tbuckley/cabot-search huggingface dataset:
Development of the triple-mutant oncolytic adenovirus for treatment of metastatic cancer by means of intravascular virus administration.
Authors: Dmitry Shayakhmetov, Nelson Cesar Di Paolo, Henry Wyche
Journal: Journal of Clinical Oncology (2018)

e14546 Background: Oncolytic virotherapy of cancers is a rapidly growing new area of translational research and development that has the potential to improve treatment of currently incurable malignancies. However, the intravascular virus delivery needed to provide access to metastatic lesions renders currently-developed therapeutic viruses vulnerable to i) inactivation by blood components, ii) sequestration within the liver, and iii) interaction with tissue resident macrophages, which trigger potent systemic inflammation. Methods: Using targeted mutagenesis of the surface proteins of human adenovirus, we developed a novel oncolytic adenovirus vector, Ad-3MT, which overcame these limitations. Results: Intravenous administration of Ad-3MT into mice resulted in no hepatocyte transduction, demonstrating its greatly improved safety profile as measured by the lack of hepatotoxicity. The analysis of activation of the inflammatory cytokines and chemokines after intravenous Ad-3MT administration further showed that this virus triggers significantly lower levels of inflammation in the spleen, compared to control adenovirus. The incubation of Ad-3MT with 90% of human sera did not lead to virus inactivation by complement and IgM, providing evidence that in its Ad-3MT configuration, the virus is resistant to inactivation by blood components, thus, making it a feasible and unique platform for the development of therapeutic oncolytic adenoviruses for treatment of disseminated metastatic disease. Ad-3MT was highly efficient at infecting and killing a panel of human non-small cell lung cancer cell lines in vitro. Intravenous administration of Ad-3MT into nude mice with established tumors, derived from human non-small cell lung cancer cells, demonstrated that Ad-3MT can transduce, replicate, and propagate through human tumor tissue. Conclusions: Collectively, our study provides evidence that the development of oncolytic adenovirus for safe intravascular administration is feasible. Future efforts are targeted to advance Ad-3MT to a definitive pre-clinical toxicology testing and Phase-I clinical trial in patients with metastatic non-small cell lung cancer.
Mortality following breast cancer in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Chaya S. Moskowitz, Joanne F. Chou, Joseph Philip Neglia, Rebecca M. Howell, Lisa Diller, Ann Partridge, Wendy M. Leisenring, Gregory T. Armstrong, Leslie L. Robison, Kevin C. Oeffinger, Tara O. Henderson
Journal: Journal of Clinical Oncology (2018)

10511 Background: Female childhood cancer survivors have a high risk of subsequent breast cancer (BC). Little is known about mortality following BC in this population. Methods: Risk of all-cause and BC-specific mortality were estimated in 274 5-year survivors of childhood cancer diagnosed with invasive (71% ER+) or in situ BC. Median age at first BC diagnosis was 38 years (range 20-58); median follow-up after BC was 8 years (range 0-26), 195 (71%) were treated with chest radiation (RT) for their primary cancer. Hazard ratios (HRs) were estimated from cause-specific proportional hazards frailty models comparing mortality with a population-based control group with BC selected in a 1:5 ratio from SEER matched on sex, race, stage, age and calendar year of BC diagnosis (69% ER+). Cumulative incidence was estimated accounting for competing risks. Results: 92 childhood cancer survivors died, 49 from BC. Risk of death from any cause after a BC diagnosis was higher among childhood cancer survivors compared to controls (HR = 2.2, 95% CI 1.7-3.0) and remained elevated after adjusting for BC treatment with RT (HR = 2.2, 95% CI 1.7-3.1), chemotherapy (HR = 2.3, 95% CI 1.8-3.2) or both (HR = 2.4, 95% CI 1.7-3.2). Risk of death after diagnosis with early stage BC was elevated compared to controls (Stage 0, 1 & 2, n = 200, HR = 2.6, 95% CI 1.9-3.7) but BC-specific mortality was not significantly higher among survivors (HR = 1.4, 95% CI 0.9-2.0). Ten-year cumulative incidence of all-cause mortality was 33% (95% CI 27-40%) among survivors and 16% among controls (95% CI 14-18%); for BC-specific mortality it was 20% (95% CI 15-25%) and 13% (95% CI 11-16%) and for deaths from other causes was 13% (95% CI 9-19%) and 3% (95% CI 2-4%), respectively. Other causes of deaths among childhood cancer survivors with BC included other subsequent neoplasms (44%) and cardiovascular disease (26%). Conclusions: Mortality after BC is high in childhood cancer survivors compared to women with BC in the general population, even in the setting of early stage disease. Future research should determine if this increased mortality reflects co-morbidity, limited therapeutic options and/or missed opportunities for risk-reducing interventions at the time of BC diagnosis.
