tbuckley/cabot-search huggingface dataset:
Veliparib (Vel) in combination with chemoradiotherapy (CRT) of carboplatin/paclitaxel (C/P) plus radiation in patients (pts) with stage III non-small cell lung cancer (NSCLC) (M14-360/AFT-07).
Authors: David E. Kozono, Tom Stinchcombe, Joseph Kamel Salama, Jeffrey Bogart, William J. Petty, Michael J. Guarino, Lyudmila Bazhenova, James Mitchell Larner, Jared Weiss, Thomas A. DiPetrillo, Steven J. Feigenberg, Beibei Hu, Silpa Nuthalapati, Yan Luo, Everett E. Vokes
Journal: Journal of Clinical Oncology (2019)

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m 2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m 2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.
Metastasectomy and BRAF mutation: An analysis of survival outcome in metastatic colorectal cancer.
Authors: Thiru Prasanna, Rachel Wong, Timothy Jay Price, Jeremy David Shapiro, Jeanne Tie, Hui-Li Wong, Louise M. Nott, David Roder, Margaret Lee, Suzanne Kosmider, Azim Jalali, Matthew E. Burge, Robert Padbury, Guy Maddern, James Moore, Scott Carruthers, Michael Sorich, Christos Stelios Karapetis, Peter Gibbs, Desmond Yip
Journal: Journal of Clinical Oncology (2019)

3531 Background: Surgical resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether such benefit is consistently observed for BRAF V600E mutant (MT) and wild type (WT) mCRC. We conducted a retrospective analysis to explore the influence of BRAF mutation status on survival outcomes after metastasectomy. Methods: Data collected from two large prospective population databases in Australia (Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) and South Australian cancer registry). Overall survival (OS) and recurrence free survival (RFS) for BRAF MT and WT mCRC were evaluated by Kaplan-Meier method and compared by log-rank test. Results: 513 patients who had undergone metastasectomy were identified, 6% were BRAF MT. Median age 63. Metastasectomy rate was lower in BRAF MT (13 v 27%). In BRAF WT, 4% underwent resection of metastases (mets) in &gt;1 organ at diagnosis and 5% had 3 or 4 metastasectomies versus none in BRAF MT. Median OS in BRAF MT v WT: 25.7 v 48.5 months (HR 1.95; 1.18-3.22). In a multivariate model adjusting for variables which were significant on univariate analysis, OS differences were not statistically significant. Right primary tumor, intact primary, &gt;1 metastatic sites at diagnosis, non R0 resection, peritoneal mets and synchronous mets were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 v 19 months, p=0.09). Rate of downsizing was higher with triplet chemo than doublet +/- bevacizumab or doublet/EGFR in BRAF WT (50 v 30%) as well as MT (33 v 11%). Conclusions: Median OS was &gt; 2 years in BRAF MT V600E after metastasectomy in this study consistent with an OS benefit. OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Presence of BRAF MT should not impact patient selection for metastasectomy.[Table: see text]
Reply to ‘Assembling the brain trust: the multidisciplinary imperative in neuro-oncology’
Authors: Kenneth Aldape, Kevin M. Brindle, Louis Chesler, Rajesh Chopra, Amar Gajjar, Mark R. Gilbert, Nicholas Gottardo, David H. Gutmann, Darren Hargrave, Eric C. Holland, David T. W. Jones, Johanna A. Joyce, Pamela Kearns, Mark W. Kieran, Ingo K. Mellinghoff, Melinda Merchant, Stefan M. Pfister, Steven M. Pollard, Vijay Ramaswamy, Jeremy N. Rich, Giles W. Robinson, David H. Rowitch, John H. Sampson, Michael D. Taylor, Paul Workman, Richard J. Gilbertson
Journal: Nature Reviews Clinical Oncology (2019)
Anti-Müllerian Hormone in PCOS: A Review Informing International Guidelines
Authors: Helena Teede, Marie Misso, Eliza C. Tassone, Didier Dewailly, Ernest Hy Ng, Ricardo Azziz, Robert J. Norman, Marianne Andersen, Stephen Franks, Kathleen Hoeger, Samantha Hutchison, Sharon Oberfield, Duru Shah, Femke Hohmann, Sasha Ottey, Preeti Dabadghao, Joop S.E. Laven
Journal: Trends in Endocrinology and Metabolism (2019)
The ctDNA in peritoneal effusion of advanced gastric cancer for auxiliary diagnosis of peritoneal metastasis.
