Neufert C, Becker C, Türeci Ö, et al.
Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK.
J Clin Invest. 2013; 123(4):1428-43 [PubMed] Free Access to Full Article

Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.

Yeo SG, Kim DY, Chang HJ, et al.
Reappraisal of pretreatment carcinoembryonic antigen in patients with rectal cancer receiving preoperative chemoradiotherapy.
Tumori. 2013 Jan-Feb; 99(1):93-9 [PubMed]

AIMS AND BACKGROUND: The pretreatment serum carcinoembryonic antigen (CEA) level is an independent prognostic factor in colorectal cancer. We aimed to investigate the significance of CEA as a prognostic or predictive factor in rectal cancer patients receiving preoperative chemoradiotherapy (CRT).
METHODS AND STUDY DESIGN: In total, 609 patients with locally advanced (cStage II-III) mid to distal rectal cancer who underwent preoperative CRT and radical surgery between 2001 and 2008 were analyzed retrospectively. Predictive factors for pathologic CRT response were determined using multivariate logistic regression. A prognostic factor analysis was performed using the log-rank test and Cox proportional hazards regression.
RESULTS: Elevated CEA levels (>5 ng/mL) were observed in 201 (33.0%) patients at diagnosis. Following preoperative CRT, downstaging (ypStage 0-I) occurred in 255 (41.9%) patients, of whom 88 had pathologic complete tumor regression. Pretreatment CEA was significantly associated with pathologic CRT response in terms of downstaging and tumor regression grade, and was the most relevant predictive factor. After a median follow-up period of 60 months, the 5-year disease-free and overall survival rates were 76.2% and 84.6%, respectively. Prognostic factors independently associated with recurrence or survival included ypStage, circumferential resection margin, and histologic grade.
CONCLUSIONS: In patients with rectal cancer who received preoperative CRT, the pretreatment CEA level was a significant and independent predictor of pathologic CRT response. However, it may not be able to predict long-term outcomes independently of ypStage.

Li XD, Ji M, Wu J, et al.
Clinical significance of CD44 variants expression in colorectal cancer.
Tumori. 2013 Jan-Feb; 99(1):88-92 [PubMed]

AIMS AND BACKGROUND: We designed the present study to observe CD44s and CD44v6 expressions in colorectal cancer and evaluate their clinical value.
METHODS: CD44s and CD44v6 expression in colorectal cancer tissues were examined by an immunohistochemical test. Survival analysis was performed with the Kaplan-Meier method, and the differences between the CD44-positive and -negative groups were evaluated with the logrank test.
RESULTS: The positive rates of CD44s and CD44v6 were 66.7% and 63.2%, respectively. There were significant associations between CD44s positive expression and Dukes' stage or tumor differentiation. There were significant associations between CD44v6 positive expression and tumor differentiation, Dukes' stage and lymph node metastasis. There was a significant difference in the 5-year survival rates between CD44v6-positive and CD44v6-negative groups (52.78% and 80.95%, respectively), but not between CD44s-positive and CD44s-negative groups (55.26% and 78.95%, respectively). Multivariate analysis indicated that CD44v6 positive expression predicts a poor prognosis.
CONCLUSIONS: CD44s and CD44v6 play important roles in the infiltration and metastasis of colorectal cancer. CD44v6 positive expression can be a predictor for a poor prognosis.

Lee S, Kim DY, Kim SY, et al.
Curative radiotherapy using different radiation techniques for isolated lung metastasis from colorectal cancer.
Tumori. 2013 Jan-Feb; 99(1):68-75 [PubMed]

AIMS AND BACKGROUND: Surgical resection remains the mainstay for the treatment of colorectal lung metastasis, but a group of patients who are medically inoperable or unsuitable for surgery are treated with radiotherapy. The purpose of this multi-institutional study was to evaluate the clinical outcome and investigate the prognostic factors affecting local control and survival in this subset of patients.
METHODS: We retrospectively analyzed 30 patients with 43 lesions who underwent curative radiotherapy for isolated lung metastasis from colorectal cancer at nine institutions from 2003 and 2008. A total dose of 42-75 Gy at the peripheral planning target volume was administered in 3-35 fractions. The median biologically equivalent dose was 84 Gy (range, 58.5-180).
RESULTS: Treatment response was complete in 10 (33.3%), partial in 13 (43.3%), stable in six (20.0%), and progressive in one patient (3.3%). The median follow-up period for all patients was 29.0 months (range, 5.0-93.8). Kaplan-Meier local control at 5 years was 44%. The median survival was 46.2 months, and the 5-year overall survival was 47%. Twenty-three patients (77%) experienced treatment failure, most of which were intrapulmonary failure. The intrapulmonary relapse-free survival and overall relapse-free survival at 5 years were 22% and 19%, respectively. Treatment response and preradiotherapy carcinoembryonic antigen level were significant prognostic factors for local control and survival. Grade 3-5 toxicity occurred in 7 patients. Three patients had grade 5 toxicity, including radiation pneumonitis, a tracheoesophageal fistula, and hemoptysis.
CONCLUSIONS: . Curative radiotherapy for isolated lung metastasis from colorectal cancer in patients who are medially inoperable or unsuitable for surgery results in long-term survival, comparable to surgical resection. Curative radiotherapy could be an effective and noninvasive alternative if dose-limiting toxicity is carefully considered, particularly in patients with bilateral or central lesions.

