tbuckley/cabot-search huggingface dataset:
Prediagnostic diabetes, body mass index, and survival of endometrial cancer: A prospective study.
Authors: Kristina Lindemann, Milada Cvancarova, Anne Eskild
Journal: Journal of Clinical Oncology (2014)

5601 Background: Diabetes and obesity are well known risk factors of endometrial cancer (EC). However, the associations of these factors with survival after EC diagnosis are not established. The aim of this population-based study was to assess the association between diabetes, BMI and risk of all-cause and EC-specific mortality. Methods: During 1984-1986 and 1995-1997 two health surveys were conducted in the Nord-Trøndelag county in Norway (HUNT 1 and 2). Women in both surveys who developed EC were identified through individual linkage to the Cancer Registry of Norway. Our primary outcome measure was risk of death from any cause after the diagnosis of EC. Follow-up time was calculated from the date of EC diagnosis until the date of death or the end of follow-up, June 30th 2012. Secondary outcome was death due to EC adjusted for competing causes of death. Both Cox proportional hazards models and Fine and Grey models (competing risk models) adjusted for age, stage of cancer and histological subtype were fitted. In stratified analyses, we studied the risk associated with diabetes in normal weight (BMI <25 kg/m2) and overweight/obese women (BMI ≥25 kg/m2). Results: Among the 31 865 women included in the HUNT surveys, 337 women who developed EC were eligible for survival analyses. During a median follow-up of 6.6 years (range 0.1-27), 166 (49%) of the women died. We found no statistically significant association between BMI and overall or EC specific mortality. However, the overall risk of death in EC patients with diabetes was more than doubled as compared to patients without diabetes (HR 2.14; 95% CI: 1.26-3.63). Also, the EC specific mortality was more than doubled in women with diabetes (SHR 2.69, 95% CI: 1.09-6.66). In stratified analyses, normal weight women with diabetes had higher, but not statistically significant, risk of both overall and EC-specific death compared to overweight/obese women. Conclusions: Diabetes, but not BMI, was associated with increased risk of all-cause and EC-specific mortality. This association between diabetes and mortality may be especially pronounced in normal weight women.
A phase I study of ADH-1 with cisplatin (Cisp) and gemcitabine (Gem) in patients (Pts) with unresectable or metastatic pancreatic and biliary tract cancers.
Authors: Lyudmyla Derby Berim, Beth M Kos, Ruby Evande, Jane L Meza, Valerie Shostrom, James K. Schwarz, Jean L. Grem
Journal: Journal of Clinical Oncology (2017)

306 Background: Pancreatic cancer cells in vitro undergo epithelial to mesenchymal transformation (EMT) by up-regulating mesenchymal markers, including N-cadherin. The EMT leads to increased motility &amp; invasiveness with collagen exposure in a pancreatic cancer mouse model, which can be inhibited by N-cadherin knockdown. ADH-1 is a small, cyclic pentapeptide with inhibitory effects on stromal &amp; endothelial cells expressing N-cadherin. Methods: Escalating doses of ADH-1 were given twice weekly for 3 wk (1,000, 2,000 &amp; 4,000 mg) with Cisp 25 mg/m 2 &amp; Gem1000 mg/m 2 /100 min days 1 &amp; 8 of a 3 wk cycle in pts with pancreaticobiliary cancers with ECOG PS 0-2 &amp; adequate bone marrow, renal &amp; hepatic function. Standard 3 + 3 dose escalation was used. Peripheral blood was collected for biomarkers prior to each dose of ADH-1 during cycle 1. Due to limited drug supply, ADH-1 was given for the 1 st 3 cycles. Results: Between 05/2013 - 04/2015, 17 pts were enrolled, received at least 1 dose of therapy, and were evaluable for toxicity: m 13/F 4; median 60 yr (range 37-81); pancreas 9 /biliary 8. 3 pts had prior adjuvant therapy. The number pts with dose-limiting toxicity during cycle 1 of ADH-1 (mg) were 0/4 at 1,000; 1/7 at 2,000 (gr 4 ANC, platelet); 2/6 pts 4,000 mg (1 pt: gr 3 pulmonary embolus and gr 4 plt; 1: gr 4 cholangitis/sepsis/multiorgan failure). 5 of 8 pts who had ≥ 6 cycles were taken off study due to cumulative toxicities rather than PD. 14 pts had ≥ 3 cycles of therapy and were evaluable for response: SD in 9 subjects; PD in 5. The median number cycles was 5.5 (range 1-30). Median time to treatment failure (TTF) for all patients was 113 days (range 7-724). Median OS was 218 days (7-853+). Pts with biliary cancer had a longer TTF and OS vs pancreatic cancer (TTF 217 vs 93 days; OS 305 vs 180 days). 6 pts survived &gt; 12 months (biliary 4, pancreas 2). Biomarker analysis (ICAM 1; E selectin; VEGF, Soluble VEGF-R 2 and 3, FGF basic) is ongoing. Conclusions: The phase II dose of ADH1 given with Cisp/Gem is 2,000 mg IV twice weekly. ADH-1 was relatively well tolerated. Most pts ultimately required dose delays or reductions due to cumulative toxicity with Cisp/Gem. Clinical trial information: NCT01825603.
Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8 T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice
Authors: Zhidong Hu, Ka-Wing Wong, Hui-Min Zhao, Han-Li Wen, Ping Ji, Hui Ma, Kang Wu, Shui-Hua Lu, Feng Li, Zhong-Ming Li, Tsugumine Shu, Jian-Qing Xu, Douglas B. Lowrie, Xiao-Yong Fan
Journal: Molecular Therapy (2017)

