tbuckley/cabot-search huggingface dataset:
Next-generation sequencing to reveal somatic mutations that confer sensitivity to everolimus.
Authors: Sun Min Lim, Hyung Soon Park, Sora Kim, Nak-Jung Kwon, Jae-Lyun Lee, Min-Hee Ryu, Jin-Hee Ahn, Jeeyun Lee, Hyo Song Kim, Hyun Ki Kim, Hye Ryun Kim, Hyun Cheol Chung, Joo-Hang Kim, Sang Woo Kim, Yoon-Koo Kang, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2015)

11010 Background: Using targeted ultradeep sequencing, we aimed to explore genomic alterations that confer extreme sensitivity to everolimus. Methods: We collected formalin-fixed paraffin-embedded tumor/normal pairs from 38 patients (21 with exceptional clinical benefit, 17 with no clinical benefit) who were treated with everolimus across various tumor types (13 gastric cancers, 15 renal cell carcinomas, 2 thyroid cancers, 1 lacrimal gland cancer, and 7 sarcomas). Ion AmpliSeq Comprehensive Cancer Panel was used to identify alterations across all exons of 409 target genes. Results: Tumors were sequenced to a median coverage of 605x. Cancer genomes are characterized by 203 somatic single-nucleotide variants (186 missense, 10 nonsense, 7 splice-site) and 51 frameshift insertions/deletions, with a median of 3.9 mutations per Mb (0 to 14.8 mutations per Mb). Overall, genomic alterations with activating effect on mTOR signaling were identified in 8 of 21 patients with clinical benefit and these include mTOR, TSC1, TSC2, NF1 and PIK3CA mutations. In a patient with ductal adenocarcinoma of the lacrimal gland in whom everolimus achieved a partial response (PR) for 8 months, a novel NF1 missense mutation (D1644A) and a novel TP53 frameshift deletion (A39fs*5) were revealed. Three mTOR missense mutations (K1771R, N1421D, I1973F) were found in patients with gastric cancer, renal cell carcinoma and angiosarcoma. A mutation in the helical domain of PIK3CA (E542K) was found in a renal cell carcinoma patient and a mutation in AKT1 (H238Y) was observed in a sarcoma patient with malignant fibrous histiocytoma. Lastly, a patient with anaplastic thyroid cancer harbored a nonsense mutation in TSC1 (p.Trp103*) and a renal cell carcinoma patient had a TSC1 splicing variant (c.1029+1G > A). Recurrent mutations in chromatin remodeling gene (BAP1; n = 2, 12%) and receptor tyrosine kinase signaling (FGFR4; n = 2, 12%) were noted only in patients without clinical benefit. Conclusions: Regardless of different cancer types, mTOR-pathway-activating mutations confer sensitivity to everolimus. Targeted sequencing of mTOR pathway genes facilitates identification of potential candidates for mTOR inhibitors.
Infiltrating neutrophils and malignant progression in intraductal papillary mucinous neoplasms (IPMN): An opportunity for identification of high-risk disease.
