bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of a chemobrain effect for adjuvant FOLFOX chemotherapy in colon cancer patients: A pilot study.
Authors: Zaniboni Alberto , Andreis Federica , Ferri Marco , Mazzocchi Maria , Meriggi Fausto , Rizzi Anna , Rota Luigina , Di Biasi Brunella , Abeni Chiara , Codignola Claudio , Rozzini Renzo
Published: March 2020

e14018

Background: Chemotherapy improves the survival rate of stage III colon cancer patients. The combination of oxaliplatin, 5-fluorouracil and leucovorin (the FOLFOX4 regimen) has emerged as the standard of care. Cognitive changes and disfunction after cancer chemotherapy are increasingly reported as a disturbing side-effect in cancer survivors. This prospective study evaluates potential alterations in cognitive function in Folfox4-treated patients. Methods: We evaluated 57 consecutive colorectal cancer patients who received adjuvant chemotherapy with FOLFOX4. Patients underwent a complete battery of neuropsychological tests at three different times: before (T0), at the end (T1) and six months after treatment (T2). Changes in neuropsychological test scores at T0, T1 and T2 were compared with a two tail t-test (T1-T0, T2-T1, T2-T0), using the repeated measure ANOVA model. Results: We have analyzed cognitive impairment (Mini Mental State Examination, MMSE), visuo-spatial memory, information processing speed (Trial Making Test-A and Trial Making Test-B), verbal memory (Rey Auditory Verbal Learning Test), emotional distress (Psychological Distress Inventory), anxiety (State and Trait Anxiety Inventory) and depression (Beck Depression Inventory). We found no cognitive impairment in time considered, as we found a median MMSE score of 27,51 ± 1,21 at T0, 27,63 ± 0,65 at T1 and 27,26 ± 1,17 at T2. We noticed some transient variations in tests evaluating verbal memory and in information processing speed performances. The only significative scores modifications were those related to anxiety and depression. Conclusions: We found no significant effect on cognitive function related to chemotherapy, the only little modification is about some emotional performance during chemotherapy. These findings may be explained by the central role of the psychological adaptation process, which occurs during the period from diagnosis to completion of treatment and is characterized by anxiety and adjustment depression. Our results seem to rule out any significant cognitive impairment due to adjuvant Folfox4 chemotherapy in colon cancer patients.
De-adoption of epidermal growth factor receptor (EGFR) inhibitors following recommendations for KRAS testing to guide treatment of metastatic colorectal cancer (mCRC).
Authors: Dotan Efrat , Li Tianyu , Hall Michael J. , Meropol Neal J. , Beck Robert J , Wong Yu-Ning
Published: March 2020

e14021

Background: KRAS mutation status is a predictive biomarker for resistance to EGFR antibodies among mCRC pts, and is recommended for use by ASCO and the FDA. Little is known about the uptake of clinical recommendations in oncology practice. We sought to study the effect of ASCO and FDA guidelines on the use of EGFR antibodies among a commercially insured population. Methods: The LifeLink Health Plan Claims Database (formerly the PharMetrics Patient-Centric Database) was used to create a cohort of >18 yo mCRC pts treated between 2004-2010. We identified treatment and diagnosis using ICD-9 or HCPCS (J) codes. We defined 1st line therapy as any chemotherapy +/- bevacizumab given after the pt had a claim for mCRC, excluding pts treated with EGFR antibodies in the 1st line. 2nd line therapy was defined as the initiation of a new chemotherapy agent (irinotecan/oxaliplatin) +/- EGFR antibody. We examined pts in two-month time intervals and calculated the fraction of pts in each interval who received EGFR antibody at any point beyond their 1st line treatment. Chi2 tests were used to compare treatment rates at the time points shown in the Table. Results: 5099 pts received 2nd line therapy of which 2603 pts received an EGFR antibody. Median age was 61 years, with 57% males. 59% received an EGFR antibody as a single agent. The remainder received this in combination with one or more of the following agents: fluorouracil 13.5%, irinotecan 36.7%, oxaliplatin 3.9%, and bevacizumab 6.1%. Rates of EGFR antibody use are outlined in the Table. Conclusions: The utilization of EGFR antibodies for mCRC treatment decreased following the presentation of clinical trial data, publication of ASCO guidelines and FDA label change. These data suggest that oncologists respond rapidly to new evidence and professional guidelines, and readily accept the use of predictive biomarkers in clinical practice. [Table: see text]
Use of germ-line variants in the WNT/β-CATENIN pathway to predict tumor recurrence in adjuvant colon cancer.
Authors: Wilson Peter M.D. , Páez David , Gerger Armin , Zhang Wu , Yang Dongyun , Labonte Melissa Janae , Benhaim Leonor , Bohanes Pierre Oliver , Ning Yan , Wakatsuki Takeru , Loupakis Fotios , Lenz Heinz-Josef
Published: March 2020

e14034

Background: The Wnt/β-catenin signaling plays a central role in the development and progression of most colon cancers. Germline variants in Wnt/β-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/β-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II colon cancer. Methods: A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4 genes by PCR-RFLP or direct DNA-sequencing. We also included NOTCH2 and GLI1 variants which belong to the Notch and Hedgehog pathways respectively. Results: The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (4.9vs10.7 years; HR: 2.48; 95%CI, (0.96, 6.38); p=0.044) in high-risk stage II colon cancer patients. This result remained significant in the multivariate Cox regression analysis. Conclusions: Despite the importance of Wnt/β-catenin pathway in the development of cancer, only the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for colon cancer patients after 5-fluorouracil-based adjuvant therapy.
KRAS aKtive, an Italian network for assessment of KRAS mutations in colorectal cancer patients: Results on 7,432 cases.
Authors: Marchetti Antonio , Pinto Carmine , Taddei Gian Luigi , Clemente Claudio , Troncone Giancarlo , Russo Antonio , Fontanini Gabriella , Larocca Luigi Maria , Mottolese Marcella , Giannini Giuseppe , Ruco Luigi , Roz Elena , Scarpa Aldo , Calabrese Giuseppe , Bortesi Beatrice , Vaccarella Salvatore , Cossu Antonio , Ludovini Vienna , Normanno Nicola
Published: March 2020