Accumulating evidence has shown the protective role of CD8+ T cells in vaccine-induced immunity against Mycobacterium tuberculosis (Mtb) despite controversy over their role in natural immunity. However, the current vaccine BCG is unable to induce sufficient CD8+ T cell responses, especially in the lung. Sendai virus, a respiratory RNA virus, is here engineered firstly as a novel recombinant anti-TB vaccine (SeV85AB) that encodes Mtb immuno-dominant antigens, Ag85A and Ag85B. A single mucosal vaccination elicited potent antigen-specific T cell responses and a degree of protection against Mtb challenge similar to the effect of BCG in mice. Depletion of CD8+ T cells abrogated the protective immunity afforded by SeV85AB vaccination. Interestingly, only SeV85AB vaccination induced high levels of lung-resident memory CD8+ T (TRM) cells, and this led to a rapid and strong recall of antigen-specific CD8+ T cell responses against Mtb challenge infection. Furthermore, when used in a BCG prime-SeV85AB boost strategy, SeV85AB vaccine significantly enhanced protection above that seen after BCG vaccination alone. Our findings suggest that CD8+ TRM cells that arise in lungs responding to this mucosal vaccination might help to protect against TB, and SeV85AB holds notable promise to improve BCG's protective efficacy in a prime-boost immunization regimen.
Deletion of TP53 (17p13) Is Associated with Poor Outcome for Newly Diagnosed High-Risk Multiple Myeloma
Authors: Erming Tian, Joshua Epstein, Pingping Qu, Christoph Heuck, Frits van Rhee, Maurizio Zangari, Antje Hoering, Jeffery Sawyer, Bart Barlogie, Gareth J Morgan
Journal: Blood (2015)
Vorinostat to restore sensitivity to aromatase inhibitor therapy in metastatic breast cancer: A phase II clinical trial with ER imaging correlates.
Authors: Hannah M. Linden, Brenda F Kurland, Jeanne Link, Vijayakrishna K. Gadi, Jennifer M. Specht, Julie Gralow, Erin K Schubert, Lanell Peterson, Janet F. Eary, David A. Mankoff
Journal: Journal of Clinical Oncology (2012)

TPS3109 Background: Endocrine refractory,Indolent, soft tissue, and bone dominant metastatic breast cancer is a clinical problem, for which alternatives to chemotherapy are needed, Histone deacetylace inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit. HDACi restore ER expression in ER-negative cells which are then sensitive to AI treatment in xenografts (Sabnis 2011) and are toxic to ER-positive cell lines (Huang 2000). Vorinostat is an FDA approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors. We hypothesized that HDACi therapy could restore sensitivity to aromatase inhibitor (AI) therapy, in patients with prior progression on AI, and allow continued endocrine therapy. Recent data suggest clinical benefit of Tamoxifen and vorinostat given continuously (Munster 2011) as well as entinostat and an AI (Yardley 2011). Our prior work has shown the feasibility of monitoring regional ER expression and ER-estrogen binding in vivo using [F-18]fluoroestradiol (FES) PET imaging (Linden 2011) providing a biomarker to interrogate the molecular target. Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on AI therapy are eligible. Patients must be off ER blocking therapies, and functionally postmenopausal. Baseline FES and FDG PET are performed and patients receive investigational vorinostat treatment at 400 mg po BID for 2 weeks followed by serial FES and FDG PET to assess the impact of vorinostat on ER expression and tumor metabolism. Patients are retreated on their prior AI as a single agent for 6 weeks, followed by paired FES and FDG and clinical assessment. Patients with clinical benefit may continue on treatment: 2 weeks of vorinostat followed by 6 weeks of AI in 8-week cycles until progressive disease or toxicity. We have enrolled 4 of a planned 20 patients.
The role of PCA3 testing in a homogenenous population of patients with low and intermediate-risk prostate cancer treated with brachytherapy.
Authors: Ana Medina, Raquel Losada, Alfonso Mariño, Arturo Candal Gómez, Inmaculada Diaz, Manuel Ramos Vazquez, Jose Luis Fernandez, Sonia Aranzazu Garcia, Carlos Mendez, Cristina Azpitarte, Lorena Paris, Venancio Chantada Abal, Sara Martinez Breijo, Luis M. Antón Aparicio, David Olmos
Journal: Journal of Clinical Oncology (2014)

