bluuebunny/crossref_metadata_2025_split huggingface dataset:
Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer: A randomized controlled trial.
Authors: Van Der Sluis Pieter Christiaan , van der Horst Sylvia , May Anne Maria , Schippers Carlo , Brosens Lodewijk , van Dijk Wouter , Joore Hans , Kroese Christiaan , Haj Mohammad Nadia , Mook Stella , Vleggaar Frank P. , Borel Rinkes Inne , Ruurda Jelle , van Hillegersberg Richard 
Published: January 2019

6 Background: The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) may reduce perioperative complications and improve functional recovery. Methods: In this randomized controlled trial, 112 patients with resectable intrathoracic esophageal cancer were randomly assigned to RAMIE or OTE. The composite primary endpoint was the occurrence of overall postoperative complications (modified Clavien–Dindo classification (MCDC) grade 2-5). Results: Postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) (RR 0.74 (0.57-0.96; P = 0.02). RAMIE resulted in a less median blood loss (400ml versus 568ml, P < 0.001), a lower percentage of surgery-related complications (RR 0.74 (0.57-0.96; P = 0.02), pulmonary complications (RR 0.54 (0.34-0.85; P = 0.005) and cardiac complications (RR 0.47 (0.27-0.83; P = 0.006)) and lower mean postoperative pain (visual analogue scale, 1.86 versus 2.62; p < 0.000) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group (RR 1.48 (1.03–2.13; P = 0.038)) with better quality of life score at discharge (mean difference quality of life score 13.4 (2.0-24.7, p = 0.02) and 6 weeks post-discharge (mean difference 11.1 quality of life score (1.0-21.1; p = 0.03)). Mean costs for RAMIE were €34.892 and mean costs for OTE were €39.463 (p = 0.07). Oncological outcomes at short term (radicality, number of lymph nodes) and long term (overall and disease-free survival) were equal at a medium follow up of 38 months. Conclusions: RAMIE resulted in a lower percentage of overall, surgery-related and (cardio)pulmonary complications with lower postoperative pain, better quality of life and a better short term postoperative functional recovery compared to OTE. Oncological outcomes were equal. This randomized controlled trial provides evidence for the use of RAMIE to improve postoperative outcome in patients with resectable esophageal cancer. Clinical trial information: NCT01544790.
Association of minimally invasive colorectal resection with elevated levels of plasma B7 homolog 1 (B7-H1) during the first month after surgery and effect on immune suppression and growth of residual metastases.
Authors: Kumara Hmc Shantha , Pettke Erica , Winkler Carl S , Jaspreet Sandhu K , Yan Xiaohong , Vesna Cekic , Gandhi Nipa Dilip , Whelan Richard L 
Published: January 2019

602 Background: The co-stimulatory molecule B7 homolog 1 (B7-H1) is a ligand for PD-1 which is an immunoinhibitory receptor of activated lymphocytes. PD-1 expression is upregulated on tumor infiltrating lymphocytes (TILs), and B7-H1 expressed on cancer cells may inhibit T-cell activation and proliferation. B7-H1 is also expressed on endothelial (EC) and intestinal epithelial cells as well as activated macrophages. B7H1 in EC is rapidly induced by IFN-gamma and TNF. B7-H1 silencing with siRNA inhibits tumor cell proliferation/invasion. B7H1 expression in keratinocytes (KC) directly downregulates CD8(+) T-cell effector function via PD-1 binding at sites of inflammation. Shed B7-H1 can be found in the blood. Surgery’s impact on plasma B7H1 levels is unknown. This study’s purpose was to evaluate plasma B7H1 levels during the first month after MICR for colorectal (CRC). Methods: MICR CRC patients in an IRB approved data/plasma bank with adequate plasma available were eligible. Clinical and pathological data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41). B7-H1 levels were analyzed in duplicate using ELISA. The Wilcoxon test was used for analysis. Results: 88 CRC patients who had a MICR met inclusion criteria (28% rectal and 62% colon lesions). The mean PreOp B7-H1 level was 51.9±20.9 pg/ml. Significantly elevated mean plasma levels were noted on POD1 (64.9±24.2 pg/ml, n = 86, p = < 0.0001), POD3 (67.3±24.6 pg/ml, n= 72, p = < 0.0001), POD7-13 (69.2±22.6 pg/ml, n = 65, p = < 0.0001), POD14-20 (72.5±28.9 pg/ml, n=23,p=0.001), POD 21-27 (79.4±66.6 pg/ml, n = 13, p = 0.001), and on POD 28-41 (56.3 ±22.7 pg/ml, n = 20, p =0.02), when compared to PreOp levels. Conclusions: Plasma B7-H1 levels are elevated for over a month after MICR for CRC. The etiology of the early increase may be the acute inflammatory response whereas late elevations may be related to wound healing-related tissue remodeling. Elevated plasma B7-H1 may suppress TIL’s which may result in increased tumor growth. Further studies are warranted.
Time to adjuvant chemotherapy in CEA-positive colon cancer: An NCDB analysis.
Authors: Zhang Yang , Aurit Sarah J , Satish Mohan , Chau Eugene , Silberstein Peter T. 
Published: January 2019

