tbuckley/cabot-search huggingface dataset:
Case 47-1983
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Harland S. Winter, David L. Gang
Journal: New England Journal of Medicine (1983)

Presentation of CaseA 7 1/2-year-old girl was admitted to the hospital because of diarrhea and arthralgia.She was well until five months previously, when dysuria developed and evidence of a urinary-tract infection was found. Ampicillin was administered, with improvement. Sixteen weeks before admission ampicillin was discontinued. The patient was subsequently well until 10 weeks before entry, when she began to have midepigastric cramps, diarrhea, and a low-grade fever. During the next few weeks her stools increased in frequency to 10 to 12 daily; they were watery and dark green and often contained mucus. Two weeks after the onset of . . .
Progression of frailty in young adult survivors of childhood cancer: St. Jude Lifetime Cohort.
Authors: Kirsten K. Ness, Robyn Partin, MS, Carrie R. Howell, Kevin R. Krull, Tara M. Brinkman, Gregory T. Armstrong, Wassim Chemaitilly, Carmen Louise Wilson, Daniel A. Mulrooney, Todd M. Gibson, Jennifer Q. Lanctot, Ruth E Johnson, Matthew R Krull, Kyla C. Shelton, Deo Kumar Srivastava, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2019)

10057 Background: Childhood cancer survivors are at risk for premature aging; over 8% (ages18-60 years) meet Fried Frailty Criteria (≥3 of low lean muscle mass, muscle weakness, slow walking speed, exhaustion, low energy expenditure). Longitudinal changes and new onset frailty has not been studied. Methods: Childhood cancer survivors (N = 1501, 51.5% male, 14.9% black, median age at diagnosis 7 [0-22] years), were evaluated clinically to ascertain frailty at baseline (median age 30 [18-45] years) and five years later. Risk factors for incident frailty and impact of baseline frailty on mortality were evaluated in proportional hazard models. Results: Frailty increased from 6.0% (95% CI 4.1-8.9) to 11.7% (95% CI 6.7-12.2) overall, and for all diagnoses (Table). Risk factors for new onset frailty among those not frail at baseline were amputation (HR 5.1, 95% CI 1.1-14.4), anthracyclines (HR 1.2, 95% CI 1.1-1.4 per 100 mg/m 2 ), and carboplatin (HR 1.3, 95% CI 1.1-1.5 per 2000 mg/m 2 ). Severe, disabling or life threatening chronic conditions (HR 1.2, 95% CI 1.1-1.4 per organ system) and inactivity (HR 2.0, 95% CI 1.2-3.2) also predicted new onset frailty. Sixty-nine participants died from baseline to follow-up. Accounting for age, sex and chronic conditions, baseline frailty was associated with a 2.9 (95% CI 1.6-5.2) increased hazard of death. Conclusions: Prevalent frailty nearly doubled in five years and was associated with increased risk for death. Given that previous treatment exposures cannot be altered, interventions to remediate chronic disease and promote activity may impact function and longevity for childhood cancer survivors. [Table: see text]
Safety and tolerability of immune checkpoint therapies and related adverse effects at a tertiary care hospital in Saudi Arabia.
Authors: Mohammed Al Nuhait, Yousef Al Awlah, Eshtyag Bajnaid
Journal: Journal of Clinical Oncology (2019)

