tbuckley/cabot-search huggingface dataset:
Assessment of clinical applications of circulating tumor DNA using an enhanced TAm-Seq platform.
Authors: Vincent Plagnol, Andrew Lawson, Tim Forshew, Abdelaziz Fahem, James Brenton, Davina Gale, Nitzan Rosenfeld
Journal: Journal of Clinical Oncology (2015)

e22057 Background: Novel biomarkers are required to assess tumor burden and response in cancer as conventional biopsies are invasive, costly and only provide a snapshot of the mutational profile at a given time and location. A promising biomarker is the detection of genomic material released from tumors into the blood plasma of patients, known as circulating tumor DNA (ctDNA). ctDNA has been detected in plasma for a wide range of solid tumors and can be distinguished from other (germline) cell-free DNA by the presence of tumor-specific DNA alterations or known hotspot mutations. However, the potential of ctDNA as a biomarker has not yet been fully realized due to technical challenges associated with its detection and analysis, including the short fragment sizes (140-170 bp), small number of amplifiable copies and low/variable allele fractions of ctDNA. Methods: We have developed an enhanced platform for tagged-amplicon deep sequencing (TAm-Seq). Using a combination of improved library preparation and bespoke data analysis methods, this platform can be used to sequence established cancer hotspots and the entire coding regions of selected genes, while preserving high levels of specificity and sensitivity. Results: Using this approach, we have developed an assay that analyzes ~20 kb of the genome (including regions of interest in more than 30 genes) with sensitivity down to a few mutant copies. Performance of this assay has been demonstrated using spike-in experiments, dilution series and clinical sample cohorts. Conclusions: Our proof of concept studies show the potential of ctDNA to be used to assess tumor mutation status, monitor tumor dynamics, assess response to treatment and identify mutations associated with acquired drug resistance and disease progression. This non-invasive approach - a “liquid biopsy” - offers a revolution in how cancer can be detected, monitored and treated.
Activity of subsequent new drugs (NDs) in post-docetaxel (DOC) failure for metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A multicenter Italian experience.
Authors: Orazio Caffo, Umberto Basso, Gaetano Facchini, Donatello Gasparro, Daniele Alesini, Marcello Tucci, Cinzia Ortega, Lucia Fratino, Enrico Campadelli, Giovanni Lo Re, Roberto Sabbatini, Giuseppe Procopio, Paolo A. Zucali, Alessandro D'Angelo, Maddalena Donini, Francesco Massari, Raffaele Ratta, Teodoro Sava, Caterina Messina, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2014)

5089 Background: Abiraterone acetate (AA), cabazitaxel (CABA), and enzalutamide (ENZ) may prolong survival in mCRPC pts progressing after DOC, although it is not clear how to use NDs, to best exploit their efficacy and avoiding their possible cross resistances. We report a large series of pts, receiving 2 NDs (or 3 in a limited series), after DOC progression in routine clinical practice. Methods: All NDs were available in Italy through a compassionate use program, or after the regulatory authorities approval (only CABA in 2012 and AA in 2013). Based on a multi-institutional collaboration, we collected data of pts who received at least 2 NDs after DOC. Results: A consecutive series of 203 mCRPC pts, median age 70 yrs (46-91), with bone (87%), nodal (57%) or visceral (17%) mets, was identified. All received NDs as 2nd and 3rd line after DOC, but 31 also as 4th line. The biochemical response rate (bRR) (PSA ¯ > 50%) was 37% in 2nd line, 17% in 3rd and 6% in 4thline, while the rate of objective response (oRR) was 17%, 16% and 6%, respectively and the median PFS was 6, 4 and 3 mos respectively. The table reports the outcomes of AA, CABA and ENZ according to the sequence adopted. Conclusions: At our knowledge this retrospective study reports the highest number of pts treated post-DOC with at least 2 NDs and it is the first to provide 4th line data. It appears from our findings that similar bRR and oRR are achieved by CABA and ENZ while AA seems less active in 3rd line and that responses in 4th line are rare (only with CABA). 2nd line 3rd line 4th line eval pts bRR (%) oRR (%) median PFS (mos) Sequence eval pts bRR (%) oRR (%) median PFS (mos) eval pts bRR (%) oRR (%) median PFS (mos) AA 114 32 15 7 AA post CABA 44 23 20 4 3 0 0 1 AA post ENZ 8 0 0 3 5 0 0 2 CABA 65 47 24 7 CABA post AA 67 27 16 5 0 - - - CABA post ENZ 16 37 19 4 9 11 11 4 ENZ 24 37 8 4 ENZ post AA 47 36 17 3 4 0 0 4 ENZ post CABA 21 38 19 6 10 0 0 3
Oxaliplatin, irinotecan, and fluorouracil in the prolonged regimen for the Ist-line therapy of metastatic colorectal cancer: New therapy regimen.
Authors: Anna Darenskaya, Natalia Valerievna Dobrova, Mikhail Lichinitser
Journal: Journal of Clinical Oncology (2015)

