tbuckley/cabot-search huggingface dataset:
Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints
Authors: Lee-Shing Chang, Romualdo Barroso-Sousa, Sara M Tolaney, F Stephen Hodi, Ursula B Kaiser, Le Min
Journal: Endocrine Reviews (2018)

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.
CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection
Authors: David V. Mathews, Ying Dong, Laura B. Higginbotham, Steven C. Kim, Cynthia P. Breeden, Elizabeth A. Stobert, Joseph Jenkins, J. Yun Tso, Christian P. Larsen, Andrew B. Adams
Journal: Journal of Clinical Investigation (2018)

Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell-mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor β-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122.
Non-tunneling technique of port insertion for chemotherapy infusions in cancer patients: A single centre study.
Authors: Akhil Palod, Abhishek Jain, Shashank J. Pandya
Journal: Journal of Clinical Oncology (2018)

e14507 Background: Infusion therapy via a subcutaneously implanted venous port system is an attractive alternative to infusion via peripheral veins, peripherally inserted central catheters or tunnelled catheters .In this study we wish to introduce
The management of BRAF mutant melanoma brain metastases upon tyrosine kinase failure.
Authors: Rahul Ladwa, Victoria Atkinson
Journal: Journal of Clinical Oncology (2017)

e21020 Background: Brain metastases (BM) failure on tyrosine kinase inhibitor (TKI) is a frequent complication in patients with BRAF mutant metastatic melanoma (MM) and is associated with a poor prognosis. We aimed to explore the outcome of these patients with modern therapeutic options. Methods: We retrospectively analysed 55 patients with treated BRAF mutant mm diagnosed with BM on TKI at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 53 (17-82) years, presence of seizures (N = 7), LDH &gt; 250 (N = 23) and presence of systemic disease (N = 54). BM were categorised as solitary (N = 8), 2-6 (N = 23), more than 6 (N = 13) and leptomeningeal disease (N = 11). Management of BM included surgical resection (N = 6), stereotactic radiosurgery (SRS) (N = 14), whole brain radiotherapy (N = 13) and best supportive care (N = 16). BRAF use post progression with BM was used (N = 10). Immunotherapy with Ipilimumab (N = 17) and PD1 inhibitor (N = 24) was used. With a median follow up of 5 months, 47 (85%) patients had died from MM. Death occurred due to progressive disease in the brain (N = 24), systemically (N = 5) or both (N = 18). The number of patients surviving over 6 months (N = 27) were associated with &lt; 6 BM, use of radiotherapy, use of anti PD1 antibodies and the use of ablative therapies with immunotherapy. Statistically improved overall survival (OS) were found with &lt; 6 BM, SRS use and PD1 inhibitor use. Ablative treatments (resection or SRS) with subsequent immunotherapy confers a median OS of 13 months in select patients. Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BRAF mutant mm on TKI who develop BM remains poor. Death is frequently due to PD within the brain. The use of ablative techniques and immunotherapy are optimal treatment options in this poor prognostic group.
microRNA-423-3p exosomes derived from cardiac fibroblasts mediates the cardioprotective effects of ischaemic post-conditioning
Authors: Hui Luo, Xiaohui Li, Tangzhiming Li, Lin Zhao, Jingni He, Lihuang Zha, Qiangqiang Qi, Zaixin Yu
Journal: Cardiovascular Research (2018)

A recent study reported the cardioprotective effects mediated by cardiac fibroblasts (CFs) during acute phase of ischaemia–reperfusion injury (IRI). Little is known about whether exosomes/microvesicles mediate this beneficial effect and whether ischaemia post-conditioning (Postcon) can regulate this process. Here, we aimed to investigate the cardioprotective effect of CFs-exosomes/microvesicles and whether Postcon can regulate this effect. By using transwells co-culture system, we found that hypoxia–reoxygenation (H/R) significantly increased the exosomes/microvesicles secretion of CFs and CFs protected H9C2 cells against H/R injury and Postcon could amplify these effects. Inhibition of CFs exosomes/microvesicles secretion led to a significant abrogation on the amplified protective effect of H/R-Postcon. We further demonstrated that Postcon enhanced the cardioprotective effect of CFs-exosomes/microvesicles both in vitro and in vivo. To detect the underlying mechanism, exosomes/microvesicles microRNAs were analysed by RNA sequencing and quantitative polymerase chain reaction, our results revealed that miR-423-3p expression was selectively enhanced by Postcon in CFs exosomes/microvesicles. By co-culture H9C2 cells with CFs-exosomes/microvesicles enriching with miR-423-3p, we demonstrated that H/R-Postcon exerted cardioprotective effects by upregulation of miR-423-3p in CFs-exosomes/microvesicles. RNA-fluorescence in situ hybridization and qPCR demonstrated that the decreasing of miR-423-3p is closely related to IRI, by inhibited miR-423-3p expression with its antagomir in vivo, we demonstrated that miR-423-3p plays an essential mediate role in I/R-Postcon-induced cardioprotection against I/R in vivo, Postcon may exert cardioprotective effect by upregulation of miR-423-3p in CFs exosomes/microvesicles. Gain- and loss-of-function approaches suggested that rescuing the down-regulated miR-423-3p might be a potential strategy to protect the cardiomyocytes against H/R. Using computational predictions tools and luciferase reporter assay, we demonstrated that miR-423-3p regulates the expression of Ras-related protein Rap-2c (RAP2C) in H9C2 cells, and knockdown of RAP2C by siRNA obviously increased cell viability and reduced apoptosis in H9C2 cells under H/R. In conclusion, we demonstrated, for the first time, that CFs participate in cardioprotective effects via an exosomes/microvesicles pathway during the acute phase of IRI and Postcon can enhance this effect by upregulating the expression of CFs exosomes/microvesicles miR-423-3p, which targets the downstream effector RAP2C.
Expression of programmed death-ligand 1 (PD-L1), mismatch repair status, and Epstein-Barr status in locally advanced gastric adenocarcinoma: Correlation to clinical outcome.
Authors: Krishna Patel, Fyza Y Shaikh, Bing Ren, Aatur D. Singhi, Changqing Ma, Weijing Sun
Journal: Journal of Clinical Oncology (2016)

