tbuckley/cabot-search huggingface dataset:
Relationship between tumor size and survival in non-small cell lung cancer (NSCLC): An analysis of the Surveillance, Epidemiology, and End Results (SEER) registry.
Authors: Jianjun Zhang, Kathryn A. Gold, Heather Lin, Stephen Swisher, Scott Michael Lippman, J. Jack Lee, Edward S. Kim, William William
Journal: Journal of Clinical Oncology (2012)

7047 Background: Tumor size is a known prognostic factor for early stage (I and II) NSCLC, but its significance in node positive or locally advanced NSCLC has not been determined. We sought to evaluate its prognostic value in early and locally advanced NSCLC and create a nomogram incorporating tumor size and other prognostic variables to predict survival. Methods: The SEER registry was queried for patients (pts) with NSCLC, aged 20-103 and diagnosed between 1998 and 2003. Pts with extra-pulmonary metastases or distant lymph node metastases were excluded. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status and primary treatment modality (surgery vs radiation). Log-rank test was performed to evaluate the relationship between these variables and overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor. Results: 52,287 eligible pts were divided into 16 subgroups based on primary tumor extension and node status. For example, in group 1, tumor was confined to one lung with no nodes involved; pts in group 12 had tumor invading the mediastinum (T4 by extent) and positive ipsilateral mediastinal nodes. Tumor size had a significant effect on OS in almost all groups after adjustment for age, sex, race, histology, node status, primary tumor extension and primary treatment modality. Our model incorporating tumor size had significantly better predictive accuracy (larger C index) than our alternative model not including this information (p&lt;0.0001). We then developed a nomogram incorporating tumor size, age, gender, race, histology, nodule stage, and tumor extension with the intent to predict OS. In subsequent bootstrap verification, the predicted 2-year OS from the nomogram was almost identical to the actual observed 2-year OS with a very slim biases of estimates. Conclusions: Tumor size is an independent prognostic factor, including pts with node positive or locally advanced NSCLC. We successfully created a nomogram incorporating tumor size and other clinical variables to predict survival.
The correlation between the severity of cetuximab-induced rash and clinical outcome for patients with head and neck carcinoma treated with chemoradiotherapy (CRT) plus cetuximab: The RTOG experience.
Authors: Voichita Bar-Ad, Qiang Zhang, Paul M. Harari, Rita Axelrod, David Ira Rosenthal, Andy Trotti, Christopher U. Jones, Adam S. Garden, Guobin Song, Robert Leonard Foote, David Raben, George Shenouda, Sharon Spencer, Jonathan Harris, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2014)

6025 Background: To evaluate the severity of cetuximab-induced rash and its correlation with clinical outcome and late skin toxicity. Methods: The analysis included patients who received definitive CRT on RTOG 0522 (70 Gy + cisplatin and cetuximab) or postoperative CRT on RTOG 0234 (60–66 Gy + cetuximab and either docetaxel or cisplatin). Patients had to have received the loading dose and at least one concurrent dose of cetuximab. Results: Six hundred two patients were analyzed: 406 on RTOG 0522 and 196 on RTOG 0234; 386 patients (64.1%) developed Grade 2-4 cetuximab rash. Patients with Grade 2-4 rash had younger age (p<0.001), fewer pack-years smoking history (p<0.001), were male (p=0.03) and had an oropharynx primary site (p=0.002). Combined across treatment groups, patients with Grade 2-4 rash, when compared to those with Grade 0-1 rash, had increased OS (HR 0.58 [95%CI 0.44-0.76)], p<0.001), increased PFS (HR 0.76 [95%CI 0.60-0.97], p=0.03), and reduced incidence of distant metastasis (HR 0.63 [95%CI 0.40-0.99], p=0.04), but no detectable difference in loco-regional failure (HR 0.80 [95%CI 0.58-1.10], p=0.17). After adjustment for prognostic factors (age, Zubrod PS, primary site, TNM stage): HR 0.69 [95%CI 0.51-0.92], p=0.01 for OS; HR 0.87 [95%CI 0.68-1.12], p=0.28 for PFS; HR 0.90 [95%CI 0.65-1.25], p=0.55 for loco-regional failure; and HR 0.67 [95%CI 0.42-1.06], p=0.08 for distant metastasis. Twenty-five percent of patients with Grade 2-4 acute in-field radiation dermatitis experienced Grade 2-4 late skin fibrosis vs 14% of patients with Grade 0-1 acute in-field radiation dermatitis (Odds ratio 1.92 [95%CI 1.23-3.00], p=0.004). Conclusions: Grade 2-4 cetuximab rash was associated with increased OS, that may be due to a reduction in incidence of distant metastasis. Grade 2-4 rash was not associated with increased PFS or decreased loco-regional failure. Grade 2-4 acute in-field radiation dermatitis was associated with higher risk of late Grade 2-4 skin fibrosis. This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Bristol-Myers Squibb.
Purine synthesis promotes maintenance of brain tumor initiating cells in glioma
Authors: Xiuxing Wang, Kailin Yang, Qi Xie, Qiulian Wu, Stephen C Mack, Yu Shi, Leo J Y Kim, Briana C Prager, William A Flavahan, Xiaojing Liu, Meromit Singer, Christopher G Hubert, Tyler E Miller, Wenchao Zhou, Zhi Huang, Xiaoguang Fang, Aviv Regev, Mario L Suvà, Tae Hyun Hwang, Jason W Locasale, Shideng Bao, Jeremy N Rich
Journal: Nature Neuroscience (2017)
Genetic disorders of nuclear receptors
Authors: John C. Achermann, John Schwabe, Louise Fairall, Krishna Chatterjee
Journal: Journal of Clinical Investigation (2017)

Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with “monogenic” conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.
Utilizing a collaborative working model to optimize molecular analysis of solid tumors in the Cancer Research UK's Stratified Medicine Programme.
Authors: Ian Walker, Fiona MacDonald, Helen Stuart, Rachel Butler, Rhianedd Ellwood-Thompson, Celia Brown, James Eden, David Gonzalez de Castro, Lisa Thompson, Sue Lillis, Debbie Mair, Vicky Cloke, Pauline Rehal, Jenny Bell, Matthew Smith, Brendan O'Sullivan, Philippe Taniere, Michael Griffiths, Peter W. M. Johnson
Journal: Journal of Clinical Oncology (2013)

11094 Background: The Stratified Medicine Programme is demonstrating large scale molecular testing of solid tumours in the UK using a range of technologies. The collaborative model has allowed three laboratories to share and compare data on mutation frequencies including mutation exclusivity, test turnaround times and failure rates, to inform a future routine service for clinical care. Methods: Phase One is a two-year pilot study of molecular analysis of surplus diagnostic FFPE tumour tissue obtained from patients with cancer of the breast, colorectum, lung, ovary, prostate or malignant melanoma. Samples are tested for specified genes of clinical and research interest (for example KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, TMPRSS2-ERG, EGFR, EML4-ALK and KIT). The labs have developed and validated protocols with comparable sensitivity for the simultaneous molecular analysis of multiple genes. Results: By 31 December 2012, 4,734 sets of molecular results were completed with 60% of tumour-site specific reports issued within the target 15 days (from sample receipt). Failure rates vary with both sample quality and the type of analysis performed. The Table illustrates the link between turnaround times and failure rates, showing that repeat testing for specimens which initially fail may reduce overall failure rates but consequently increase average turnaround times. Conclusions: We will report comparative data across the three testing labs and identify multiple factors that affect mutation detection rates, failure rates, turnaround times and reporting procedures. The Stratified Medicine Programme acknowledges funding from Cancer Research UK, AstraZeneca, and Pfizer. [Table: see text]
Evaluation of the frequency of MET expression and amplification in Chinese hepatocellular carcinoma patients and their association with survival.
Authors: Xiao-Dong Zhu, Jia Fan, Hui-Chuan Sun, Hui Zhou, Jacqueline Huang, Zhiqiang Du, Fanny Zhang
Journal: Journal of Clinical Oncology (2015)