Authors: Changsong QI, Pansong Li, Yanting Hu, Lianpeng Chang, Yi Wu, Yuhua Gong, Jing Gao, Yanfang Guan, Xiaotian Zhang, Xuefeng Xia, Xin Yi, Lin Shen
Journal: Journal of Clinical Oncology (2019)

e15516 Background: Peritoneal metastasis (PM) is the most frequent mode of distant metastasis in advanced gastric cancer (GC). Most PM could cause peritoneal effusion. However, the cytological examination of cancer cells in peritoneal effusion is less sensitive to the identification of PM early; the specificity of serum biomarkers in peritoneal effusion is poor. It is necessary to assess the feasibility of peritoneal effusion circulating tumor DNA (ctDNA) for the PM diagnosis. Methods: 22 GCs with clinically confirmed PM as positive subjects and 11 non-cancers without PM as negative control were recruited. GC tissues were collected from 16 positive subjects. Peritoneal effusion supernatant (AS), peritoneal effusion cells (AC), and plasma were collected from each subject. Next generation sequencing (NGS) was performed using a 1021-gene panel. Sensitivity and specificity for the diagnosis of GC with PM were assessed. Results: Median age of 22 GCs with PM was 57 yrs. 12 patients were male. Diffused and mixed-type accounted for 73%. For 45% of patients, primary tumor was found in gastric body. In tissue samples, recurrent genes were TP53 (63%), CDH1 (50%), RHOA (19%), TGFBR1 (19%), KRAS (13%), and PIK3CA (13%). Private and tumor-derived mutations were found in the AS, AC, and plasma. 95% of (21/22), 82% (18/22), and 77% (17/22) of AS, AC, and plasma samples carried mutations, respectively. AS had more mutations than AC and plasma (Wilcoxon’s matched-pairs signed-ranked test, AS vs AC, p= 0.006; AS vs plasma, p = 0.013). 98% of the AC and 80% plasma mutations were contained in AS, Variant allele frequency (VAF) in AS was higher than others (Mann Whitney test, AS vs AC, p= 0.038; AS vs plasma, p&lt; 0.001). In 22 GCs with PM, 3 were identified with no cancer cells in AS using cytological examination. Of these, 3 were detected with mutations in AS, one with mutations in AC. Mutations were detected in only one negative control AS and AC. Receiver operating characteristic (ROC) curve showed the number of mutations was related to PM (AS: AUC 0.93, 95% CI 0.82-1.00, p&lt; 0.001; AC: AUC 0.85, 95% CI 0.70-1.00, p= 0.001). When the threshold was determined with one mutation, the sensitivity and specificity were 95% and 91% in AS, 82% and 91% in AC, respectively. Conclusions: Peritoneal effusion ctDNA contained tumor-derived and specific mutations. Peritoneal effusion ctDNA can be used for the auxiliary diagnosis of PM.
