bluuebunny/crossref_metadata_2025_split huggingface dataset:
Next-generation sequencing (NGS) of serum microRNA in hepatocellular carcinoma (HCC) patients treated with sorafenib and an mTOR inhibitor.
Authors: Kelley Robin Kate , Chang Aaron N. , Anguiano Esperanza , Hwang Jimmy , Stoppler Hubert J. , McWhirter Ryan M. , Parks Anna L. , Hameed Bilal , Fix Oren K. , Wayne Elizabeth M. , Nimeiri Halla Sayed , Munster Pamela N. , Venook Alan Paul , Goga Andrei 
Published: February 2017

LBA204 Background: Noninvasive biomarkers are urgently needed in HCC. MicroRNA (miRNA) are small, noncoding RNA that regulate mRNA expression and are detectable in tumor tissue and extracellular compartments. miRNA signatures in blood specimens show association with HCC diagnosis but have not been explored as pharmacodynamic or predictive biomarkers. We present a pilot study to identify differentially expressed miRNA using NGS on serum from HCC patients at baseline and on targeted therapy, compared to controls. Methods: Serum samples were obtained from HCC patients enrolled on a clinical trial of sorafenib plus temsirolimus. Control sera were obtained from patients with non-malignant liver diseases (NMLD) and healthy volunteers (HV). Total RNA was extracted using RNAzol followed by library construction for each sample. Small RNA were separated by gel purification and sequenced by Illumina HiSeq 2500 at 5M+ reads per sample. Raw sequencing reads were mapped using Novoalign and quantified. Counts were normalized using an exogenous spike-in miRNA. Comparisons between HCC vs. control and baseline vs. on treatment cohorts were performed by linear regression (one-way ANOVA) and multiple-test corrected using Benjamini-Hochberg statistics. Candidate signature miRNA were derived using fold change, p-value, and abundance cutoffs. Results: Cohorts: HCC baseline (n=23) and paired on treatment (n=20), NMLD (n=12), and HV (n=10). HCC cohort: HBV+/dual 40%, HCV+ 32%. NMLD cohort: HCV+ 83%. Median RNA yield/200 µL was 410 ng (range: 69-1066) for HCC, 406 ng (range: 224-1100) for NMLD. The mapping rate ranged from 10-70%. Elevated AFP was associated with up-regulated miRNA identified in TCGA HCC cases, including miR-10a/b. No significant differences were observed for HBV+ vs. HCV+. Multiple oncomiRs appeared downregulated on treatment including Let-7 and miR-17/92 family members. Some miRNA isoforms were differentially regulated in each cohort. Conclusions: Serum miRNA in HCC patients demonstrate changes on treatment and can be characterized by NGS. Certain miRNA implicated in HCC appeared related to clinical covariates and warrant further study as novel biomarkers.
Multimodality treatment of colorectal peritoneal metastasis with perioperative systemic chemotherapy, cytoreductive surgery (CRS), and HIPEC: First safety results of the COMBATAC trial.
Authors: Piso Pompiliu , Koller Michael , Arnold Dirk , Schlitt Hans J. , Glockzin Gabriel 
Published: February 2017

LBA382 Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising therapeutic option as part of an interdisciplinary multimodal treatment regimen for selected patients with peritoneal metastasis arising from colorectal cancer. The COMBATAC trial evaluates the feasibility, safety, and efficacy of perioperative cetuximab-containing systemic polychemotherapy, CRS and bidirectional oxaliplatin-based HIPEC. Methods: The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial recruiting patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal metastasis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Results: Preliminary data of the first 16 documented patients show a total number of 51 adverse events. According to CTCAE v4 the distribution of AE was 23 grade 1, 14 grade 2, 13 grade 3, and one grade 4, respectively. Of the 14 grade 3/4 adverse events three were chemotherapy-related, four surgery-related, and seven not directly treatment-related. Most common grade 3/4 complications were infection, thrombosis, and urinary tract obstruction. Conclusions: First data indicate that perioperative systemic polychemotherapy including cetuximab in combination with CRS and bidirectional HIPEC is feasible and might not lead to increased morbidity and toxicity rates. Nevertheless, the COMBATAC trial is still recruiting, and data regarding progression-free survival (PFS) and overall survival (OS) is not yet available. Clinical trial information: NCT01540344.
Final results and subgroup analyses of the phase 3 CAIRO3 study: Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC).
Authors: Koopman Miriam , Simkens Lieke , May Anne , Mol Linda , van Tinteren Harm , Punt Cornelis J. A. ,   on behalf of the CAIRO3 Study Group
Published: February 2017

