bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generation and application of a colorectal cancer microarray library to identify a novel prognostic biomarker, adipose differentiation related protein (adipophilin).
Authors: Hogan John , O Byrne Laura , O Callaghan Michael , Kalady Matthew F. , Coffey John C. 
Published: February 2017

508 Background: Substantial volumes of genetic expression data are archived within public gene expression repositories (PGER). Although the data contained is reported according to particular standards, it is not feasible to search the data using clinically relevant search terms (i.e., oncologic outcome). This study aimed to generate an archive of microarray expression data that could be searched using oncologically-relevant terminology, and then to test this facility. Methods: A UL Colorectal Cancer Archive was established based on data derived from the Gene Expression Omnibus (GEO). A software (Rover) was developed to permit clinically relevant searches using terminology such as stage and disease-free survival. As a first test, experiments were identified that compared early and late stage colorectal cancer. From these, consensus profiles were developed and adipocyte differentiation related protein identified as the top-most frequently dysregulated gene. As a second test, the cancer archive was again challenged to identify data sets annotated with outcome data. The association between ADFP and outcome was assessed using a regression-tree (CRT) based approach and Kaplan-Meier estimates. Results: The UL Colorectal cancer archive was constructed so as to permit the novice-user to search for gene expression data associated with particular clinical parameters. Rover was a graphic user interface that permitted these searches. ADFP was identified as dysregulated across the majority of experiments comparing early and late stage colorectal cancer. CRT-analyses identified levels of ADFP above which adverse outcomes were identified. In general, increasing ADFP was independently associated with adverse disease-free outcomes in stage II and III cancer. Conclusions: A novel archive of gene expression data was generated that (a) related to colorectal cancer and (b) could be searched using clinically-relevant terms. Using this archive ADFP was identified as dysregulated between early and late stage colorectal cancer. Increasing ADFP expression levels were associated with adverse disease-free survival in stages II and III colorectal cancer.
c.35 G > A KRAS-mutant genotype and clinical outcome of patients with metastatic colorectal cancer.
Authors: Bruera Gemma , Cannita Katia , Alesse Edoardo , Ficorella Corrado , Ricevuto Enrico 
Published: February 2017

512 Background: KRAS genotype does not significantly affect prognosis of MCRC patients treated with bevacizumab-containing chemotherapy. Codon 12 mutations increase aggressiveness by differently modifying mutated KRAS and downstream signalling, thus conferring worse clinical behavior. Prognostic relevance of the prevalent c.35 G > A KRAS mutation in MCRC patients fit and unfit for first-line bevacizumab added to triplet chemotherapy (FIr-B/FOx) was evaluated. Methods: KRAS codon 12/13 mutations were screened. Efficacy was evaluated and compared by log-rank. Results: Fifty-nine fit patients were treated with firstline FIr-B/FOx: wild-type, 31 (53%); mutant, 28 (47%). KRAS mutations: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). Wild-type compared to mutant status did not significantly affect PFS (14 and 11 months) and OS (38 and 20 months). c.35 G > A mutant showed: no significantly different PFS compared to wild-type; significantly worse OS (14 months) compared to wild-type and to other mutant (39 months). After progression, wild-type compared with mutant did not show significantly different PFS (10 months equivalently) nor OS (17 and 12 months); c.35 G > A compared to wild-type and/or other mutant showed significantly worse PFS and OS. Among 39 unfit patients, treated with conventional regimens, wild-type compared to mutant significantly affected PFS (8 and 6 months), and not OS (13 and 8 months); c.35 G > A mutation significantly affected worse PFS and OS compared to wild-type and/or other mutant. Conclusions: KRAS genotype does not significantly affect clinical outcome of MCRC patients treated with first line FIr-B/FOx, while mutant status may significantly affect worse PFS in patients unfit for intensive treatments. c.35 G > A mutant status, compared to wild type and other mutant, may significantly affect worse clinical outcome in MCRC patients treated with first line intensive FIr-B/FOx and after progression, as well as in patients unfit for FIr-B/FOx, due to increased biological aggressiveness. It did not affect worse PFS only in patients treated with FIr-B/FOx, probably due to effectiveness of triplet chemotherapy plus VEGF inhibitor.
Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first disease progression (PD) in patients with metastatic colorectal cancer (mCRC) previously treated with BEV-based therapy: Outcomes according to KRAS status and first-line CT backbone in the ML18147 study.
Authors: Kubicka Stefan , Greil Richard , André Thierry , Bennouna Jaafar , Sastre Javier , Van Cutsem Eric , Von Moos Roger , Osterlund Pia J. , Hegde Priti , Sersch Martina A. , Osborne Stuart , Hermann Frank , Arnold Dirk ,   on behalf of the ML18147 Study Investigators
Published: February 2017