Tool like receptors as a risk factor for infection and death in cancer elderly patients.
Authors: Leuridan Torres, Maria Julia Gonçalves Mello, Jurema Telles O Lima, Luiz Claudio Santos Thuler, Anke Bergmann
Journal: Journal of Clinical Oncology (2016)

10046 Background: the elderly cancer is a heterogeneous and growing group. In the elderly, the genes of toll-like receptors (TRL) has been described as related to immunosenescence process, carcinogenesis, transcription of cytokines with systemic inflammatory response syndrome and sepsis. The relationship of this gene family with carcinogenesis and immunoregulatory responses to infection seems a promising field. Methods: Between 2015 and 2016, a prospective cohort study in 346 elderly patients with incident cancer ( = > 60 years) at the time of admission, assessed and collected sociodemographic and clinical variables and collected analysis of peripheral blood in translational exploratory study Experimental using real-time PCR for determination of toll-like receptor 2, 4 and 9 and cytokines in the peripheral blood at the beginning of anti-cancer therapy in older patients with cancer. Results: 346 elderly patients were included with incident cancer, age of 71.13 years (SD 7.41) means. Most were male (50.9%) and black or brown skin color self-reported (71.4%) .The topography of prostate cancer was more frequent (29.4%) followed by the digestive system (24.3%). They were mostly patients with advanced stage (III and IV) at nutritional risk (52.6%) and reported using up to 5 medications (77.2%). Patients were followed on average 128 days (SD 54.37). During this period, there were 39 deaths (11.3%) with a mean overall survival of 165 days (95% CI 161.25 to 170.02) and 22.3% developed infection (first time). There are significant differences in TRL4 average (% high) in monocytes in patients who were infected to uninfected (p = 0.0187) and death (p = 0.0048) between the groups of older people with and without cancer cancer (P = 0.0048). the difference between the means of groups TRL 4 tumor (% higher) in breast monocytes (p = 0.0312) the gastrointestinal tract (p = 0.0349), prostate (p = 0.0053) and lung (p = 0.0030) in control group, respectively, also significant. Conclusions: Overexpression of toll-like receptor 4 may be a risk factor for the occurrence of infection and death in the elderly patient with cancer. Overexpression of toll-like receptor 4 occurs differently according to the primary tumor site, was higher in prostate and lung cancer.
TCT-608 Effect of Chronic Liver Disease on the Outcomes, Readmissions, Length of Stay and Cost of Transcatheter Aortic Valve Replacement and Surgical Aortic Valve Replacement.
Authors: Habib Khoury, Yas Sanaiha, Sarah Rudasill, Hanning Xing, Peyman Benharash, Ramin Ebrahimi
Journal: Journal of the American College of Cardiology (2018)
Preliminary results from phase II study of combination treatment with HF10, a replication-competent HSV-1 oncolytic virus, and ipilimumab in patients with stage IIIb, IIIc, or IV unresectable or metastatic melanoma.
