bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of increased time from chemoradiation to surgery on the pathologic complete response rate in patients with esophageal cancer.
Authors: Shaikh Talha , Ruth Karen , Scott Walter Joseph , Burtness Barbara , Cohen Steven J. , Konski Andre A. , Cooper Harry S , Astsaturov Igor A. , Meyer Joshua E. 
Published: February 2017

84 Background: Studies have demonstrated that pathologic complete response (pCR) in patients undergoing tri-modality treatment for esophageal cancer predicts for decreased local and distant recurrence, as well as increased survival. Increased time from chemoradiation (CRT) to surgery has been shown to increase pCR rates in rectal cancer. This study assessed the effect of the time between the end of CRT and surgery on pCR rates in esophageal cancer. Methods: Clinical records identified 231 patients with resectable esophageal cancer who were treated with CRT from 2000 to 2011, of which 89 underwent subsequent surgery. The records were analyzed for predictors of pCR. Univariate and multivariable analyses were used to determine the significance of all predictors of pCR. Results: Of 89 patients completing trimodality therapy, 76 were male, and the median age was 61 years (range=36-80). Adenocarcinomas comprised 75 patients, and 14 were squamous cell carcinomas. Nine patients had T1/T2 lesions and 80 patients had T3/T4 lesions; 68 patients had node positive tumors. 72 patients received 5FU-based therapy and 17 patients received carboplatin-based therapy. The median radiation dose was 5040 cGy (720-6000) and median follow-up was 24 months. Overall, pCR was seen in 21 patients (24%). The median time from CRT to surgery for a pCR was 102 days vs. 87 days for less than a pCR (p=0.06). By quartile of time from CRT to surgery, pCRs were 18% for <81 days, 13% for 81-88 days, 18% for 89-102 days, and 45% for 103+ days (p=0.05). Multivariable logistic regression showed a trend towards a difference in pCR rates by interval quartile (p=0.06); OR for the highest vs lowest quartile was 5.3 (95% CI=1.1 to 25.6). T stage, N stage, histology, radiation dose and type of chemotherapy were not predictive of a pCR. Conclusions: In this retrospective study, increased time between CRT and surgery was associated with a trend toward increased pCR rates; patients in the longest interval quartile (103+ days) had more pCRs than patients in the shortest interval quartile (<81 days). These data suggest further evaluation of time from CRT to surgery is warranted.
Infectious complication and recurrence after surgery for gastric cancer.
Authors: Hayashi Tsutomu , Tsuburaya Akira , Yoshikawa Takaki , Cho Haruhiko , Ogata Takashi , Aoyama Toru 
Published: February 2017

85 Background: There are many known prognostic indicators following surgery for gastric cancer. However, the impact of infectious complication on prognosis is less clear. The aim of the present study was to evaluate the relationship between infectious complication and relapse-free survival in patients undergoing potentially curative resection of gastric cancer. Methods: A consecutive series of 657 patients who underwent macroscopically curative resection between 2000 and 2005 in Kanagawa Cancer Center were retrospectively studied. Five-year relapse-free survival rates in each stages (TNM7th) were calculated. Infectious complications (≥Grage2 by Clavien-Dindo classification) were classified as pneumonia, anastomotic leakage, intra-abdominal abscess, septicaemia, colitis, pancreatic-fistula, and wound infection. Results: Mean age was 61 years; male-female ration was 4:1; the number of patients in TNM7th stages were I :389, II :93, III :116, and IV :59. Infectious complications occurred in 57 patients (8.7%) including 8.5% in stage I, 3.2% in stage II, 12.1% in stage III, and 11.9% in stage IV, respectively. Five-year relapse-free survival rates in patients without infectious complications and with infectious complications were 93.1% vs 81.6% in stage I, 84.4% and 100% in stage II, 55.8% and 28.6% in stage III, and 9% and 0% in stage IV, respectively. In stage III, patients with infectious complication had significantly poorer outcome in relapse-free survival compared with those without one (p<0.05). Conclusions: This study indicates a correlation between infectious complications and cancer recurrence in advanced but localized gastric cancer. Immunologic response of the host against postoperative infection could influence the viability of microscopic residual disease. Further clinical and basic study are needed to improve outcome for this category of patients.
Post-radiation metabolic tumor volume (MTV) and survival in esophageal cancer.
Authors: Cruz Alex , Chuong Michael D. , Weber Jill M. , Eikman Edward , Lomas Harry , Pimiento Jose Mario , Almhanna Khaldoun , Shridhar Ravi , Hoffe Sarah E. , Meredith Ken 
Published: February 2017