e22193 Background: MET is a potential therapeutic target in hepatocellular carcinoma (HCC). This study evaluated MET expression and amplification in Chinese HCC patients and investigated the relationship with clinical outcomes. Methods: Resection tumor samples from HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage C were retrospectively assessed for MET protein levels by immunohistochemistry (IHC, Research-Use-Only, Dako) and MET gene copy numbers by fluorescence in situ hybridization (FISH, Research-Use-Only, Dako). MET-positive: membrane protein staining in ≥25% tumor cells (25% cut-off), or intermediate (2+) or strong (3+) staining of the membrane (2+/3+). MET-amplified: METto centromere 7 ratio ≥2.0. Tests for the association between Kaplan-Meier RFS, OS and MET status (log-rank test) and clinical parameters (Fisher’s exact), and the association between MET expression and amplification (Pearson Correlation) conducted. Results: A total of 264 eligible patients provided IHC samples; 88 (33.3%) and 86 cases (32.6%) showed high MET expression with definitions of 25% cutoff and 2+/3+, respectively. Of 265 patients with valid FISH results, the MET amplification rate was 9.1%. Liver cirrhosis status was associated with MET amplification (p=0.018) but not MET expression. Borderline significant OS and RFS difference was identified when high MET expression was defined as IHC 2+ or 3+, detailed RFS and OS data by MET status are shown (table). In 258 of patient samples, MET high expression with strong staining (3+) was associated with MET gene copy number (r=0.63). Conclusions: Borderline significant difference was found when high MET expression was defined as IHC 2+ or 3+. A larger prospective analysis of the potential prognostic role of MET in HCC patients is needed. RFS OS MET high expression 25% cut-off (MET high vs. MET low) 5.85 vs. 6.53 months (p=0.76) 13.1 vs. 11.5 months (p= 0.74) IHC 2+/3+ (MET high vs. MET low) 5.03 vs. 6.73 months (p=0.06) 10.5 vs. 13.9 months (p=0.076) MET amplification MET/centromere 7 ratio≥2.0 (MET amplified vs. non-amplified) 5.13 vs. 6.3 months (p=0.69) 14 vs. 11.5 months (p=0.95)
Omentin as a biomarker associated with improved overall survival in serous ovarian cancer.
Authors: Michaela Onstad, Laura L. Holman, Chi Lam Au Yeung, Rosemarie Schmandt, Samuel C Mok, Mark F. Munsell, Karen H. Lu
Journal: Journal of Clinical Oncology (2015)

5584 Background: Omentin is a protective adipokine secreted by the mesothelial cells of visceral adipose tissue. Its expression is inversely related to obesity and low levels have been found to be associated with disease states, such as diabetes and hypertension. Recently it has been found to have tumor suppressor activity in ovarian cancer, leading to decreased ovarian cancer cell proliferation, motility and invasion potential. We sought to explore whether omentin could be used as a biomarker to predict overall survival among patients with serous ovarian cancer. Methods: Serum samples were obtained from 148 women with serous ovarian cancer at the time of initial surgery. Circulating omentin levels were quantified using a commercially available ELISA kit. Clinical and demographic data were obtained from the electronic medical record. Overall survival was measured from the date of omentin collection to the date of last follow-up or death. A multivariate analysis of overall survival was performed to account for potential confounding variables. Results: Among women with serous ovarian cancer, a higher omentin level (per 100 units) is significantly associated with a decreased risk of death (p = 0.0004). Using a cutoff point of 350ng/mL, a Kaplan-Meier curve demonstrates a significantly improved survival for women with omentin > 350ng/mL at the time of initial surgery (p < 0.0001). A multivariate analysis was performed to consider other risk factors that may contribute to risk of death, including stage and grade of cancer, optimal debulking, use of neoadjuvant chemotherapy, BMI, menopausal status, diabetes and metformin use. After adjusting for these factors, the relationship between omentin and overall survival remained statistically significant (p < 0.0001). Conclusions: Omentin levels > 350ng/mL are predictive of improved overall survival among women with serous ovarian cancer, after adjusting for potential confounders. This may be reflective of the tumor suppressor activity of this adipokine, or may be due to the ability of ovarian cancer cells to down-regulate production of omentin. These findings warrant validation in another large ovarian cancer dataset.
Effect of advances in the management of hepatocellular carcinoma patients on improved survival.
Authors: Assaf Moore, Salomon M. Stemmer
Journal: Journal of Clinical Oncology (2015)