Authors: Robert Hans Ingemar Andtbacka, Merrick I. Ross, Sanjiv S. Agarwala, Matthew H. Taylor, John T. Vetto, Rogerio Izar Neves, Adil Daud, Hung T. Khong, Richard S. Ungerleider, Aislyn Boran, Maki Tanaka, Kenneth F. Grossmann
Journal: Journal of Clinical Oncology (2016)

9543 Background: HF10 is a replication-competent oncolytic virus derived from HSV-1. We report on preliminary safety data and antitumor activity of HF10 + ipilimumab (ipi) combination in an ongoing Phase 2 trial in melanoma. Methods: Key entry criteria: age ≥ 18 yrs, ECOG ≤ 2, Stage IIIB, IIIC or IV unresectable/unresected melanoma, ipi naïve (IV administration) and measurable non-visceral lesion(s) suitable for injection. HF10 injected into single or multiple tumors (1 x 107 TCID50/mL/dose, up to 5mL depending on tumor size and number); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) are administered at q3wk. AEs assessed per CTCAE 4.0. Tumor responses assessed per mWHO and irRC at 12, 18 and 24 wks and at 36 and 48 wks, for patients (pts) continuing on HF10 monotherapy. Primary endpoint is Best Overall Response Rate (BORR) at 24 wks. Dose limiting toxicity defined as ≥ G3 nonhematologic/hematologic toxicity, ≥ G2 neurologic toxicity or allergic event occurring within 1st 3wks of therapy. Results: Of 43 pts enrolled and treated at abstract data cut-off 01Feb16: 58% men, age range 29 to 92 yrs, disease stage 21% IIIB, 44% IIIC and 35% IV and 49% with ≥ 1 prior cancer therapy. Majority of HF10-related AEs are ≤ G2, similar to HF10 monotherapy and consistent with other oncolytic viruses. No DLTs or ≥ G4 AEs were reported. G3 AEs were experienced by 11.6% of pts. Of 3 pts with HF10-related G3 AEs, 1 had left groin pain, a thromboembolic event and lymphedema, 1 had hypoglycemia and 1 had diarrhea. Of 37 efficacy evaluable pts, BORR by irRC at 24 weeks is 37.8% (13.5% CR and 24.3% PR) and disease stability rate is 56.8% (18.9% SD). Enrollment and treatment are ongoing. Conclusions: The combination with HF10 does not appear to exacerbate ipi toxicity. Efficacy evaluation (overall and local) suggests that HF10+ipi has both local and systemic antitumor activity and substantially improves the response rate of ipi alone. Intratumoral HF10 serial injections are safe and well-tolerated in combination with ipi and are a potential novel therapeutic approach for metastatic melanoma.
Differential response to radiation treatment in molecular subtypes of diffuse large B-Cell lymphoma (DLBCL).