e15526 Background: The Cancer Genome Atlas project proposed 4 subtypes of gastric cancer based on molecular classification. Among them, the Epstein-Barr Virus (EBV) subgroup showed elevated expression of PD-L1, and microsatellite instability (MSI)-high cancers demonstrated elevated mutation rates. Preliminary studies show clinical benefits of immune checkpoint inhibitors in metastatic gastro-esophageal cancer patients with PD-L1 expression or MSI high status. However, the potential predictive value of PD-L1, MSI and EBV status in clinical outcomes is unclear. Methods: Medical records and pathological data of 40 patients with locally advanced gastric cancer (T3-4N0 or Tany N1-2) were collected and analyzed. Patients’ specimens were classified as EBV positivity, MSI or microsatellite stable (MSS) tumors based on their IHC staining. Positive PD-L1 expression was defined as membranous staining in either tumor cells or tumor immune infiltrates, and further subgrouped based on the level of expression (0%, < 5%, or > 5%). The correlation of overall survival with the expression of EBV, MSI/MSS, and PD-L1 was analyzed. Results: Of the 40 locally advanced cases, mean age was 74 years. Seven tumors were EBV+, 16 were MSI, and 17 were EBV-/MSS. PD-L1 expression was seen in 31 (78%) cases and was predominately seen in gastric cancers with MSI. Thirteen patients received neoadjuvant therapy, and 19 received adjuvant therapy. At the time of data collection, 13 patients had notable recurrence by imaging, and 14 patients were deceased. The data suggested potential longer overall survival in those patients with PD-L1 expression (92 v 48 months, P = .369) and with MSI (89 v 65 months, P = .938), though not with EBV positivity. Conclusions: Due to a small sample size, the potential overall survival advantages of PD-L1 expression and MSI in locally advanced gastric adenocarcinoma were only trending to statistical significance. This study suggests the predictive value of PD-L1 and MSI in locally advanced gastric adenocarcinoma, which may also guide future target-oriented therapy including immune checkpoint inhibitor(s) in this disease group.
Abstract 14884: Visit-to-Visit Variability in Body Weight and Risk of Cardiovascular Outcomes: Insights From the Treating to New Targets Trial
Authors: Sripal Bangalore, Rana Fayyad, David DeMicco, David D Waters
Journal: Circulation (2015)

Introduction: Previous studies have demonstrated a relationship between body weight and cardiovascular events. However, whether visit-to-visit variability in body weight affects cardiovascular outcomes is not known. Hypothesis: Variability in body weight is associated with increase in the risk of cardiovascular events Methods: We evaluated patients enrolled in the TNT trial with at least one post baseline measurement of body weight. Visit-to-visit variability in body weight was evaluated using various measures of variability: Standard deviation (SD), average successive variability (ASV), coefficient of variation (CV), and variation independent of mean (VIM) with the first 2 measures used as the primary measures. Primary outcome was any coronary events (composite of coronary heart disease death, non-fatal MI, resuscitated cardiac arrest, revascularization or angina) with the secondary outcomes of any cardiovascular event (composite of any coronary event, cerebrovascular event, peripheral vascular disease or heart failure), death, MI or stroke. Results: Among the 9921 patients included in the analysis,in the adjusted model, each 1-SD (1.62 kg) increase in body weight variability (as measured by ASV) increased the risk of any coronary event by 6% (HR=1.06; 95% CI 1.04-1.08; P &lt;0.0001), any cardiovascular event by 7% (HR=1.07; 95% CI 1.05-1.08; P &lt;0.0001), death by 8% (HR=1.08; 95% CI 1.05-1.11; P &lt;0.0001), myocardial infarction by 6% (HR=1.06; 95% CI 1.03-1.10; P = 0.0002) and stroke by 7% (HR=1.07; 95% CI 1.03-1.12; P=0.001) independent of treatment effect and mean body weight. The results were consistent with other variability measures. Conclusions: In subjects with coronary artery disease, visit-to-visit variability in body weight is a strong and independent predictor of cardiovascular events suggesting perhaps that the swings in body weight are harmful.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR), serum albumin and sequence of immunotherapy (Immuno.) on overall survival (OS), and progression free survival (PFS) in patients with metastatic non-small cell lung cancer (NSCLC) treated with ramucirumab plus docetaxel (RD).
Authors: Ibtihaj Fughhi, Philip D. Bonomi, Sanjib Basu, Mary J. Fidler, Jeffrey Allen Borgia, Marta Batus
Journal: Journal of Clinical Oncology (2018)