e15132 Background: Hepatocellular Carcinoma (HCC) is the sixth most common malignancy and the third most common cause of cancer mortality worldwide. Unique staging systems such as the Barcelona-Clinic Liver Cancer Staging Classification (BCLC) guide treatment of HCC patients. This study describes the outcomes of HCC patients treated in a single cancer center. Methods: A descriptive retrospective study based on medical records of HCC patients diagnosed between the year 2000 and 2013 and evaluated and treated by a multidisciplinary team. Results: The charts of 321 patients were reviewed. The median age was 64 years, 74.8% males, 74.1% were viral carriers, 76.0% had liver cirrhosis, 56.7% were diagnosed at an early stage – BCLC stage A. Median overall survival (OS) for all patients was 22.73 months, and 43.30, 13.86, 9.92 and 3.35 months for BCLC stage A, B, C, and D respectively. The differences in OS were statistically significant between all stages (p = 0.0001). Multivariate analysis revealed that the estimated hazard ratio for the effect of the year of diagnosis 2007-2013 versus 2000-2006 on survival is 0.72 (0.54-0.96, p = 0.027). The estimate was adjusted for gender, age at diagnosis, stage at diagnosis and hepatitis status. 92.1% of transplanted patients within the Milan Criteria remained disease free. 56.9% of resected patients recurred or developed a second cancer in the liver. Median disease free survival was 22.46 and 19.65 months for resection and percutaneous methods respectively, and is larger than 100 months (not reached) for transplantation. Median progression free survival was 11.86, 6.80, 3.81 and 5.49 months for radiotherapy, arterial embolization, Sorafenib and clinical trials respectively. Median OS following treatment with Sorafenib was 13.86 months. Conclusions: Patient selection, technological and pharmaceutical innovations have led to advancement in the treatment of HCC. Since there was no significant difference in the proportion of patients undergoing surgical procedures during the years, improved management of advanced stage patients may have led to better survival. The effect of advanced treatment options needs to be further assessed by prospective trials.
Feasibility and potential benefits of adjuvant chemotherapy with S-1 in patients with curative resected advanced biliary tract cancer: A multicenter trial.
Authors: Yoshikazu Toyoki, Keinosuke Ishido, Daisuke Kudo, Norihisa Kimura, Taiichi Wakiya, Yutaka Umehara, Shigeru Tohyama, Masaaki Endoh, Hiroshi Tateoka, Susumu Ohishi, Kenichi Hakamada
Journal: Journal of Clinical Oncology (2013)

e15179 Background: S-1 chemotherapy is reported to be effective for treating metastatic and unresectable biliary tract cancer (BTC). We assessed the safety and feasibility of adjuvant S-1 chemotherapy in patients with curative resected advanced BTC. Methods: Patients with pathological stage II, III, or IVa BTC (according to JSBS) who underwent radical resection received oral S-1 (80 mg/m 2 /day) for 2 consecutive weeks every 3 weeks (1 cycle). Patients were aged 20–80 years, had a performance status of &lt;1, and provided informed consent. The treatment was repeated until 1 year after surgery. The primary endpoint was feasibility of the adjuvant chemotherapy with S-1. The secondary endpoints were safety, disease-free survival (DFS), and overall survival (OS). Results: We enrolled 40 patients, but 5 patients were excluded on the basis of eligibility criteria (4 patients) or no drug administration (1 patient). We analyzed data from 35 patients (29 men and 6 women with a median age of 68 years) between January 2009 and November 2011. The feasibilities of 6-month and 12-month administration of S-1 were 65.7% (95% confidence interval [CI]: 47.8–80.9%) and 45.7% (95% CI 28.8–63.4%), respectively. Grade 3 neutropenia and anemia were observed in 2.9% and 5.7% of cases, respectively. Grade 3 non-hematological toxicities included anorexia in 14.3%, fatigue in 8.6%, and nausea in 2.9% of cases. No grade 4 hematological or non-hematological toxicities were observed, and no treatment-related deaths occurred. The 1-year OS was 91.4% (95% CI: 76.6–97.2%), and the 1-year DFS was 68.6% (95% CI: 51.7–81.7%). Conclusions: Adjuvant chemotherapy with S-1 for curative resected advanced BTC patients was both safe and feasible. Although the follow-up period was insufficient to evaluate OS and DFS, adjuvant chemotherapy with S-1 is believed to have improved the prognosis.
Primary prophylactic granulocyte colony-stimulating factor (GCSF) in Gilbert’s disease patients treated with FOLFIRI first line for metastatic colorectal cancer (mCRC): Final results of the FFCD 0604 study.
Authors: Thierry Lecomte, Olivier Bouche, Alice oden-Gangloff, Karine Le Malicot, Thomas Aparicio, Emmanuel Mitry, Laurent Bedenne, Gael Deplanque, Julien Volet, David Tougeron, Franck Bonnetain, Marie Moreau, Etienne Dorval, Marie-Anne Loriot, Pierre Laurent-Puig, Come Lepage
Journal: Journal of Clinical Oncology (2013)