LBA388 Background: The optimal duration of chemotherapy and bevacizumab (bev) in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine (cap) + bev versus observation in mCRC patients (pts) not progressing during induction treatment with cap, oxaliplatin, and bev (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after six cycles of CAPOX-B were randomized between observation (arm A) or maintenance treatment with cap 625 mg/m2 bid daily continuously + bev 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were to be treated with CAPOX-B until 2nd progression (PFS2, primary endpoint). Secondary endpoints were overall survival (OS) and time to 2nd progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1, and quality of life. Preplanned subsetanalyses were performed. Results: A total of 558 pts were randomized. Median follow-up is 48 months. Upon PFS1, CAPOX-B was reintroduced in 61% of pts in arm A and 48% in arm B. Multivariable analyses for survival, with treatment adjusted for a series of pre-specified potentially confounding factors at baseline showed significant interactions for treatment (observation vs. maintenance) with resection of the primary tumor (yes vs. no) and synchronous or metachronous metastases at baseline (p values for interaction <0.0001). Especially pts with synchronous metastases with resected primary tumor (n=180) appear to benefit from maintenance treatment; median OS 18.0 months (observation arm) vs. 25.0 months (maintenance arm) (log-rank p value: <0.0001). Conclusions: Multivariable analysis showed significant interaction of treatment with some baseline covariates which were not equally distributed among both arms. The positive effect on survival for maintenance treatment with cap + bev is most obvious in pts with synchronous disease in whom the primary tumor was resected. Further details and final results on survival will be presented at the meeting. Clinical trial information: NCT00442637.
FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Brodowicz Thomas , Vrbanec Damir , Kaczirek Klaus , Ciuleanu Tudor-Eliade , Knittelfelder Regina , Lindner Elisabeth , Messinger Diethelm , Zielinski Christoph , Streubel Berthold 
Published: February 2017

LBA391^ Background: Efficacy and safety of first-line FOLFOX4 plus either cetuximab (weekly or every two weeks) have been reported to be similar in 152 patients with KRAS exon 2 wt mCRC within the randomized phase II CECOG/CORE2 study. Recent analyses have shown that also mutations in KRAS exons 3/4 and NRAS (exons 2, 3, and 4) are associated with an inferior PFS and OS with EGFR-targeted monoclonal antibody containing therapy. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study were investigated. Methods: Tumor samples of 148 randomized KRAS exon 2 wild-type metastatic colorectal cancer patients were available for testing of additional mutations by conventional Sanger sequencing. Objective response rate (ORR), PFS and OS were compared in patients with KRAS (exons 2, 3, and 4) and NRAS (exons 2, 3, and 4) wild-type tumors [RAS wt] versus patients with mutations in KRAS (exons 3 and 4) or NRAS (exons 2, 3 and 4) [RAS mt]. Patients with BRAF mutations were excluded from this comparison. The Cochran-Mantel-Haenszel procedure was used to compare the ORR. Kaplan-Meier methods, log-rank test and Cox proportional hazard methods were used to analyze PFS and OS. Results: Of the 148 KRAS exon 2 wt patients 124 patients had RAS and BRAF wt tumors, 10 patients had RAS mutations only and 14 had only BRAF mutations. In the RAS wt and the RAS mt groups ORR was 61.3% (95% CI 52.1-69.9) and 40% (95%CI 12.2-73.8), (Odds ratio 0.43, p=0.1966). Median PFS was 9.7 months (95% CI 8.9-11.2) versus 7.2 months (95% CI 6.7-10.8) (hazard ratio HR=0.56, p=0.1135). Median OS was 28.5 months (95% CI 24.0-31.3) versus 16.3 months (95% CI 15.9-20.7), (HR=0.43, p=0.0199). The difference in OS remained statistically significant in the Cox model, if adjusted for significant confounding factors. ORR, PFS, and OS in BRAF mt and RAS mt patients were similar. Conclusions: RAS wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to RAS mt patients. This analysis supports the findings of other trials that RAS mutational analyses in metastatic CRC disease is recommended prior to initiation of an EGFR-targeted monoclonal antibody therapy. Clinical trial information: NCT00479752.
Final results of the Montpellier prostate cancer intensity modulated radiotherapy pilot study.
Authors: Charissoux Marie , Fenoglietto Pascal , Ailleres Norbert , Thézenas Simon , Rebillard Xavier , Llacer Moscardo Carmen , Thuret Rodolphe , Hay Meng Huor , Segui Bruno , Faix Antoine , Dubois Jean-Bernard , Azria David 
Published: February 2017