Di Genesio Pagliuca M, Turri L, Munoz F, et al.
Patterns of practice in the radiation therapy management of rectal cancer: survey of the Interregional Group Piedmont, Valle d'Aosta and Liguria of the "Associazione Italiana di Radioterapia Oncologica (AIRO)".
Tumori. 2013 Jan-Feb; 99(1):61-7 [PubMed]

AIMS AND BACKGROUND: To report the survey about the main aspects on the use of radiotherapy for the treatment of rectal cancer in Piedmont and Liguria.
METHODS AND STUDY DESIGN: Sixteen centers (11 from Piedmont and 5 from Liguria) received and answered by email a questionnaire data base about clinical and technical aspects of the treatment of rectal cancer. All data were incorporated in a single data base and analyzed.
RESULTS: Data regarding 593 patients who received radiotherapy for rectal cancer during the year 2009 were collected and analyzed. Staging consisted in colonoscopy, thoracic and abdominal CT, pelvic MRI and endoscopic ultrasound. PET/CT was employed to complete staging and in the treatment planning in 12/16 centers (75%). Neoadjuvant radiotherapy was employed more frequently than adjuvant radiotherapy (50% vs 36.4%), using typically a total dose of 45 Gy with 1.8 Gy/fraction. Concurrent chemoradiation with 5-fluorouracil or capecitabine was mainly employed in neoadjuvant and adjuvant settings, whereas oxaliplatin alone or in combination with 5-FU or capecitabine and leucovorin was commonly employed as the adjuvant agent. The median interval from neoadjuvant treatment to surgery was 7 weeks after long-course radiotherapy and 8 days after short-course radiotherapy. The pelvic total dose of 45 Gy in the adjuvant setting was the same in all the centers. Doses higher than 45 Gy were employed with a radical intent or in case of positive surgical margins. Hypofractionated regimens (2.5, 3 Gy to a total dose of 35-30 Gy) were used in the palliative setting. No relevant differences were observed in target volume definition and patient setup. Twenty-six patients (4.4%) developed grade 3 acute toxicity. Follow-up was scheduled in a similar way in all the centers.
CONCLUSIONS: No relevant differences were found among the centers involved in the survey. The approach can help clinicians to address important clinical questions and to improve consistency and homogeneity of treatments.

Du Z, Wang Y, Zhou Y, et al.
First-line irinotecan combined with 5-fluorouracil and leucovorin for high-grade metastatic gastrointestinal neuroendocrine carcinoma.
Tumori. 2013 Jan-Feb; 99(1):57-60 [PubMed]

AIM AND BACKGROUND: High-grade gastrointestinal neuroendocrine neoplasms, ie, poorly differentiated neuroendocrine carcinomas, with no effective therapeutic approaches, have a high ability to metastasize.
METHODS: A review of the hospital information system was performed. Patients with histologically proven gastrointestinal neuroendocrine carcinoma who were treated with irinotecan combined with 5-fluorouracil and leucovorin in a first-line setting were eligible for analysis. We extracted information on age, sex, disease stage, laboratory findings, radiological findings, pathological findings, chemotherapy, effectiveness and adverse events of therapy, and outcomes.
RESULTS: Eleven patients were included in the study. Partial response was observed in 7 patients. Median progression-free survival and overall survival were 6.5 (95% CI, 5.1-7.9) and 13.0 (95% CI, 9.8-16.2) months, respectively. No treatment-related deaths occurred.
CONCLUSIONS: The results demonstrated that irinotecan combined with 5-fluorouracil and leucovorin is an active regimen with acceptable toxicity for patients with metastatic high-grade gastointestinal neuroendocrine carcinoma that merits further investigation in prospective trials.