Authors: Elaine Patricia Lunsford, Dana E. Martin, Cheng B. Saw, Christopher A. Peters, Shagufta H. Khan, Zenaida P. Lopez-Dee, Michael P. Kearney, Jun Ling
Journal: Journal of Clinical Oncology (2016)

e19058 Background: The use of radiation therapy (RT) in the treatment of DLBCL is a topic of debate that continues to evolve as clinical trials reveal the heterogeneous nature of the disease. Molecular profiling has classified DLBCL into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes that show remarkable differences in treatment response and outcomes with standard chemotherapy. Response to RT in DLBCL subtypes has yet to be determined; however, may provide insight into who should receive treatment. Methods: Four DLBCL cell lines: WSU-DLCL2 and SUDHL-6 (GCB); Riva and SUDHL-2 (ABC), were irradiated with single doses over a range of 0-10Gy using photon beams from a Varian 6 MV linear accelerator. Viability and cell cycle were measured at 24 and 48 hrs post-RT using the Muse cell analyzer (EMD Millipore) and FACSAria II (BD Biosciences), respectively. Clonogenic survival in methylcellulose media (0.8%) was determined by imaging after 1 week culture. Results: Overall, RT inhibited cell growth in a dose- and time-dependent manner. At 24 hrs post-RT, SUDHL-6 and WSU-DLCL2 (GCB), as well as SUDHL-2 (ABC) cells showed significantly increased survival as compared to Riva (ABC) at doses of 2Gy (p < 0.05) and higher (p < 0.001). By 48 hrs, SUDHL-6 and SUDHL-2 remained more viable than Riva at doses of 4Gy and higher (p < 0.005), while WSU-DLCL2 became less viable with a pattern similar to Riva. Cell cycle analyses showed the majority of Riva cells in G2/M phase at all doses and time points (71.9%, SD = 0.07), while WSU-DLCL2 and SUDHL-6 cells shifted from G0/G1 to G2/M with increasing doses. Clonogenic survival was higher in WSU-DLCL2 than that of Riva at all radiation doses tested. Conclusions: While the ABC subtype of DLBCL is known for chemoresistance, our data suggest that in some cases, the opposite may be true for radiation therapy–Riva (ABC) showed decreased viability and clonogenic survival compared to GCB subtypes (WSU-DLCL2; SUDHL-6) after RT. In contrast, SUDHL-2 (ABC) behaved like SUDHL-6 and maintained increased viability when compared to Riva and WSU-DLCL2. These findings illustrate the potential impact of disease heterogeneity on the use of RT for patients with different molecular subtypes of DLBCL.
Multicenter phase 2 study of nintedanib in patients (pts) with advanced progressing carcinoid tumors.
Authors: Renuka V. Iyer, Bhavana Konda, Dwight Hall Owen, Kristopher Attwood, Suman Sarker, Sheryl-Ann Suffren, John Wilton, Robert Bies, Danielle Casucci, Diane Lauren Reidy, Manisha H. Shah
Journal: Journal of Clinical Oncology (2018)

4105 Background: Serotonin is the cause of carcinoid symptoms and can signal the formation of fibroblasts via fibroblast growth receptors (FGFR). Nintedanib is an oral inhibitor of the FGFR pathway and several angiogenic signaling pathways thought to drive carcinoid tumor progression. We hypothesized that nintedanib may slow tumor progression in pts with progressing carcinoids in a phase 2 study. Methods: Thirty pts with unresectable/metastatic carcinoids on stable dose of somatostatin analogue for ≥3 months were included from two sites (NCT02399215). Primary Endpoint: progression free survival (PFS) rate at 16 wks. Secondary Endpoints: Objective response (complete + partial responses) using standard RECISTv1.1 criteria; overall survival (OS); change in QOL throughout treatment using EORTC QLQ–GI.NET21 questionnaire for carcinoid pts; and toxicity (graded using the NCI CTCAE version 4.0). Results: Baseline characteristics: M/F: 15/15), ECOG PS: 0/1/2: 11/17/2; Median age (years): 64.9 (45.1-77.2); site of origin: small bowel (13), colon (7), lung (4), gastric (1), unknown primary (5); PD on prior everolimus: 10/30 (30%). PFS rate at 16 wks was 86.7%; 95%CI: 72-95.3% (26 pts). The study was designed to compare to a historic PFS rate of 0.30 with everolimus. Kaplan Meier median PFS and OS estimates were 11 and 27.6 months, respectively, with 6 pts currently on active treatment. RECIST response: PR 1(4%), SD 20(83%), PD 2(8%), NE 1(4%). Reasons for coming off therapy: progression 14 (58%), toxicity 5(21%), other (17%), death due to disease 1(4%). QOL was maintained or improved in at least 50% of subjects while on therapy. Treatment was held in 7 pts (23%) due to AEs. Highest grade AEs: gr2 in 14(47%) and gr3 in 8(27%) pts. The most common gr 2 were GI (9), heme (8) and gr 3 were hypertension (6) and decreased appetite (2). From individual Bayesian analysis using the nintedanib pop PK model developed, correlation between actual and predicted exposures, with 61% variability in the absorption rate between pts was seen. Conclusions: Nintedanib is active and well tolerated in pts with advanced carcinoids. PFS data are encouraging and expected to mature. Ongoing biomarker studies may allow optimal pt selection. Clinical trial information: NCT02399215.