e14042

Background: The KRAS aKtive program was started on March 2009, promoted by the Italian Association of Medical Oncology (AIOM) and the Italian Society of Surgical Pathology and Cytopathologyy (SIAPEC) to support the activity of oncologists and pathologists involved in the management of metastatic colorectal cancer patients who need the assessment of the mutational status of the KRAS gene. Methods: The program was specifically devised to facilitate the exchange of biologic material, clinicopathological data and diagnostic reports within a network of oncologist, pathologists and pathology/molecular biology reference laboratories throughout Italy, connected through the site www.kras-aKtive.it. KRAS mutation analysis was performed by Sanger sequencing (SS), real time PCR or other techniques, including pyrosequencing and hybridization strip assays. Data were collected in a common database. Results: The KRAS aKtive program has involved 478 oncologists, 144 pathologists, and 24 reference laboratories. A total of 7,432 KRAS mutations analyses were performed. The tests were informative in 7,265 cases (98%). The vast majority of tests (5,626 cases, 77.4%) were conducted by SS. In 529 (7.3%) cases a real-time PCR assay was used, other detection techniques were used in 1,110 (15.3%) cases. KRAS mutations at codons 12-13 were detected in 2,874 cases (39,6%). The frequency of mutations detected by real-time PCR or other techniques (45%, and 43%, respectively) was significantly higher (p=0.002, and p=0.008%, respectively) than that observed by SS (38%). The percentage of cases evaluated by non-SS-based methods has increased during the first three years of the program. Conclusions: The results of this large survey allow an accurate estimation of the actual prevalence of KRAS mutations and their types in caucasian colorectal cancer patients. Our data indicate that the frequency of mutations detected by non-SS-based methods is higher than that obtained by SS.
Phase I/II study of preoperative concurrent chemoradiotherapy with S-1, irinotecan, and cetuximab for locally advanced rectal adenocarcinoma.
Authors: Ota Mitsuyoshi , Goto Ayumu , Ichikawa Yasushi , Suwa Yusuke , Watanabe Jun , Watanabe Kazuteru , Tanaka Kuniya , Akiyama Hirotoshi , Fujii Shoichi , Endo Itaru
Published: March 2020

e14050

Background: Recent studies reported that the cetuximab regimen including irinotecan has high tumor-response rates as a neoadjuvant chemotherapy for colorectal cancer patients. The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for irinotecan combined use of S-1 and cetuximab as a preoperative chemoradiotherapy and to evaluate the feasibility and effect in patients with locally advanced rectal cancer. Methods: Patient s with adenocarcinoma of the lower rectum were enrolled in a phase I trial. Wild type KRAS was confirmed by biopsy specimen in all eligible patients. Also, UGT1A1 gene polymorphism was examined to avoid irinotecan-induced severe neutropenia and homozygous type (*28/*28, *6/*6, *28/*6) patients were excluded from this study. A total dose of 50.4 Gy was delivered in 28 fractions over 6 weeks, and 80 mg/m2 of S-1 was orally administered twice a day on days 1–14 and 22–35. Irinotecan was given 125 mg/m2 (level 1) to 150 mg/m2 (level 2) on day 1 and 22. Cetuximab was given 400 mg/m2 on day 7 as a loading and 250 mg/m2 weekly on day 1 to 35. Surgical resection was scheduled 6–8 weeks after the completion of chemoradiation. Results: Among the 5 patients, who received 125 mg/m2 irinotecan, dose-limiting toxicity (DLT); perforation occurred in 1 patient. Grade 3 neutoropenia occurred in 2 patients, who recovered within a week. Within grade 2 of anal pain and acne-like erythema was occurred in all patients. A pathological complete response (pCR) was not observed, pathological downstaging was observed in 4/5 patients (80%), and a tumor volume reduction of 68% was obtained. Conclusions: In phase I, the maximum-tolerated dose was not reached, and the recommended dose (RD) of irinotecan was seemed to be 125 mg/m2. This new protocol referred to KRAS and UGT1A1 profile is well tolerated, and should proceed to a phase II trial to evaluate the effectiveness.
The relationship between tumor expression of phosphorylated STAT3 and pathology and outcome in colorectal cancer.
Authors: Guthrie Graeme JK , Platt Jonathan J , Mohammed Zahra MA , Roxburgh Campbell SD , Horgan Paul G , Mcmillan Donald C. , Edwards Joanne E.
Published: March 2020