Authors: Eran Sadot, Olca Basturk, David S. Klimstra, Mithat Gonen, T. Peter Kingham, Michael Ian D'Angelica, Yuman Fong, Ronald P. DeMatteo, William R. Jarnagin, Peter J. Allen
Journal: Journal of Clinical Oncology (2014)

4137 Background: There is a strong link between neutrophil infiltration and malignant progression. Inflammatory proteins (IP) released by these cells play a pivotal role in the crosstalk between neoplastic and inflammatory cells. We evaluated tumor associated neutrophils (TAN) and their association with malignant progression in IPMN, and studied the cyst fluid from these lesions for biomarkers of the inflammation-carcinogenesis association. Methods: We evaluated 78 patients with resected IPMN (2004-2013). Patients were divided into 3 groups: low-risk (low and moderate grade dysplasia: n=48), high grade dysplasia (HGD, n=21), and invasive carcinoma (n=9). TAN were examined in representative areas on 2 slides of a given tumor. The number of TAN was assessed using the mean value of high power fields. Areas with <10 TAN/100 tumor cells were considered ‘negative’ and areas with 11–15 TAN/100 tumor cells were designated as ‘low’ while those with >15 TAN/100 tumor cells were regarded as ‘high’. A multiplexed protein assay (Luminex Corp.) was performed on cyst fluid to evaluate for inflammatory cytokines and tumor-associated markers. Results: Significant positive correlation between grade of dysplasia and TAN level was found. High TAN were identified in 2.1%, 33.3%, and 88.9% of patients from the low risk, HGD, and invasive carcinoma groups, respectively (p<0.001). Within the cyst fluid, IP(e.g. IFN-g, TIMP-1, MIF, TNF-a, and MMP-9) were also found to have positive correlation with higher grades of dysplasia. Higher levels of TAN correlated with increased cyst fluid concentrations of the IP (e.g. IL-1b, TNF-a, IFN-g, IL-4), and 90% of these proteins were also found to be associated with higher grades of dysplasia. Multivariate analysis of clinical, radiographic, and molecular findings identified cyst fluid MMP-9 and CA 72-4 to be independent predictors for higher grades of dysplasia. Conclusions: Tumor associated neutrophils are strongly associated with malignant progression in IPMN. Measurement of IP in the cyst fluid may be a surrogate marker for IPMN progression and allow for the identification of high-risk disease.
Quality of life assessment in patients with advanced renal cancer: CAVIREN study.
Authors: Luis Leon Mateos, Ignacio Duran, Enrique Gallardo Diaz, Sergio Vazquez-Estevez, Javier Puente, Enrique González-Billalabeitia, Aranzazu Gonzalez del Alba, Martin Lázaro Quintela
Journal: Journal of Clinical Oncology (2015)

e20654 Background: The increased life expectancy of patients with advanced renal cell carcinoma (mRCC) achieved with the introduction of new drugs, is propelling a more judicious assessment of patients quality of life (QoL). This study aimed to evaluate how oncologists perceive QoL and also whether maintaining or improving QoL could be a therapeutic target itself. Methods: A committee of 8 mRCC experts developed a questionnaire with 27 closed questions. Following the Delphi methodology, 62 Spanish oncologists with experience in mRCC management answered the questionnaire in two rounds (R) (McNemar/Bowker statistical tests). Results: According to second R responses all participants believe that mRCC and its treatment have a large impact on QoL. Moreover, 97% agreed that an assessment of the patient’s QoL helps to provide better treatment and considered that QoL improvement/maintenance should be a therapeutic target in itself. Despite these results, 60% do not routinely measure QoL in clinical practice. More surprisingly, even in the event of a functional decline, 61% of participants never assess QoL. Main reasons are lack of time in clinical practice (95%) and the complexity of questionnaires (61%) (Table 1). Conclusions: Although oncologists acknowledge the relevance of QoL and believe that its evaluation helps to provide an appropriate care,, QoL is rarely measured in clinical practice due to complexity and lack of time. A new tool is being developed to overcome the difficulties expressed by the responders and increase its applicability. CAVIREN results. Statement 1st R 2nd R Agree/Completely agree (%) mRCC and its treatment have a large impact on QoL 100 97 An assessment of the patient’s QoL helps to provide better treatment 98 97 QoL improvement/maintenance should be a target in itself 94 97 Do not measure routinely QoL 48 60 Causes: Lack of time in clinical practice 92 95 Complexity of questionnaires 60 61 The study has been funded by GSK.
Prognostic role of androgen receptor expression in triple-negative breast cancer.