Prognostic role of tumor-inflating lymphocytes in gastric cancer: A systematic review and meta-analysis.
Authors: Der Sheng Sun, Jung Soo Lee, Soon Auck Hong, Hye Sung Won, Yoon Ho Ko
Journal: Journal of Clinical Oncology (2017)

e15578 Background: Tumor-infiltrating lymphocytes(TILs) may act as major determinants of the host immune response to tumor cells. However, the potential prognostic value of TILs in gastric cancer remains controversial. This meta-analysis analyzed the associations between TILs and survival outcomes in gastric cancer. Methods: Eligible 24 published studies were identified by searching the PubMed and Google scholar databases. The primary clinical outcome was defined as overall survival (OS) or disease-free survival (DFS), which were analyzed by subgroups such as TILs subtype. The total of the study sample sizes in eligible 24 published studies was 3,229, which ranged from 52 to 273 (median, 120) patients. All studies were non-randomized and retrospective study. The only multivariate hazard ratio(HR) among patient survival data were pooled, and pooled multivariate HR with 95% confidence intervals (95% CI) were used to calculate the strength of this association between TILs expression and survival outcome. Results: The pooled multivariate hazard ratios suggested that high expression of TILs was associated with better overall survival outcome (pooled HR = 0.69, 95% CI 0.57–0.82), compared to low TILs expression in twenty-three eligible studies, particularly in CD8(+) lymphocytes (pooled HR = 0.63, 95% CI 0.48 –0.83). In contrast, a pooled analysis of the FOXP3 (+) T cells or T reg subgroup showed that high FOXP3 (+) expression was negatively correlated with OS (pooled HR = 1.88, 95% CI 1.34 –2.63). In an analysis of seven studies on DFS, the infiltration by TILs, CD4(+) or CD8(+) lymphocytes (pooled HR = 0.59, 95% CI 0.42 –0.81), not by the infiltration of FOXP3 (+) T lymphocytes (pooled HR = 1.82, 95% CI 1.30 – 2.53), was significantly associated with better survival outcome. Conclusions: The results from this meta-analysis suggest that TILs and TILs subsets expression can be a potential prognostic biomarker in patients with gastric cancer. Key Words: Tumor-infiltrating lymphocytes, gastric cancer, prognosis, meta-analysis
Clinical and biochemical features of FIC1 (ATP8B1) and BSEP (ABCB11) disease.
Authors: L N Bull, N Freimer, P Czubkowski, J Pawlowska, I Jankowska, F Lacaille, P McLean, A van Eerde, L Klomp, R Houwen, B Bourke, D Barton, A Antoniou, A S Knisely, G Mielli-Vergani, S Strautnieks, R Thompson
Journal: Hepatology (2002)
TCT-126 Percutaneous coronary intervention of chronic total occlusions is not associated with a higher risk for contrast-induced nephropathy compared to revascularization of non-occlusive stenoses
Authors: Ozan Demir, Francesca Lombardo, Enrico Poletti, Alessandra Laricchia, Alessandro Beneduce, Davide Maccagni, Massimo Slavich, Francesco Giannini, Mauro Carlino, Alberto Margonato, Alberto Cappelletti, Antonio Colombo, Lorenzo Azzalini
Journal: Journal of the American College of Cardiology (2018)
Human papillomavirus (HPV)-related oropharyngeal cancer cofactors: Viral co-infections, second cancers, and survival trends—A single Veterans Administration (VA) institution.