e14082 Background: Immunotherapies associated with many toxicities with a potential immune-mediated cause and has been associated with many adverse events in the literature. As the incidence of emergency room (ER) visits in adult patients receiving immune checkpoint therapies and most frequent immune-related adverse events are not yet established well for our population since this class of medications is newly introduced in the oncology field. This research is aimed to shed the light on this new class of medications. Methods: This is a single-center retrospective cohort study to determine incidence of ER visits in adult patients receiving immune checkpoint therapies and to explore most frequent related adverse events. The study involved adult patients who were treated at King Abdulaziz Medical City. Study participants were identified by identified using our electronic health care system to identify patients who were treated with immunotherapies during the study period (January 2016 to December 2018). Inclusion criteria was patients aged more than 18 years who had received immunotherapies. Results: A total of 53 patients met the specified inclusion criteria for our study. The number of patients in each treatment group were as follows: Nivolumab 37, Atezolizumab 10 and Pembrolizumab 6. Average age was 59 years. The percentages of cancer patients presenting to the ER with various related adverse effects after beginning immune checkpoint therapy were (65%) Nivolumab, (80%) Atezolizumab and (83%) Pembrolizumab. The average number of ER visits after beginning immune checkpoint therapy was 3 visits (SD = 2.8). Renal adverse events were occurred following the immunotherapy use, 9 patients (17%) and none of cases experienced a grade≧3 event. 13 patients (24.5%) experienced hepatic adverse event. Only one patient experienced a grade≧3 event that lead to discontinuation of treatment. For diarrhea, among all patients received the immunotherapies, 14 (26%) experience diarrhea and five of them experience grade≧3 event. Thyroxine abnormalities occurred in 7 patients (13%) after use of immunotherapies. (7.5 %) of patients had pneumonitis with immunotherapy. Other adverse events were noted with immune therapies (skin reaction, nausea, vomiting, thrombocytopenia, neutropenia and neurological adverse events). All others adverse events that is reported had a grade 1-2 adverse events. Conclusions: Patients treated with immunotherapies may have a spectrum of adverse drug events that might lead to discontinue the treatment and increase ER visits.
SWOG 1609 (DART): A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors.
Authors: Sandip Pravin Patel, Megan Othus, Young Kwang Chae, Frank Giles, Jourdain Hayward, Christine McLeod, Helen X. Chen, Elad Sharon, Edward Mayerson, Christopher W. Ryan, Melissa Plets, Charles David Blanke, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2019)

TPS2658 Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in advanced rare solid tumors. We sought to investigate the activity of ipilimumab and nivolumab in previously unstudied rare solid tumors, with planned biomarker evaluation pending including whole exome sequencing, RNAseq, and multiplex immune profiling via the NCI CIMACs. Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1mg/kg iv q6weeks) plus nivolumab (240mg iv q2weeks) across 37 cohorts of rare tumors. Eligible patients had incurable rare cancer, defined histologically with an incidence of less than 6 in 100,000 per year, and did not have an approved or standard therapy available that had been shown to prolong overall survival. Patients were required to be 18 years of age or older, have a Zubrod performance status of 0-2, with absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 75,000/mcL, hemoglobin ≥ 8 g/dL, creatinine clearance ≥ 50 mL/min, total bilirubin ≤ 2.0 x institutional upper limit of normal (IULN), AST and ALT ≤ 3.0 x IULN, TSH or free T4 serum ≤ IULN, and normal adrenocorticotropic hormone (ACTH) ≤ IULN. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) ≥ 6 months, and toxicity. The primary objective of this Phase II trial was to evaluate the overall response rate (ORR, confirmed complete and partial responses [CR and PR]) by RECIST v1.1. Our objective was to distinguish between a true ORR 15% (null hypothesis) versus 30% (alternative hypothesis). A Simon’s two-stage design was used, which required an analysis on the first 6 eligible patients who received therapy. If 1 or more of the 6 patients had a response (confirmed CR or PR), an additional 10 patients were to be accrued. The study was activated on 1/13/17 with the first patient treated on 3/1/17. The trial is currently open at 862 sites across the NCTN (with 352 sites having enrolled patients) and 554 patients enrolled to date. Clinical trial information: NCT02834013.
Long-term outcomes after high-dose chemoradiotherapy for non-surgical management of distal rectal cancer.
Authors: Edina Dizdarevic, Ane L Appelt, Torben Hansen, John Ploeen, Henrik Jensen, Jan Lindebjerg, Soeren Rafael Rafaelsen, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2019)