Authors: Yanru Wang, Fang Yang, Yucai Wang, Fengming Zhong, Xiaoxiang Guan
Journal: Journal of Clinical Oncology (2015)

1076 Background: Expression of androgen receptor (AR) was reported to be associated with estrogen receptor (ER) expression and predict better disease-free survival (DFS) and overall survival (OS) in early breast cancer. The prognostic role of AR expression in triple-negative breast cancer (TNBC) is unclear. We performed a meta-analysis of published clinical studies to date. The Cancer Genome Atlas (TCGA) data was used to evaluate the association of AR expression with survival outcomes in TNBC. Methods: PubMed was searched for eligible clinical studies that investigated the association of AR expression with clinical outcomes (DFS and/or OS) of TNBC. Pooled hazards ratios (HRs) for survival outcomes with 95% confidence interval (CI) were calculated using Comprehensive MetaAnalysis (v2). AR mRNA expression, clinical information and survival data of breast cancer patients were extracted from the TCGA Data Portal. OS of TNBC patients with different levels of AR expression was compared using Cox-proportional hazards model and Kaplan-Meier method in Statistical Analysis System (SAS. v9.3). Results: Ten retrospective studies including 2463 patients were included in the meta-analysis. AR was expressed in 590 (24.1%) patients. Expression of AR was associated with significantly better DFS (HR = 0.70, 95% CI = 0.54-0.89, P = 0.005) in TNBC. Although there was a trend toward longer OS in TNBC patients with AR expression, it was not statistically significant (HR = 0.76, 95% CI = 0.56-1.04, P = 0.083). In the TCGA dataset, mRNA expression, clinical information and survival data were available for 971 female breast cancer patients. There were 149 TNBC cases for further analysis. AR expression was significantly lower in TNBC than adjacent normal tissue (P = 0.001). Again although there was a trend toward longer OS in cases with higher AR expression, the difference was not statistically significant (HR = 0.71 for > 10% vs ≤ 10% AR expression, P = 0.583; HR = 0.66 for > 15% vs ≤ 15% AR expression, P = 0.470; and HR = 0.70 for > 50% vs ≤ 50% AR expression, P = 0.452). Conclusions: Expression of AR in TNBC is associated with better DFS. Though there is a trend for better OS in patients with high levels of AR expression, this requires validations by additional large studies.
Immune responses and clinical outcomes in STAND, a randomized phase 2 study evaluating optimal sequencing of sipuleucel-T (sip-T) and androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC) after local therapy failure.
Authors: Emmanuel S. Antonarakis, Adam S. Kibel, George W. Adams, Lawrence Ivan Karsh, Aymen Elfiky, Neal D. Shore, Nicholas J. Vogelzang, John M. Corman, Johnathan Cartwright Maher, Todd DeVries, Candice McCoy, Nadeem A. Sheikh, Charles G. Drake
Journal: Journal of Clinical Oncology (2015)

5030 Background: STAND (NCT01431391) assessed optimal sequencing of sip-T and ADT in men with BRPC at high risk of metastases after local therapy (i.e. prostate specific antigen doubling time [PSADT] < 12 mo). Methods: Men (n = 68) were randomized to sip-T then ADT (2 wks post infusion 3; Arm 1) or ADT (3 mo lead-in) then sip-T (Arm 2). Cellular and humoral immune responses, and clinical outcomes were analyzed. PSA recurrence was defined as ≥ 2 serial rises in PSA and an absolute PSA value of ≥ 0.2 ng/mL (prior radical prostatectomy) or ≥ 2.0 ng/mL (prior radiotherapy alone). PSADT post-ADT was analyzed. Time to next anticancer intervention (TTACI) was measured from first ADT to the day of the next systemic therapy. Rate of metastases at 24 mo was also investigated. Results: All men received 3 sip-T doses, and 96% received 12 mo ADT. Cellular and humoral responses to PA2024 increased following treatment vs baseline (BL) and were sustained at all post-sip-T timepoints through 24 mo (p < 0.05). PA2024-specific T cell proliferation responses were higher in Arm 1 vs Arm 2 (p<0.001). The number of PA2024 antibody (Ab) responders (post-BL Ab titer ≥ 25,600) was similar between arms. Sip-T-mediated antigen spread was observed in both arms vs BL and maintained through 24 mo (p < 0.001). No significant differences between arms were observed in clinical outcomes: median time to PSA recurrence (21.8 vs 22.6 mo, HR: 0.70, 95% CI: 0.39–1.28; p = 0.357), PSADT (2.54 vs 2.58 mo, p = 0.944), metastases at 24 mo (6/31 vs 3/26, p = 0.419), or TTACI (medians not reached, p = 0.199). However, across the entire cohort, PA2024 Ab responses correlated with longer time to PSA recurrence (p = 0.007). Adverse events occurring in >20% were hot flashes, fatigue, headache, and chills. Conclusions: In men with non-metastatic BRPC, sip-T + 12 mo ADT induced a robust immune response that persisted for 24 mo. Data suggest a greater anti-PA2024 T cell proliferative response in Arm 1 (sip-T then ADT). Induction of a PA2024 Ab response may correlate with longer time to PSA progression. Clinical trial information: NCT01431391.