520 Background: ML18147 is the first randomized phase III study to show that continuing BEV + standard CT as second-line (2L) treatment significantly improves overall survival (OS) and progression-free survival (PFS) in patients with mCRC who progressed after receiving a standard first-line (1L) BEV-containing regimen. Here we report an exploratory analysis of outcomes based on CT backbone and KRAS status. Methods: Patients with unresectable, histologically confirmed mCRC who progressed ≤3 months after discontinuing 1L BEV were randomised to 2L CT (crossed over from oxaliplatin to irinotecan and vice versa) ± BEV. This post-hoc analysis evaluated OS, PFS, overall response rate (ORR) and disease control rate (DCR) according to 1L CT backbone (irinotecan- or oxaliplatin-based) and KRAS status (Scorpion ARMS test for KRAS codons 12 and 13). Results: In total, 616 patients (75% of the ITT population) were included in this analysis; 316 had wild-type (WT) and 300 had mutant-type (MT) KRAS status; 355 received 1L irinotecan and 261 received 1L oxaliplatin. BEV+CT beyond PD prolonged OS and PFS vs CT alone, regardless of whether oxaliplatin- or irinotecan-based CT was used in the 1L and whether patients had WT or MT KRAS (Table). Adverse events were not increased when continuing BEV+CT beyond PD and were consistent with previous findings. Conclusions: This post hoc analysis suggests that continuing BEV + 2L oxaliplatin or irinotecan-based CT (following crossover) leads to prolonged OS and PFS, regardless of KRAS status or if oxaliplatin or irinotecan-based CT was used in the 1L. Clinical trial information: NCT00700102. [Table: see text]
Predictors of early mortality in colorectal cancer patients undergoing chemotherapy: Results from a global prospective cohort study.
Authors: Sohal Davendra , Kuderer Nicole Maria , Shepherd Frances A. , Pabinger Ingrid , Agnelli Giancarlo , Liebman Howard A. , Vicaut Eric , Meyer Guy , Lyman Gary H. , Khorana Alok A. 
Published: February 2017

532 Background: Early mortality is a major problem in colorectal cancer and our understanding of risk factors and predictors is incomplete. A venous thromboembolism (VTE) Risk Score, comprising primary site, baseline hemoglobin, leukocyte and platelet counts, and body mass index [Khorana et al, Blood, 2008], has been shown to be associated with early mortality in solid tumors [Kuderer et al, 2008; Ay et al, 2013]. We evaluated the value of this Risk Score and other key prognostic variables in predicting early mortality for colorectal cancer (CRC) patients. Methods: CANTARISK was a prospective, non-interventional, global cohort study in patients with CRC and lung cancer initiating a new chemotherapy regimen. Clinical data were collected at 0, 2, 4, and 6 months. All data were compiled centrally and analyzed after the study closed. Risk score categories were as defined previously [Blood, 2008]. Statistically significant univariable associations and a priori prognostic variables were tested in multivariable models; adjusted odds ratios (OR) are presented. Results: A total of 1,789 CRC patients were enrolled from 2011-12; data on 1,533 evaluable patients are presented. Median age was 62 years; 71% were Caucasian. Geographic distribution was Europe 37%, North America 28%; Asia 23%; South America 12%. One-third (33%) had a rectal primary and 65% had metastatic disease. There were 184 deaths (10.3%) on study. For low, intermediate and high Risk Score, there were 8.1%, 11.2%, and 32.5% deaths, respectively. In multivariate analyses, the Risk Score remained an independent predictor of death (OR for high/intermediate vs. low score = 1.70, p = 0.0027), in addition to age (OR for each incremental year = 1.03, p = 0.0014), presence of metastatic disease (OR = 3.28, p < 0.0001), and ECOG performance status ≥2 (OR = 3.85, p < 0.0001). VTE itself was not associated with death. Conclusions: This prospective global cohort study demonstrates that the Risk Score is prognostic of early mortality in CRC patients, in addition to age, stage, and performance status. Intermediate or high-risk patients, as defined by the Risk Score, may benefit from additional interventions aimed at reducing early mortality.
Colorectal high-grade neuroendocrine carcinoma: A single institution experience.
Authors: Conte Bruno , George Ben , Dasari A. , Overman Michael J. , Estrella Jeannelyn , Jiang Zhiqin , Machado Karime , Mello Celso Lopes , Ferrarotto Renata , Hoff Paulo M. , Yao James C. , Rashid Asif , Kopetz Scott 
Published: February 2017