e21163 Background: High (NLR) has been associated with inferior (OS) in patients (pts) with advanced stage NSCLC. Case series suggest potentially improved benefits of cytotoxic chemotherapy administration post immuno. but little is known about NLR associations with outcomes in patients receiving salvage ramucirumab plus docetaxel (RD). We evaluated the potential predictive value of NLR and timing of PD1 inhibition with PFS and OS in pts with metastatic NSCLC treated with RD. Methods: Retrospective analysis pts with metastatic NSCLC who received at least one treatment with RD regimen between April 2015 and May 2017. Associations between NLR and both PFS and OS were assessed using Mann-Whitney-Wilcoxon tests. Cutoffs of NLR of 5.0 (based on published data) were analyzed for differences in median OS and PFS. Results: 62 pts were analyzed: 47% were male, 85% former/current smoker, 76% Caucasian. 47 of these also received immuno. during their treatment course, 66% prior to RD regimen whereas 34% received immuno. after RD. Pts who received immune. had significantly superior OS than those who did not receive immuno. (median not reached vs 7.43 mos, p = 0.03) within one-year follow-up. Whether pts received RD followed by immuno. or immuno. followed by RD there were no significant survival differences from start of treatment. For entire cohort, baseline NLR ≤ 5 was associated with superior survival (median OS 20.86 mos for NLR ≤ 5 vs 5.78 mos for NLR > 5, p = 0.01) and superior PFS (median PFS 6.01 mos for NLR ≤ 5 vs 2.76 mos for NLR > 5, p = 0.03). Albumin at baseline (HR = 0.44, p = 0.01) and 6 weeks was significantly associated with OS(HR = 0.38, (p = 0.01) on RD. Conclusions: Low NLRs and higher albumins at baseline & 6 wks were associated with a prolonged PFS and OS in advanced NSCLC pts treated with RD. In this small retrospective study, pts who did not receive immune. had shorter OS. Comparison of the sequence of RD and immune showed no significant PFS or OS difference. Additional data are needed to evaluate the potential impact of treatment sequence.
Analysis of potential disparities by race, ethnicity, and age in adult accruals to NCI National Clinical Trials Network (NCTN) breast, lung, prostate, and colorectal trials.
Authors: Grace Mishkin, Sarah Madhu Temkin, Andrea Denicoff, Elise C. Kohn, Holly A. Massett, Margaret M. Mooney, Jeffrey S. Abrams, Lori M. Minasian
Journal: Journal of Clinical Oncology (2017)

e18072 Background: Previous studies have raised concerns about disparities in patient accrual to NCI cancer trials and how this could impact the generalizability of trial results. This study compared the demographics of patients enrolled in NCTN cancer trials to the incident US population. Methods: We analyzed US adult accruals aged 40 or older to NCTN breast, lung, prostate, and colorectal cancer treatment trials between the launch of the NCTN on 3/1/14 and 12/31/16. Accruals were compared to the proportion of patients with these cancers by race, ethnicity, and age in the US population estimated using census-adjusted SEER incidence data for 2010-2013. Results: There were 14,247 accruals across 56 NCTN group treatment trials in breast (39.7% of accruals), prostate (25.9%), lung (23.9%), and colorectal cancers (10.5%). Hispanic and black patients were underrepresented in prostate, lung, and colorectal trials, but overrepresented in breast trials (see table). American Indian/Alaska Native populations were slightly overrepresented in 3 of 4 disease areas, and Asian populations in 2 of 4. Elderly patients were underrepresented in breast, lung, and colorectal cancers, with the greatest disparities in colorectal cancer patients over age 70 (19% of accruals versus 48% of incident patients). However, prostate cancer patients aged 65 to 84 were overrepresented (46% versus 36%). Conclusions: Disparities in race and ethnicity between patients accrued to NCTN studies and the incident population were smaller than seen in previous studies. However, challenges remain in certain diseases, and particularly in enrollment of elderly patients. Improvement efforts should focus on key disparities. [Table: see text]
Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: Uptake of genetic assessment and testing and impact on patient-reported stress, anxiety and depression.
Authors: Sarah S. Lee, Melissa Kristen Frey, Deanna Gerber, Zachary Schwartz, Jessica Martineau, Kathleen Lutz, Erin Reese, Emily Dalton, Anne Olsen, Bhavana Pothuri, Leslie R. Boyd, John Patrick Curtin, Stephanie V. Blank
Journal: Journal of Clinical Oncology (2018)