9 Background: PET-CT is an important tool for staging and evaluating treatment response in esophageal cancer. Metabolic tumor volume (MTV) has been reported as a prognostic factor in other malignancies. We evaluated the utility of post-radiation MTV in esophageal cancer patients treated with chemoradiotherapy (CRT). Methods: We evaluated pre- and post-treatment PET/CT scans in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC) treated with neoadjuvant/definitive intent. We measured the significance of the post-treatment MTV2.0-5.0 which was defined as the metabolic volume above a threshold SUV of x. Cox regression models were used to determine any significance between MTV2.0 -5.0 and disease free survival (DFS) or overall survival (OS). Multivariate analysis was performed. Results: We identified 63 patients (13 SCC, 50 AC) with a median follow-up of 12.0 months (range, 1.9-38.6). The median time to post-radiation PET/CT scan after completion of CRT was 40.1 days (range, 20-93). Thirty-seven (58.7%) patients underwent surgical resection. Univariate analysis revealed no significant correlation between post-treatment MTV and OS (MTV2.0 p = 0.968; MTV3.0 p = 0.945; MTV4.0 p = 0.890; MTV5.0 p = 0.316). There was also no significant correlation with respect to DFS (MTV2.0 p = 0.956; MTV3.0 p = 0.658; MTV4.0 p = 0.695; MTV5.0 p = 0.690). Multivariate analysis revealed that SCC histology and surgical resection were associated with improved OS while age, gender, post-radiation MTV2.0-5.0, and stage were not. Earlier stage and surgical resection were associated with improved DFS while post-radiation MTV2.0-5.0, age, gender, and histology were not. Conclusions: Although other studies have shown post-radiation MTV to be a significant prognostic factor, our data demonstrate no significant correlation with MTV and survival among esophageal cancer patients.
Phase III trial of everolimus (EVE) in previously treated patients with advanced gastric cancer (AGC): GRANITE-1.
Authors: Van Cutsem Eric , Yeh Kun-Huei , Bang Yung-Jue , Shen Lin , Ajani Jaffer A. , Bai Yu-Xian , Chung Hyun Cheol , Pan Hong-Ming , Chin Keisho , Muro Kei , Kim Yeul Hong , Smith Heind , Costantini Chiara , Musalli Sara , Rizvi Syed , Sahmoud Tarek , Ohtsu Atsushi 
Published: February 2017