3614 Background: Gilbert’s disease patients (pts) (homozygotous for the UGT1A1*28 allele) have a major risk (&gt;30%) of severe, life-threatening, neutropenia when treated with Irinotecan (IRI). The aim of this study was to demonstrate that, in these pts, treated with IRI 1 st line for mCRC, primary prevention with GCSF (lenograstim) reduces under 10% the risk of grade 4 or febrile neutropenia. Methods: This is a prospective, multicenter, phase II study of FOLFIRI + bevacizumab 1 st line (IRI 180 mg/m² every 2 weeks) and primary prophylactic GCSF (D5 to D11 each course) in mCRC pts with Gilbert’s disease. Pre-chemotherapy UGT1A1 genotyping was centralized and standardized using a biological molecular technique applied on DNA blood-extracted lymphocytes. Using a 2-step Fleming design, (α=5% and β=90%), 30 pts had to be included with an interim analysis (IA) planned after 20 pts and 4 months of follow-up. Results: Twenty pts from 7 centers were included between 10/2007 and 02/2012 and 19 analysed for the IA. Median pts age was 63 years (range: 45-73), 60% were females, 90% were PS 0 or 1, 80% had a colic primary site and 73% hepatic metastases. The primary site was non- resected in 1/3 of pts. The total number of administered courses of chemotherapy was 229 with a median of 12 per pt (range: 1-40). Among all these courses, 213 were administered with GCSF. IRI was administered as defined by the protocol with a nearly 100% rate of received /theoretical dose. Grade 3 neutropenia rate was 10.5%. No grade 3-4 diarrhea, no grade 4 or febrile neutropenia and no toxic death were observed. No declared SAEs were related to GCSF. In term of best response at 6 months, 7 pts were in complete or partial response and 9 had stable disease. Median progression free survival and overall survival were respectively 8.7 months (4.9; 13.4) and 24.4 months (12.6; ND). Conclusions: This study is the first to demonstrate that a pharmacogenetic approach based on a simple genetic test easy to perform can achieve a high rate of safe and performant administration of IRI in high risk mCRC pts. Clinical trial information: NCT00541125.
Efficacy and safety of IMO-2055, a novel TLR9 agonist, in combination with erlotinib (E) and bevacizumab (bev) in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following prior chemotherapy.
Authors: David A. Smith, Paul Conkling, Donald A. Richards, Maria Regina C. Flores, John J. Nemunaitis, Thomas E. Boyd, Alain C. Mita, Guillaume de La Bourdonnaye, David Wages, Alice Susannah Bexon
Journal: Journal of Clinical Oncology (2012)

e18047 Background: IMO-2055 is a novel TLR-9 agonist with potential to enhance the efficacy of biologics and small molecules through immune stimulation. Xenograft data show anti-tumor synergy between IMO-2055, E and bev; E-bev has been evaluated in 2 nd line NSCLC. Methods: Primary objective was to determine the recommended dose (RD) of IMO-2055 (dose range 0.08-0.48 mg/kg/w s.c.) with E 150mg/day p.o. and bev 15mg/kg q3w i.v. in a standard 3+3 design. An expansion cohort at the RD further determined safety and efficacy. Pts had AJCC stage 3/4 inoperable, histologically proven NSCLC where standard chemotherapy was not an option. Treatment was until progression (PD) or toxicity. Results: 36 pts were enrolled at 10 US sites from Nov ‘07 to Mar '11. 35 were treated/evaluable for safety; 33 for efficacy. Median age was 64, 58% were men, 81% white, 81% PS 1 with 69% adenocarcinomas and median 17 months since diagnosis. 44% pts were &gt;2 nd line. Pts received a median of 4.3 3-week cycles. 19 pts entered dose-escalation: 4 at 0.08 mg/kg, 6 at 0.16 mg/kg, 6 at 0.32 mg/kg, and 3 at 0.48 mg/kg IMO-2055. Two pts had DLTs: 1 grade 3 dehydration at 0.16 mg/kg, and 1 grade 3 fatigue at 0.48 mg/kg. RD was 0.32 mg/kg based on pharmacodynamic and clinical data: 17 more pts were treated at this dose. The most common AEs were diarrhea, nausea, fatigue and rash; most frequent grade 3-4 AEs were fatigue (9%), diarrhea (9%), anemia and dyspnea (both 6%), with no clear dose-relationship to IMO-2055. G3-4 hypertension was 0%, ATE 6% and hemorrhage 3%. Five pts died of PD on or within 30 days of study drug administration. Response rate was 12% with 79% disease control (SD+PR). Median PFS was 5.6 months (95% CI 3.9-7.2) and OS 16 months (95% CI 7.5-17.8) with 55% pts alive at 1 year. Conclusions: Addition of IMO-2055 to E-bev was well tolerated with no unexpected toxicity. The RD of IMO-2055 with E-bev is 0.32 mg/kg/w s.c. Median PFS and OS in this heavily pretreated population compare favorably with published E-bev data. IMO-2055 should be further explored in NSCLC.