bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer spectrum among Irish DNA mismatch repair gene mutation carriers.
Authors: Farrell Michael P. , Lyons Tomas , Gogarty Darragh S , Dorman Naoise Maria , O' Brien Loretto , Mac Mathuna Padraic M. , Gallagher David J. 
Published: February 2017

424 Background: Pathogenic germline mismatch repair (MMR) mutations confer a high lifetime risk of colorectal cancer (CRC). Certain extra-colonic malignancies are also considered part of the Lynch syndrome (LS) spectrum including endometrial cancer, gastric, ovarian, small intestine, uroepithelial, pancreas, brain and skin cancer. A genotype-phenotype association has been reported. MSH2 mutation carriers appear to have a higher risk of developing extra-colonic cancer than individuals with a MLH1 mutation. We investigated the cancer spectrum in Irish LS kindreds and the likely association of these cancers with MMR deficiency. Methods: We identified 52 LS patients and family members with confirmed pathogenic DNA MMR mutations among 14 kindreds. Clinical data was extracted from the medical records and cancer diagnoses were confirmed from medical records and pathology reports. Tumour tissue was acquired. Immunohistochemistry (IHC) was completed for 4 MMR proteins and tumour lymphocyte infiltration is ongoing. Results: Spectrum of cancers identified include: CRC, endometrial , gastric, ovarian, renal, breast, prostate, urothelial, NHL, CML, lung, vocal cord, sebaceous carcinoma and cervix. Median age of diagnosis was 44. Thirteen individuals were diagnosed with two primary malignancies, 11 individuals were diagnosed with three primaries and one individual had four cancers. IHC analysis of three breast cancer cases demonstrated loss of MMR protein expression consistent with familial mutation. Conclusions: Early-onset cancers not traditionally considered manifestations of LS were identified in 14 LS kindreds. An additional 60 pedigrees are being worked up and further IHC and lymphocyte quantification will be reported at the meeting. An expanded LS-associated spectrum of malignancies may exist in certain families.
Impact of diabetes on clinicopathologic and genetic features of colorectal cancer formation.
Authors: Wong Hui-li , Jorissen Robert N. , Sieber Oliver , Lipton Lara Rachel , Desai Jayesh , Tie Jeanne , Kosmider Suzanne , Bae Susie , Jones Ian , Croxford Matthew , Steel Malcolm , Bui Andrew , Gibbs Peter 
Published: February 2017

426 Background: Diabetes mellitus is reported to increase the risk of colorectal cancer (CRC) development and has been associated with poor tumour-specific outcomes. Here we assessed the impact of diabetes on the clinicopathologic features and tumour mutation profiles of CRC. Methods: Analysis of a prospective series of patients diagnosed with CRC between January 2000 and December 2010. Fresh-frozen and formalin-fixed, paraffin-embedded tumour specimens were retrieved and genomic DNA extracted for analysis of microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and mutations in BRAF, KRAS, PIK3CA, TP53 and APC genes. Propensity-score matching and logistic regression were used to estimate the association of diabetes with tumour molecular profile, controlling for age, sex, tumour stage, body mass index (BMI), smoking and socio-economic status. Results: Of the 1,348 patients assessed, 288 (21.4%) had a history of diabetes mellitus. Compared to patients without diabetes, diabetics were more likely to be older (age > 70 yrs: 56% vs 47%, p = 0.006), male (57% vs 47%, p = 0.002) and have a higher BMI (BMI > 25: 82% vs 65%, p < 0.0001). There were no statistically significant differences in tumour site, differentiation or lymphovascular invasion. Propensity scores were used to match 260 diabetic patients to an equal number of nondiabetics. In multivariate regression analysis, diabetes was associated with BRAF-mutated tumours (OR 2.81, 95% CI 1.16-7.59, p = 0.029) and showed a trend towards MSI-high tumours (OR 1.54, 95% CI 0.91-2.63, p = 0.110). Results are shown in the Table. Survival analysis is planned. Conclusions: CRC patients with diabetes are older, more likely male and have higher BMI than non-diabetics. In this preliminary analysis, an association between diabetes and BRAF-mutant CRC was found, and may explain reported differences in outcomes for diabetic CRC patients. [Table: see text]
STAT3 as a potential molecular target to sensitize colorectal cancer cells to chemoradiotherapy.
Authors: Grade Marian 
Published: February 2017