LBA3 Background: The prognosis for patients with AGC after failure of first-line chemotherapy is poor. Currently, there is no level 1 evidence established for second-line treatment. EVE inhibits the PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, metabolism, and angiogenesis, and has shown efficacy against AGC in preclinical and phase I/II studies. Methods: In a randomized, double-blind, multicenter, phase III study, patients age ≥18 years with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to oral EVE 10 mg/d plus best supportive care (BSC) or placebo (PBO) plus BSC. Randomization was stratified by region (Asia vs rest of world) and previous lines of chemotherapy (1 vs 2). Study drug was discontinued upon progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), and safety. The final analysis was performed when 526 deaths occurred. Results: A total of 656 patients from 23 countries were enrolled from Jul 2009 to Dec 2010; 439 were randomized to EVE, 217 to PBO. Baseline characteristics were well balanced between arms; 73.6% were men, 55.3% were enrolled in Asia, 47.7% received 1 previous line of chemotherapy, and 50.6% had a gastrectomy. Median OS was 5.39 months with EVE vs 4.34 months with PBO (HR, 0.90; 95% CI, 0.75-1.08; P=0.1244). Median PFS per local investigator assessment was 1.68 months with EVE vs 1.41 months with PBO (HR, 0.66; 95% CI, 0.56-0.78; p<0.0001). Six-month PFS estimates were 12.0% with EVE and 4.3% with PBO. OS and PFS results were consistent across the various subgroups. ORR (95% CI) was 4.5% (2.6%-7.1%) with EVE vs 2.1% (0.6%-5.3%) with PBO. The most common grade 3/4 adverse events were anemia (16.0% with EVE vs 12.6% with PBO), decreased appetite (11.0% vs 5.6%), and fatigue (7.8% vs 5.1%). Conclusions: EVE monotherapy did not significantly improve OS in patients with AGC previously treated with 1 or 2 lines of systemic chemotherapy. EVE did improve PFS. Results for OS and PFS were consistent across the various subgroups. The safety profile was consistent with that previously observed with EVE.
Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care (BSC) versus placebo plus BSC in patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after standard therapies.
Authors: Grothey Axel , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Lenz Heinz-Josef , Yoshino Takayuki , Cihon Frank , Wagner Andrea , Van Cutsem Eric 
Published: February 2017

LBA385 Background: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in pts with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Pts continued on treatment until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results: From May 2010 to March 2011, 760 pts were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between two arms. Preliminary results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.773 (95% CI: 0.635, 0.941; 1-sided p=0.0051). Median OS was 6.4 mos (95% CI: 5.9, 7.3) for regorafenib and 5.0 mos (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.493 (95% CI: 0.418, 0.581; 1-sided p < 0.000001). Median PFS was 1.9 mos (95% CI: 1.88, 2.17) for regorafenib and 1.7 mos (95% CI: 1.68, 1.74) for PL. ORR was 1.6% for regorafenib and 0.4% for PL. DCR was 44% for regorafenib and 15% for PL (p < 0.000001). Since the prespecified OS efficacy boundary was crossed (nominal α: 0.0093), the Data Monitoring Committee recommended to unblind the study and pts on PL were allowed to cross over to regorafenib. The most frequent grade 3+ AEs in the regorafenib arm were hand-foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%). Updated results will be presented. Conclusions: Statistically significant benefit in OS and PFS was observed for regorafenib over PL in pts with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.
Prospective analysis of prostate cancer (PC) circulating tumor cells (CTCs) to predict response to docetaxel (DOC) chemotherapy.
Authors: Nanus David M. , Loftus Matthew , Akhtar Naveed Hassan , Tagawa Scott T. , Beltran Himisha , Goodman Oscar B. , Zhou Xi Kathy , Bander Neil Harrison , Giannakakou Paraskevi 
Published: February 2017

100 Background: Taxane chemotherapy induces cellular microtubule stabilization (bundling) leading to mitotic arrest and apoptotic cell death. We recently reported that in castration-resistant PC, stabilizing of microtubules by taxanes inhibits ligand-induced androgen receptor (AR) nuclear translocation and activation of ARE-gene transcription (Cancer Res 2011;71:6019). This suggests the clinical activity of DOC results from inhibition of AR signaling. A pilot analysis of CTCs from 14 CRPC pts receiving taxanes revealed that predominant cytoplasmic AR and decreased total AR intensity each was associated with increased odds of response (P<0.001). We initiated a prospective trial to determine if CTC analysis could predict DOC response. Methods: Eligibility: Patients (pts) receiving DOC q21 days for CRPC with >5 CTCs determined by CellSearch. On cycle 1 d1 + d8, CTCs are isolated by ficoll tube separation and by CellSearch enrichment. Cells are stained for expression of prostate specific membrane antigen (PSMA), CD45, AR and acetylated tubulin (AcTub) as a marker of microtubule stabilization. AR localization and total fluorescence intensity, and AcTub intensity are quantitated by confocal microscopy and correlated with response to DOC using PCWG2 criteria. 72 pts are planned to provide 80% power to detect an association. Results: 28 of 72 pts have been prospectively enrolled to assess AR and AcTub as a biomarker of response. 20 pts have discontinued DOC. Day 1 samples were obtained from 27 pts and day 8 on 22 (5 pts on days 9 to 21). Immunofluorescence staining and evaluation of PSMA, CD45, and acetylated tubulin was performed successfully in 8 pts analyzed to date. CTCs can be identified in all pts. Cells are scored for AR and AcTub intensity (scale 1- 4) and AR nuclear vs cytoplasmic localization. Conclusions: Our results to date indicate that PC CTCs can be readily isolated from men receiving DOC chemotherapy in a multicenter fashion and assayed for AR localization and AcTub. Preliminary results suggest that monitoring AR subcellular localization and microtubule bundling in CTCs may predict clinical responses to DOC chemotherapy, warranting further study, including our prospective trial.
Serum proteomics guided discovery of predictive biomarkers of response to androgen ablation (AA) in prostate cancer.
Authors: Kohli Manish , Oberg Ann L. , Mahoney Douglas W. , Riska Shaun M , Zenka Roman M , Sahasrabudhe Deepak M. , Zhang Sheng 
Published: February 2017

