bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tim-3 expression and function in natural killer cells from advanced melanoma patients.
Authors: Pires Da Silva Ines Esteves Domingues , Jimenez-Baranda Sonia , Gallois Anne , Kuchroo Vijay , Osman Iman , Bhardwaj Nina 
Published: March 2020

8571 Background: The concept of CD8+ T cell exhaustion in the context of metastatic cancer has been reinforced by the recent success of immunotherapies targeting the exhaustion markers CTLA-4 and PD-1 in advanced melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker, is also expressed in natural killer (NK) cells, however its role is still unknown. Recent reports have shown that NK cells, innate immune cells that eliminate tumors through cytotoxicity and IFN-g production, are functionally impaired in advanced melanoma patients, although no receptor has been linked with that phenotype so far. In this study, we characterize the role of Tim-3 in NK cells, particularly in the presence of its natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted by some tumor cells including melanoma. Methods: We compared 20 advanced melanoma donors NK cells with 40 healthy donors NK cells as it relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity, IFN-γ production and proliferation). NK cells cytotoxicity was measured by lamp-1 expression, and two different target cells were used: i) K562 cells (Gal-9-) and ii) Gmel Gal-9+ and Gmel Gal-9- sorted melanoma cells. Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2. Recombinant rhGal9 effect was tested in cytotoxicity and IFN-γ production. Results: Melanoma patients NK cells express higher levels of Tim-3 compared to healthy donors NK cells (p<0.05). Melanoma patients NK cells have a defect in cytotoxicity, proliferation and IFN-γ production. Tim-3 expression by itself (without engagement of specific ligands) does not negatively affect NK cell functions (p<0.05). However, when rhGal9 is added to the system, a decrease in NK cell cytotoxicity and IFN-γ production (p<0.05) was observed. Finally, the expression of Gal-9 by the target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9+ vs Gmel Gal-9-). Conclusions: These data suggest that advanced melanoma patients NK cells are exhausted, although it still remains unclear if Tim-3 is involved in this phenotype. In addition,the expression/secretion of Galectin-9, immunosuppressive for NK cells, may be a possible mechanism for tumors to evade immune surveillance.
Surgery for patients receiving ipilimumab: Safety profile and immunological insights.
Authors: Gyorki David E. , Yuan Jianda , Mu Zhenyu , Zaidi Bushra , Gallardo Humilidad F. , Brady Mary Susan , Gutin Philip H. , Coit Daniel G. , Wolchok Jedd D. , Ariyan Charlotte Eielson 
Published: March 2020

8583 Background: Ipilimumab (ipi), a monoclonal antibody blocking CTLA-4, demonstrated survival benefit in metastatic melanoma in two randomized controlled trials. With its approval by the FDA, the use of this immunotherapy is increasing. The surgical safety of ipi has not been reported. Methods: From our prospective database, we identified patients undergoing surgery within 30 days of receiving a dose of ipi or on maintenance ipi between October 2007 and August 2011. Surgical toxicity was graded 1-5 by the Clavien classification. In 10 patients matched blood and tumor infiltrating lymphocytes were harvested. Phenotype of T cell subsets were analyzed by flow cytometry. Results: 23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipi (1-123 weeks). Indications for surgery were symptomatic, progressive, or isolated persistent disease in 52%, 39% and 9% respectively. Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures (Table). Grade 1 wound complications were seen in 17% of patients. One patient had a Grade 2 wound complication. No Grade 3-5 complications were seen. With a median follow up from starting ipi of 86 weeks, 3 patients have no evidence of disease, 10 are alive with disease and 10 have died of disease. Analysis of the T cell infiltrate and peripheral blood from 10 patients with progressive or symptomatic disease shows an elevated % of CD4+FOXP3+ T regulatory cells and a 2.8 fold reduction in CD8+/ CD4+FOXP3+ T regulatory ratio in the tumor compared to blood (p=0.02). Conclusions: Results from this single-center experience suggest that surgery is safe in patients receiving ipi. Immune modulation caused by CTLA-4 blockade does not appear to impact wound healing, even in the bowel. In carefully selected patients metastectomy may be appropriate for breakthrough metastases. The high percentage of T regulatory cells and low T effector cells in the progressive tumors suggests a mechanism of immune escape. [Table: see text]
Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-mediate gastrointestinal adverse events.
Authors: Shahabi Vafa , Berman David Mark , Chasalow Scott D. , Wang Lisu , Tsuchihashi Zenta , Hu Beihong , Panting Lisa , Jure-Kunkel Maria , Ji Rui-Ru 
Published: March 2020