3611 Background: Surgery is standard treatment for rectal cancer, but neoadjuvant chemoradiotherapy (CRT) may result in clinical complete response (cCR) in selected patients, allowing for non-surgical management (NSM). Prospective studies of NSM strategies are sparse however, and long-term data on quality of life (QoL) are limited. We conducted a single-arm phase II trial of high-dose CRT for NSM of distal rectal cancer; we report secondary long-term patient-reported outcomes (PROs), local regrowth and overall survival (OS) in patients managed non-surgically. Methods: Fifty-one patients with resectable, T2 or T3, N0–N1, low adenocarcinoma received 65Gy (IMRT, brachytherapy boost) and oral tegafur-uracil. Patients with cCR 6 weeks after treatment (clinical examination, MRI, biopsy) were referred for observation, and followed closely with clinical examinations, endoscopies, PET-CTs, and PROs for 5 years. Overall colorectal cancer specific QoL and specific symptom scores were compared between timepoints using paired Wilcoxon tests. Local regrowth was estimated using cumulative incidence; overall survival using Kaplan-Meier estimates. Results: Forty patients achieved cCR after treatment; 28 were in follow-up at 24m, 21 at 36m, 18 at 60m. Patients left the trial due to local tumor regrowth (n=12), distant metastases (n=3), new primary cancers (n=6) and loss to follow-up (n=1). Average QoL score did not differ between baseline (median 11.1) and 24m (13.7), 48m (11.1,) or 60m (6.9). See Table for individual scores; only rectal bleeding deteriorated from baseline (significantly worse at 24m). At median follow-up of 5.0 years, local regrowth rate and OS were 31% (95 CI 15%-47%) and 85% (95 CI 75%-97%), respectively. Conclusions: Long term follow-up after NSM of early rectal cancer showed excellent general colorectal cancer QoL and local symptom scores. (NCT00952926). EORTC QLQ – CR 29. Proportion reporting ‘quite a bit’ or ‘very much’ on symptom scales. Clinical trial information: NCT00952926. [Table: see text]
A comparison of platinum-based chemotherapy versus capecitabine-based chemotherapy in the treatment of breast cancer metastasis to the liver.
Authors: Yimeng Chen, Hongnan Mo, Jiayu Wang, Yiqun Li, Xiuwen Guan, Zijing Wang, Shaoyan Lin, Zongbi Yi, Binghe Xu
Journal: Journal of Clinical Oncology (2019)

e12595 Background: Liver metastasis have long been known to indicate an unfavourable disease course in breast cancer (BC). A variety of drugs have been used in first choice for anthracycline-resistant and/or taxane-resistant breast cancer. This study aimed to systematically investigate the impact of different treatments. Methods: Between January 2003 and December 2013, we examined the clinical outcome of breast cancer patients with liver metastases from database in China National Cancer Center. 284 patients who received platinum or capecitabine based chemotherapy as first-line treatment were analyzed and followed up until December 2018. Results: Overall, 284 patients (female:280/284 (98.6%); male:4/284 (1.4%)) breast cancer with liver metastasis were available for this analysis. 205/ 284 patients (72.2%) received capecitabine-based chemotherapy including docetaxel/capecitabine (TX) and vinorelbine/capecitabine(NX), while 79/284 patients (27.8%) received platinum-based chemotherapy including docetaxel/ platinum (TP) and vinorelbine/platinum(NP).The median PFS (10.1 vs 8.3 months; P = .329; 95%), and the median overall survival (OS) (35.3 vs 19.8 months; P = .012) in the TX/NX group appeared to be longer compared with those in the NP/TP group, among which NP group seemed to be the poorest. Patients aged ≥50 years who were postmenopausal were more likely to benefit from the TX/NX regimens in terms of OS, however hormone receptor and human epidermal growth factor receptor 2 status did not affect differences in PFS and OS between the TX/NX and TP/NP groups. Conclusions: Capecitabine-based chemotherapy for advanced breast cancer with liver metastasis led to longer OS than platinum-based chemotherapy. These findings should be validated in more prospective cohorts.
A RNA signature predicts outcomes in immune checkpoint blockade treated gastrointestinal cancer patients.
Authors: Zhihao Lu, Huan Chen, Shuang Li, Xi Jiao, Lihong Wu, Jianing Yu, Lin Shen, Henghui Zhang
Journal: Journal of Clinical Oncology (2019)