e14054

Background: Cancer-associated inflammation has recently been identified as a key determinant of disease progression and survival in colorectal cancer(CRC). The signal transducer and activator of transcription 3(STAT3) pathway is central to the inflammatory response, and has been implicated in cancer development and progression. This study aimed to evaluate tissue expression of cytoplasmic and nuclear STAT3 expression in CRC and its association with clinicopathological variables and survival. Methods: Patients were identified from a prospectively maintained CRC database. Using immunohistochemistry on a tissue microarray, cytoplasmic and nuclear expression of phosphorylated STAT3 (p-STAT3) at both the tyrosine 705(tyr705) and serine 727(ser727) phosphorylation sites was assessed using the weighted histoscore. Associations between p-STAT3 expression and clinicopathological factors and survival were examined. Results: In 273 patients, cytoplasmic and nuclear p-STAT3 expression was examined and considered positive if staining was observed in more than 15% of tumour cells. When colonic and rectal tumours were considered together, cytoplasmic and nuclear p-STAT3 expression at both phosphorylation sites (tyr705 and ser727) showed no significant relationship with clinicopathological variables. Similarly, when colonic tumours were considered alone, cytoplasmic and nuclear p-STAT3 expression showed no association with clinicopathological factors. In rectal cancer, although cytoplasmic p-STAT3 was not significantly associated with survival, nuclear p-STAT3 expression was associated with improved survival(tyr705 p=0.007, ser727 p=0.098). Similar to the colon cancer group, rectal cancer nuclear p-STAT3 expression showed no correlation with clinicopathological variables. Conclusions: Tumour nuclear p-STAT3 expression and its association with outcome appears to depend on tumour site with improved survival associated with nuclear p-STAT3(tyr705) expression in rectal but not colon cancer. The basis of this observation is not clear and further assessment of the role of p-STAT3 in the tumour microenvironment is required.
Association between a specific miRNA signature and pathological response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) patients.
Authors: Bandres Eva , Arias Fernando , Guerrero David , Lopez Ines , Gonzalez-Huarriz Marisol , Gomez Dorronsoro Maria Luisa , Montes Marta , Monzon Francisco , Torrea Natalia , Armendariz Pedro , Balen Enrique , Viudez Antonio , Asin Gemma , Chicata Victor , Hernandez Irene , Eito Clara , Garcia-Foncillas Jesus
Published: March 2020

e14057

Background: MicroRNAs (miRNA), small non-coding RNA molecules act as post-transcriptional regulators of gene expression and have shown diagnostic and prognostic potential in cancer. We profiled miRNA expression in LARC patients treated with neoadjuvant CRT to assess whether a miRNA signature correlated with the degree of pathological response. Methods: FFPE-derived tumour samples from 85 LARC patients treated with preoperative CRT (45 Gy plus 5.4 Gy boost, 180-cGy daily fractions and concurrent capecitabine) were analyzed for miRNA signature generation and IHQ-EGFR protein expression. Pathological response was scored according to the Mandard’s TRG scale. Expression profile of 667 mature miRNAs obtained by TLDA Human MicroRNA Panel or individual TaqMan MicroRNA Assays were normalized using RNU48, selected as the best normalizer by Normfinder program. The correlation between miRNA expression profile and pathologic response was assessed by class-comparison, unsupervised hierarchical cluster analysis and U-Mann Whitney test. Results: A pathological complete response was achieved in 12 patients (14%), whereas no response (TRG 3-4) was observed in 49 patients (58%). As expected, TRG correlated with both relapse and disease-free survival (p<0.01). We identified a miRNA signature that correctly differentiated extreme-phenotype of responder patients (TRG-1 vs TRG-4). The top 10 of them were selected to be validated by individual Q-RT-PCR in the global series. While up-regulation of miR-21*, miR-99*, miR-125b, miR-125b1*, let-7c and miR-490 significantly correlated with a higher likelihood of achieving pathological response (TRG-1-2), miR-21 and miR-125a-3p downregulated levels were found to be associated with a TRG-4 response. High EGFR protein expression levels, determined by IHQ, were seen in the 93% of poor-responders patients (TRG-4). Interestingly, miR-21 and miR-21* levels inversely correlated with EGFR expression. Conclusions: A differential expression of miRNAs may predict the degree of pathological response to CRT in LARC patients. A miRNA-mediated role for EGFR pathway in CRT resistance warrants further research.
Prognostic value of KRAS in terms of efficacy and safety of bevacizumab as neoadjuvant or conversion treatment in patients with colorectal liver metastasis.
Authors: Garcia Alfonso Pilar , Muñoz Martin Andrés Jesús , Alvarez Sonsoles , Riesco M. Carmen , Blanco Codeisido Montse , Ruperez Blanco Ana Belen , Custodio Cabello Sara , Tapia Gonzalo , Mondejar Solís Rebeca , Martin Miguel
Published: March 2020

e14058

Background: Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, only a small proportion has initially resectable metastases. Bevacizumab (BEV) added to chemotherapy (CT) is active for metastatic CRC. This study aimed to assess efficacy and safety of BEV as neoadjuvant or conversion treatment in patients with CRC liver metastases. Methods: Observational retrospective review in CRC patients with liver metastases who have undergone neoadjuvant or conversion CT with BEV as first or second line treatment. Results: 34 patients analyzed: 53% male; median age 55; 77% had metastases at diagnosis; ECOG 0-1 (38-62%); primary tumor location: 52% colon, 37% rectum, 11% colon/rectum; 84% had synchronic metastases; 16% initially resectable metastases 9% irresectable and 75% potentially resectable. 77% and 24% received first and second line BEV prior surgery respectively. Complete resection was achieved in 85%. All patients with initially unresectable metastases become resectable. 44% suffered post-operative complications; most frequent being abdominal and wound infection (12-9%). Complete pathologic response of liver metastases was seen in 7% and 61% reached major response. Median OS after surgery was 46 months. Disease free survival (DFS) since surgery was 8.8 months without significant differences between those receiving BEV as first or second line treatment. 88% of patients did not expeirence grade 3-4 toxicity. KRAS mutation was detected in 10 of 26 patients with available KRAS status (39%). Median DFS was significantly longer in wild type wt-KRAS patients compared with those mutated m-KRAS (12 vs 7 months p<0.001) thus confirming KRAS as a prognostic biomarker. Major pathologic response rate was significantly improved in wt-KRAS patients vs m-KRAS (84% vs 25% p<0.001). Conclusions: Neoadjuvant or conversion CT with BEV is an active treatment option for patients with CRC liver metastases with an adequate safety profile and without an apparent increase of surgical complications. While both wt-KRAS and m-KRAS patients benefit from treatment with BEV, wt-KRAS patients obtain greater pathologic response and significant longer DFS.
Phase II trial of preoperative radiotherapy (RT) and panitumumab (PAN) in KRAS wild type (wt) rectal cancer (RC).
Authors: Mardjuadi Feby Ingriani , Canon Jean-Luc , Coche Jean-Charles , Jouret-Mourin Anne , Sempoux Christine , Goeminne Jean-Charles , Delaunoit Thierry , Carrasco Javier , Vuylsteke Peter , Humblet Yves , Meert Nicolas , Van den Eynde Marc , Moxhon Anne , Machiels Jean-Pascal H.
Published: March 2020