Kodera Y
Gastric cancer with minimal peritoneal metastasis: is this a sign to give up or to treat more aggressively?
Nagoya J Med Sci. 2013; 75(1-2):3-10 [PubMed]

Peritoneal metastasis from gastric cancer is often undetectable by routine imaging studies. Even a microscopic metastasis detected only by cytologic examination of the peritoneal washes denotes a dismal prognosis, and surgery is ruled out as futile for patients who turn out to be cytology-positive by staging laparoscopy. On the other hand, recent developments in cancer chemotherapy have improved the outcome of the cytology-positive population to the point where a certain proportion of these patients survive for 5 years through a straightforward strategy of radical surgery followed by chemotherapy. Thus, there is certainly a role for surgeons in patients with minimal peritoneal metastasis, both in clinical practice and in clinical trials where multimodal treatment strategies including surgery are to be explored. Even in this category of patients, surgery in combination with various types of chemotherapy remains the only hope for a cure.

Wong CK, Lam CL, Wan YF, Rowen D
Predicting SF-6D from the European Organization for Treatment and Research of Cancer Quality of Life Questionnaire scores in patients with colorectal cancer.
Value Health. 2013 Mar-Apr; 16(2):373-84 [PubMed]

OBJECTIVES: To develop a mapping model for estimating six-dimensional health state short form (SF-6D) utility scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (QLQ-C30 and QLQ-CR29) scores in patients with colorectal cancer (CRC), with and without adjustment for clinical and demographic characteristics.
METHODS: Ordinary least squares regression models were applied to a cross-sectional data set of 216 patients with CRC collected from a regional hospital in Hong Kong. Item responses or scale scores of cancer-specific (QLQ-C30) and colorectal-specific health-related quality-of-life (QLQ-CR38/CR29) data and selected demographic and clinical characteristics of patients were used to predict the SF-6D scores. Model goodness of fit was examined by using exploratory power (R(2) and adjusted R(2)), Akaike information criterion, and Bayesian information criterion, and predictive performance was evaluated by using root mean square error, mean absolute error, and Spearman's correlation coefficients between predicted and observed SF-6D scores. Models were validated by using an independent data set of 56 patients with CRC.
RESULTS: Both scale and item response models explained more than 67% of the variation in SF-6D scores. The best-performing model based on goodness of fit (R(2) = 75.02%), predictive ability in the estimation (root mean square error = 0.080, mean absolute error = 0.065), and validation data set prediction (root mean square error = 0.103, mean absolute error = 0.081) included variables of main and interaction effects of the QLQ-C30 supplemented by QLQ-CR29 subset scale responses and a demographic (sex) variable.
CONCLUSIONS: SF-6D scores can be predicted from QLQ-C30 and QLQ-CR38/CR29 scores with satisfactory precision in patients with CRC. The mapping model can be applied to QLQ-C30 and QLQ-CR38/CR29 data sets to produce utility scores for the appraisal of clinical interventions targeting patients with CRC using economic evaluation.

Hoyle M, Peters J, Crathorne L, et al.
Cost-effectiveness of cetuximab, cetuximab plus irinotecan, and panitumumab for third and further lines of treatment for KRAS wild-type patients with metastatic colorectal cancer.
Value Health. 2013 Mar-Apr; 16(2):288-96 [PubMed]

OBJECTIVES: To estimate the cost-effectiveness of cetuximab monotherapy, cetuximab plus irinotecan, and panitumumab monotherapy compared with best supportive care (BSC) for the third and subsequent lines of treatment of patients with Kirsten rat sarcoma wild-type metastatic colorectal cancer from the perspective of the UK National Health Service.
METHODS: An "an area under the curve" cost-effectiveness model was developed. The clinical effectiveness evidence for both cetuximab and panitumumab was taken from a single randomized controlled trial (RCT) in each case and for cetuximab plus irinotecan from several sources.
RESULTS: Patients are predicted to survive for approximately 6 months on BSC, 8.5 months on panitumumab, 10 months on cetuximab, and 16.5 months on cetuximab plus irinotecan. Panitumumab is dominated, and cetuximab is extended dominated. An incremental cost-effectiveness ratio (ICER) of £95,000 per quality-adjusted life-year (QALY) was estimated for cetuximab versus BSC and is likely to be relatively accurate, because the relevant clinical evidence is taken from a high-quality RCT. The estimated ICER for panitumumab versus BSC, at £187,000 per QALY, is less certain due to assumptions in the adjustment for the substantial crossing-over of patients in the RCT. The ICER for cetuximab plus irinotecan versus BSC, at £88,000 per QALY, is least certain due to substantial uncertainty about progression-free survival, treatment duration, and overall survival. Nonetheless, when key parameters are varied within plausible ranges, all three treatments always remain poor value for money.
CONCLUSIONS: All three treatments are highly unlikely to be considered cost-effective in this patient population in the United Kingdom. We explain how the reader can adapt the model for other countries.