Weekly vinorelbine (VIN) vs weekly docetaxel (DOC) for metastatic breast cancer failing anthracyclines. Planned interim analysis of a randomized trial
Authors: C. R. Meier, H. J. Illiger, M. Steder, M. Braun, H. Deertz, H. T. Oeney
Journal: Journal of Clinical Oncology (2004)

744 Background: Optimal therapy is controversial for metastatic breast cancer no longer eligible for anthracyclines. VIN and DOC are known active regimens. Methods: Randomized patients (pts) received VIN 30 mg vs DOC 35 mg/m2 weekly x 6 for ≤ 4 cyles of 8 weeks duration. Upon progression, crossing of treatment arms (CTA) was offered. Primary endpoint is time to progression (TTP), others are survival (OS), response, toxicity, and quality of life (not reported here). Analysis at 120 of 240 pts accrued was planned for evaluation of trends. Results: Of 121 pts randomized from 11/98 til 07/03, 112 are currently evaluable, VIN (n=57) vs DOC (n=55). Common risk factors are well balanced. 65 CTA pts had VIN (n=31) or DOC (n=34) as 2nd therapy. Overall median follow-up is 230 days (5–1588). Before or without CTA, VIN pts had a median of 7 doses (1–28) for a TTP of 81 days (CI: 67–99), while DOC pts had a median of 11 doses (2–24) for a slightly longer TTP of 103 days (CI: 98–119), (p= 0.1178, log-rank-test). OS for initial VIN vs DOC was 253 (CI: 173–331) vs 288 days (CI: 231–424), (p= 0.1895, log-rank-test). One year survival was 31% for VIN (CI: 20–46%) vs 44% for DOC (CI: 30–60%). More VIN pts (42%) than DOC pts (18%) had disease progression as best response (p=0.00751, Fisher's exact test, double sided); other responses slightly favored initial DOC (not significant). After CTA, DOC produced more responses (35% vs 3%, p≤ 0.0014, Fisher's exact test, double sided), but again without significant benefit in terms of TTP and OS, respectively. Generally, VIN vs DOC resulted in more treatment delays (76% vs 46%), more leukopenia (61% vs 10%) or neutropenia (43% vs 7%) grade 3/4, but less mucositis/stomatitis (1% vs 8%)-(all p<0.05, Fisher's exact test, double sided). 2/5 VIN pts with severe adverse event (SAE) died of neutropenic sepsis, or pulmonary embolism, respectively. 1/10 DOC pts with SAE died of DIC and multiorgan failure. Conclusion: DOC was more efficient at response and less toxic than VIN, both before and after crossing of treatment arms, but so far with marginal or no benefit at TTP or OS. TTP benefit may become apparent once accrual is complete. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis
Prognostic significance of obesity in high-grade serous carcinoma of the ovary
Authors: M. Schlumbrecht, D. Urbauer, D. Gershenson, R. Broaddus
Journal: Journal of Clinical Oncology (2009)