434 Background: Resistance to preoperative chemoradiotherapy represents a major clinical problem in the treatment of patients with locally advanced rectal cancer. Therefore, the identification of molecular biomarkers that differentiate responsive and resistant tumors is exceedingly important, because this may lead to the identification of novel molecular targets whose modification could be harnessed to sensitize a priori resistant tumors to multimodal treatment. Methods: We recently established an in vitro model for 5-FU based chemoradiotherapy, and correlated differences in treatment sensitivity of 12 colorectal cancer cell lines with pretherapeutic gene expression profiles. One gene the expression of which correlated positively with treatment resistance was the signal transducer and activator of transcription 3, STAT3. To test the functional relevance of this observation, we first determined STAT3 mRNA and protein expression levels in all cell lines. Next, we established doxycycline-inducible stable shRNA single-cell clone (SCC) populations. Successful silencing of STAT3 was detected by Western blot analysis. The induced SCCs were treated with 3 µM 5-FU, and subsequently exposed to 0, 1, 2, 4, 6, and 8 Gy of X-rays. In addition, STAT3 was inhibited using two different siRNAs, and a small-molecular inhibitor (STATTIC). Results: STAT3 was significantly overexpressed in resistant cells. In SW480 and SW837 cells, both shRNA- and siRNA-mediated silencing as well as STATTIC-induced inhibition of STAT3-phosphorylation resulted in a significantly increased chemoradiosensitivity, with dose-reduction factors of 1.8 to 2. Conclusions: These results highlight the potential relevance of STAT3 as a novel molecular target to sensitize a priori resistant tumor cells to chemoradiotherapy.
Distant recurrences of colorectal cancer: Incidence, systemic treatment, and survival in daily practice.
Authors: van Gestel Yvette , van Herk-Sukel Myrthe , de Hingh Ignace , Rutten Harm , Creemers Geert-Jan , Lemmens Valery E. P. 
Published: February 2017

441 Background: To provide population-based data on the patterns, risk factors, treatment, and survival of distant recurrences of colorectal cancer (CRC). Methods: All patients (n=6,066) diagnosed with CRC M0 in 10 large Dutch non-academic hospitals between 2003 and 2008 were included. By means of active follow-up, data on distant recurrences and systemic treatment were collected. Median follow-up was 4.4 year. Results: 1,074 (18%) patients were diagnosed with distant recurrent disease during follow-up of which 85% within 3 years. Most common affected sites were liver (60%), lung (39%), extra-regional lymph nodes (22%) and peritoneum (19%) (multiple sites possible). Male sex (female=ref (17%), 19%/HR 1.1 95%CI 1.0-1.3), advanced primary tumor stage (T1=ref (4%), T2 9%/HR 3.0 95%CI 1.8-4.9, T3 21%/HR 6.1 95%CI 3.8-9.9, T4 29%/HR 11.0 95%CI 6.7-18.1), advanced lymph node stage (N0=ref (11%), N1 29%/HR 2.8 95%CI 2.4-3.3, N2 41%/HR 4.5 95%CI 3.7-5.4), primary tumor localization (left colon=ref (17%), right colon 16%/HR 0.8 95%CI 0.7-1.0, rectum 25%/HR 1.2 95%CI 1.0-1.4), and tumor differentiation grade (well differentiated=ref [16%], poorly differentiated 26%/HR 1.4 95%CI 1.2-1.7) were associated with increased risk recurrences while chemotherapy for the primary tumor was associated with reduced risk (HR 0.8 95%CI 0.7-0.9). Recurrence rates did not differ between hospitals. 52% of patients with recurrences received systemic therapy, ranging from 34-62% between the 10 hospitals (p<0.01). Half of these patients (52%) was also treated with bevacizumab, ranging from 39-73% between hospitals (p<0.05). Median survival since diagnosis of recurrence was 31 months for patients with lung metastases only, 16 months for liver metastases only, 14 months for lung metastases only, and 5 months for metastases confined to the peritoneum. Conclusions: The development of distant recurrent disease was strongly related to tumor characteristics, but not correlated with hospital of primary treatment. Population-based data on distant recurrences may ultimately contribute to more accurate patient information, and more efficient follow-up schemes.
Role of overexpressions of ALEX1 gene in human colorectal tumorigenesis.
Authors: Takeda Akihiko 
Published: February 2017