5552 Background: To determine if a patient-centered, facilitated genetics referral pathway whereby all women with newly-diagnosed ovarian cancer are proactively contacted by a genetics navigator (GN) for genetic assessment (GA) increases rates of GA and genetic testing (GT) uptake without increased patient-reported stress, anxiety or depression Methods: Patients with epithelial ovarian cancer were referred for GA by their gynecologic oncologist within six weeks of diagnosis. Patients were contacted by a GN and offered an appointment for GA and GT within six weeks of contact. English-speaking patients completed quality of life (QoL) instruments (Impact of Events Scale, State-Trait Anxiety Questionnaire, Hospital Anxiety and Depression Scale) immediately pre-and post-GA and 6-9 months later. Primary outcome was feasibility of this pathway as defined by presentation for GA or declining GA within 6 weeks of contact by a GN. Results: From 10/2015-12/2017, 88 patients were enrolled. Seventy-one (81%) patients had GA and 62 (70%, 87% of those who had GA) underwent GT. Median time from diagnosis to GA was 28 days (range 9-75). Among patient who underwent GT, 11 (18%) had a pathogenic mutation (BRCA1-6, BRCA2-4, MSH2-1) and 25 (40%) had a variant of uncertain significance. Forty-one patients completed QoL assessments which demonstrated mild to moderate stress, normal to clinically significant anxiety and borderline levels of depression. QoL assessments were not associated with the GT result and with no significant changes in stress, anxiety or depression when comparing QoL measurements for each patient obtained pre/post-GA and 6-9 months later. Conclusions: A facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective and efficient, resulting in GA in 81% of patients within 4 weeks of diagnosis, GT in 70% of patients and discovery of pathogenic mutations in 18% of those tested, and does not demonstrate a psychologic toll. Concern about emotional distress should not deter clinicians from early genetics referral as GT in this population can yield important prognostic and therapeutic information.
A hydroxylated collagen peptide in urine as biomarker for the detection of colorectal liver metastases.
Authors: Robert R.J. Coebergh van den Braak, Zarina S. Lalmahomed, Mirelle E. BrÃ¶ker, Nick A. van Huizen, Lennard J.M. Dekker, Cornelis Verhoef, Ewout W. Steyerberg, Dimitris Rizopoulos, Theo M. Luider, Jan N.M. IJzermans
Journal: Journal of Clinical Oncology (2016)

e15081 Background: Of all patients undergoing curative surgery for primary colorectal cancer, 40% will have or develop colorectal liver metastases (CRLM). Therefore, these patients are monitored for five years using a combination of serum CarcinoEmbryogenic Antigen (CEA) levels and imaging. With a sensitivity of 64%, the value of CEA as a biomarker to detect CRLM is limited. In 2010, our group identified and validated the occurence of a specifically hydroxylated collagen peptide AGPP(-OH)GEAGKP(-OH)GEQGVP(-OH)GDLGAP(-OH)GP (AGP) in a significantly higher concentration in urine samples of patients with CRLM compared to urine samples of healthy kidney donors using mass spectrometry. The current study aimed to assess the sensitivity and specificity of the AGP concentration in urine combined with serum CEA level. Methods: Urine samples were collected from 100 patients with CRLM and three control groups: healthy kidney donors (n = 100), patients with a minimum disease free interval of 24 months after metastasectomy of CRLM (n = 20) and patients with localized primary colorectal cancer (n = 18). A stable isotope labeled peptide was used to determine the concentration of AGP in the urine samples using mass spectrometry. Results: The sensitivity for serum CEA level and AGP concentration in urine was 66% and 68% respectively. Serum CEA levels and urine AGP levels did not correlate (r2= 0.08) and, therefore, were complementary. Combining serum CEA level and AGP concentration in urine produced a significant increase in sensitivity to 85% compared to serum CEA level alone (p < 0.001) with an acceptable decrease of specificity from 91% to 84%. Conclusions: The concentration of AGP in urine may be a useful biomarker to detect CRLM in patients after curative resection of colorectal cancer. Longitudinal sampling is expected to be of value and improve the sensitivity, as increases within patients can be monitored.