e14617 Background: Treatment of colorectal cancer patients (CRC, pts) with multiple large metastases is a great challenge. New chemotherapy regimen includes combination of Oxaliplatin, Irinotecan and Fluorouracil in prolonged regimen for the Ist line therapy of CRC. Methods: 18 pts with histologically verified diagnosis (adenocarcinoma) were enrolled in the study. All pts had multiple large metastases in liver and/or lungs. Size of metastases reached 4-10 cm (8 pts) and 10-18 cm (5 pts). Therapy regimen: Oxaliplatin 65 mg/m2, Irinotecan 100 mg/m2, i.v. every 2 weeks, Fluorouracil 200 mg/m2/day, continuous infusion, on days 1-14 with 2 weeks intervals. 102 courses were completed. Average number of courses – 6. Results: Complete (CR) or partial (PR) remission was achieved in 17 (94.4%) of total 18 pts. CR was registered in 3 pts: 2 of them underwent surgery (hemi-hepatectomy) after 5 and 9 therapy courses. Follow up period of CR pts was 22 mon+, 20 mon+, 7 mon+. PR was noted in 14 pts: progression-free period was 6-8 mon in 4 pts and 22 mon in 1 pt; 9 pts continue therapy (4+ - 7+mon). 14 (77.8%) of 18 pts had significant decrease of CEA and CA 19.9. Adverse events were insignificant: grade I peripheral neuropathy – 8.8%, grade II diarrhoea – 5.9%, grade II neutropenia – 4.9%. Conclusions: New therapy regimen was highly effective, objective response was achieved in 94.4% of CRC pts with multiple large metastases. The study is continuing.
Multimodal therapy in patients with node-positive (stage IIIC) uterine papillary serous carcinoma: A National Cancer Database study.
Authors: Jeff Feng-Hsu Lin, Paniti Sukumvanich, Keila Parada, Thomas C. Krivak, Sushil Beriwal, Joseph L. Kelley, Alexander Olawaiye
Journal: Journal of Clinical Oncology (2013)

5585 Background: Uterine papillary serous carcinoma (UPSC) is an aggressive endometrial cancer that carries a 30-40% risk of nodal metastasis. Adjuvant systemic chemotherapy has become standard of care in advanced UPSC, but the role of additional adjuvant radiotherapy is unclear. This study aims to evaluate survival outcomes of multimodal therapy through the use of the National Cancer Data Base (NCDB). Methods: All patients diagnosed with surgically-staged FIGO stage IIIC uterine papillary serous carcinoma were identified in the NCDB from 1/1998 through 12/2010. Patients were divided into those who received chemotherapy only (CT) and both chemotherapy and radiation therapy (CT+RT). Overall survival was estimated using the Kaplan-Meier method. Univariate comparison by log rank test and multivariable analysis by Cox regression modeling were performed to identify and control for prognostic factors. Results: A total of 13,356 cases of uterine cancer were identified, of which 794 were UPSC. Of these patients, 387 underwent lymphadenectomy (median 14 nodes removed) with 75 patients (median age 65) found to have stage IIIC disease. Median follow up is 20.4 (range: 0-114) months. There were no significant differences were found between the RT and CT+RT group with regards to patient demographic, medical comorbidity, treatment facility or disease characteristics. The median overall survival was 23.2 (95% CI 14.5-31.9) and 40.3 (95% CI 31.5-49.1) months, (p&lt;0.05) for the CT and CT+RT groups, respectively. Multivariate analysis controlling for age, race, income, Charlson-Deyo comorbidity index, treatment facility type, year of diagnosis, number of lymph nodes removed, number of positive lymph nodes and tumor size found radiotherapy independently predicted improved survival [HR death 0.024 (95% CI 0.001-0.668)]. Conclusions: Patients with stage IIIC UPSC benefit from adjuvant radiotherapy in addition to adjuvant chemotherapy.
EP-100 + paclitaxel to overcome taxane resistance in patients with recurrent LHRH-receptor expressing ovarian cancer.
Authors: Alpa Manchandia Nick, Renata Urban, Mary E Gordinier, Carola Leuschner, Thomas Rado, Linda M. Bavisotto, John Whisnant, Robert L. Coleman
Journal: Journal of Clinical Oncology (2015)