540 Background: Colorectal high-grade neuroendocrine carcinoma (HGNEC) is a rare and aggressive disease that lacks standard management recommendations. Methods: The records of all patients with colorectal HGNEC diagnosed at MD Anderson Cancer Center between 1991 and 2013 were retrospectively reviewed for clinicopathological features and clinical outcomes. Results: One hundred patients with histologically confirmed colorectal HGNEC were identified. Median age at diagnosis was 55 years with 51 males. Family history of cancer was present in 59% (first degree) of patients and a tobacco smoking history in 54%. Most frequent symptoms at diagnosis were: abdominal or rectal pain (52%), rectal bleeding (49%) and change in bowel habit (52%). Small cell carcinoma was the most common histology (89%), with large cell neuroendocrine carcinoma in 8% and mixed histology 2%. The expression of chromogranin, synaptophysin and neuron specific enolase was positive in 58%, 93% and 87%, respectively. In our institution, 40% of HGNECs arise in the rectum, compared to 25% of adenocarcinomas (P<0.001 for comparison). Sixty four patients (64%) presented with metastatic disease at diagnosis. Median overall survival (OS) was 11.8 months, with 19.3 versus 8 months for localized and metastatic disease, respectively (p<0.01). Two and five year OS was 23% and 8%, respectively. Cecal primaries had a higher rates of metastatic disease at presentation (OR=5, P=0.026), but stage-specific outcomes did not differ by tumor location. Treatment with a platinum-based chemotherapy (CT) was used in 63 (81%) patients in first line palliative CT and the objective response rate was 43%. For localized disease, neoadjuvant treatment was used in 36% of patients and adjuvant therapy in 47% and was associated with a trend toward improved survival (median OS 20.4 versus 15.4 months, P=0.08). Conclusions: Colorectal HGNEC has an aggressive biology with rectum being the most common site and cecum the site most associated with distant metastases at diagnosis. For localized disease early diagnosis and multimodality approach are important for better outcomes while systemic CT appears to be the mainstay of treatment for advanced disease.
Randomized controlled trial on the skin toxicity of panitumumab in third-line treatment of KRAS wild-type metastatic colorectal cancer: HGCSG1001 (Japanese Skin Toxicity Evaluation Protocol with Panitumumab; J-STEPP).
Authors: Iwanaga Ichiro , Komatsu Yoshito , Yuki Satoshi , Kobayashi Yoshimitsu , Sakamoto Naoya , Uebayashi Minoru , Okuda Hiroyuki , Kusumi Takaya , Sogabe Susumu , Miyagishima Takuto , Tateyama Miki , Tsuji Yasushi , Hatanaka Kazuteru , Nakamura Michio , Konno Jun , Yamamoto Fumiyasu , Iwai Kazuhiro , Onodera Manabu , Oba Koji , Sakata Yuh 
Published: February 2017

541 Background: Panitumumab (Pmab), a fully human monoclonal antibody targeting the EGFR, has been demonstrated the efficacy in patients with KRASwild-type metastatic colorectal cancer (mCRC). Though STEPP study (Lacouture et al, JCO 2010) showed that pre-emptive skin treatment reduced skin toxicities compared with reactive treatment among patients receiving Pmab, the data of Asians has not been reported. We planned a randomized controlled open-label trial to verify the differences between pre-emptive and reactive treatment for skin toxicities in Japanese patients. Methods: Patients receiving Pmab-containing treatments as third line regimen for mCRC were randomly assigned 1:1 to pre-emptive or reactive skin treatment group. In the pre-emptive treatment group, patients received skin moisturizers, sunscreen, topical steroid and minocycline. In the reactive treatment group, patients received only skin moisturizers. The primary endpoint was the cumulative incidence of ≥ grade 2 skin toxicities during the 6-week treatment period. Retrospectively, dermatologist reviewed skin toxicities with photographs in blinded manner. Results: Out of 95 enrolled patients, 47 patients were randomly assigned to pre-emptive group, and 48 to reactive group. The incidence of ≥ grade 2 skin toxicities during the 6-week treatment period (according to investigator’s assessment) was 21.3% and 62.5% (risk ratio [RR] = 0.34, 95% CI 0.19 - 0.62; p<0.001) for the pre-emptive and reactive treatment groups, respectively. A similar trend was observed in central review by dermatologist (18.6% and 50.0%, respectively [RR = 0.37, 95% CI 0.19 - 0.74; p = 0.002]). The concordance rate between them was 75.8%. Median time to first occurrence of ≥ grade 2 skin toxicities was not reached in the pre-emptive group and 3.2 weeks (95% CI 1.9 - 6.1) in reactive group (p < 0.001). Conclusions: The pre-emptive skin treatment could reduce the severity of the skin toxicities during the Pmab treatment. Our data clearly validate that the pre-emptive treatment is also recommended in Japanese patients. Clinical trial information: 000004883.
Semi-automated validation of centralized independent review of radiological data in the OPUS trial.
Authors: Piessevaux Hubert , Zhao Binsheng , Tejpar Sabine , Schwartz Lawrence H. 
Published: February 2017