8593 Background: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for treatment of metastatic melanoma (MM), is associated with a number of immune-mediated Adverse Events (imAEs) such as colitis and skin rash. Predictive biomarkers that can help identify patients (pts) who might experience these imAEs could enhance the management of these toxicities. Methods: Gene expression profiling (using Affymetrix gene chip HT-HG-U133A) was performed on the whole blood samples from 162 MM pts at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and -007). Overall, 49 pts experienced Grade 2 or higher GI-imAE (G2+) during the course of treatment. A repeated measures ANOVA was used to evaluate the differences in mean expression levels between the two groups and at the three time points. Uncorrected p-value of 0.05 was used as a cutoff for this analysis. Results: In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, p < 0.05) between G2+ pts and others. Most of these genes belonged to three functional categories: immune system, cell cycle or intracellular trafficking. Changes in gene expression over time were also characterized. In the G2+ pts, 58 and 247 genes had a ≥ 1.5 fold (p < 0.05) change in expression from baseline to week 3 and 11 post-treatment, respectively, compared to 17 and 73 in other pts. In particular, the on-treatment increases of the expression of CD177 and CEACAM1, two neutrophil activation markers, were closely associated with G2+ GI-imAE, suggesting a possible role of neutrophils in ipilimumab associated GI-imAEs. In addition, the expression of several Ig genes increased over time, with higher increases in the G2+ pts. These observations were reproduced in another ipilimumab monotherapy study in MM (CA184078). Conclusions: Gene expression profiling of peripheral blood resulted in the identification of a set of potential biomarkers that may be predictive of severe GI-imAEs before, or early in the course of treatment with ipilimumab. Further validation of these biomarkers in a larger patient cohort is warranted.
Detection of BRAF mutations in melanoma: Rate of mutation detection at codon 600 using Sanger sequencing as compared to the cobas 4800 method.
Authors: Qu Kevin Z. , Pan Qiulu , Zhang Xi , Rodriguez Luis , Uyeji Jennifer , Li Hairong , Ho Albert , Sanders Heather , Sferruzza Anthony , Jones Daniel , Waldman Frederic ,   Quest Diagnostics Nichols Institute
Published: March 2020

8596 Background: Detection of BRAF V600 mutations is currently a prerequisite for approved use of vemurafenib in patients with metastatic melanoma. The cobas 4800 BRAF V600 Mutation Test (Roche Molecular Diagnostics), a PCR-based assay approved to aid in selecting patients for vemurafenib therapy, primarily detects V600E. It is also reported to detect V600K, which has been associated with vemurafenib response as well. We compared the mutation detection rate of the cobas assay with that of Sanger sequencing. Methods: 125 de-identified FFPE tissues submitted for BRAF mutation analysis that all showed histologically-confirmed melanoma were tested. BRAF mutations were detected using both the cobas kit and bidirectional Sanger sequencing using BigDye kits (Applied Biosystems). DNA was extracted from 5-um sections without macrodissection using the cobas DNA extraction kit (for the cobas test) or from 5-10-um sections using Agencourt extraction kits (Beckman Coulter) following macrodissection. Results: The two methods showed agreement in 104/125 (83.2%) of cases (Table). Sanger sequencing detected V600 dinucleotide mutations in 9 samples that were negative by the cobas assay. Sanger sequencing produced no results in 10 cases owing to suboptimal PCR, including 2 that were positive by the cobas assay. The cobas assay produced 2 invalid results, including 1 that was positive for V600E by Sanger.The cobas assay detected 7/11 V600K mutations. Conclusions: Overall agreement between cobas and Sanger sequencing was 83.2%. The Sanger method had higher analytic sensitivity, resulting in nine additional V600 mutations not called by cobas compared to the two seen by cobas but not Sanger sequencing. Thus, 16% (9/57) more patients would be identified as candidates for vemurafenib therapy using the Sanger method. [Table: see text]
Dexamethasone (DM) for cancer-related fatigue: A double-blinded, randomized, placebo-controlled trial.
Authors: Yennurajalingam Sriram , Frisbee-Hume Susan , Delgado-Guay Marvin Omar , Bull Janet , Phan Alexandria T. , Tannir Nizar M. , Litton Jennifer Keating , Palmer J. Lynn , Reddy Akhila Sunkepally , Hui David , Dalal Shalini , Massie Lisa , Vadhan-Raj Saroj , Reddy Suresh K. , Reuben James M. , Bruera Eduardo 
Published: March 2020