5582 Background: EP-100 (E) is a synthetic cytolytic peptide conjugated to Luteinizing Hormone Releasing Hormone (LHRH). It targets cells that overexpress LHRH receptors and kills by membrane disruption. Preclinical studies demonstrate synergy between E and paclitaxel (P). This randomized phase 2 trial explored the efficacy, safety and toxicity of E+P in women with advanced ovarian cancer. Methods:
Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System
Authors: M G Della Porta, C H Jackson, E P Alessandrino, M Rossi, A Bacigalupo, M T van Lint, M Bernardi, B Allione, A Bosi, S Guidi, V Santini, L Malcovati, M Ubezio, C Milanesi, E Todisco, M T Voso, P Musto, F Onida, A P Iori, R Cerretti, G Grillo, A Molteni, P Pioltelli, L Borin, E Angelucci, E Oldani, S Sica, C Pascutto, V Ferretti, A Santoro, F Bonifazi, M Cazzola, A Rambaldi
Journal: Leukemia (2017)
25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model
Authors: Chunfeng Li, Yong-Qiang Deng, Shuo Wang, Feng Ma, Roghiyh Aliyari, Xing-Yao Huang, Na-Na Zhang, Momoko Watanabe, Hao-Long Dong, Ping Liu, Xiao-Feng Li, Qing Ye, Min Tian, Shuai Hong, Junwan Fan, Hui Zhao, Lili Li, Neda Vishlaghi, Jessie E. Buth, Connie Au, Ying Liu, Ning Lu, Peishuang Du, F. Xiao-Feng Qin, Bo Zhang, Danyang Gong, Xinghong Dai, Ren Sun, Bennett G. Novitch, Zhiheng Xu, Cheng-Feng Qin, Genhong Cheng
Journal: Immunity (2017)
Comparison of efficacy between irinotecan and paclitaxel monotherapy as second- or third-line chemotherapy after S-1 containing regimen for advanced or recurrent gastric cancer.
Authors: Tetsuya Kusumoto, Eiji Oki, Shoji Hiroshige, Kenkichi Hashimoto, Kousuke Suzuki, Teijiro Hirashita, Toshifumi Matsumoto, Hideya Takeuchi, Hiroshi Matsuura, Yoichi Muto, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2012)