e14060

Background: The addition of anti Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies (mabs) to preoperative chemoradiation in RC has produced low pathological complete response (pCR) rate. The postulated reasons for the poor outcome are: lack of patient selection, suboptimal treatment sequencing, and potential negative interaction between anti EGFR mabs and chemotherapy (CT) when used concurrently as radiosensitizers. Given these issues, we conducted a phase II trial of PAN in combination with preoperative RT in Kras wt RC. Methods: We studied several treatment sequences in murine models of Kras wt human colorectal cancer. Next, we used our preclinical results to design the treatment schedule of the phase II trial. PAN (6mg/kg/q2w) was combined with RT (45 Gy) to treat T3-4, Kras wt RC. Surgery was done 6-8 weeks after the end of RT. The primary endpoint, the pCR rate on surgical specimen, was assessed centrally (Simon: H0=5%, H1=17%, α=0.05, β=0.2). Results: In our murine models, the addition of anti EGFR mabs to RT significantly improved response when anti EGFR mabs were started during RT and extended after the end of RT (p<0.05). No benefit was found when anti EGFR mabs were given before the start of RT. In the phase II trial, we therefore started RT on day 1 and introduced PAN 7 days later (day 8). After RT ended (day 36), PAN treatment was continued to day 50. To fully explore PAN’s potential as radiosensitizer, CT was not given during RT but postoperatively. 19 patients were evaluable for pCR. 47% of tumours were cT3N+. Hypomagnesemia (16%) and hypophosphatemia (16%) were most common grade ≥3 toxicities. As no pCR was found, the study was closed prematurely for lack of efficacy according to the statistical rule. 7 patients (41%) had >50% pathological tumour regression (grade 3 Dworak) and 12 (70%) showed >2mm of tumour-free circumferential resection margin. Conclusions: Preclinical data confirm the need of optimal treatment sequencing to potentiate synergism between anti EGFR mabs and RT. However, the pCR rate in our phase II trial remains low despite adequate patient selection and optimized study design. Thus, we do not recommend the concurrent use of anti EGFR mabs and RT in the neoadjuvant treatment of RC.
Predictors of survival during treatment of metastatic colorectal cancer with an intermittent chemotherapy regimen.
Authors: Kronborg Camilla J S , Jensen Anni Ravnsbæk
Published: March 2020

e14063

Background: Patients with metastatic colorectal cancer (mCRC) undergo month to year-long therapy with different chemotherapy regimens and biological agents. We aimed to identify predictors of mortality during an intermittent treatment regimen in an unselected cohort of patients with mCRC. Methods: Consecutive patients, treated from August 2007 until June 2011, were included. Standard 1st line treatment was biweekly FLIRI plus Bevacizumab. Clinical information was obtained from patient files. The outcome was overall survival. Cox regression analysis was used to identify predictors of outcome. We analyzed reduction in chemotherapy dosage (no reduction, ≤75% or >75%), administration of Bevacizumab to ≤50% of chemotherapy treatments, best response during the first 6 months of treatment (NC, RD or PD), and local treatment of metastases (any type). We adjusted for following baseline variables: Gender, age, PS, primary tumor site, resection of primary tumor, metachronous metastases, more than two metastatic sites, liver-only metastases, and low albumin Results: We included 314 patients (median age 64.5 IQ (57-70) years, 194 (61.8%) male). Median follow-up for survival was 471 IQ (257-708) days. One-year survival was 79%, CI (74-84%). Median overall survival was 676 days, CI (577-750). Chemotherapy reduction did not influence outcome, ≤75%: HR 1.08 CI (0.64-1.83), p=0.77, >75%: HR 0.66 CI (0.29-1.5), p=0.32. Local treatment of metastases was borderline significant: HR 0.45 CI (0.20-1.00), p=0.051. Bevacizumab was administered in 262 patients and a reduction in bevacizumab treatments was associated with increased mortality: HR 1.90 CI (1.12-3.23), p=0.018. Regression vs. NC improved outcome HR 0.48 (0.30-0.78), p=0.003, whereas PD vs. NC increased mortality HR 3.84 (1.75-8.42), p=0.001. Conclusions: In an unselected cohort of mCRC patients, using an intermittent treatment regimen, administration of Bevacizumab to less than 50% of chemotherapy treatments and PD were associated with increased mortality. Regression improved outcome compared to stable disease. Local treatment of metastases was borderline significant. Reduction in chemotherapy dosage did not influence outcome.
PPP1R13L variant as a prognostic factor in patients with rectal cancer.
Authors: Chae Yee Soo , Kim Jong Gwang , Sohn Sang Kyun , Lee Soo Jung , Kang Byung Woog
Published: March 2020