104 Background: Currently there are no serum predictive markers of response to AA. We used a proteomic based analytic approach to identify candidates. Methods: Serum from three non-localized prostate cancer cohorts was analyzed. The first included15 paired untreated hormone-sensitive “pre-AA” and 3-month “post-AA” specimens; the second included 10 “early AA failure” (median time to AA failure:11 months) and the third included 10 “late AA failure” specimens (median time to AA failure: 95 months). Proteomic analysis was performed with isobaric mass tags for relative and absolute quanititation (iTRAQ) analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). Differentially expressed candidate proteins were identified by comparisons of (i) paired pre/post-AA proteomes and (ii) post-AA proteome with the combined AA failure cohorts at a False Discovery Rate of 0.2. ELISA assays were used to verify candidate markers in a second stored aliquot of first cohort specimens. This cohort was followed for AA failure. Association of post-AA ELISA levels of candidate markers with time to AA failure was performed using Cox proportional hazards regression, summarized as relative risk (RR) for AA failure. Results: Median PSA in pre/post-AA first cohort were 3.15 ng/ml and 0.29 ng/ml. Median PSA in the second and third cohorts were 27.3 and 4.3 ng/ml. Between post-AA and AA failure cohorts, 149 proteins were differentially expressed. Between early and late AA failure 98 proteins were differentially expressed; 47 proteins were common in both comparisons. ELISA assays verified expression levels of 2/47 proteins in the first cohort; zinc alpha-2 macroglobulin (ZAG), and Neuropilin-2 (NPL2). Median change in ZAG decreased by 2073.5 ng/ml (post versus pre-AA) while median change in NPL2 levels increased by 2.9 ng/ml. After a median follow-up of 43 months from the post-AA time-point, 4/15 first cohort subjects had failed AA. The RR of AA failure for ZAG levels below the median change was 3.8 (95% CI: 0.4-37) and 3.0 (95% CI: 0.3-29) for NPL2. Conclusions: A global proteomic analysis identified ZAG and NPL2 as candidate serum predictive markers of AA response which needs further validation.
Identifying cancer mutations in neuroendocrine prostate cancer (NEPC) through massively parallel DNA sequencing of formalin-fixed paraffin-embedded (FFPE) tissue.
Authors: Beltran Himisha , Park Kyung , Tagawa Scott T. , Yelensky Roman , Lipson Doron , Frampton Garrett , Stephens Philip J , Cronin Maureen T. , Nanus David M. , Mosquera Juan Miguel , Rubin Mark A. 
Published: February 2017