e14722 Background: S-1 is effective and clinically important agent in the initial chemotherapy against advanced or recurrent gastric cancer (ARGC) in Asia. Although several prospective studies on the second-line chemotherapy for ARGC are currently in progress in Japan, the sufficient investigation on the proposition has not been made. We assessed here the clinical efficacy of irinotecan (CPT-11) and paclitaxel (PTX) as the second or thirdline chemotherapeutic agents following the S-1 based treatment, as those has been frequently used in practice. Methods: We conducted the retrospective review of the data of 30 patients with unresectable ARGC who received CPT-11 or PTX monotherapy after administration of S-1 as prior treatment. Each 15 patients were given chemotherapy including CPT-11 and PTX monotherapy treatments, after S-1 containing regimens, as second or third line treatments. The objective response, adverse events, progression-free survival (PFS), and overall survival (OS) were compared between CPT-11 and PTX monotherapy groups. Results: The similar data of the overall response rates (ORRs) were obtained between two groups. Survival data showed that the MST was 329 days and the median PFS was 220 days for the administration of CPT-11, compared with 297 days and 132 days in PTX group from the beginning of these drugs administration, were not significantly different. The OS was 707 days in CPT-11 group, compared with 751 days in PTX group, were not significantly different. Conclusions: There is no order of priority of regimens including CPT-11 or PTX after S-1 containing chemotherapy treatments. We believe that both awareness of the next line chemotherapy and the selection of drugs were important of survival prolongation for patients with ARGC.
PROCAPP: A randomized, open-label phase III trial comparing mapisal and urea hand-foot cream as prophylaxis for capecitabine-induced hand-foot skin reaction (HFSR) in patients (pts) with gastrointestinal (GI) tumors or breast cancer—A study of the AIO Quality of Life Working Group.
Authors: Deniz Gencer, Andreas Schneeweiss, Holger Schulz, Michael Stahl, Susanna Hegewisch-Becker, Luisa Mantovani Loeffler, Ursula Kronawitter, Georg Bolz, Jochen Potenberg, Salah-Eddin Al-Batran, Ralf Hofheinz
Journal: Journal of Clinical Oncology (2014)

9631 Background: HFSR is a frequently occurring dermatologic reaction associated with capecitabine (CAPE). Thus far, no effective prophylaxis has been established, but urea-containing skin ointments are frequently used. Mapisal (medac, Wedel, Germany) is a topically applied ointment with high radical protection factor currently investigated as a prevention strategy against HFSR. It has shown preliminary activity as prophylaxis against HFSR in patients treated with pegylated liposomal doxorubicin. Methods: This randomized phase-III study compared treatment with Mapisal and an urea (10%) containing cream as prophylaxis for HFSR in pts with GI tumors or breast cancer treated with CAPE. The primary endpoint was prevention of HFSR of any grade within 6 weeks based on a standardized patient diary. Pts were randomized in a 1:1 ratio and stratified according to sex and CAPE dose. The study had 80% power to show an absolute 20% reduction of the incidence of overall grade HFSR with Mapisal (30% -> 10%) with a type I error of 5%. Herein, we report on the first preliminary data. Secondary endpoints were time to develope HFSR >grade 1, CAPE dose intensity, and Qol analyses (EORTC QlQ C30 & DLQI). Results: Between 05/12 and 09/13, 160 pts were enrolled. 152 pts are evaluable for the current analysis. Median age was 65 years, 96 pts were female (60.0%). 63 pts had breast cancer (41.4%), 89 pts had GI tumors. In total, 47 / 152 pts experienced HFSR (30.9%). 30 out of 77 pts (39.0%) receiving Mapisal experienced HFSR (grades 1/2/3 [%]: 66.7 / 26.7 / 6.7 of total events). In the urea arm, 17 out of 75 pts (22.7%) reported HFSR (grades 1/2/3 [%]: 52.9 / 41.2 / 5.9). Using Mantel-Haenszel chi-squared test the stratified common odds ratio was 2.365 (95%-CI 1.154 – 4.848; p=0.027). Conclusions: Mapisal failed to show superiority over an urea-containing cream as prophylaxis for CAPE-associated HFSR. The final analysis will be presented at the meeting. Studies on the use of Mapisal as prophylaxis of HFSR in patients receiving pegylated liposomal doxorubicin are ongoing. Clinical trial information: NCT01626781.
Definitive results of a phase II study with carboplatin (CBDCA) plus etoposide (VP16) and sequential topotecan in small cell lung cancer (SCLC). (an INTER-GON trial)
Authors: J. M. Vieitez, C. G. Girón, C. Madroñal, Y. Fernandez, E. Lastras, A. Modolell, J. Fra, C. Julia, J. M. Yglesias, A. J. Lacave
Journal: Journal of Clinical Oncology (2004)