e14074

Background: Genetic variants related with apoptosis and DNA repair pathways may play a meaningful role in cancer progression as well as carcinogenesis. Among them, PPP1R13L and ERCC1 polymorphisms was found to synergistically affect these pathways. The aim of this study was to investigate the association between these genetic variants and prognosis of colorectal cancer (CRC) operated curatively. Methods: A total of 349 CRC patients underwent curative surgery between March 2003 and August 2006 were consecutively enrolled. DNA was extracted from fresh frozen normal tissue and each polymorphism (PPP1R13L rs1005165 and rs967591; ERCC1 rs11615 and rs735482) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: No statistical significance between these 4 variants and survival in a multivariate analysis for all CRC patients. However, the CC genotype of the PPP1R13L rs1005165 was significantly associated with worse survival in 164 patients with rectal cancer (HR = 2.10 and p = 0.037 for RFS; HR = 2.27 and p = 0.039 for DSS, respectively) as a recessive model of the C allele in a multivariate analysis. Meanwhile, no statistical differences in clinicopathologic characteristics were observed according to the rs1005165 genotype in rectal cancer patients. Conclusions: Our results suggest that PPP1R13L variant is possible prognostic marker in Korean patients with operated rectal cancer.
Smoothelin as a marker of muscularis propria in biopsies of colorectal carcinomas.
Authors: Stoemmer Peter E. , Torres-Galea Patricia
Published: March 2020

e14076

Background: Preoperative staging is of eminent importance for the treatment of colorectal carcinomas (CRCs). Especially the distinction of carcinoma in situ (not permigrating the muscularis mucosae (MM)), the pT1 stage (limited to the submucosa) and pT2 and above, infiltrating the muscularis propria(MP) in endoscopic biopsies could change the therapeutic regimen. Smoothelin (SMT) is a robust marker of the MP in normal colon, which is not expressed in MM; therefore, we analysed its expression in biopsies and resections of CRCs, to test its predictive value in staging of CRCs. Methods: 50 CRCs, diagnosed in biopsy particles and staged in the surgical specimens were analysed by IHC for expression of smoothelin (MoAb R4A, DCS Hamburg), Desmin and smooth muscle antigen SMA (all DAKO ) in MP and MM in the vicinity of invading carcinoma cells and in distance to the tumor. Semiquantitative grading REMMELE. Results: Desmin and SMA were consistently expressed in the smooth muscle cells of MM and MP near and distant to carcinoma cells. SMT showed no or little expression in the muscle cells of MM. The penetration of the MM by tumorcells did not alter their reactivity. In the MP however, the invasion by carcinoma cells caused a total or subtotal loss of SMT in the cytoplasm of the smooth muscle cells. The diameter of the nucleus and the longitudinal axis in SMT-deprivated cells did not change, but the transversal diameters of the cells were decreased. Reducing the mechanical stress of smooth muscle cells diminishes also the expression of SMT. No predictive correlation between biopsy-estimated depth and real depth of tumorinfiltration was seen. Conclusions: Expression of SMT correlates to functional status of the cells. The reliable difference in the IHC-expression of SMT in MM and MP in normal colon is not seen in the colon near carcinomas: the muscle cells of MP also lose their STM expression. Thus, negativity for SMT in smooth muscle cells near tumorcells does not necessarely proof, that this will be MM; as well, it could be SMT-deprivated cells of the MP. To rely upon SMT in biopsies for the determination of the depth of invasion is highly dangerous.
Predictive biomarkers of response to cetuximab in Chinese patients with metastatic colorectal cancer.
Authors: Ma Brigette , Loong Herbert , Liem Giok Siong , Mo Frankie , Tong Joanna , Wong SC Cesar , Chan Anthony T. C. , To Ka Fai
Published: March 2020

e14085

Background: The paraffin-embedded tumor samples of 183 Chinese patients (pts) with metastatic colorectal cancer (mCRC) who had chemotherapy (chemo) over a period of 3.3 years were analyzed for the presence of KRAS, PIK3CA and BRAF mutations. Methods: PCR-direct sequencing was performed in micro-dissected tumor cells. The relationship between mutation and survival was evaluated using the Proportional Hazard Model, and relationship with drug response was evaluated with logistic regression. Multivariate analysis was used to adjust for the influence of age, sex, prior lines of chemo, use of bevacizumab (Bev) and the number of sites of metastases. Results: The median age was 58 yrs, over 50% of pts had > 2 lines of chemo and 50% had cetuximab. The prevalence of KRAS, BRAF and PI3KCA mutations were: 55%, 5%, 20% respectively. The prevalence of each KRAS mutation subtype was: G12D (36%), G12V (22%) and G13D (16%). KRAS mutation and prior use of Bev were independent prognostic factors with respective hazard ratios (HR) of 1.5 (95% CI = 1.05-2.16, p = 0.03) and 0.51 (95% CI = 0.3-0.87, p = 0.01). In the subgroup of patients who received cetuximab and chemotherapy in the first-line setting, KRAS mutation was associated with a lack of response to chemo with odd ratio (OR) of 0.1 (95% CI = 0.01-0.79, p=0.03). There was no correlation between the presence of BRAF and/ or PIK3CA mutations and OS or drug response. Five pts had co-expression of KRAS and PIK3CA mutations and none of them responded to cetuximab. Of the 14 pts who had complete response or prolonged disease stabilization to cetuximab-chemo, 4 had KRAS mutation, 1 had PIK3CA mutation and none had BRAF mutations. Conclusions: The prevalence of KRAS, BRAF and PIK3CA mutations reported in this Chinese cohort is consistent with reports from other non-Asian populations. KRAS mutation is an independent negative prognostic factor in chemo-treated pts with mCRC. KRAS mutation was associated with poorer response to 1st line cetuximab-based chemo.
Frequency of KRAS mutations in female colorectal cancer (CRC) patients: Findings of a Brazilian cohort of 8,234 cases.
Authors: Ferreira Carlos G. M. , Zalis Mariano , Zalcberg-Renault Ilana , Bonamino Martin H , de Pinho Marcos Barcelos , Helal Rafaela Cordeiro , Salem Jonas Hauben , Victorino Ana Paula Ornelas , Vieira Fernando Meton
Published: March 2020