603 Background: It is well accepted that positive serum carcinoembryonic antigen (CEA) levels are associated with inferior survival in patients with advanced non-metastatic colon cancer; however, it is not fully elucidated whether this prognostic factor can inform clinical decisions, specifically for the optimal timing of adjuvant chemotherapy after definitive surgical treatment. This study was aimed to determine the relationship between onset of adjuvant chemotherapy and rate of survival in stage III colon cancer patients who tested CEA-positive, and thus, potentially identifying the optimal timing to increase survivorship. Methods: We identified 19,180 patients from the NCDB with TNM pathologic stage IIIB and IIIC adenocarcinoma of the colon who also had a recorded CEA test result and whom had received adjuvant chemotherapy. We examined unadjusted overall survival based on CEA status with the Kaplan-Meier method. A multivariable Cox regression model was estimated to determine the association of CEA status and overall survival after controlling for site, stage, days from surgery to chemotherapy, demographic background, and facility characteristics. All analyses were conducted with SAS version 9.4 (SAS Institute Inc., Cary, NC) with a statistical threshold of p < 0.05. Results: Based on the log-rank χ2 test, a positive CEA test result was significantly associated with worse survival. We adjusted for patient and facility level characteristics, and found a 49.7% increased risk of death for a patient with a positive CEA result (95% CI: 41.7% to 58.2%). We found a median number of 43 days from definitive surgery to initiation of chemotherapy; after adjusting for all other variables, we found for every ten-day delay in receiving adjuvant therapy after definitive surgical intervention, there was a 1.6% increased risk of death (95% CI: 1.0 to 2.2%). Conclusions: In this cohort of patients who tested CEA-positive, delays in receiving adjuvant chemotherapy had a negative linear association on survival. Adjuvant therapy should be considered as soon as patient’s clinical condition permits.
Oxaliplatin desensitization after hypersensitivity reaction: A single-center experience on more than 300 procedures.
Authors: Le Roy Florence , Rigault Eugénie , Regnault David , Hubert Nicole , Burtin Pascal , Hollebecque Antoine , Malka David , Boige Valerie , Ducreux Michel 
Published: January 2019

610 Background: Oxaliplatin is an essential drug in gastrointestinal oncology. Hypersensitivity reactions (HSR) occur frequently (incidence varying from 10% to 25%), leading to permanent treatment discontinuation. The present study aimed to report our experience of oxaliplatin desensitization in patients with history of HSR to oxaliplatin. Methods: We retrospectively reviewed all patients who received at least one infusion of oxaliplatin according to a desensitization protocol after prior history of HSR to oxaliplatin, from June 2011 until June 2017. HSRs were classified from NCI CTC-AE grade 1 (transient rash, fever < 38°C) to grade 4 (anaphylaxis). We applied in all cases a desensitization protocol in which the oxaliplatin infusion rate is gradually increased from 1mL/hr. to 150mL/hr., on an inpatient basis. Intravenous or hepatic arterial infusion was used depending on clinical setting. Results: Overall, 54 patients were included in this study, in whom HSR to oxaliplatin occurred after a median of 9 infusions (range, 1-31). The severity of HSRs was grade 1-2 in 33 patients (61%) and grade 3-4 in 21 patients (39%). A total of 305 oxaliplatin infusions according to a desensitization protocol were performed in these 54 patients (median, 5 infusions; range, 1-20). These infusions were by intravenous route in 42 patients (78%), by hepatic arterial route in 11 patients (18%), and both in 2 patients (4%). Infusions were well tolerated in 41 patients (76%), without new HSR. The remaining 13 patients (24%) experienced HSR recurrence (grade 2, 9 patients [69%]; grade 3, 4 patients [31%]). No anaphylaxis or oxaliplatin-related death occurred. In the 21 patients with a prior history of severe (grade 3-4) HSR, oxaliplatin desensitization procedure was effective and sustained in 16 patients (79%). Among 32 evaluable patients, 23 (72%) experienced disease control (14 partial responses, 9 stable diseases). Conclusions: Rechallenging Oxaliplatin desensitization procedure was successful in three out of four patients with prior history of HSR to oxaliplatin. Our retrospective study confirms that oxaliplatin desensitization is safe, and allows patients who developed HSR to continue an effective treatment.
Evaluation of lesion-based response at 12 weeks (LBR12) of treatment (Rx) in metastatic colorectal cancer (mCRC): Findings from 9,092 patients (pts) in the ARCAD database.
Authors: Ou Fang-Shu , Lou Yiyue , Van Cutsem Eric , Saltz Leonard , Schmoll Hans-Joachim , Goldberg Richard M. , Hoff Paulo , Douillard Jean-Yves , Hecht J. Randolph , Hurwitz Herbert , Punt Cornelis J. A. , Bokemeyer Carsten , Fuchs Charles S. , Diaz-Rubio Eduardo , Tebbut Niall , Falcone Alfredo , Kabbinavar Fairooz F. , De Gramont Aimery , Grothey Axel , Shi Qian 
Published: January 2019