Ueno H, Hashiguchi Y, Shimazaki H, et al.
Objective criteria for crohn-like lymphoid reaction in colorectal cancer.
Am J Clin Pathol. 2013; 139(4):434-41 [PubMed]

We aimed to determine semiquantitative evaluation criteria for Crohn-like lymphoid reaction (CLR). We reviewed 1,032 patients with colorectal cancer and evaluated CLR by counting all peritumoral lymphoid aggregates (LAs) and by measuring the maximum diameter of the largest LA. The maximum diameter of the largest LA, rather than the number, had a significant impact on survival. Active CLR determined by the 1-mm rule was significantly associated with MLH1/MSH2 immunohistochemical staining deficiency. The group with LAs 1 mm or larger had lower recurrence (P = .0008) and a higher survival rate (P < .0001) than that without LAs 1 mm or larger. These results were similarly observed in another cohort of 500 patients with colorectal cancer. The k values for CLR evaluation among 8 observers were 0.67 for the 1-mm rule and 0.50 for Graham's criteria. The size of the largest LA best reflects the specific characteristics of CLR, and the 1-mm rule is expected to improve assessment reproducibility.

Kazarin O, Vlodavsky E, Guralnik L, et al.
Association between esophageal leiomyomatosis and p53 mutation.
Ann Thorac Surg. 2013; 95(4):1429-31 [PubMed]

Li-Fraumeni syndrome is a cancer predisposition syndrome associated with a variety of neoplasms, mainly soft tissue sarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma, and leukemia. Esophageal leiomyomatosis involves the presence of several rare benign neoplastic lesions composed of proliferating smooth muscle cells in the esophageal wall. The current case report presents a patient with recurrent diffuse leiomyomas of the esophagus and confirmed p53 mutation with clinical criteria of Li-Fraumenilike syndrome.

Ghosh S, Sau S, Mitra S, et al.
Palliation of dysphagia in advanced, metastatic or recurrent carcinoma oesophagus with high dose rate intraluminal brachytherapy--an eastern Indian experience of 35 cases.
J Indian Med Assoc. 2012; 110(7):449-52 [PubMed]

Oesophageal cancer, a disease with high morbidity and mortality, has a relatively high incidence in eastern India, usually presenting at advanced stage. The main aim of treatment for majority of patients remains palliation of dysphagia, which can be effectively done by intraluminal brachytherapy with or without external radiotherapy. Between January 2006 to January 2010 a total of 35 patients with advanced/metastatic (24/35) or recurrent (11/35) oesophageal carcinoma were treated with intraluminal high dose rate (HDR) iridium192 source brachytherapy at Medical College Hospitals, Kolkata. Selection for palliative brachytherapy includes one or more of the following criteria: Lesion more than 5 cm long on imaging studies or upper GI endoscopy, Karnofsky performance status < or = 50%, Locoregional recurrence. Palliative external radiotherapy (20 Gy/5# or 30 Gy/10#) was given to 11 patients (31.42%) before brachytherapy. All patients treated with 2 fractions of high dose rate-intraluminal brachytherapy (HDR-ILRT) one week apart with 600 cGy per fraction at 1 cm off axis. Thirty-five patients were treated with palliative HDR-ILRT. Significant improvement in swallowing status was seen in 20 patients (57.14%) since just after treatment up to 7.5 months. However, 9 patients (25.71%) showed no improvement, and 6 patients (17.14%) showed no changes in dysphagia scoring. Only 3 patients developed ulceration and 2 developed fistula immediately after treatment and 5 patients developed stricture. Median dysphagia-free survival was 6 months. Median overall survival was 8 months. It is concluded that intraluminal brachytherapy is an effective method for palliation of dysphagia for reasonably prolonged period.

Deenen MJ, Dewit L, Boot H, et al.
Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.
Int J Radiat Oncol Biol Phys. 2013; 85(5):e201-7 [PubMed]

PURPOSE: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses.
METHODS AND MATERIALS: Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinal lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m(2) (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m(2) b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD).
RESULTS: A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m(2) b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed.
CONCLUSIONS: SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m(2) b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.