Inhibition of carboplatin-induced DNA repair by 9-β-D-arabinofuranosyl-2-fluoroadenine in both proliferating and quiescent cells with different combinational effect
Authors: Kazutaka Takagi, Yasukazu Kawai, Takahiro Yamauchi, Takanori Ueda
Journal: Cancer Research (2005)

5002  Carboplatin has been widely used in patients with solid tumors. However, the clinical experience in the patients with aggressive lymphoma and leukemia have not been satisfactory. Previous in vitro studies including ours have demonstrated that DNA repair induced by DNA damaging agents is an important target for enhancing it′s cytotoxic action of 9-β-D-arabinofuranosyl-2-fluoroadenine (fludarabine) by incorporation into the repair patch. The aim of the present study was to evaluate whether fludarabine inhibited carboplatin-induced DNA repair equally in proliferating cells (CCRF-CEM and K562) and quiescent cells (normal human lymphocytes), and elicited a positive combinational effect in both groups. To address this hypothesis, carboplatin-induced DNA damage and repair was evaluated by the alkaline comet assay. When both human leukemia cells and normal lymphocytes were exposed to carboplatin for 90 min, a rapid increment in the tail moment was observed in a dose-dependent manner, indicating that carboplatin substantially induced DNA damage in both groups. During incubation in fresh media after treatment with carboplatin for 90 min, the tail-moment decreased in proportion to the incubation-period, and recovered to the control level at 4 h in both proliferating and quiescent cells. This steep decrement in the tail-moment indicated that both proliferating and quiescent cells were equally repair-proficient, and have an ability to complete DNA re-joining after removal of damaged DNA. When cells were pulse-treated with fludarabine and carbpolatin for 90 min in combination then transferred to fresh media to allow DNA repair, these repair processes were similarly inhibited by fludarabine in both proliferating and quiescent cells. This inhibitory effect was fludarabine concentration-dependent manner, and was almost complete in the presence of 3 μM fludarabine, indicating that a clinically achievable concentration of fludarabine efficiently inhibited DNA repair in vitro. Under this condition, substantial accumulations of fludarabine triphosphate were observed. The cytotoxic action of these two drugs in combination was evaluated by the trypan blue dye-exclusion method. In lymphocytes, continuous exposure to fludarabine and carboplatin in combination produced an enhancement of cytotoxic effect, in contrast, only additive cytotoxic effect was observed in CCRF-CEM cells. These data suggested that carboplatin provids a new opportunity for incorporation of fludarabine into the repair patch in quiescent cells, leading to an enhancement of cytotoxic action. The mechanistic interaction of F-ara-A with carboplatin may be effective against a dormant population of lymphoma, which may contribute in vivo to drug resistance, as these cells are free from targets of S-phase specific anticancer agents.
Recycling of residual liquid drug formation following pressurized intra-peritoneal aerosol chemotherapy (PIPAC).
Authors: Haris Chaudhry, Tanja Khosrawipour, Saher Aslam, Agata Mikolajczyk, Justyna Schubert, Alessio Pigazzi, Veria Khosrawipour
Journal: Journal of Clinical Oncology (2019)

e14215 Background: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is becoming an increasingly widespread approach in which intra-peritoneal chemotherapy (IPC) is delivered in the shape of a chemoaerosol formed by an aerosol creating device. Disadvantages of current PIPAC applications include nearly instant liquid drug accumulation in the recto-uterine pouch. This study aims to investigate the feasibility of respraying the accumulated liquid to prevent local cytotoxicity and tissue trauma as well as to possibly adjust drug concentrations and improve both distribution patterns and penetration levels. Methods: A well-established, previously described postmortem swine model was used. 200ml of doxorubicin solution were aerosolized within the abdominal cavity at a pressure of 12 mm Hg C0 2 and 37° degrees Celsius . A suction tube was placed in the recto-uterine pouch and accumulating liquid doxorubicin solution following aerosol formation was collected and recycled in consecutive PIPAC repetitions. PIPAC repetitions were performed by using only the remaining liquid drug within the pouch. Consecutive residual volumes within the recto-uterine pouch were measured, as well as tissue penetration rates at different locations of the peritoneal wall. Results: Liquid formation was continuously reduced with each consecutive spray cycle. Tissue penetration rates were significantly higher following the recycling process (p &lt; 0.05). Drug distribution pattern showed a significant improvement following the recycling process vs. after initial aerosol formation (p &lt; 0.05). Conclusions: Respraying the accumulated liquid drug in the recto-uterine pouch is both feasible and important to eliminate liquid accumulation following PIPAC application. Preliminary data gathered in this study suggest that such a recycling process both improves drug distribution and increases penetration levels. However, recycling might also increase the technical complexity of the entire applicational procedure.
Germline genetic testing in ovarian cancer patients: Identifying barriers to care and opportunities for improvement.