e14101

Background: Although major advances in the last decades, there are still important gaps in our understanding of CRC carcinogenesis, particularly whether sex-linked factors play any role. Some groups, including ours, observed that KRAS mutation may be more frequent in female than male (Ferreira C.G. et al. J Clin Oncol 28: 2010 suppl abstr 3614; Uetake H. et al. J Clin Oncol 29: 2011 suppl abstr 3605). Methods: Between July 2008 and July 2011, we analyzed 8,234 consecutive patient samples sent to a reference laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exon 1 was amplified by PCR and submitted to direct sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and well balanced according to gender with 51.9% of male and 48.1% female patients. The percentage of wild-type and mutated KRAS was 66.4 and 33.6%, respectively. Corroborating previous findings a significant difference in the percentage of mutated KRAS patients was observed between female and male (34.8% versus 32.5%, p = 0.03). However there were no differences in the distribution of any specific KRAS mutation according to gender. Among the 2,626 mutated cases, 83% were in codon 12 versus 17% in codon 13. Mutation Gly12Asp was the most common being detected in 36% of the mutated cases. Conclusions: This is one of the largest cohorts of KRAS genotyping in CRC patients. In line with previous data our present findings indicate that KRAS-mutations are more frequent in female than male. Further research is required to better address the impact of gender differences and/or hormones as potential drivers of CRC carcinogenesis.
Baseline predictors of survival in metastatic colorectal cancer.
Authors: Jensen Anni Ravnsbæk , Kronborg Camilla J S
Published: March 2020

e14105

Background: Patients with non-resectable metastatic colorectal cancer can survive several years with palliative chemotherapy and newer biological agents. However, survival varies greatly within this group. The aim of the present study was to identify baseline predictors of overall mortality in an unselected cohort of patients with metastatic colorectal cancer. Methods: Clinical information was collected from patient files in consecutive patients treated with palliative chemotherapy from August 2007 until June 2011. The primary outcome was overall survival. Cox regression analysis was used to examine the effect of predictive variables on time to outcome. The variables analysed were: Gender, age, performance status, primary tumor site (colon or rectum), status of primary tumor (resected or un-resected), metachronous metastases, more than two metastatic sites, liver-only metastases, and low albumin. Results: We included 314 patients (Median age 64.5 IQ (57-70) years, 194 (61.8%) male). Median follow-up for survival was 471 days IQ (257-708). One-year survival was 79%, CI (74-84%). Median overall survival was 676 days, CI (577-750). Following baseline variables were independent predictors of all-cause mortality: Primary tumor site colon HR: 1.49, CI (1.03-2.16), p=0.036, un-resected primary tumor HR 2.92, CI (1.85-4.62), p<0.001, metachronous metastases HR 1.72, CI (1.06-2.79), p=0.027 and more than two metastatic sites HR 3.46, CI (1.71-6.99), p=0.001. Both Performance status and low albumin were statistically significant in the univariate analysis, but not in the multivariate analysis. Conclusions: In daily clinical practice, baseline predictors of mortality in metastatic colorectal cancer were colon as the primary tumor site, un-resected primary tumor, metachronous metastases, and more than two metastatic sites.
Baseline lymphopenia as a prognostic marker for colorectal carcinoma.
Authors: Erdem Dilek , Yucel Idris , Yilmaz Bahiddin , Demirag Guzin , Kemal Yasemin , Teker Fatih
Published: March 2020

e14107

Background: Baseline lymphopenia has been proved to be a marker for poor prognosis, chemotherapy-induced toxicity and increased risk of febrile neutropenia, trombocytopenia and anemia in advanced solid neoplasms. This study aims to evaluate the effect of pretreatment lymphopenia on prognosis and hematological toxicity in colorectal cancer patients who received first line systemic chemotherapy. Methods: Lymphocyte count was evaluated in 386 pretreated colorectal cancer patients who do not have a seconder malignancy, HIV infection, bone involvement and primary G-CSF prophylaxis. Overall survival, progression free survival and disease free survival were calculated from date of diagnosis to date of relapse, progression and death. Kaplan-Meier, chi-square and Student-t test were used. Results: Mean follow-up was 30 months (range 1-180 months). Mean age was 57.4±12.5 years. Of all patients, 160 (41 %) were women. Rectum ( 26.2 %) and transvers colon (4.7 %) were the most and the least common anatomic locations, respectively. Mean lymphocyte count before treatment was 1964/µl (170-7000/µl). There were no relationship between lymphopenia and age, sex, performans status, presence of initial metastasis, adjuvant or palliative chemotherapy and hematological toxicity (p>0.05). Grade 3-4 hematological toxicity was found in 40 patients and was significantly higher in patients receiving bi- or tri-chemotherapy regimen (p:0.017). Among 208 patients with relapse or progression, 40 patients had lymphopenia (19.2 %). 1, 3 and 5-year OS were significantly lower in lymphopenic patients (p:0.033). DFS was longer in non-lymphopenic patients but this data didn’t have statistical significance (p>0.05). Conclusions: This study support that lymphocyte number prior to chemotherapy may be a simple but useful prognostic and predictive marker in untreated colorectal cancer patients. Patients with lower pretreatment lymphopenia have lower OS when compared to others (p<0.05). This study has the highest colorectal cancer population in the literature.
The relationship between serum and tumoral CRP, Akt, MAPK, and survival in patients undergoing potentially curative resection for colorectal cancer.
Authors: Powell Arfon , Shepherd Scott , Orange Clare , Mcmillan Donald C. , Horgan Paul G , Edwards Joanne E.
Published: March 2020