105 Background: Thirteen hundred prostate cancer patients have been treated with Intensity modulated radiotherapy (IMRT) since 2001. We present the final results of the pilot study concerning the first 373 patients with a median follow-up of 72.7 months (range 0 to 130). Methods: All patients received the entire treatment course to a prescribed total dose of 80 Gy. No pelvic irradiation was applied. Androgen ablation therapy was delivered for 6 months and 2 to 3 years in intermediate and high-risk patients, respectively (n=142, 38%). Prostate-specific antigen (PSA) failure was defined as nadir + 2. Toxicity was assessed according to the National Cancer Institute (NCI)/Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Multivariate analysis using the Cox model was performed to assess factors that may impact on PSA relapse. Logistic regression was used to correlate clinical and physical parameters with grade 2 or higher gastro-intestinal and genitourinary toxicities. Results: Median age was 69 (range 40 to 81). One hundred thirty nine (37.3%), 167 (44.8%), and 67 (18%) patients were classified as low (group 1), intermediate (group 2), and high-risk (group 3) patients, respectively. The 5 year biochemical relapse-free survival (5y-biochemical recurrence-free survival [bRFS]) was 85.7% (95% CI, 0.81-0.89). For the three prognostic groups, 5y-bRFS was 91% (95% CI, 0.85-0.95), 82% (95% CI, 0.75-0.87), and 80% (95% CI, 0.67-0.88) for groups 1, 2, and 3, respectively. Multivariate analysis showed that the absence of hormonotherapy in the group 2 and the number of positive biopsies impact on PSA relapse (p=0.04, HR 1.8 and p=0.01, HR 2.13, respectively). The incidence of late grade 2 or higher rectal and urinary toxicities were 10.5% and 12.7%, respectively. The dose received by 50% (D50) of the rectum was the only factor significantly correlated with late grade 2 or higher rectal toxicities (p = 0.04). Similarly, the dose received by 50% (D50) of the bladder was the only factor significantly correlated with late grade 2 or higher bladder side-effects (p = 0.02). Conclusions: IMRT to 80 Gy can provide good to excellent carcinologic results and low late toxicity rates in all prostate cancer subgroups. Hormonotherapy combined to high dose IMRT seems to be a serious option to consider in intermediate-risk patients. Clinical trial information: ICM 2001-13.
Molecular profiling of advanced refractory prostate cancer.
Authors: Feldman Rebecca A. , Basu Gargi Dan , Xiu Joanne , Arguello David , Millis Sherri Z. , Bender Ryan , Gatalica Zoran , Paul Les , Myers Charles E. 
Published: February 2017