Authors: Elizabeth Stock, Matthew Cowan, Iris L Romero, Seiko Diane Yamada
Journal: Journal of Clinical Oncology (2019)

e13142 Background: Despite recommendations that all patients with non-mucinous high grade epithelial ovarian cancer (EOC) undergo germline genetic testing, only 10-15% of patients nationwide are tested. The aim of this study was to determine the rate of genetic testing at a single academic institution, identify patient characteristics associated with undergoing testing and improve delivery of care by identifying barriers to testing. Methods: An IRB-approved single institution ovarian cancer database was used to identify patients with non-mucinous high grade EOC treated between 1996 and 2017. The rate of genetic testing was calculated and the referral and testing process was mapped. Patient demographics, clinical characteristics and family history was obtained from the medical record. Univariate and multivariate logistic regression was performed. Results: From 1996 to 2017, 588 patients were treated for non-mucinous EOC. Of those, 200 patients (34%) were referred for genetic counseling and 175 (30%) were tested. Younger patients were more likely to undergo testing. Fewer African Americans had genetic testing than Caucasians (18% vs 33%, p = 0.003) and patients with public insurance were less likely to undergo testing compared to those with private insurance (23% vs 34%, p = 0.005). Patients with recurrent disease were less likely to undergo testing but rates did not vary by cancer stage or histology. A family history of cancer was the most significant predictor (43% vs 11%, OR = 5.85, p &lt; 0.001). For patients diagnosed in the past 5 years, the testing rate improved to 57.9%. When the referral and testing process was mapped, a complex internal referral system was revealed. Barriers to testing included provider awareness, additional patient visits, patient preference and insurance coverage. Conclusions: Rates of germline genetic testing for patients with ovarian cancer have increased over time as guidelines for genetic testing have evolved, however, over two thirds of patients were not tested and African Americans were less likely to be tested. These findings support increasing provider education and patient counseling, testing directly in the gyn/oncology office and consideration for instituting a Traceback program.
AB1205 BURDEN DISEASE OF OSTEOARTHRITIS IN COLOMBIA, 2015
Authors: Francy Cuervo, Ignacio Angarita, Ana María Santos, Eugenia-Lucia Saldarriaga, Juan Camilo Rueda, Jesús G. Ballesteros, Rodrigo Giraldo, Ingris Peláez-Ballestas, Diana Díaz-Jiménez, Pedro Santos-Moreno, Diana Padilla-Ortiz, Viviana Reyes, Carlos Castañeda-Orjuela, John Londono
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Osteoarthritis (OA) is the most prevalent rheumatic disease in Colombia, as reported by the COPCORD 2015 study. The prevalence is 10.81% (IC 95, 9.68-12.06) (1). <h3>Objectives:</h3> To estimate the disease burden of OA for 2015 <h3>Methods:</h3> A descriptive study was developed. The reference data of the population was taken by DANE (Departamento Administrativo Nacional de Estadística) and the WHO (World Health Organization). It was necessary to develop an algorithm to determine the distribution in percentages of severity levels, according to the GBD definitions. A Markov model was elaborated to calculate the years of life lost due to premature mortality (YLL), years lived with disability (YLD) and Disability-Adjusted Life Year (DALY). <h3>Results:</h3> Figure 1 shows the distribution of cases by age of OA, with the highest frequency of cases over 50 years in both sexes. Figure 2 describes the distribution of the severity levels of the disease, with most cases being moderately severe. The YLLs were 781 and the YLDs were 245,626. Finally, the DALYs calculated were 246,408 for a rate of 752.69 per 100,000. When compared with that reported data by the GBD 2016, the burden of disease for OA was 204 (IC95% 143-278). The results of the present