612 Background: mCRC is a heterogeneous disease leading to possible disparate responses among lesions in a single pt. This study assesses the heterogeneity of lesion responses and evaluates the prognostic value of LBR12 and its mortality risk discrimination beyond RECIST responses. Methods: Pts with ≥ 2 lesions and no new lesions at 12 weeks (wks) were eligible. For each pt, after 12 wks of Rx, each lesion was categorized as progressive disease (L-PD: ≥20% increase in the longest diameter [LD]), partial response (L-PR: ≥30% decrease in LD), or stable disease (L-SD: neither L-PD nor L-PR). LBR12 was defined, per patient, by the combination of lesion responses: homogeneous LBR12 (L-PD, L-SD, L-PR only) and heterogeneous LBR12 (mixture of L-PD/L-SD, L-PD/L-PR, L-SD/L-PR). LBR12 and overall survival (OS) were correlated using stratified multivariate Cox models after adjusting for age, gender, and ECOG PS. Results: Among 9,092 mCRCs (Rx: chemo alone 44%; chemo + VEGF inhibitor [VEGFi] 42%; chemo + EGFR inhibitor [EGFRi] 10%) from 16 1st-line studies. Median OS: 2.2 years. Per RECIST at 12 wks, CR 0%; PR 36.1%; SD 60.9%; PD 3.0%. Responses in 52% were heterogeneous (Table). VEGFi and EGFRi treated pts had the highest rate of L-SD/L-PR (45%) and L-PR only (22%) status, respectively. Median OS increased monotonically across pts with more L-PRs and fewer L-PDs (Table). Pts with L-SD/L-PR status, among which 51% had SD per RECIST, had longer OS than those with L-SD only status (HRadj.= .81, padj.< .0001), but shorter OS than those with L-PR only status (HRadj.= 1.46, padj.< .0001). Pts with L-PD/L-SD status, among which 71% were SD per RECIST, had shorter OS than those with L-SD only status (HRadj.= 2.22, padj.< .0001). These associations were consistent across treatment regimens. Conclusions: The lesion-based response captures the heterogeneity of within pt lesion responses and provides refinement in predicting outcome beyond RECIST response at 12 wks. [Table: see text]
Genomic evolution and acquired resistance to preoperative chemoradiation therapy (CRT) in rectal cancer.
Authors: Kamran Sophia C. , Lennerz Jochen K , Margolis Claire , Liu David , Reardon Brendan , Wankowicz Stephanie A , Wo Jennifer Yon-Li , Willers Henning , Corcoran Ryan Bruce , Van Allen Eliezer Mendel , Hong Theodore S. 
Published: January 2019