443 Background: Arm protein lost in epithelial cancers, on chromosome X (ALEX) is a novel subgroup within the armadillo family which has several ARM repeat domain. Our studies have revealed that overexpression of ALEX1 suppressed colony formation ability of stable human colorectal carcinoma cell lines. But clinical significance of ALEX1 expression in colorectal cancer patients is largely unknown. Methods: We examined the expression level of ALEX1 mRNA in matched tissue pairs of normal colorectal mucosa and colorectal tumor tissue by quantitative real-time RT-PCR Tumor specimens along with adjacent normal tissues were obtained from 49 patients with primary colorectal cancer undergoing complete surgical resection of tumors and lymph nodes, followed by adjuvant systemic therapy in some cases. All tissue samples were stored at -80°C until use. The 49 colorectal specimens comprised 26 well-differentiated and 23 moderately-differentiated adenocarcinoma. Corresponding extraneoplastic normal colon tissues from the same 49 patients were also examined. The pathological stages of the patients were as follows: stage I, 9 patients; stage II, 16 patients and stage III, 24 patients by pTNM classification. The post-surgical treatment observation period was from 277 to 3,631 days (1625.0 ± 1033.0 days). Results: In 34 cases out of 49 (69%) colorectal tumor tissues, greater than a 50% reduction of the ALEX1 mRNA level was observed in comparison to adjacent normal mucosa tissues. ALEX1 mRNA was significantly reduced in colorectal tumor tissues than those in normal mucosa (p=0.01459, Mann–Whitney U-test). The 17 cases with higher ALEX1 gene expression (tumor/normal value ³a0.20) significantly revealed a better disease-free survival rate than the other 32 cases (< 0.20; p = 0.045, log-rank test), which showed significant correlations between ALEX1 expression and better prognosis. There was no significant relationship between ALEX1 expression and the other clinicopathological features. Conclusions: Our findings may support that ALEX1 functions as a tumor suppressor in colorectal cancer progression. Examination of ALEX1 expression might be helpful for predicting the prognosis of patients with curative resected colorectal cancer.
A case of the utilization of genomic information in the management of metastatic colorectal cancer.
Authors: Peixoto Renata D'Alpino , Li Yvonne , Pleasance Erin , Yip Stephen , Zhao Yongjun , Schein Jacquie , Shen Yaoqing , Lim Howard John , Renouf Daniel John , Gelmon Karen A. , Huntsman David , Jones Steven , Marra Marco , Laskin Janessa J. 
Published: February 2017

444 Background: Anectodal success using genomic information to personalize and guide cancer therapy in rare tumours has been reported. This is a case report of the use of genomic information in the management of metastatic colorectal cancer. Methods: A 31 year old female presented with metastatic disease from the colon to the liver and retroperitoneal lymph nodes. She was treated with aspirin and 4 cycles of 5FU/Irinotecan/Bevacizumab before blood and liver biopsies were taken. Sections from the primary tissue embedded in paraffin were compared to metastatic disease in the liver and blood. Two platforms were used: a targeted deep sequencing of 46 genes via a cancer specific amplicon assay and whole genome sequencing and RNA sequencing followed by bioinformatics approaches were employed to identify genes with somatic variants, copy number variations, losses of heterozygosity, structural variation, and expression changes. Results: Genome sequencing followed by bioinformatics analysis detected ~100 somatic mutations, ~100 amplified genes with increased expression, and ~90 down-regulated genes with copy number loss in the metastasis. Other interesting observations included increased allelic frequencies in BRAF V600E, and SMAD4 R361C as well as high gene copy amplifications in VEGFA and MAGI from the primary to the metastasis, and lack of somatic mutation in KRAS. Conclusions: The upregulation of VEGF pathways from the primary compared to the metastasis suggests a significant shift in tumour biology likely as a result of the bevacizumab and COX-2 inhibition from aspirin; this may have implications when anti-VEGF therapy is withdrawn. The BRAF mutation and wild type KRAS status may suggest that combination of a BRAF inhibitor with EGFR inhibition is warranted. This information demonstrated the benefit of therapy on a genomic level and aided in determining possible future targets and modifications to conventional therapy.
Outcome of patients (pts) with relapsed, advanced upper gastrointestinal (GI) carcinoma treated in a specialist oncology phase I unit.
Authors: Khan Khurum Hayat , Ang Joo Ern , Starling Naureen , Shah Krunal Jitendrakumar , Molife L. Rhoda , Banerji Udai , De Bono Johann Sebastian , Cunningham David , Kaye Stanley B. 
Published: February 2017