e14110

Background: Serum CRP was previously reported in myeloma to activate membrane bound Fcγ receptors which in turn activated Akt, and MAP kinase and inhibited caspase cascade activation resulting in increased tumour cell proliferation and inhibition of apoptosis. This study investigated the hypothesis that serum C-reactive protein (CRP) may activate signalling pathways in colorectal tumour cells. Methods: A cohort of 147 colorectal tumours was established and immunohistochemistry performed to assess protein expression of CRP, MAP kinase and Akt phosphorylated at serine 473 (pAkt). In addition, reverse transcriptase PCR for CRP mRNA expression was performed on 31 malignant colorectal specimens, 20 non-malignant colorectal specimens and 30 liver specimens. Results: No association between patient survival and tumour expression of CRP, pAkt and MAPK was observed, but serum CRP was independently associated with cancer-specific survival (p<0.001). When analysed according to tumour site, cytoplasmic CRP expression was associated with cancer specific survival in left sided tumours (p=0.022) and cytoplasmic pAkt was associated with cancer specific survival (p=0.029) in rectal tumours. No correlations were observed between serum CRP and tumour expression of CRP, pAkt and MAPK in the cohort as a whole or when subdivided by site. Conclusions: No link was established between serum CRP and signalling within the tumour. However, our results do support the concept of colorectal tumour heterogeneity, as different proteins were associated with patient survival depending on site. Further work is therefore required to elucidate the mechanisms underlying colorectal development and progression in tumour subtypes.
Evaluation of cost-effectiveness of early KRAS testing in high-risk recurrence colorectal cancer patients in Italy.
Authors: Pinto Carmine , Barone Carlo , Normanno Nicola , Cognetti Francesco , Falcone Alfredo , Capussotti Lorenzo , Mantovani Lorenzo
Published: March 2020

e14113

Background: KRAS testing is relevant for the choice of the most appropriate first-line therapy for metastatic colorectal cancer (CRC) patients (pts). Early KRAS testing in surgically resected CRC pts at high risk of recurrence might result cost-effective when the results of KRAS test are not available in acceptable time following the diagnosis of metastatic disease. Methods: This study adopted the Delphi technique to reach a consensus to define high risk recurrence CRC and KRAS test optimal timing. We used validated decision analyses models employed by technology assessment agencies (NICE and SMC) for the assessment of KRAS wild-type CRC pts. Alternative therapeutic strategies include FOLFOX4, FOLFIRI, FOLFOX4 + cetuximab, FOLFIRI + cetuximab, FOLFOX4 + bevacizumab. We adapted the models to take into account early KRAS testing in high risk pts for which the test would not be available on time to drive appropriate treatment. The models have been populated with Italian specific cost data incorporating pts’ access schemes. Results: Issues related to KRAS testing were proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The following parameters to define CRC pts at high risk of recurrence were identified: pT4, high grading, pN2, intestinal occlusion-perforation, isolated peritoneal carcinomatosis surgically removed and/or positive peritoneal washing and/or removed ovarian metastases. A time interval of more than 10-15 days for KRAS testing was defined as a limit for the therapeutic choices. Early KRAS testing in high risk CRC pts generates incremental cost effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained, depending on alternative treatment of choice. In extensive sensitivity analyses, ICER’s were always below 15,000 Euro per QALY gained, far within the 60,000 Euro/QALY gained threshold currently accepted in Italy. Conclusions: In metastatic CRC a time interval of more than 10-15 days for the response of KRAS testing limits the therapeutic choices. Early KRAS testing in high-risk CRC pts who would not have KRAS test in a reasonable time when they develop metastases is a cost effective strategy.
Impact of diabetes on site-specific oncologic outcome in stage I-III colorectal cancer.
Authors: Jeon Justin Y , Jeong Deok Hyun , Park Min Keun , Ligibel Jennifer A. , Meyerhardt Jeffrey A. , Kim Nam Kyu
Published: March 2020