613 Background: Following pre-operative CRT for locally advanced rectal cancer, ~20% of patients achieve a pathologic complete response and 20-40% have little to no response (NR) at time of surgery. Pathologic downstaging after CRT is associated with improved outcomes but molecular predictors of response are poorly understood. The objective of this study was to characterize somatic mutations and derive genomic biomarkers distinguishing complete and excellent partial responders (R) vs NR through whole exome sequencing (WES) in pre- and post-CRT tumor samples. Methods: Rectal cancer patients treated with pre-operative CRT and having either a R or NR were identified. DNA extraction from clinical FFPE samples and WES were performed on pre/post-CRT tumor and matched germline DNA followed by genomic analysis to identify somatic mutations, insertion/deletions, and clonal/subclonal mutational evolution. RNA extraction/sequencing and GSEA was performed in parallel. Results: We identified 34 pre- and post-CRT matched tumor samples from 17 patients treated with pre-operative fluoropyrimidine-based CRT (50.4 Gy) followed by surgery within 8-10 weeks. Nine and 8 patients were classified as NR and R, respectively. All FFPE passed quality control metrics and were successfully sequenced. Mean somatic mutational burden pre-CRT was 3.78 mutations/Mb (rg, 2.25-8.43), which, unexpectedly, was not significantly increased in the post-CRT samples (4.23 mutations/Mb; rg, 1.74-8.96). NR cases had more concurrent KRAS/TP53 (KP) mutations than R cases (67% vs 13%, p < 0.05). Related to this finding, NR was associated with epithelial-to-mesenchymal transition (p < 0.001) and potentially linked to high intra-tumoral heterogeneity pre-CRT (p = 0.08). Conclusions: We have established feasibility and a pipeline for performing WES on pre- and post-CRT FFPE tumor samples. Our data suggest that evolution of CRT resistance is not through hypermutation. In conjunction with recent observations from our group (Hong, JNCI 2017; Wang, Cancer Res 2017), our findings strongly support the clinical utility of the KP genotype as a biomarker of CRT resistance and begin to offer insight into the underlying mechanisms on a genomic level.
Immunoscore to provide prognostic information in low- (T1-3N1) and high-risk (T4 or N2) subsets of stage III colon carcinoma patients treated with adjuvant FOLFOX in a phase III trial (NCCTG N0147; Alliance).
Authors: Sinicrope Frank A. , Shi Qian , Hermitte Fabienne , Heying Erica N , Benson Al Bowen , Gill Sharlene , Goldberg Richard , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Sargent Daniel J. , Galon Jerome , Alberts Steven R. 
Published: January 2019

614 Background: A consensus interpretation of the IDEA colon cancer study results suggested that risk categories based on T/N stage grouping be used to guide decision-making for duration (3 vs 6 months) of adjuvant FOLFOX or CapeOX chemotherapy. Given the prognostic potential of immune biomarkers, we examined the immunoscore and individual T and B lymphocyte markers in low and high risk T/N subsets of stage III colon carcinoma patients (N=600) treated with adjuvant FOLFOX. Methods: Immunoscore (CD3+, CD8+) and individual T-cell and CD20+ B-cell immunostain densities in central tumor (CT) and invasive margin (IM) of FFPE sections were quantified by image analysis. A predetermined immunoscore categorization was used [high (2-4) vs low (0-1)]. Individual markers were analyzed by backwards selection wherein CD3+ IM was most robust for prognosis and an optimized cutoff was then determined. Associations with disease-free survival (DFS) were analyzed by multivariable Cox regression adjusting for age, T/N stage, sidedness, KRAS/BRAF, and DNA mismatch repair. Results: In low and high risk T/N patient subsets, the immunoscore and CD3+ IM were each significantly discriminant for prognosis. Among low risk (T1-3N1) patients, a high vs low immunoscore was associated with a 91% vs 77% 3-year DFS [HR 0.57, 95% confidence interval (CI) 0.34-0.95, adjusted (adj) P= 0.026]. Among high risk (T4 or N2) patients, a high vs low immunoscore was associated with a 68% vs 54% 3-year DFS (HR 0.64, 95% CI 0.42-0.98, Padj= 0.034]. Similarly, a high vs low intratumoral CD3+ density at the invasive margin (IM) was significantly associated with prognosis in low risk [HR 0.37, 95% CI 0.21- 0.66), Padj< 0.0003] and in high risk [HR 0.47, 95% CI, 0.27- 0.80), Padj< 0.0028] patient subsets. Conclusions: Immunoscore and CD3+ IM were shown to prognostically stratify FOLFOX-treated patients within both low and high risk T/N subsets. These data underscore limitations of the T/N risk classification for adjuvant treatment decisions in stage III patients, and demonstrate the ability of T-cell markers to enhance prognostication to guide clinical decision-making.
Impact of microsatellite instability (MSI) on tumor clonal evolution in metastatic colorectal cancer (mCRC).
Authors: Willis Jason , Morelli Maria Pia , Morris Van Karlyle , Loree Jonathan , Lam Michael , Pereira Allan Andresson Lima , Raghav Kanwal Pratap Singh , Kee Bryan K. , Vilar Sanchez Eduardo , Eng Cathy , Manuel Shanequa , Crosby Shadarra , Wolff Robert A. , Lanman Richard B. , Talasaz AmirAli , Janku Filip , Overman Michael J. , Kopetz Scott 
Published: January 2019