9002 Background: Cancer-related-fatigue (CRF) is the most common and distressing symptoms in patients with advanced cancer. Currently, there is no standard treatment for CRF. Although corticosteroids have been used in the treatment of CRF, there are no well-powered placebo-controlled trials that used a validated CRF outcome measure. The primary objective of this prospective, randomized, double-blind, placebo-controlled study is to compare the effect of DM versus placebo on CRF. Methods: Advanced cancer patients with fatigue ≥ 4/10 on the Edmonton Symptom Assessment Scale (ESAS) and at least 2 other CRF-related symptoms (pain, nausea, appetite, depression, anxiety or sleep disturbance ≥ 4/10), normal cognition, no infections and hemoglobin ≥ 9 g/L were eligible for enrollment. Patients were randomized to either receive dexamethasone 4 mg orally twice a day for 15 days (primary end point) or matching placebo. The primary outcome was the day 15 change in Functional Assessment of Chronic Illness-Fatigue (FACIT-F) subscale scores. Differences in the group means (normal distribution) were analyzed using the two-sample t-test. Results: In 83 evaluable patients (43 DM and 40 placebo), median age was 60 years, 61% were white, and 53% were female. There was no difference in the demographics and fatigue (FACIT-F subscale) between DM and placebo groups except for sex (p=0.02). The mean (SD) FACIT-F subscores at baseline and at day 15 for DM were 18 (11) and 27 (11) (p<0.001) and for placebo were 21 (9) and 24 (12) (p=0.06), respectively. Mean improvement in FACIT-F subscale was significantly higher in the DM group compared to placebo (9.6 (11) vs. 3.1 (9.7), p=0.005). We found a significant difference in ESAS physical distress (p=0.02), but no differences in ESAS overall symptom distress (p=0.11) and ESAS psychological distress (P=0.88) between DM and placebo. There were insignificantly higher numbers of grade ≥3 toxicities in patients who received DM than in patients who received placebo (20/42 vs. 18/47, p=0.37). Conclusions: Dexamethasone was more effective than placebo in reducing CRF in patients with advanced cancer. Long-term safety studies are needed.
Cluster-randomized trial of early palliative care for patients with metastatic cancer.
Authors: Zimmermann Camilla , Swami Nadia , Rodin Gary , Tannock Ian , Krzyzanowska Monika K. , Leighl Natasha B. , Oza Amit M. , Moore Malcolm J. , Rydall Anne , Donner Allan 
Published: March 2020

