors (TCR) were sequenced using PCR amplification. Results: TIL were expanded successfully in all 15 cases. TIL phenotype studied from 7 freshly resected colorectal cancer metastases revealed a higher percentage of immunosuppressive T cells (CD4+CD25HIFoxP3+) compared to adjacent normal tissue and blood (respectively 5.4 ± 1.0%, 1.3 ± 0.5%, and 1.0 ± 0.4% of CD3+ cells). Interferon-gamma release by TIL after their first outgrowth upon coculture with cryopreserved FrTu was significant in all 6 cases studied, with positive results ranging from 7% (3/42) to 89% (8/9) of patient’s distinct cultures. Two newly established cancer cell lines allowed extensive investigation of TIL reactivity. In a case of gastric cancer, 65% of the CD3+CD8+ TIL expanded from liver metastases expressed the same TCR. TIL clones expressing this TCR could recognize the autologous cancer cell line with a high degree of specificity, suggesting that within this tumor a productive immune response occurred. In a case of metastatic cholangiocarcinoma, two TIL clones with distinct TCR represented less than 1% of the CD3+CD8+ cells grown from an omental metastasis and the malignant ascites, but could nonetheless lyse the autologous tumor with specificity. Conclusions: Despite the immunosuppressive microenvironment of GI cancer metastases, CD8+ TIL that recognize autologous tumor with specificity can be identified and expanded in vitro. The adoptive transfer of TIL for the therapy of metastatic GI cancer patients is currently being studied.
Wireless optofluidic brain probes for chronic neuropharmacology and photostimulation
Authors: Raza Qazi, Adrian M. Gomez, Daniel C. Castro, Zhanan Zou, Joo Yong Sim, Yanyu Xiong, Jonas Abdo, Choong Yeon Kim, Avery Anderson, Frederik Lohner, Sang-Hyuk Byun, Byung Chul Lee, Kyung-In Jang, Jianliang Xiao, Michael R. Bruchas, Jae-Woong Jeong
Journal: Nature Biomedical Engineering (2019)