study show that the burden of the disease is higher, and the conditional factor is the YLDs. <h3>Conclusion:</h3> Osteoarthritis is a frequent and disabling rheumatic disease that confers a large burden of rheumatic disease affecting people over 50 years of age. The treatment of OA should be focused on reducing disability and holistic intervention strategies to promote good quality of life. <h3>References</h3> [1] Londono J, Peláez I, Cuervo F, et al. Prevalencia de la enfermedad reumática en Colombia, según estrategia COPCORD-Asociación Colombiana de Reumatología. Estudio de prevalencia de enfermedad reumática en población colombiana mayor de 18 años. Rev Colomb Reum [Internet]. 2018;1–12. Available from: https://doi.org/10.1016/j.rcreu.2018.08.003 <h3>Disclosure of Interests:</h3> Francy Cuervo: None declared, Ignacio Angarita: None declared, Ana María Santos: None declared, Eugenia-Lucia Saldarriaga: None declared, Juan Camilo Rueda: None declared, Jesús G Ballesteros: None declared, Rodrigo Giraldo: None declared, Ingris Peláez-Ballestas: None declared, Diana Díaz-Jiménez: None declared, Pedro Santos-Moreno Grant/research support from: Dr Santos has received research grants from Janssen, Abbvie and UCB, Speakers bureau: Dr Santos has received speaker fees from Sanofi, Lilly, Bristol, Pfizer, Abbvie, Janssen and UCB, Diana Padilla-Ortiz: None declared, Viviana Reyes: None declared, Carlos Castañeda-Orjuela: None declared, John Londono: None declared
PSMA heterogeneity and DNA repair defects in prostate cancer.
Authors: Alec Paschalis, Beshara Sheehan, Ruth Riisnaes, Daniel Nava Rodrigues, Bora Gurel, Claudia Bertan, Ana Ferreira, Maryou B. Lambros, George Seed, Wei Yuan, David Dolling, Jon Welti, Antje Neeb, Semini Sumanasuriya, Pasquale Rescigno, Diletta Bianchini, Nina Tunariu, Suzanne Carreira, Adam Sharp, Johann S. De Bono
Journal: Journal of Clinical Oncology (2019)

5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( &gt; median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expression levels, commonly exhibiting areas without detectable PSMA (CSPC – 100%; mCRPC – 84%), while heterogeneous mPSMA expression between metastases from the same patient was also observed. Subsequent genomic analysis showed that mCRPC patients with deleterious DNA damage repair (DDR) aberrations have higher (p = 0.016) mPSMA expression (87.5 [25.0-247.5]) than those without these (20 [0.3-98.8]). Furthermore, 9 of the 11 patients (82%) responding to PARP inhibition had a mPSMA H-Score above the median. The association between mPSMA expression and DDR aberrations was validated in an independent cohort with known DDR aberrations. Tumors with DDR aberrations had significantly higher mPSMA (ATM 212.5 [136.3-300] p = 0.005; BRCA2 300 [165-300] p = &lt; 0.001) than unselected mCRPC biopsies (55.0 [2.75-117.5]). Finally, analyses of 122 mCRPC biopsy transcriptomes confirmed a negative correlation between PSMA and BRCA2 mRNA expression (p = 1.5x10 -5 ). Conclusions: mPSMA expression in CSPC and mCRPC exhibits marked intra- and inter-patient heterogeneity, limiting the clinical utility of PSMA-targeted theranostics. We show for the first time that DDR gene aberrations associate with high mPSMA expression and may serve as predictive biomarkers for PSMA-targeted therapies.
New understanding in the treatment of cough (NEUROCOUGH) ERS Clinical Research Collaboration: improving care and treatment for patients with cough
Authors: Lorcan McGarvey, Lieven Dupont, Surinder S. Birring, Jeanette Boyd, Kian Fan Chung, Marta Dabrowska, Christian Domingo, Giovanni Fontana, Laurent Guilleminault, Peter Kardos, Eva Millqvist, Alyn H. Morice, Jaclyn A. Smith, Jan Willem van den Berg, Charlotte Van de Kerkhove
Journal: European Respiratory Journal (2019)

<b>The NEUROCOUGH ERS Clinical Research Collaboration brings together clinicians, scientists, patients and industry from Europe and beyond, with a focus on improving care and treatment for patients with chronic cough</b>http://bit.ly/2Q6l0ER