e16528 Background: Obesity is an epidemic public health problem in the United States. In gynecologic oncology, obesity is an established risk factor for endometrial cancer. However, its role in the pathogenesis and survival in ovarian cancer is debated. Recent studies have attempted to elucidate a possible relationship, but variations in design and heterogeneity in patient characteristics make it difficult to draw definitive conclusions. The purpose of our study was to determine if body mass index at the time of treatment initiation for high grade serous ovarian carcinoma has an effect on patient outcome. Methods: Nine-hundred four patients treated for ovarian cancer at M.D. Anderson Cancer Center were identified between 2002 and 2007. Patients were excluded for low grade or non-serous histology, neoadjuvant treatment, or if presenting with recurrent disease. Clinicopathologic data were extracted by retrospective chart review. Patients were stratified by body mass index (BMI) as normal (BMI&lt;25), overweight (BMI 25-&lt;30), or obese (BMI&gt;30). All were treated with primary cytoreduction and standard platinum/taxane chemotherapy. Chemotherapy was dosed using adjusted body weights. Outcomes included time to recurrence, overall survival, success of surgical debulking, and chemotherapeutic toxicities. Statistical analysis was performed using Fisher's exact test, Wilcoxon test, and Kaplan-Meier estimates. Results: A total of 127 patients were included for analysis. Patients were followed for a mean of 37 months (range 3–86 months). Twenty-one patients were obese (16.5%), and 35 were overweight (27.5%). Diabetes was more prevalent in the obese cohort (p = 0.0038). There was a trend towards greater likelihood of suboptimal debulking in obese patients, but this did not reach statistical significance (p = 0.06). BMI had no effect on recurrence-free survival (HR 0.69 [CI 0.39–1.23], p = 0.21) or overall survival (HR 0.95 [CI 0.68–2.43], p = 0.91). There was no difference in chemotherapy side effects or chemoresistance across BMI strata. Conclusions: Body mass index has no effect on survival in women with high grade serous ovarian cancer. Effectively managing comorbidities and ensuring adequate chemotherapy dosing in the obese patient is crucial for optimizing outcome. No significant financial relationships to disclose.
Significance of preoperative planning software for puncture and channel establishment in percutaneous endoscopic lumbar DISCECTOMY: A study of 40 cases
Authors: Zhouyang Hu, Xinhua Li, Jian Cui, Xiaobo He, Cong Li, Yingchao Han, Jie Pan, Mingjie Yang, Jun Tan, Lijun Li
Journal: International Journal of Surgery (2017)
Artificial Thymic Organoids Permit Allelic Exclusion and Efficient Generation of Naïve TCR-Engineered T-Cells from Human Hematopoietic Stem Cells In Vitro
Authors: Christopher S Seet, Chongbin He, Michael Bethune, Suwen Li, Brent Chick, Eric Gschweng, Yuhua Zhu, Kenneth Kim, David Baltimore, Donald B Kohn, Amelie Montel-Hagen, Gay M Crooks
Journal: Blood (2016)
Evaluation of the clinical activity of ipilimumab (IPI) plus nivolumab (NIVO) in patients (pts) with NIVO-refractory metastatic urothelial cancer (UC).