107 Background: Prostate cancer is the second leading cause of cancer-related death among men in the U.S. Forty percent of men diagnosed will develop metastatic disease, which has few treatment options. We aim to describe the molecular profile of prostate cancer tumors and potential for novel therapeutic options. Methods: We reviewed profiling data of over 330 patients from a large referral laboratory (Caris Life Sciences, Phoenix, AZ) for biomarkers of drug response. Multiple methodologies were employed: sequencing (NGS, Sanger, pyrosequencing), in-situ hybridization (fluorescent and chromogenic), and immunohistochemistry. Results: High expression was observed for AR, MRP1, TOPO1, TLE3 and EGFR, with positivity rates of 89%, 87%, 63%, 48%, and 47%, respectively. Low expression was observed for TS, PGP, TUBB3, RRM1, PTEN and MGMT, with negativity rates of 94%, 87%, 75%, 69%, 54%, and 45%, respectively. Gene copy number increases for EGFR and cMYC were observed in 13% of patients. Sequencing data showed a 48% mutation rate for TP53, 18% for PTEN, 9% for CTNNB1, 8% for PIK3CA, 5% for RB1, ATM, and cMET, and approximately 2% for K/HRAS, ERBB4, ALK, BRAF, and cKIT. Targeted therapy options include imatinib for patients with high cKIT or PDGFRA (9 to 10%) and cetuximab for patients with EGFR positivity (13 to 47%). Promising agents may be considered, including cabozantinib, based on 4% of cohort with cMET aberrations or PAM pathway inhibitors (BEZ234, everolimus) based on approximately 30% of cohort with PIK3CA pathway activation. Lastly, HDAC inhibitors have recently been linked to cMYC driven cancers (13% amplified). 5-FU, gemcitabine, and temozolomide chemotherapies may be options, as approximately 70% of cohort with low TS, RRM1, or MGMT. Biomarker guidance for common prostate cancer drugs such as cabazitaxel is also provided, based on approximately 70% of cohort with low TUBB3 or PGP, or high TLE3. Also, continued dependence on androgen signaling is exhibited by 89% of cohort with high AR, indicating potential utility of anti-androgen agents like enzalutamide. Conclusions: Tumor profiling identified small subsets of patients that may benefit from targeted agents approved for other solid tumors (imatinib, cetuximab), promising therapies in clinical trials (cabozantinib) or agents not routinely used for prostate cancer (gemcitabine).
Patient-reported outcomes using a validated LENT-SOMA questionnaire for post-prostatectomy radiotherapy.
Authors: Choudhury Ananya , Agarwal Arjun , Swindell Ric , Tran Anna , Alam Nooreen Sarah , Coyle Catherine , Livsey Jacqueline E. , Wylie James , Logue John P. , Elliot Tony 
Published: February 2017

118 Background: Although local post-operative radiotherapy (RT) improves biochemical progression free survival, there is no evidence of overall survival benefit. With a trend for radical prostatectomy (RP) and radiotherapy for more advanced disease, the debate continues about the merits of multimodality treatment in these patients and the importance of survivorship. We assessed prospectively the effect of combination surgery and radiotherapy on the long term outcomes of patients. Methods: A validated LENT-SOMA (LS) questionnaire was posted to 238 UK patients treated from 2004 to 2009 with post-RP RT to assess patient-reported outcomes after prostate cancer treatment. Patients were treated with hypofractionated 3D conformal RT using image guidance delivering 52.5Gy in 20 fractions over 28 days to the prostate bed, but not to whole pelvis. LS responses were compared with patient perception of their bowel, bladder and sexual function post-RP. Results: Median follow up from RT was 6.26 years. Fifty five percent (130 out of 238) of patients returned questionnaires. Median maximum LS scores for bladder and bowel were three with over 75% of patients reporting at least one occasion of bowel or bladder difficulty in the past month. There was no difference in mean LS scores when compared pre and post RT. No patients had grade 3/4 RTOG toxicities. The median maximum LS score for sexual function was four. There was a significant difference in mean LS scores for sexual function (p=0.001) when compared pre and post radiotherapy. LS scores were not affected by post-RT hormones (26 out of 130 patients) or the time between RP and RT (median 1.76 years). Conclusions: The validated LS questionnaires revealed changes in sexual function post-RT compared with pre-RT were greater than bowel or bladder function. It remains difficult to determine the relative contributions of RP and RT to the late toxicity of multimodality treatment. Ongoing large multi-centre randomised control trials such as the UK-led RADICALS trial will answer questions about timing of RT and need for additional hormones. With the increasing importance of survivorship, it should be noted that prostate-specific antigen control at the expense of toxicity without an overall survival advantage should be treated with caution.
Long-term treatment with testosterone undecanoate injections and its effect of prostate cancer incidence in hypogonadal men.
Authors: Haider Ahmad , Zitzmann Michael , Yassin Aksam 
Published: February 2017