e16091 Background: The prostate cancer associated gene 3(PCA3) is a promising and specific prostate cancer (PCa) biomarker. PCA3 can be detected in a urine sample becoming an easy and affordable test. Actually, its current use is mainly allocated in the diagnosis stage, supporting PSA testing and digital rectal exam. Its role in patients that are already diagnosed is uncertain. We have analyzed the values in a homogeneous population of patients going brachytherapy. These are categorized as low and intermediate risk patients and present PSA values bellow 20 ng/ml. We present the analysis of the value of PCA3 in this population never before explored. Relative quantitation of mRNA levels were calculated. Methods: First void urine from 39 patients with low/intermediate PCa have been collected after a digital rectal massage before brachytherapy treatment. mRNA PCA3 has been extracted and processed through quantitative reverse transcriptase polymerase chain reaction (PCR) assay. Gene expression of hypoxanthine phosphoribosyltransferase (HPRT) like housekeeping gene, kallikrein-related peptidase 3 (KLK3) and PCA3 has been analyzed. Relative quantitation of PCA3/HPRT ratio and PCA3/KLK3 ratio have been calculated as relative expression of mRNA levels. Results: Median age was 66 (53-77); with a 87.2% presenting Gleason score 6; 10.3% and 2.6% with 7 and 8 Gleason score respectively. Median PSA value was 5.4 ng/ml (0.10-13.70). Hormonal therapy was given in 9 patients. Range PSA values in patients without hormonal therapy was 0,5 to 13.70 ng/ml. Of the 39 patients, only in 18 (46%) patients mRNA PCA3 could be quantified. Relative quantification of the mRNA expression levels (median) of PCA3/HPRT was 0.54 (0.09-1.41) and PCA3/KLK3 was 0.41 (0.09-1.43). In patients with PSA<4, PSA between 4-10 and PSA over 10 ng/dl, medians PCA3/HPRT were 0.53, 0.55 and 0.23; and PCA3/KLK3 were 0.45, 0.3 and 0.13. Conclusions: In patients with confirmed diagnosis of low/intermediate risk of PCa, PCA3 was detectable in 46% of the patients. The values of the relative quantification of mRNA PCA3 show a downward trend as the higher the levels of PSA.
Association of pathologic complete response following neoadjuvant chemotherapy with survival among young women with breast cancer.
Authors: Rachel Adams Greenup, Aditya Bardia, Julliette M Buckley, Andrzej Niemierko, Melissa Camp, Suzanne Coopey, Michele Gadd, Lidia Schapira, Alphonse G. Taghian, Barbara L. Smith, Michelle Connolly Specht
Journal: Journal of Clinical Oncology (2012)