Authors: Margaret K. Callahan, Brooke Elizabeth Kania, Gopa Iyer, Jessica Mary Clement, Samuel Funt, Asia S. McCoy, Grace Hettich, Etay Ziv, Mark J. Bluth, Phillip Wong, Jedd D. Wolchok, Dean F. Bajorin, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2017)

384 Background: Programmed cell death –1 (PD-1) and its ligand (PD-L1) serve as checkpoints that regulate the interaction between the immune system and tumors. Antibodies blocking PD-1 or PD-L1 enhance antitumor activity in pts with UC. NIVO, a PD-1 blocking antibody, has clinical activity in UC as a single agent. IPI, an antibody blocking the checkpoint molecule CTLA-4, has demonstrated biologic activity in UC. Dual checkpoint blockade with both NIVO and IPI also has clinical activity in UC, but has not been systematically studied in NIVO-refractory UC. We sought to evaluate whether the addition of IPI to NIVO is feasible and clinically beneficial in pts whose UC is refractory to single agent NIVO. Methods: Forty pts with advanced or metastatic UC were treated with NIVO (3 mg/kg every 2 weeks) as part of a single arm, IRB-approved, investigator initiated study (NCT02553642). The study offered the option of treatment with the combination of IPI (1 mg/kg) and NIVO (3 mg/kg) for pts who had confirmed progression after treatment with NIVO monotherapy. The combination was dosed once every 3 weeks for 4 doses and followed by NIVO monotherapy. Pts were monitored for response and toxicity. Results: Ten pts who were refractory to NIVO monotherapy were treated with the combination of IPI and NIVO. There was a modest increase in the frequency of toxicities associated with the combination, compared to NIVO alone. One pt developed grade 3 diarrhea after treatment with the combination. No grade 3/4 toxicities were observed in pts treated with NIVO monotherapy. One pt achieved a confirmed partial response. Three additional pts achieved stable disease after documented progression. Pharmacodynamic changes in peripheral blood immune cells were monitored during treatment with NIVO monotherapy and combination therapy. Conclusions: The combination of IPI and NIVO is well tolerated and may have clinical activity in pts with UC who fail to respond to PD-1 blockade. Further studies to evaluate the magnitude of clinical activity and predictors of response for this combination are needed. Clinical trial information: NCT02553642.
Weak correlation of overall survival and time to progression in advanced hepatocellular carcinoma.
Authors: Liping Huang, Yoriko De Sanctis, Minghua Shan, Jordi Bruix, Josep Llovet, Ann-Lii Cheng, Gerold Meinhardt, Keiko Nakajima
Journal: Journal of Clinical Oncology (2017)

233 Background: Time to progression (TTP) is a potential surrogate endpoint in oncology clinical trials. The correlation of TTP and overall survival (OS) in advanced hepatocellular carcinoma (HCC) has been studied by meta-analyses (Terashima et al, Hepatol Res 2016;46:650); however, these analyses may be biased by trial selection and heterogeneity. We assessed the correlation between TTP and OS using simulated trials based on patient level data from 2 large sorafenib trials in patients (pts) with unresectable HCC (uHCC). Methods: To assess the correlation between OS and TTP, a bootstrap approach was applied to simulate 10,000 trials based on data from the randomized, phase III sorafenib trials in uHCC pts (SHARP [n = 602] and Asia-Pacific [AP; n = 226]). Individual data correlation between OS and TTP was conducted for 828 pts included in SHARP and AP. Pearson correlation was calculated between estimated median OS (mOS) and estimated median TTP (mTTP) for sorafenib and placebo (PLA) arms separately. Pearson correlation of log rank test statistics and hazard ratios were calculated to compare sorafenib and PLA for OS and TTP. Results: Simulated mOS and mTTP trial data were similar to that reported in SHARP and AP (Table). In SHARP, the correlation between mOS and mTTP was 0.270 for sorafenib and 0.218 for PLA, and in AP, 0.333 for sorafenib and 0.251 for PLA. The correlation of log rank test statistics comparing sorafenib and PLA was 0.387 in SHARP and 0.540 in AP. Conclusions: The simulated mOS/mTTP data was representative of pt population data in SHARP and AP. Our analysis showed a weak correlation between OS and TTP. This finding challenges TTP as a surrogate endpoint in HCC and should be considered when interpreting TTP results for the evaluation of treatment effect in uHCC. These data reinforce that the pattern of progression is potentially more relevant to OS than tumor progression as suggested by Reig et al ( Hepatol 2013;58:2023). Clinical trial information: NCT00105443; NCT00492752. [Table: see text]