9003 Background: Patients with metastatic cancer have compromised quality of life (QOL), which tends to worsen towards the end of life. We conducted a cluster-randomized trial of early versus routine palliative care in patients with metastatic cancer, to assess impact on QOL, symptom control and satisfaction with care. Methods: Twenty-four medical oncology clinics were randomized, stratified by tumour site (4 lung clinics, 8 gastrointestinal, 4 genito-urinary, 6 breast, 2 gynecological), to intervention and follow-up (at least monthly) by a palliative care team, or to routine cancer care. Eligible patients had ECOG performance status 0-2 and a clinical prognosis of 6 months to 2 years. Patients completed measures of QOL (FACIT-Sp, including physical, social, emotional, functional and spiritual well-being; range 0-156, with higher scores indicating better QOL), symptom severity (Edmonton Symptom Assessment System; range 0-90, with higher scores indicating worse symptom severity), and satisfaction with care (FAMCARE-P16; score range 16-80) at baseline and monthly for 4 months. The primary outcome was the change in FACIT-Sp at 3 months. The planned sample size was 225 patients per arm, assuming 80% power and a 2-sided significance level of 0.05. Results: From December 2006 to September 2010, 461 patients completed baseline measures (228 intervention, 233 control); 442 patients completed at least one follow-up assessment (mean patients/cluster 18.8±11.6 control, 18.1±12.6 intervention). At 3 months, patients in the intervention group had marginally improved QOL (mean change in intervention vs. control, 1.6±14.5 vs. -2.0±13.6, p=0.07) but not symptom severity (0.1±16.9 vs. 2.1±13.9, p=0.34). At 4 months the change in QOL was more marked (2.5±15.5 vs. -4.0±14.2, p=0.008) and symptom severity was marginally better (-1.3±16.0 vs. 3.2±13.9, p=0.05). Improvement in satisfaction with care was evident at one month (p=0.001) and remained significant at both 3 months (2.3±9.1 vs.-1.8±8.2, p=0.001) and 4 months (3.7±8.6 vs. -2.4±8.3, p<0.001). Conclusions: In patients with metastatic cancer, early palliative care intervention immediately improved satisfaction with care, while QOL and symptom control improved later.
ZOOM: A prospective, randomized trial of zoledronic acid (ZOL; q 4 wk vs q 12 wk) for long-term treatment in patients with bone-metastatic breast cancer (BC) after 1 yr of standard ZOL treatment.
Authors: Amadori Dino , Aglietta Massimo , Alessi Barbara , Gianni Lorenzo , Ibrahim Toni , Farina Gabriella , Gaion Fernando , Bertoldo Francesco , Santini Daniele , Rondena Roberta , Bogani Paola , Ripamonti Carla 
Published: March 2020

9005 Background: ZOL (4 mg q 4 wk) is an established therapy for reducing the risk of debilitating skeletal-related events (SREs) in patients (pts) with bone metastases (mets) from BC. As BC treatments continue to improve pt survival, long-term SRE-reduction is increasingly important, and evaluation of modified ZOL dosing to retain efficacy with reduced adverse events (AEs) is warranted. Methods: ZOOM, a phase III prospective, randomized, open-label, multicenter study, assessed the safety and efficacy of quarterly (4 mg q 12 wk; Arm 1) vs monthly (4 mg q 4 wk; Arm 2) ZOL for ~1 yr in pts with BC who have ≥ 1 bone met, and have received ~1 yr of prior ZOL treatment (9 to 12 doses over ≤ 15 months; last dose ≤ 3 months prior). The primary endpoint was skeletal morbidity rate (SMR; number of SREs/pt/yr). Sample size to detect non-inferiority with 80% power (1-sided a = 0.025) was 420 pts. Secondary endpoints included time to first SRE, bone pain, bone marker (N-telopeptide of type I collagen; NTX) levels, and safety. Results: 425 pts were enrolled (209 in Arm 1; 216 in Arm 2); arms were well balanced for pt and disease characteristics, and anticancer therapies. SMR was similar between arms: 0.26 (95% confidence interval [CI] = 0.15, 0.37) in Arm 1 vs 0.22 (95% CI = 0.14, 0.29) in Arm 2; between-arms difference = 0.04 (upper limit of 1-tailed 97.5% CI = 0.17). Despite the proximity of 0.17 to the adjusted non-inferiority margin (0.19), the non-inferiority of Arm 1 vs 2 remains statistically significant. Safety analyses showed that ZOL was well tolerated. Renal AEs were reported in similar proportions of pts in both arms; 7 cases of osteonecrosis of the jaw were reported (1.65% overall; 4 cases in Arm 1 vs 3 in Arm 2). Conclusions: ZOOM is the first randomized trial to compare ZOL q 12 wk vs ZOL q 4 wk in BC pts after 1 yr of standard ZOL therapy. SMR was similar between arms. Limitations in study design suggest the need to confirm non-inferiority of ZOL q 12 wk in other ongoing phase III trials.
Cognitive function and fatigue in colorectal cancer (CRC) patients: A prospective longitudinal controlled study.
Authors: Vardy Janette L. , Dhillon Haryana M. , Pond Gregory Russell , Rourke Sean , Xu Wei , Renton Corrinne , Dodd Anna , Beale Philip James , Clarke Stephen John , Tannock Ian 
Published: March 2020