e14114

Background: Background: Conflicting results have been reported whether pre diagnosis diabetes mellitus (DM) influence survival of colorectal cancer patients or not. Therefore, we determine the influence of DM on long-term outcomes of stage 1-3 patients with resected colon and rectal cancer. Methods: This prospective study include a total of 4,131 participants who were treated for cancer between 1995 and 2005 in South Korea in a single hospital (Non DM: 3,614 patients, DM: 517 patients) with average follow up period of 12 years. We analyzed differences in all cause mortality, disease free survival (DFS), recurrence free survival (RFS) and colorectal cancer-specific mortality between colorectal patients with DM and those without DM. Results: After adjustment for potential confounders, pre-diagnosis DM significantly associated with increased all cause mortality (HR: 1.46, 95% CI: 1.11-1.92), and recurrence free survival reduced DFS (HR: 1.45, 95%CI: 1.15-1.84) and RFS (HR: 1.32, 95% CI: 0.98-1.76) in colon cancer patients but not in rectal cancer patients. In colon cancer patients, DM negatively affects the survival outcome of proximal colon cancer (HR: 2.08, 95%CI: 1.38-3.13), but not of distal cancer (HR:1.34, 95% CI: 0.92-1.96). Conclusions: To our knowledge, the current study first reported the effects of pre-diagnosis DM on survival outcome of colorectal cancer are site specific (proximal colon, distal colon and rectum). The current study was supported by the National Research Foundation of Korea (KRF) (No. 2011-0004892) and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1120230). [Table: see text]
Involvement of K-RAS mutations and amino acid substitutions in the survival of metastatic colorectal cancer patients.
Authors: Pérez-Ruiz Elisabeth , Alcaide Julia , Pereda Teresa , Bautista Dolores , Rivas Ruiz Francisco , Villatoro R. , Redondo Maximino , Perez Diego , Rueda Antonio
Published: March 2020

e14116

Background: The efficacy against of epidermal growth factor therapy was found to be limited to those wild-type K-RAS tumours, suggesting a predictive value of response. However, the prognostic value of K-RAS status is controversial. The aim is to determine the relationship between K-RAS mutations and types of amino acid changes with the survival (OS) of metastatic colorectal patients (mCRC). Methods: The retrospective analysis included 120 patients diagnosed of mCRC. The presence and type of K-RAS mutations were analysed. Similarly, the clinical and pathological variables were also collected including OS. Results: The sample characteristics were summarized in Table 1. 53.3% of tumours were wild-type and 46.7 mutated KRAS. In mutated patients, codon 12 was affected in 76.79% and codon 13 in 23.21%. The median OS for wild-type was 31.6 months. In mutated patients (codon 12 or 13), median OS was 24.8 and 17.8 months (p=0.37), respectively. In the univariate analysis, mutated K-RAS was associated with stage IV at diagnosis (p<0.005). The relationship between OS and amino acid mutation are summarized in table 1. Conclusions: Our study suggest that the types of mutation or amino acid changes of KRAS in mCRC provides prognostic information. These data need to be confirmed in prospective or controlled trials. [Table: see text]
Comorbidity and other predictors of survival in veterans with colorectal cancer (CRC).
Authors: Zhong Fengming , Wang Trent P , Barnes Tanganyika , Gonzalez Melanie L. , Chang Victor T , Einhorn Jan , Sullivan Maryann , Kasimis Basil
Published: March 2020

e14125

Background: The role of comorbidity as a prognostic marker is an area of great interest. This study aimed to determine whether comorbidity indices predict survival in Veterans with CRC. Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA Medical Center from 1/1/2003 to 12/31/2007. Demographics, stage, grade, ECOG performance status (PS), CEA, hemoglobin (HGB), Albumin (ALB) at diagnosis, history of surgical resection (SR) were abstracted. Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Kaplan-Feinstein Index (KFI), the Cumulative Illness Rating Scale (CIRS), and VA Comorbidity Scale (VACS). We developed a survival model with stage, ECOG PS, HGB, ALB, SR, and ECOG PS. Comorbidity indices were tested by determining if they were independent predictors of survival after inclusion in this model. Cox regression analyses were performed with SAS V9.2. Results: There were 175 pts with colorectal ca with 111 colon (C) and 64 rectal ca (R) pts. The median (M) age at diagnosis was 71 (45-90). 54% of study population was deceased at the time of data collection. Median survival was 1157 days (5-3256). Results of multivariate analyses with comorbidity indices are summarized in the table. Conclusions: Charlson, CIRS 16 and CIRS 19 comorbidity indices were significant predictors for veterans with colorectal cancer and appear to be important for the subset of veterans with colon cancer. Confirmatory studies should be done in larger populatins. These indices may be used in the design of future clinical trials. This was supported by the New Jersey Commission for Cancer Research 09-1133-CCR-EO. [Table: see text]
Comparison of long-term survival outcomes of operative versus nonoperative management of recurrent rectal cancer.
Authors: Bhangu Aneel , Ali Mohammed , Cunningham David , Brown Gina , Tekkis Paris P
Published: March 2020

e14132

Background: Complete surgical resection is considered the best treatment for recurrent rectal cancer (RRC). The aim of the study was to compare survival outcomes from operative and non-operative patients presenting with RRC. Methods: Patients with RRC whose management was discussed by a tertiary referral specialist multidisciplinary team between January 2007 and August 2011 were identified from a prospectively maintained database. The primary endpoint was 5-year overall survival estimated by Kaplan-Meier survival method. Results: Of 127 patients with RRC, 105 were isolated to the pelvis and 22 were associated with distant disease at presentation. From the time of primary surgery to first recurrence, 1, 3, 5 and 10-year local recurrence rates were 22%, 72%, 85% and 96% respectively. Of 70 patients (55%, 70/127) who underwent pelvic resection of recurrence, 64% underwent R0, 20% R1 and 16% R2 resections. Corresponding 5-year overall survival was R0: 60%, R1: 42% and R2: 0% (log-rank p=0.004). There was no significant difference in survival between R2 resection and those managed non-operatively (hazard ratio 0.738, 95% confidence interval 0.341-1.600, p=0.559). Five year disease-free survival was 53% with R0 resection and 30% with R1 resection. Conclusions: Most recurrences occur within 5 years of primary surgery, although some occur up to 10 years later. R0 resection is the treatment of choice that leads to long-term survival and is suitable as an early surrogate marker for long-term survival. There was no survival benefit of R2 resection over non-resected recurrences.