110 Background: NEPC is an aggressive and lethal variant of prostate cancer that most commonly arises from existing prostate adenocarcinoma (PCA). Little is known about the underlying biology of NEPC, as metastases are rarely biopsied. The purpose of this study is to determine the spectrum of somatic mutations in NEPC by using a novel DNA sequencing platform and to evaluate for targetable molecular alterations. Methods: 44 NEPC and mixed NEPC/PCA were evaluated and 77 high density foci of NEPC, PCA, and benign areas were selected for DNA extraction. Massively parallel sequencing via HiSeq2000 was performed using indexed seq libraries constructed by adapter ligation followed by hybridization with optimized capture probes. Data was processed using publicly available and newly validated software tools to make mutation assignments for base alterations, indels, and CNAs in 182 cancer associated genes and common sites of rearrangement for 15 genes. Results: 5/8 biopsies and 62/65 (overall 93%) of prostate foci yielded sufficient DNA (>50 ng) for analysis from 40m of FFPE tissue. Average median sequence coverage was 934x. TMPRSS2-ERG fusion was present in 28% of NEPC. Recurrent homozygous deletions involving PTEN and RB1 were seen, and 1 tumor with BRCA2 loss. Several high confidence non-synonymous mutations were identified including TP53 (40%), CTNNB1 (12%), and less frequently mutations involving PTEN, PIK3CA, AR, as well as other novel mutations/fusions. There was high concordance between NEPC and PCA foci in mixed tumors, as well as between primary tumor and metastases. High confidence lesions were validated with exome sequencing and FISH. Conclusions: This study shows feasibility of an in-depth DNA analysis using FFPE tissue, and even biopsy material. Comprehensive genome sequencing has nominated novel biologic pathways and provides insight into disease progression from PCA to NEPC, as well as potential new drug targets for a tumor that is currently lethal. This is a useful and comprehensive sequencing tool to evaluate tumors such as NEPC and other metastatic tumors, where obtaining tissue is challenging.
Impact of PCA3 on the number of repeat prostate biopsies and sensitivity to detect high-grade cancer in the placebo cohort of the REDUCE study.
Authors: Tombal Bertrand , Andriole Gerald L. , Smets Louis , Stoevelaar Herman 
Published: February 2017

111 Background: 10-35% of men with a negative initial biopsy (Bx) have prostate cancer (PCa) found on repeat Bx (rBx). Fear of missing significant cancer frequently results in, often negative, rBx. As Bx is associated with pain, anxiety and complications, a better individualization of the decision for rBx to reduce the number of rBx and overdiagnosis of indolent PCa is needed. Recently, we used the RAND Appropriateness Method (RAM) to develop a model for rBx patient selection, based on expert recommendations and including the PROGENSA PCA3 Assay (Tombal B, et al. World J Urol 2011;doi:10.1007/s00345-011-0721-0). PCA3 has been shown to predict the probability that a rBx will be positive and may be indicative of PCa significance (Aubin SMJ, et al. J Urol 2010;184:1947-52). In the current analysis, we tested the expert recommendations model on the placebo cohort of the REDUCE study. Methods: The RAM expert recommendations were applied to the placebo cohort of the REDUCE study in which 1073 men with a baseline PSA 2.5-10 ng/mL and a prior negative Bx had a PCA3 test before the planned 2-year and 4-year rBx2. For each scenario (with and without PCA3), the number of rBx and the number of missed high-grade (Gleason sum ≥ 7) cancers were assessed. Results: Data from 1024 subjects were available for analysis. In the scenario without PCA3 consideration (reflecting the experts’ recommendations using PSA, DRE, number of previous negative Bx, prostate volume and life expectancy), 267 (26%) of study-mandated rBx were considered inappropriate and the number of missed high-grade cancers was 14. The scenario including also PCA3 consideration led to a reduction of the number of rBx (656 or 64%), while the number of missed high-grade cancers was decreased to 8. The diagnostic accuracy was superior in the model with PCA3: sensitivity for high-grade cancer was 85% vs. 75%, specificity 67% vs. 26%, positive predictive value PPV 13% vs. 5%, NPV 99% vs. 95%. Conclusions: Application of RAM expert recommendations for rBx that include the PCA3 Score can reduce the number of rBx for men with an elevated PSA while maintaining the sensitivity to detect high-grade cancer.