45 Background: Conventional chemotherapy in advanced upper GI cancer after progression on first line therapy yields low response rates and no clear survival benefit. In this context, some pts are offered experimental treatments, including participation in Phase I clinical trials. Methods: Baseline pt and tumour characteristics, toxicity, response and outcome data of pts with upper GI cancers consecutively treated within the Drug Development Unit, Royal Marsden Hospital, from 2005 to 2009, were documented. Results: Ninety-six pts (median age 59 years [range 24-77]; male/female ratio 3.6, median of 2 [range 0-4] prior lines of chemotherapy) with oesophageal (42%), gastric (14.5%), pancreatic (26%) and oesphagogastric junction (7%) carcinomas were treated in 30 Phase I trials; of these, 36% participated in studies containing conventional cytotoxic chemotherapies. The overall response rate by RECIST was 11% with a disease control rate of 49%. The overall clinical benefit rate (i.e. no disease progression at 6 months) was 14%, respectively. In all pts, the median progression free survival (PFS) and overall survival (OS) were 7.0 weeks (95% CI: 5.6-8.4) and 19 weeks (95% CI: 17-21), respectively; these were not superior in pts who received chemotherapy-containing regimens (p=0.364, p=0.897). Pts with CBR ≥6 months a median OS of 55 weeks (95% CI: 46-64); 59% of them were treated with single-agent molecular targeting agents. Grade 3 or 4 toxicities were observed in 37 pts (39%) and led to trial discontinuation in nine (9%); no toxicity-related death occurred in these pts. In the multivariate analysis of baseline factors, serum albumin (<35 g/dl, HR 2.0 [95%CI: 1.3-3.2] p=0.002) and serum lactate dehydrogenase (LDH) (>192 umol/l, HR 1.7 [95% CI: 1.1-2.6], p=0.016) were prognostic of OS. Conclusions: Phase I clinical trials should be considered a valid option in pts with advanced upper GI cancers with disease relapse after first-line chemotherapy In our experience the risk of toxicity is low/moderate and there is the potential for clinical benefit.
Prospective evaluation of a 12-gene assay on treatment recommendations in patients with stage II colon cancer.
Authors: Srivastava Geetika , Renfro Lindsay Anne , Behrens Robert J. , Lopatin Margarita , Chao Calvin , Soori Gamini S. , Dakhil Shaker R. , Mowat Rex Bradford , Kuebler J. Phillip , Kim George P. , Mazurczak Miroslaw , Lee Mark , Alberts Steven R. 
Published: February 2017

453 Background: A 12-gene assay (Oncotype DX Colon Cancer) has been clinically validated as a predictor of recurrence risk in stage 2 colon cancer patients following surgery. We conducted the first prospective study to characterize the impact of Recurrence Score results on medical oncologists’ recommendations regarding adjuvant chemotherapy in T3, Mismatch Repair-proficient (MMR-P) stage 2 colon cancer patients. Methods: Consecutive patients with resected stage 2A colon cancer who were candidates for adjuvant chemotherapy were consented and enrolled by 105 medical oncologists from 17 sites in the Mayo Clinic Cancer Research Consortium. Each patient’s tumor specimen was assessed by the Recurrence Score test (quantitative RT-PCR) and MMR (IHC). Prior to and after receiving these results, physicians completed surveys indicating their planned treatments given hypothetical or known MMR results, recorded as Observation (Obs), 5FU-based chemotherapy (5FU), or 5FU + Oxaliplatin (Oxal). Change in treatment recommendation intensity from baseline to follow-up was defined as: increased if change from Obs to 5FU +/- Oxal or from 5FU to 5FU+Oxal, decreased if change from 5FU + Oxal to 5FU or Obs, or from 5FU to Obs, or no change. Results: 187 of 221 patients enrolled were evaluable including 141 who were MMR-P (avg age 63, 65% ECOG PS 0, med tumor size 5 cm, 11% high grade, 91% with 12+ nodes examined). In the primary analysis treatment recommendations changed for 63 (45%) of 141 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy (5-FU +/- Oxal) decreased from 73 (52%) patients pre-assay to 42 (30%) post-assay. Increased treatment intensity was more likely at higher Recurrence Score values and decreased intensity at lower Recurrence Score values (p=0.011), and any change was more likely when MMR status was unknown at baseline (p = 0.041). Conclusions: In this prospective study, quantitative recurrence risk information provided by the Recurrence Score test was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients. Use of the 12-gene assay may lead to overall reductions in chemotherapy.
The role of miRNA-145 in esophageal adenocarcinoma.
Authors: Derouet Mathieu Francois , Ko Michael Augustine , Waddell Thomas K. , Liu Geoffrey , Darling Gail 
Published: February 2017