7266 Background: Topotecan is an active agent in SCLC, in first and second line. A better tolerance and a better activity is assumed with the precocious use of this agent, but this philosophy can not been easily applied because of toxicity founded with the association of topotecan and other agents. Methods: In XI/99 a phase ll was initiated with 4 course of CBDCA (300 mg/m2 day 1/3 weeks) plus VP16 (100/m2 days 1, 2, 3/3 weeks) and 3 courses of sequential topotecan. This trial was designed to obtain an additional 20% ORR with topotecan after CBDCA +VP16 in patients in whom CR were not achieved after CBDCA+VP16. Secondary objectives were OR after the 7 cycles of QT, toxicity, and survival. Results: Up to June 2002, 51 patients were included; 27 with extensive disease (ED) and 24 with localised disease(LC); median age was 59 years (range 37–75) and performance status was generally good (median karnosky of 70; range 60–90). Treatment is well tolerated with median nadir of neutrophils, leukocytes and platelets counts of 1000/microgram and 870/microgram, 3400/micgrogram and 2700/microgram and 148000/dL and 103000/dL for CBDCA+VP16 and topotecan respectively. Overall response for topotecan in 38 patients eligible for response was 44% (95% CI, 28–61). Conclusions: additional improvement in the size of the tumor can be obtained with this schedule although median survival do not seems to be improved. No significant financial relationships to disclose.
Efficacy of local treatment in patients with prostate cancer with clinically pelvic lymph node-positive disease at initial diagnosis.
Authors: Firas Abdollah, Thomas Seisen, Malte Vetterlein, Patrick Karabon, Tarun Jindal, Akshay Sood, Luigi Nocera, Paul L. Nguyen, Toni K. Choueiri, Quoc-Dien Trinh, Mani Menon
Journal: Journal of Clinical Oncology (2017)

164 Background: There is limited evidence supporting the use of local treatment (LT) for prostate cancer (PCa) patients with clinically pelvic lymph node-positive (cN1) disease. Against this backdrop, we sought to examine the efficacy of any form of LT+/-androgen deprivation therapy (ADT) in treating these individuals. Methods: Within the National Cancer Data Base (2004-2012), we identified 2,967 individuals who received LT+/-ADT vs. ADT alone for cN1 PCa. Only radical prostatectomy (RP) and radiation therapy (RT) were considered as definitive LT. Instrumental variable analyses (IVA) were performed using a two-stage residual inclusion approach to compare overall mortality-free survival between patients who were treated with LT+/-ADT vs. ADT alone. The same methodology was used to further compare overall mortality-free survival between patients who were treated with RP+/-ADT vs. RT+/-ADT. Results: Overall, 1,987 (67.0%) and 980 (33.0%) patients received LT+/-ADT and ADT alone, respectively. In the LT+/-ADT group, 751 (37.8%) and 1,236 (62.2%) patients received RP+/-ADT and RT+/-ADT, respectively. In IVA, LT+/-ADT was associated with a significant overall mortality-free survival benefit (HR = 0.31; 95% CI = [0.13-0.74]; P= 0.007), when compared to ADT alone. At 5-year, overall mortality-free survival was 78.8% (95% CI: 74.1%-83.9%) vs. 49.2% (95% CI: 33.9%-71.4%) in the LT+/-ADT vs. ADT alone groups. When comparing RP+/-ADT vs. RT+/-ADT, IVA showed no significant difference in survival between the two treatment modalities (HR = 0.54; 95% CI = [0.19-1.52]; P= 0.24). Conclusions: Our study shows a significant overall mortality-free survival benefit for cN1 PCa patients who were treated with LT+/-ADT as compared to their counterparts treated with ADT alone. Conversely, no significant survival difference was observed between patients treated with RP+/-ADT vs. RT+/-ADT.
An analysis of the prevalence of <i>HER2</i> and <i>KRAS</i> mutations, and ALK rearrangements and clinical outcomes in Cancer and Leukemia Group B [CALGB (Alliance)] trial 30406 in advanced non-small cell lung cancer (NSCLC).
Authors: Tom Stinchcombe, Lynette M. Sholl, Xiaofei F. Wang, Lin Gu, Mark A. Socinski, Scott J. Rodig, Marzia Capelletti, Jeffrey Crawford, Martin J. Edelman, Miguel Angel Villalona-Calero, Robert Arthur Kratzke, Everett E. Vokes, Vincent A. Miller, Pasi Antero Janne
Journal: Journal of Clinical Oncology (2013)