1122 Background: Neoadjuvant chemotherapy is increasingly being used in the treatment of breast cancer, yet data on efficacy and significance of pathologic complete response (pCR) is limited among young women. We sought to determine whether timing of chemotherapy impacted disease-free (DFS) or overall survival (OS), and whether pCR is associated with improved prognosis among young women with breast cancer. Methods: We performed an IRB-approved review of women ≤40 years old who received treatment for stage I-III breast cancer during 1996-2008 at our institution. DFS and OS were determined through use of state tumor registry, death certificate data, and Social Security Master Death Index. Tumor biology was categorized as hormone receptor positive (HR+), HER-2+, or triple negative (TN) breast cancer. pCR was defined as lack of invasive cancer in the breast and axilla on final pathologic review. Cox regression analyses were conducted to evaluate the hazard ratios (HRs) of the association between chemotherapy and outcomes. Results: 370 women ≤40 years old (median age = 36.5, range: 22-40) were treated with systemic therapy for stage I-III breast cancer. 54.7% of tumors were HR+, 20.9% were HER-2+, and 24.4% were TN. After adjusting for stage, there was no difference in DFS or OS among women who received neoadjuvant versus adjuvant chemotherapy (p=0.6 and 0.5 respectively). pCR following neoadjuvant chemotherapy was higher among HER-2+ (50%) and TN (28.6%) tumors when compared to HR+ tumors (17.6%). Among women who received neoadjuvant chemotherapy, 10-year DFS and OS rates were significantly higher when pCR was achieved when compared to lack of pCR (HR=0.20, p value=0.01 and HR=0.13, p=0.05). pCR with neoadjuvant chemotherapy trended towards higher 10-year DFS and OS when compared to women who received adjuvant chemotherapy (HR=0.30, p value=0.08 and HR=0.20, p=0.1). Conclusions: pCR after neo-adjuvant chemotherapy is associated with improved disease-free and overall survival in young women with breast cancer. Pathologic complete response may be a valuable surrogate marker for survival, and aid in the evaluation of therapeutic efficacy in young breast cancer patients.
A randomized phase III trial of combined paclitaxel, carboplatin, and radiation therapy followed by either weekly paclitaxel or observation in patients with stage III non-small cell lung cancer
Authors: D. L. Carter, A. M. Keller, R. C. Tolley, D. B. Johnson, J. Hathorn, R. J. Mundis, M. A. O'Rourke, D. Ilegbodu, L. Asmar
Journal: Journal of Clinical Oncology (2004)

7076 Background: This study investigates the efficacy and safety of additional consolidation chemotherapy delivered after standard chemotherapy and radiation therapy (XRT) in stage III NSCLC. The goal was to increase the median survival time beyond the standard of 12 months and the 5-year survival rate by 8%. Methods: Eligible patients (N=220) had confirmed stage IIIA or IIIB NSCLC, and an ECOG performance status 0–1. All patients were initially treated with induction chemotherapy consisting of paclitaxel 200 mg/m2 + carboplatin AUC=6 every 3 weeks for 2 cycles. Patients then received weekly paclitaxel 45 mg/m2 plus carboplatin AUC=2 for 7 weeks, with concurrent daily XRT to a cumulative dose of 66.6 Gy in 37 daily fractions. After initial standard therapy, 101 were not randomized, due to: progressive disease (34), toxicity (33), patient request (13), death (7), or other (14). Following completion of this standard therapy, the remaining 119 patients were randomly assigned to either non-consolidation or 6 months of additional consolidation weekly paclitaxel (70mg/m2IV). In the consolidation arm, a median of 7 weekly cycles were delivered. Results: For the non-consolidation vs. consolidation arms, the overall response rate was 71% vs. 63%, the estimated 3-year PFS was 19% vs. 7% (median 9.5 months vs. 8.2 months), and the estimated 3-year survival was 34% vs. 23% (median 26.9 months vs. 16.1 months). The frequency of grade 3 (71% vs. 66%) and grade 4 (17% vs. 15%) toxicity was similar in the non-consolidation vs. the consolidation arms. Conclusion: In this trial, the median survival in both arms surpassed the standard, most notably the 26.9 month survival in the non-consolidation arm. Consolidation chemotherapy when added to a regimen of both induction and concurrent chemoradiotherapy did not improve clinical outcomes, with clinical endpoints favoring the non-consolidation arm. Supported by Bristol-Myers Squibb, Plainsboro, NJ. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Clinical characteristics of NSCLC harboring ALK 2p23 translocation at Cleveland Clinic.
Authors: Yan Feng, Nathan A. Pennell, Julia Samsa, Christopher Lanigan, A. Valeria Arrossi, Carol Farver, Raymond R. Tubbs, Patrick C. Ma
Journal: Journal of Clinical Oncology (2012)