542 Background: There is increasing evidence that evaluation of tumor shrinkage on a continuous scale early on during treatment in metastatic colorectal cancer (mCRC) contains predictive information on long term treatment benefit. These findings were more specifically observed in trials evaluating addition of cetuximab to chemotherapy in first line mCRC (Piessevaux, JCO, 2013). Precise tumor measurements are necessary to implement these findings in clinical trials and practice. Independent central review has been advocated to improve the validity of the radiological measurements in clinical trials. In the phase II mCRC OPUS trial, we compared tumor shrinkage assessments given by an independent review committee (IRC) to results of a semi-automated software algorithm (SOFT). Methods: IRC measurements were performed and reported previously. SOFT requires a seed placement in a metastatic deposit. Once the seed placement is made, the computer automatically generates the boundary of the lesion and calculates the maximal diameter. The original digital radiological data from 217/337 ITT patients was available for review. Early tumor shrinkage, defined as the relative change at week 8 of the sum of the longest diameters was calculated with both measures and compared (ETS-IRC vs. ETS-SOFT). Results: The intra-class coefficient of correlation between ETS-IRC and ETS-SOFT was 0.689 (95%CI 0.604-0.759). When the population was split according to treatment group we observed the following ICC: 0.874 (95%CI: 0.815-0.914) in the chemotherapy with cetuximab arm and 0.486 (0.307-0.632) in the chemotherapy alone arm. Conclusions: Secondary independent review of radiological data from the OPUS trial showed discrepancies between IRC and SOFT. These discrepancies are potentially due to target lesion number and selection. Treatment group seems to differentiate cases more prone to discrepant review. This finding may be related to enhanced reliability when treatment effect is more pronounced. Further comparisons of traditional IRC reviews to semi-automated algorithm-based reviews with regard to outcome evaluation are warranted.
Angiotensin converting enzyme inhibitor and angiotensin receptor blocker use and outcomes in patients with colorectal cancer.
Authors: Tuazon Sherilyn Alvaran , King Gentry Teng , Sta. Cruz Joanna Paula Pingol , Ong Kian Koc Jean B. , Chae Young Kwang , Leighton John Charles , Daskalakis Constantine 
Published: February 2017

544 Background: Increasing evidence implicates angiotensin in the pathophysiology of carcinogenesis. Both Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs) have shown in-vitro activity in Colorectal Cancer (CRC) via inhibition of both VEGF and IGF-1 and present a novel therapeutic strategy. This study aimed to investigate the association of these agents in outcomes of patients with CRC. Methods: We reviewed the medical records of patients with stage I-III CRC from 2004-2008. ACEI and ARB use was defined as consumption for at least 3 months in patients with no evidence of disease after initial diagnosis and treatment. Outcomes were Disease Free Survival (DFS) and Overall Survival (OS). Kaplan-Meier and Cox proportional hazards regression were used. Results: A total of 222 patients were included, with a median follow up of 39 months. A total of 105 (47%) were identified as users of ACEI/ARBs. Multivariate analysis, adjusted to age, sex, race, stage, grade, tumor location, adjuvant chemotherapy, radiotherapy, statin and ASA use showed significantly improved DFS among users of ACEI and/or ARBs compared to non-users (HR = 0.44, p = 0.003). Considered separately, users of ACEIs only and users of ARBs only had better DFS than non-users (HR = 0.43 and 0.53, respectively). Compared directly, users of ACEIs did not have significantly different DFS than users of ARBs (HR = 0.81, p = 0.678). With regards to OS, multivariate analysis showed that, compared to non-users, patients with ACEI or ARB use had better OS, although non-significantly (HR = 0.59, p = 0.219). However, the magnitude of the impact on OS was comparable to that seen for DFS. Conclusions: The use of ACEIs and/or ARBs is associated with improved disease-free survival in CRC patients. There was a statistically insignificant trend toward improved OS, which may be related to the low power to the study. This observation warrants further exploration.
Occurrence and timing of organ space surgical site infections (SSI) in rectal cancer patients: A NSQIP database review.
Authors: Miyagaki Hiromichi , Kumara HMC Shantha , Xiaohong Yan , Cekic Vesna , Whelan Richard L. 
Published: February 2017