8039 Background: CALGB (Alliance) 30406 was a randomized phase II trial that investigated erlotinib alone or in combination with carboplatin and paclitaxel in patients (pts) with a never or light smoking history with advanced NSCLC. Tissue collection was mandatory. Methods: Between August 2005 and April 2009 188 pts were enrolled. Tumor specimens were assessed using ALK immunohistiochemistry (IHC; clone D5F3; Cell Signaling); KRAS and HER2 mutations were tested. Results: The rate of mutations was: KRAS 10% (17/164), HER2 2% (3/164), and ALK + 7% (8/114). Given the small numbers of KRAS, HER2 and ALK positives, the analysis combines data from both arms. Pts with ALK + compared to ALK- NSCLC had an inferior ORR and PFS (Table). No statistically significant differences in ORR, PFS, OS between pts with KRAS or HER2 mutant and wild-type NSCLC were observed. In multivariate analysis pts with ALK+ compared to ALK- tumors experienced a statistically significant worse PFS (HR=2.67, p=0.0114) but not OS (HR=1.48, p=0.3217). One pt was identified as having an EGFR exon 21 mutation and ALK +; the pt experienced a best response of progressive disease, a PFS of 2.9 months, and OS of 17.4 months. Conclusions: (1) Pts with ALK+ compared to ALK- NSCLC have a lower ORR, worse PFS, but not OS with erlotinib alone or with carboplatin and paclitaxel. (2) The prevalence ALK+, KRAS and HER2 mutations observed was 7%, 10% and 2%, respectively. Clinical trial information: 00126581. [Table: see text]
CGH array and matching gene expression profiling for identification of distinct molecular variants among type II papillary renal cell carcinomas.
Authors: Laurence Albiges, Nathalie Auger, Audrey Le Formal, Gregory Verhoest, Marc Olivier Timsit, Alain Ravaud, Yann Neuzillet, Herve Baumert, Laurent Salomon, Sophie Couve, Cedric Orear, Guillaume Meurice, Jean Jacques Patard, Sophie GAD, Toni K. Choueiri, Bernard J. Escudier
Journal: Journal of Clinical Oncology (2014)

4527 Background: Type II papillary renal cell carcinoma (pRCC) is a heterogeneous entity with poor prognosis. Limited biological data are available to date. Methods: 220 frozen pRCC were collected through French RCC Network, quality controlled for percentage of malignant cells >70% and subsequently RNA and DNA extraction were performed. Gene expression data generated with human whole genome Agilent 8x60K arrays was assessed on 98 pRCC, including, 45 type II pRCC. Copy number alterations were analysed using Agilent Human 2x400K or 4x180 on 37 type II pRCC. Results: Using gene expression profiling (GEP), we identified two distinct subgroups of type II pRCC that were associated with distinct pathological features: group A included tumors with higher grade, higher stage and more lymph nodes involvement (p<0.05) pRCC than group B harboring more favorable features. CGH array analysis of tumors clustering in GEP groups A vs B identified distinct patterns of copy number alterations (Group A: -1p, -11, +12, -15, Group B: +2, +5, +20). More interestingly, CDKN2A/2B (9p) loss was more likely to be observed in group A tumors 19% vs. 8% in group B tumors, in line with previous report of 9p loss to be associated with a dismal prognosis in pRCC (Klatte 2009). Four cases out of 37 (11%) presented chromothripsis (catastrophic genome rearrangements). This incidence is higher than in other solid tumors reports (<2%). Chromothripsis previously reported in neuroblastoma, melanoma, myeloma and acute myeloid leukaemia has been strongly linked to poor survival and therefore its diagnosis has potential to aid prognosis and stratification in pRCC. Conclusions: We report the first cohort of type II pRCC assessed by copy number analysis and matching gene expression profiling in type II pRCC. Gene expression profiling identifies two subgroups among type II pRCC. CDKN2A/2B loss as well as chromothripsis events appear as recurrent mechanism in the biology of type II pRCC.