46 Background: Carcinoma of the esophagus has become one of the fastest growing solid tumors in the world over the past 20 years and the 6th most common cause of death in the world. We previously conducted a study to profile the expression of miRNAs in esophageal adenocarcinoma (EAC) pre and post induction therapy. Out of the miRNAs discovered, miR-145, a known tumor suppressor miRNA, was upregulated 8-fold upon induction therapy however its expression was associated with shorter disease-free survival. This unexpected result was explored. Methods: In order to study the role of miR-145 in EAC, miRNA-145 was overexpressed in the EAC cell line OE33 (OE33 miR145). After validation of the expression of miR-145, several hallmarks of cancer such as cell proliferation, resistance to apoptosis and cell adhesion were analyzed. Results: There was no difference in cell proliferation and resistance to radiation between OE33 miR145 and OE33 control. However, there was a significant difference in cell adhesion. OE33 miR145 cells reattach faster than the OE33 control (72.3% cells reattached against 40.5% cells reattached after 3h, n=3, p<0.05). Furthermore, OE33 miR145 cells are able to recover better than OE33 control cells after 72 hours culture in suspension (126.5 colonies against 63.5 colonies after 5 days of culture, n=2, p<0.05). Conclusions: While there was no difference between the two OE33 populations in an attached state, clear differences appeared when cells were in a detached state. Although more work is required to confirm this effect, expression of miR-145 could help EAC cells in circulation by protecting them against apoptosis and helping them to reattach faster which could in turn facilitate distant metastasis.
Racial inequality with radiation oncology referral and treatment in metastatic colorectal cancer.
Authors: Murphy James Don , Le Quynh-Thu 
Published: February 2017

470 Background: Black patients with colorectal cancer have worse outcomes compared to white patients, however the underlying source of this racial disparity remains unclear. This population-based study evaluates the impact of race on referral patterns and subsequent treatment with chemotherapy or radiotherapy in metastatic colorectal cancer. Methods: This study used the Surveillance, Epidemiology, and End Results–Medicare linked database to identify 11,125 patients with stage IV colorectal cancer diagnosed between 2000-2007. Patient demographic data were abstracted from the SEER database, and referral and treatment information were derived from Medicare claims data. Multivariate logistic regression models determined the impact of race on 1) consultation patterns with medical oncology and radiation oncology, and 2) subsequent treatment with chemotherapy and radiation therapy. Results are presented as adjusted odds ratios (OR) that control for potential confounding factors including age, comorbidity, socioeconomic status, geography, gender, marital status, and year of diagnosis. Results: Of the entire patient cohort, 2,025 (18%) were seen in consultation by a radiation oncologist, and among these patients, 1,221 (60%) ultimately received radiotherapy. Black patients had significantly lower rates of consultation with a radiation oncologist compared to white patients (OR=0.79, 95% CI=0.65-0.96; p=0.016). Among patients with a radiation oncology consultation, fewer black patients were subsequently treated with radiotherapy (OR=0.67, 95% CI=0.46-0.99; p=0.046). There was no difference between black and white patients in time from diagnosis to radiation treatment, and no difference in radiation treatment duration. We found no race-related difference in medical oncology consultation rates (p=0.24), nor in subsequent treatment with chemotherapy (p=0.95). Conclusions: This study shows racial disparity in radiation oncology consultation rates, and in radiation therapy treatment. Further research evaluating these barriers to care will help us achieve equality in treatment of metastatic colorectal cancer.