119 Background: Concerns regarding the safety of testosterone treatment, particularly regarding prostate cancer in elderly men, still hamper the use of testosterone in hypogonadal men. Methods: Registry studies of 942 men with testosterone levels less than or equal to 12.1 nmol/L from three German centers. Patients received testosterone undecanoate for up to 16 years. Results: In cohort A (mean age: 57.70 ± 6.76 years; Bremerhaven), prostate-specific antigen (PSA) increased from 1.77±0.97 to 2.0±1.01 ng/ml (p=0.0021). Prostate volume increased from 28.34±10.79 to 30.72±14.28 ml (p<0.0001). Five out of 300 patients were diagnosed with prostate cancer. The proportion was 1.7% with an incidence of 39.4 per 10,000 patient-years. In cohort B (mean age: 59.53 ± 8.35 years; Norderstedt), PSA increased from 0.86±0.57 to 1.38±0.49 ng/ml (p<0.0001). Prostate volume increased from 27.9±8.15 to 36.98±7.22 ml (p<0.0001). Six out of 261 patients were diagnosed with prostate cancer. The proportion was 2.3% with an incidence of 54.5 per 10,000 patient-years. One patient in cohort B was treated with external beam radiation, all other patients underwent radical prostatectomy. In cohort C (mean age: 42.6 ± 13.4 years; Muenster), PSA increased from 1.6±0.4 to 1.9±0.4 (p<0.001). Prostate volume increased from 16.9±5.1 to 19.9±5.3 ml (p<0.001). No patient was diagnosed with prostate cancer. Conclusions: The PLCO trial reported an incidence of 116 per 10,000 patient-years (Andriole, NEJM 360(13):1310-9), the ERSPC trial 96.6 (Schröder, NEJM 366(11):981-90). Although these screening trials cannot be directly compared to our registries of hypogonadal men receiving testosterone replacement therapy, the incidence of prostate cancer in our registry studies does not suggest an increased risk in hypogonadal men on long-term testosterone treatment.
Molecular and genomic characterization of invasive circulating tumor cells (iCTCs) from men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Friedlander Terence W. , Premasekharan Gayatri , Ngo Vy , Doty Shaun , Harris Anna , Winter Michael , Gilbert Elizabeth , Craik Charles , Paris Pamela 
Published: February 2017

120 Background: Identification, enumeration, and genomic analysis of circulating tumor cells (CTCs) may allow for a better understanding of the mechanisms of resistance to therapies in metastatic castration-resistant prostate cancer (mCRPC). The Vitatex VitaAssay platform captures invasive CTCs (iCTCs) in a cell surface marker-independent fashion based on their ability to invade a fluorescently-labeled cell-adhesion matrix (CAM), allowing for the analysis of multiple CTC subpopulations. Here we sought to estimate epithelial, mesenchymal, and stem-like iCTC subpopulation diversity in men with CRPC starting abiraterone acetate therapy, to compare the genomic profiles of iCTCs to matched metastatic biopsies, and to explore the potential for 2D and 3D CTC culture. Methods: iCTCs were isolated from men with mCRPC using the CAM platform, and paired metastatic biopsies were performed. iCTCs were defined as CAM+/CD45-/CD14-/DAPI+, mesenchymal iCTCs as vimentin+/CAM+/CD45-/CD14-/DAPI+, and stem-like iCTCs as CD44+/CAM+/CD45-/CD14-/DAPI+. iCTCs were enumerated and purified using FACS. Agilent array comparative genomic hybridization (aCGH) of iCTCs and paired biopsies was performed, and to explore the potential for ex-vivo cell expansion and spheroid formation, iCTCs were cultured separately in CAM and in matrigel for up to 10 days. Results: iCTCs were isolated using the CAM platform from 29 men, of whom seven have undergone paired metastatic biopsy. The median pre-FACS purity was 1.06% (range 0.11%-10.16%). Post-FACS purity was increased to greater than 90%, and a median of 60 (range 2 to 1,314) iCTCs/7.5ml were detected by FACS. Both vimentin+ and CD44+ iCTCs are detectable, and compromise between 10 to 50% of total iCTCs. iCTC aCGH profiles resemble paired soft tissue biopsy, in vitro iCTCs culture is feasible, and iCTC spheroids were observed. Conclusions: Multiple CRPC iCTC subpopulations are identifiable from men starting abiraterone therapy, and cell sorting techniques increase iCTC purity. iCTCs resemble metastatic CRPC tissue and can be expanded in culture. Further enumeration, genomic profiling, and clinical correlation of paired iCTCs taken from men with abiraterone-resistant CRPC is underway, and may shed light on mechanisms of abiraterone resistance.