e18085 Background: The ALK 2p23 translocation, ALK(+), is an important druggable target in 5-7% of non-small cell lung cancer (NSCLC). However, the break-part FISH assay is labor-intensive. Better understanding of the target population’s clinical features and alternative screening tests are desirable to enable cost-effective patient selection for molecular therapy. Methods: NSCLC patients (N=120) seen at the Cleveland Clinic (CC) who had clinical screening ALK 2p23 FISH (Abbott Molecular) were included in this retrospective analysis. Biopsy specimens were also tested using immunohistochemistry (IHC) for ALK overexpression via clone D5F3 (Cell Signaling Tech.) with OptiView ultrasensitive detection (Ventana Medical Sys.). Clinical data were extracted from electronic medical records. Comparison was performed using Fisher’s exact test, Wilcoxon rank sum test or log-rank test. Results: Of the 120 tumors tested, 34 (28.3%) were ALK(+) by FISH, predominantly adenocarcinomas (33/34). 97% of the samples were also tested by ALK-IHC, with a concordance rate of 99%. Comparing to ALK (-) group, ALK(+) patients were younger (median 53 vs 65, p&lt;0.01) and mostly never/light smokers (91% vs 43%, p&lt;0.01). ALK(+) tumors tended to have higher number of metastatic sites at diagnosis, especially for liver metastasis (26.5% vs 10.5%, p=0.04). Interestingly, venous thrombosis (DVT/PE) was also significantly more common in ALK(+) patients (35.3% vs 16.3%, p=0.03). 17 (50%) patients were treated with crizotinib in the ALK(+) group. Two cases with positive screening ALK-IHC helped to identify FISH(+) tumor areas. Of those tumors with EGFR status available (n=103), 6 were EGFR mutation-positive, all being ALK(-). No significant OS difference was seen in ALK(+)/EGFR(-) patients (n=28) compared to ALK(-)/EGFR(-) patients (n=69). Conclusions: ALK 2p23 (+) NSCLC at CC was more commonly seen in younger patients and never/light smokers. They tended to have greater number of metastases, especially in the liver, and significantly higher risk of venous thrombosis. ALK-ultrasensitive IHC using the D5F4 clone helped to identify FISH(+) tumor areas and may be considered a cost-effective screening test demonstrating high concordance with ALK FISH.
O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress
Authors: Weiqi Xu, Xiang Zhang, Jian-lin Wu, Li Fu, Ken Liu, Dabin Liu, George Gong Chen, Paul Bo-san Lai, Nathalie Wong, Jun Yu
Journal: Journal of Hepatology (2017)

O-GlcNAc transferase (OGT) is a unique glycosyltransferase involved in metabolic reprogramming. We investigated the functional role of OGT in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC).The biological function of OGT in NAFLD-HCC was determined by gain- or loss- of OGT functional assays in vitro and in nude mice. OGT target factors and pathways were identified by liquid chromatography-tandem mass spectrometry (LC-MS), promoter luciferase assay, DNA binding activity assay and Western blot.OGT was upregulated in 12 out of 18 (66.7%) NAFLD-HCC tumor tissues by transcriptome sequencing, which was confirmed in additional NAFLD-HCC tumor tissues and cell lines. Biofunctional investigation demonstrated that OGT significantly increased cell growth (p<0.001), clonogenicity (p<0.01), migration and invasion (p<0.05) ability in vitro, and promoted xenograft tumor growth as well as lung metastasis in nude mice. The oncogenic effect of OGT was investigated, we found that OGT significantly induced palmitic acid production identified by LC-MS, which enhanced the protein expression of endoplasmic reticulum (ER) stress masters of glucose-regulated protein 78 and inositol-requiring enzyme 1α. Consequently, OGT significantly activated JNK/c-jun/AP-1 cascade by increasing protein expression of p-JNK, p-c-Jun and activation of AP-1; and induced NF-κB pathway through enhancing the protein levels of p-IKKα/ p-IKKβ, p-p65, p-p50 and the NF-κB DNA binding activity. Notably, OGT inhibition by its antagonist (ST045849) suppressed cell proliferation in vitro (p<0.001) and in xenograft mice models (p<0.05).OGT plays an oncogenic role in NAFLD-associated HCC through regulating palmitic acid and inducing ER stress, consequently activating oncogenic JNK/c-jun/AP-1 and NF-κB cascades.OGT, a unique glycosyltransferase enzyme, was identified to be upregulated in non-alcoholic fatty liver disease-associated hepatocellular carcinoma tissues by transcriptome sequencing. Here, we found that OGT plays a role in cancer by promoting tumor growth and metastasis in both cell models and animal models. This effect is mediated by the induction of palmitic acid.
Efficacy and Safety of Bortezomib Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) Vs R-CHOP in Japanese Patients (Pts) with Newly Diagnosed Mantle Cell Lymphoma (MCL) Not Considered for Transplantation Enrolled in the International, Randomized, Phase 3 LYM-3002 Study (NCT00722137)
Authors: Michinori Ogura, Lixia Pei, Brendan Rooney, Helgi van de Velde, Franco Cavalli
Journal: Blood (2014)