9021 Background: A subset of cancer patients has cognitive impairment and fatigue after chemotherapy (CTh). We evaluated these symptoms and potential mechanisms in CRC patients and healthy controls (HC). Methods: Cognitive function was evaluated in CRC patients and HC at baseline (pre-CTh), 6 and 12 months. Group 1A (Stage II/III) received CTh and Gr 1B (Stage I/II) no CTh. Gr 2 had limited metastatic CRC. All subjects completed cognitive assessment and questionnaires for fatigue, QOL, anxiety/depression, and perceived cognitive function. Blood tests evaluated: 10 cytokines, clotting factors, sex hormones, CEA, CBC and apolipoprotein genotyping as potential causal factors. Primary endpoints: cognitive function and fatigue (Gr. 1A & 1B) at 12 months. Associations between results and demographic and disease-related factors were sought. Results: 359 CRC patients (173 Gr 1A, 116 Gr 1B, 70 Gr. 2) and 72 HC were assessed. Median age 58 (23-75 years); 58% male. Cognitive impairment: baseline Gr 1A 34% vs 1B 32.5% (p=.9), Gr 1 33% vs HC 10% (p<0.001); 12 months Gr 1A 21% vs 1B 16% (p=0.43), Gr 1 19% vs HC 2% (p=0.001). Cognitive domains most affected: verbal & visual memory, processing speed. Men had greater impairment than women (p<0.009). Cognitive decline from 0-12 months: Gr 1A 30%, Gr 1B 19%, Gr 2 24%, and HC 16%. Perceived cognitive impairment at 12 months: Gr 1A 19% vs 1B 7% (p=.04), Gr 1 14% vs HC 0% (p=.009). Fatigue was greatest in Gr 1A (70%) at 6 months; at 12 months Gr. 1A 46% vs 1B 31% (p=0.056), Gr 2 60%, HC 36%. Cytokines were elevated in CRC patients compared to HC. No association was found with cognitive function and: fatigue, QOL, anxiety/depression, cytokines, sex hormones, clotting factors, CEA or apoE genotype. Objective cognitive function was associated with perceived cognitive function at baseline only. Fatigue at baseline was associated with hemoglobin and at 12 months with neutrophil count. Conclusions: Compared to HC, CRC patients had more cognitive impairment at baseline, 6 and 12 months; but impairment was not significantly different between those who did and did not receive CTh. The mechanisms of cognitive impairment remain unknown. Fatigue improved with time.
Subjective cognitive complaints one year after ceasing adjuvant endocrine therapy for early-stage breast cancer: Findings from the Breast International Group (BIG) 1-98 trial.
Authors: Phillips Kelly-Anne , Ribi Karin , Aldridge Julie , Thompson Alastair Mark , Harvey Vernon J. , Thurlimann Beat J. K. , Cardoso Fatima , Pagani Olivia , Coates Alan Stuart , Goldhirsch Aron , Price Karen N. , Gelber Richard D. , Bernhard Juerg ,   BIG 1-98 Collaborative Group and International Breast Cancer Study Group
Published: March 2020

9022 Background: We have previously reported that, in the BIG 1-98 trial, objective cognitive function improved in postmenopausal women one year after cessation of adjuvant endocrine therapy for breast cancer. Here we evaluate changes in subjective cognitive function (SCF). Methods: One hundred postmenopausal women, randomized to receive five years of adjuvant tamoxifen, letrozole, or sequences of both, completed self-reported measures on SCF, psychological distress, fatigue and quality of life during the fifth year of trial treatment (year 5) and one year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. SCF and its correlates were explored. Results: Mean age of participants was 63.9 years [SD=7.1 years]. SCF and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement in hot flushes (p=0.0005). No difference in changes was found between women who were taking tamoxifen or letrozole at year 5. SCF was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman’s R=0.80). Correlations between SCF and the other patient-reported outcomes were generally low. Conclusions: Although objective cognitive function improved after cessation of adjuvant endocrine therapy in the BIG 1-98 trial, improvement in SCF was not evident. The underlying reason for the clear disconnect between objective and subjective cognitive function seen in this and most other studies, is a crucial issue. It should be a research priority in order to effectively tackle the concerns of women about their cognition during and after breast cancer treatment.