e14071 Background: Cancer therapy has been greatly revolutionized in recent years by the conceptual developments in the field of cancer immunology. Growing evidence support the utility of immune checkpoint inhibition (ICB) in gastrointestinal (GI) cancer. However, a central question lies in understanding how therapeutic responsiveness is predicted. Methods: To address this, we evaluated tumor FFPE specimens from 97 patients who received ICB treatment. All patients were randomly assigned into discovery (60%) and validation (40%) cohorts. Tumor RNA before ICB treatment was analyzed on a multiplex RNA immune oncology (RNA IO) profiling sequencing panel. Results: We show that four immune-related gene expression signatures were upregulated in responders versus non-responders in the discovery cohort. Three of the four signatures showed significant correlation with clinic response and disease control rates. However, two previously reported RNA signatures, PD-L1 expression and MMR status revealed less predictive values in GI cancers. More importantly, we identified that higher levels of a 19-gene signature were remarkably associated with favorable overall survival (OS) and progression-free survival (PFS) when compared to patients with lower levels of signature in both the discovery and validation cohorts. Of note, a joint biomarker of tumor mutation burden (TMB) and the 19-gene signature may better stratify responders from non-responders in GI cancer patients. Conclusions: Our data provide evidence that a responsive feature, defined by a multi-gene expression pattern across different GI cancer types, can be obtained via a RNA quantitative strategy and may be explored as a future pan-cancer biomarker.
FBXO4 as a novel ubiquitin ligase that targets Cyclin D in the pathogenesis of breast cancer.
Authors: Ruby Dhar, Goura Kishor Rath, Subhradip Karmakar
Journal: Journal of Clinical Oncology (2019)

e14722 Background: Members of ubiquitin ligase family are reported to be associated with cancer. Genome wide RNAi screen using Dharmacon on target Plus RNAi library identified FBXO4 as one of the potential hit . We therefore aimed to study its detailed role on proliferation of MCF7 breast cancer cells with special focus on cell cycle genes. We want to expand it further and study its involvement in context to E2 signaling in breast cancer. We hypothesized that increase in CCND1 expression, could mimic some of the E2 transcriptional regulation and that CCND1 overexpression could lead to E2 independent ER alpha binding to estrogen response element (ERE). Methods: Cell lines: MCF7 grown in MEM alpha supplemented with 10% FBS . For stimulation studies, cells were maintained in phenol free MEM alpha supplemented with 10% FBS and 10 nM estradiol. RNAi knockdown studies: On-target plus siRNA were used to knockdown FBXO4 in MCF7 cells. Western Blot: Western Blot was performed following standard protocols. IHC/Tissue Array: Paraffin embedded malignant breast cancer (ER/PR/EGFR +ve) tissue samples that are scored by pathologist were used for the study. Gene Expression Studies: Microarray and NGS based approach. Results: FBXO4 has been identified as a potential hit in our RNAi screen showing a hyper-proliferative phenotype in MCF7 cellsupon its knockdown. Western blot and ubiquitination assay identified cyclin D (CCND1) as a dedicated FBXO4 target as revealed by confocal microscopy where FBXO4 knockdown showed an enrichment of CCND1 in cytoplasm. Ingenuity pathway analysis and ChIP assay revealed an exploitation of E2 signaling and enhanced recruitment of ER alpha to estrogen response element (ERE) in FBXO4 depleted cells. CCND1 further seems to co-occupy ESR binding motifs thereby representing ER functions. These effects were observed even in absence of any E2 stimulation. Further we observed a significant overlap of differentially expressed genes in E2 stimulated and FBXO4 knockdown cells that were nullified by CCND1 siRNA. Conclusions: Our study elucidated that CCND1 is spared from degradation following loss of FBXO4 which in turn leads to a hyper-proliferative state. Our findings co-related with TCGA and METABRIC databases indicating a poor patient survival and relapse in FBXO4 low and CCND1 high cohorts of ER +ve breast cancer thereby implying a diagnostic value. Along with traditional hormonal therapy, an effective targeted therapy in breast cancer should be aimed to restore FBXO4 levels.
Efficacy and safety of nivolumab monotherapy as the late line for patients with advanced gastric cancer in the real-world.
Authors: Tetsuya Kusumoto, Kenkichi Hashimoto, Keiji Yoshinaga, Eiji Kusumoto, Yoshihisa Sakaguchi, Koji Ikejiri, Eiji Oki
Journal: Journal of Clinical Oncology (2019)