Authors: George Anthony Dawson, Yue Hua Zhang, Angela Laurio, Patricia Smith, Michael Dellatto, Fiona T. Innis-Gordon, Anthony Reino
Journal: Journal of Clinical Oncology (2017)

e17531 Background: Oropharyngeal cancers related to HPV are increasing in number. Common factors associated with HPV related head and neck cancers include ethnicity, young age, and low usage of alcohol and tobacco. All are typical of HPV+ related Oropharyngeal cancer in non-VA populations. Methods: This IRB approved chart review of 73 documented patients with Oropharyngeal cancers from co-HPV infections from 01/01/2011 - 12/31/2016. In this version of report we discuss second cancers, trends and other co-factors. Results: Overall trend was notable for a reversal (more HPV+ / less HPV- ) cases. All cancers were squamous cell variety. 2011 /2012 /2013/ 2014/2015/2016 HPV +: 4 / 4 / 0 / 6 / 11 / 7. HPV -: 6 / 8 / 4 / 8 / 6 / 5. Clinical stage: Evident adenopathy - (N2 to N3) was noted in 51/73(70%) cases: HPV+ 30/36 (83%) / HPV- 21/37(57%). As noted, there are ~40 co-factor events in each group with no clear association with HPV + or – status numbers of cases were too small for meaningful analysis. Second Cancers HPV+: PROSTATE 7 / BLADDER 2 / TESTICULAR 1 / RENAL 1 / LUNG 1 / SKIN 4. HPV- : FOM 2 / LARYNX 2 / TONSILLAR 1 / PAROTID 1 / BLADDER 1 / SKIN 5 / PROSTATE 1 / LUNG 1. Survival data results: There was evidence in our data that survival was prolonged in patients who are HPV negative, but this sample was too small to show statistical significance. Further, it appears white race improves the odds of survival p-value 0.073, however, not statistically significant, due to the small sample. Conclusions: As in the non-VA community, our data noted an increase in HPV+ oropharyngeal cancers treated at the Bronx VA during review period. Further, our HPV+ group had predominant advanced adenopathy, and whites had longer survival regardless of HPV status. Second cancers in HPV- group followed field cancerization effects in regards number new or old head / neck cancer events. Interestingly, with almost equal tobacco / alcohol use in both groups, no 2nd head and neck cancers in the HPV+ group were discovered. Potential immuno-protection for HPV+ 2nd h and N cancers.[Table: see text]
Utility of adding clinical data to a molecular results portal for improving clinical trial prescreening efficiency.
Authors: Mia Alyce Levy, Travis John Osterman, Neha Jain, Kathleen F Mittendorf, Christine Micheel
Journal: Journal of Clinical Oncology (2017)

e18182 Background: Bioportals that aggregate patient genomic results and diagnosis data elements can be used as a tool for identifying potentially eligible patients for molecularly-driven clinical trials. However, over time, increasing numbers of patients will be deceased, making this process less efficient. Methods: We sought to evaluate the addition of minimal clinical data to a clinical trial prescreening workflow utilizing these bioportals. We selected three molecularly-driven clinical trials currently enrolling patients at Vanderbilt-Ingram Cancer Center and evaluated the incremental contribution of genomic and clinical data to refinement of cohort identification. Utilizing data from the enterprise data warehouse (EDW), we assessed the potentially eligible patient population after addition of gene-level, alteration-level, vital status (known to be deceased), and date of last contact data elements to the data extraction query. Results: Utilizing gene-level and diagnosis data elements only, 68 potentially eligible patients were identified for these trials from a total of 7,200 patients whose NGS data was added to the EDW between 2010 and 2016. Addition of alteration-level detail eliminated 29% of these patients. Of the 53 remaining patients, incorporating vital status resulted in paring the potentially eligible cohorts by an additional 42%. Conclusions: This study demonstrates the added value of querying structured clinical and molecular data stored in the EDW to improve prescreen workflow efficiency and decrease manual review requirements. [Table: see text]