616 Background: For mCRC, the contribution of clinical and pathologic factors to concordance between formalin-fixed, paraffin-embedded (FFPE) tissue-based and ctDNA-based mutation profiling remains unclear. MSI is hypothesized to confer a higher rate of somatic alteration resulting in clonal evolution over time compared to microsatellite stable (MSS) patients, but this has not been previously confirmed. Methods: All mCRC patients were consented for a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]) using CLIA-certified platforms. Archived tumor DNA from primary or metastatic tissue was sequenced on a 46- or 50-gene panel (Ion Torrent). Paired ctDNA samples were isolated from blood and sequenced with an ultra high-sensitivity assay (Guardant360). Mutation data were normalized by excluding genomic regions not covered on both platforms and were filtered to remove germline or synonymous variants. Results: An initial cohort of 139 patients was included in our analyses, with a median of two lines of intervening chemotherapy between FFPE and plasma DNA collection; 6 (4.3%) of the patients had MSI (MSI-H) mCRC. We detected 472 total mutations in either tissue or ctDNA, with a global concordance rate of 34.5%. Global concordance was not associated with tissue source, nor treatment with specific standard cytotoxic and/or biologic agents. Mutations detected in MSI-H CRC showed significantly greater discordance compared to MSS CRC (OR = 2.5, p = 0.025). This finding was validated using an independent cohort of 17 MSI-H mCRC patients (OR = 2.78, p = 0.00015). Among recurrently altered genes, we found that MSI-H cases were significantly more likely to have gained new TP53 mutations (OR = 8.17, p = 0.001) and to have lost PIK3CA mutations (OR = 8.04, p = 0.036) in ctDNA compared to MSS cases. Conclusions: MSI correlates with discordance between tissue DNA and ctDNA-based mutation profiling, which suggests that MSI-H CRC undergoes distinct patterns of clonal evolution including acquisition of new TP53 mutations. This may have implications for targeted and immunologic therapies in this unique population, and suggests a utility for repeated molecular testing.
Associations of incidence of common adverse events (AEs) and survival outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first line chemotherapy: Findings from 9,812 pts in the ARCAD database.
Authors: Ferraro Danielle Angela , Zalcberg John Raymond , Shi Qian , Meyers Jeffrey P. , Seymour Matthew T. , Saltz Leonard , Maughan Tim , Goldberg Richard M. , Van Cutsem Eric , Heinemann Volker , Hurwitz Herbert , Falcone Alfredo , Diaz-Rubio Eduardo , Chibaudel Benoist , Fuchs Charles S. , Porschen Rainer , Bokemeyer Carsten , De Gramont Aimery , Price Tim , Adams Richard 
Published: January 2019

617 Background: There is limited, often conflicting evidence about AE timing, severity or associations with outcomes with the use of cytotoxic agents in cancer treatment. We investigated the impact on overall survival (OS) and progression-free survival (PFS) of selected common AEs (neutropenia, diarrhea, nausea, vomiting, neuropathy) occurring in patients receiving first line oxaliplatin (Oxa)- and/or irinotecan(Iri)-based regimens for mCRC. Methods: The CTCAE grading scores of at least one AE of interest were available on 9812 pts treated with chemotherapy alone (median age 63; 62.4% male, 50.1% ECOG PS 0) from 17 1st-line randomized trials. Patients who also received biologics were excluded in the primary analyses. AEs occurring during the first 6 weeks of treatment and entire treatment were analyzed by stratified multivariable Cox models in relationship to OS/PFS. 55.7% pts received Oxa- regimens, 35.7% Iri-regimens, and 8.6% combined Oxa- and Iri-regimens. Results: Within the first 6 weeks of treatment, G3+ neutropenia (HRadj= 1.3, 95% CI, 1.06-1.59, padj 0.01), diarrhea (HRadj= 1.48, 95% CI, 1.23-1.79, padj < .0001), nausea (HRadj= 1.53, 95% CI, 1.17-1.99, padj 0.002) and vomiting (HRadj= 1.56, 95% CI, 1.18-2.07, padj 0.002) were associated with significantly worse OS for Iri-regimens, but only G3+ nausea predicted for worse OS for Oxa- regimens (HRadj= 1.61, 95% CI, 1.18-2.21, padj 0.003). For AEs experienced at any time, G3+ neutropenia and neuropathy were significantly associated with longer PFS and OS for Oxa-regimens, while G3+ vomiting and nausea were associated with worse OS for both Oxa- and Iri-based regimens. Sensitivity analysis showed largely concordant results by including pts who also received biologics. Conclusions: The association between more severe selected AEs and outcome varies between AEs and is influenced by timing of the occurrence. More severe selected AEs occurring early in treatment are associated with worse outcomes. In contrast, for AEs occurring at any time, G3+ neutropenia and neuropathy predicted for longer PFS and/or OS in Oxa-treated pts.