e14074 Background: The ATTRACTION-2 study found that nivolumab showed a significant survival benefit for the patients with unresectable metastatic or locally advanced gastric cancer (AGC) following more than 2 regimens. Based on this trial, nivolumab was currently proved to be one of the most effective regimens for the patients with AGC as the 3rd-line treatment in Japan. We herein examined the clinical significance and validation of nivolumab as late line chemotherapy in patients with AGC. Methods: In October 2017 to December 2018, 26 patients received nivolumab monotherapy in our institute. We conducted a retrospective review of the data of 23 patients with AGC who received more than 2 cycles of nivolumab following the standard chemotherapy regimens including fluoropyrimidines, platinum derivatives and taxanes. Adverse events, tumor responses, and survival data were analyzed. Results: Only 2 patients enrolled here showed ECOG performance status (PS) 2 in the study. The time to treatment failure of them were shorter than those of the other patients with PS 0/1. Four patients quitted the continuation of nivolumab except for the progressive disease, due to non-hematological toxicities higher than grade 3 including myositis, hypothyroidism, dermatitis and liver dysfunction. The rate of hematological toxicities, which showed severe anemia of higher than grade 3 was 21.7%. The ORR and the DCR were 4.3% and 52.3% for the patients in this study. The survival data showed that the median PFS and the OS after nivolumab administration were 75 days and 274 days, respectively. Conclusions: Nivolumab monotherapy might be one of the best regimens for Japanese patients with AGC as the late line treatment following the standard chemotherapy.
Re-evaluating eligibility criteria: Analysis of factors leading to nonparticipation and outcomes of patients (pt) with advanced cancer who signed consent but were not treated in early-phase immunotherapy (IO) trials.
Authors: Roberto Carmagnani Pestana, Ishwaria Mohan Subbiah, Kenneth R. Hess, Le Huang, Shuang Liu, Kimberly Beltran, Holly Harrison, Angela Bryant, Jennifer Eshon, Timothy A Yap, Shubham Pant, Aung Naing, David S. Hong, Funda Meric-Bernstam, Vivek Subbiah
Journal: Journal of Clinical Oncology (2019)

2552 Background: Eligibility criteria protect the safety of trial pt and delineate the study population. Excessively restrictive criteria, however, can negatively impact accrual and prevent access to beneficial investigational treatments. Recently, ASCO issued a statement on the need to broaden eligibility criteria and make trials more representative. We aim to characterize the factors leading to non-participation and the outcomes of pt who signed consent for phase I IO trials but ultimately did not receive any therapy on that trial. Methods: We identified 696 consecutive pt w/ advanced cancer who consented to participate on IO phase I trials from 10/2015-12/2017, and collected pt characteristics as well as clinical outcomes, and compared participants (P) to non-participants (NP). Results: Among the 696 pt who initially consented to participate on IO phase I trials, 178 (25.6%) were never treated. Median age was 60 in both groups, and there were no differences regarding median number of metastatic sites (n = 2 vs 2 ) or sex distribution (F 53% vs 54%); NP had received less lines of therapy (median = 3 vs 4, p = 0.016). Reasons for non-participation were: 48 (26%) alternate therapy (for 18, geography was the main reason), 29 (16%) clinical progression/ decline in PS, 14 (8%) did not have enough biopsy tissue, 13 (7%) new lab abnormality, 11 (6%) new brain mets, 63 (35%) had other reasons (death, concurrent medications, financial factors). Median time from signature of consent to final exclusion of trial was 19 days (0-82). 54 of NP eventually enrolled in other trial, including 29 in immunotherapy trial. Median overall survival (OS) was significantly lower for NP vs P (median 6.9 vs 18.0, HR 0.5; p &lt; .0001). Conclusions: One quarter of patients who signed consent for early-phase immunotherapy trials were unable to start on study. NP had significantly decreased OS. Detailed examination of these reasons can lead to recognition of modifiable factors and streamline the pretrial period, to guarantee this vulnerable population has maximal access to start therapy on study.