552 Background: This study’s aim was to determine the incidence and date of presentation of organ space SSI (in this setting most likely due to anastomotic leak or pelvic abscess) in rectal cancer resection patients. A second purpose was to determine which variable(s) impacted the timing of the presentation. Methods: The NSQIP database was queried from 2007 to 2011 for elective rectal cancer resections. Exclusion criteria included; ASA 5 status, preoperative(preop) shock/sepsis, SIRS, and recent surgery. Demographic parameters, comorbidities, lab data, and incidence and timing of organ space SSI were assessed. The statistical methods used were Fisher’s exact test (categorical variables) and Wilcoxon’s rank tests (continuous variables). Results: 8,093 rectal cancer patients were identified (Male/Female; 60.1%/39.9%; median age, 60; APR, 28 %; sphincter saving procedures,72%). The incidence of organ space SSI was 6 % (485 patients; 2.7% presented before and 3.3% after discharge). The rate was significantly greater for men, younger patients (< 60), smokers, sphincter saving resections (vs. APR). Preop radiotherapy (RT) did not increase the rate of and stomas did not protect against the formation of organ space SSI. The mean date of detection was 14.6±7.3 days after surgery (Mean±SD). A further delay was noted in those who had preop RT regardless of the operation performed (n=184, added delay 2.7 days, p<0.05). Significant delays (p<0.05) were also noted in patients that had APR (n=112, mean delay 2.4days), stoma formation (n=285, mean delay 1.6days) and open surgery (n=368, mean delay 1.8 days). Multivariate analysis revealed preop RT (p=0.0002) and APR (p=0.0258) as independent risk factors for delayed presentation. Conclusions: Most organ space SSI after rectal cancer surgery occur after hospital discharge. The mean presentation date is about 2 weeks after surgery. Patients who received preop RT or underwent APR presented about 2.5 days later than the mean date. Rectal cancer patients should be followed closely for 3 weeks as regards organ space SSI.
Comparison of sizes of sentinel and non-sentinel lymph nodes in colorectal cancers (CRCa).
Authors: Saha Sukamal , Koduru Ujwala , Burke Jacob , Korant Alpesh K. , Saha Supriya Kumar , Dhar Vikrom K. , Johnston Gregory , Wiese David , Arora Madan L. , Singh Trevor 
Published: February 2017

557 Background: Sentinel lymph node (SLN) mapping (M) in CRCa with ultrastaging of SLNs find more nodes per patient (Pt) and more metastasis in the SLNs than non-SLNs (NSLNs) compared to conventional methods. We hypothesized that SLNs may represent a subset of nodes smaller than those detected by routine pathological exam, and hence missed by conventional methods. Hence, we compared the sizes of SLNs and NSLNs in CRCa pts undergoing SLNM. Methods: 365 pts underwent subserosal peritumoral injections of blue dye for SLNM. Blue stained nodes were tagged as SLNs. SLNs were sectioned at 5 levels, 4 stained with H & E, one with cytokeratin (CK-IHC). The non-SLNs were sectioned at one level and stained with H & E. Greatest diameter of nodes for sizes were measured on glass slides or from gross examination. Results: Of the total of 5,601 LNs (Average 15.3/pt) included, 912 were SLNs and 4689 non-SLNs. Of the total lymph nodes removed, 78% were 5mm or less; 69% of positive LNs and 97% of negative LNs were less than 9mm (Table). On average, the size of SLN was bigger (5.7mm) than NSLN (4.0mm). Both positive and negative SLNs were also bigger than positive and negative NSLNs (Table). Conclusions: Our study confirms that on average, SLNs are bigger than NSLNs whether positive or negative or as a whole. This also highlights diligent efforts needed by the pathologists, as 77% of all lymph nodes were less than 5mm. [Table: see text]