Tanis PJ, Doeksen A, van Lanschot JJ
Intentionally curative treatment of locally recurrent rectal cancer: a systematic review.
Can J Surg. 2013; 56(2):135-44 [PubMed] Free Access to Full Article

BACKGROUND: There is a lack of outcome data beyond local recurrence rates after primary treatment in rectal cancer, despite more information being necessary for clinical decision-making. We sought to determine patient selection, therapeutic modalities and outcomes of locally recurrent rectal cancer treated with curative intent.
METHODS: We searched MEDLINE (1990-2010) using the medical subject headings "rectal neoplasms" and "neoplasm recurrence, local." Selection of cohort studies was based on the primary intention of treatment and availability of at least 1 outcome variable.
RESULTS: We included 55 cohort studies comprising 3767 patients; 8 studies provided data on the rate of intentionally curative treatment from an unselected consecutive cohort of patients (481 of 1188 patients; 40%). Patients were symptomatic with pain in 50% (796 of 1607) of cases. Overall, 3088 of 3767 patients underwent resection. The R0 resection rate was 56% (1484 of 2637 patients). The rate of external beam radiotherapy was 100% in 9 studies, 0% in 5 studies, and ranged from 12% to 97% in 37 studies. Overall postoperative mortality was 2.2% (57 of 2515 patients). Five-year survival was at least 25%, with an upper limit of 41% in 11 of 18 studies including at least 50 resections. We found a significant increase in reported survival rates over time (r2 = 0.214, p = 0.007).
CONCLUSION: More uniformity in treatment protocols and reporting on outcomes for locally recurrent rectal cancer is warranted. The observed improvement of reported survival rates in time is probably related to better patient selection and optimized multimodality treatment in specialized centres.

Njei B, Sanchez H
Neurofibromatosis type 1, recurrent pulmonary embolism, and a periampullary carcinoid tumor: is there a link?
Conn Med. 2013; 77(2):77-80 [PubMed]

Neurofibromatosis type 1 (NF1), a relatively common autosomal dominantly inherited condition with complete penetrance but extremely variable phenotypic expressivity, is caused by mutations in the NF1 gene. The disease is defined clinically by its cutaneous (cafe-au-lait macules, inguinal and axillary freckles) and neural (neurofibromas, plexiform neurofibromas, Lisch spots, optic nerve gliomas) signs, but it can involve many other systems including the gastrointestinal, pulmonary, respiratory, skeletal and vascular systems. Involvement of these other systems can sometimes manifest itself in clinically confusing ways. For example, the literature includes reports of patients with NF1 that has caused pulmonary hypertension, spontaneous hemothorax, and gastrointestinal bleeding. We present the case of a man with NF1 who presented with recurrent unexplained thromboembolic disease and died suddenly in the hospital. In addition to confirming his suspected massive pulmonary thromboembolus (PE), an autopsy revealed an unsuspected periampullary duodenal carcinoid tumor. The potential connections between the patient's NF1, duodenal tumor, and fatal PE are discussed. The case highlights the importance of bearing in mind the protean clinical manifestations of NF1.

Danese E, Minicozzi AM, Montagnana M, et al.
Lack of an association between circulating adiponectin levels and risk of colorectal adenoma.
Clin Lab. 2013; 59(1-2):211-4 [PubMed]

BACKGROUND: The putative association between serum adiponectin levels and colorectal adenomas is actually under debate. The aim of this study was to investigate this association in relation to factors known to influence the levels of adiponectin such as anthropometric, metabolic, inflammatory parameters as well as lifestyle individual characteristics.
METHODS: 40 patients with adenomas and 40 controls were enrolled. Body weight, height, waist circumference, and blood pressure were recorded. Fasting plasma glucose, lipids, C-reactive protein, and adiponectin levels were measured. Metabolic Syndrome was defined and lifestyle characteristics assessed.
RESULTS: No differences were found in adiponectin values between patients and controls (p = 0.101). Adiponectin levels were significantly higher in females than in males (p = 0.004). Adiponectin levels did not result in significant association with colorectal adenomas even after adjustment for metabolic and life style parameters.
CONCLUSIONS: This study did not confirm the hypothesis that high levels of adiponectin confer decreased risk of colorectal adenomas.

Yin H, Liang Y, Yan Z, et al.
Mutation spectrum in human colorectal cancers and potential functional relevance.
BMC Med Genet. 2013; 14:32 [PubMed] Free Access to Full Article

BACKGROUND: Somatic variants, which occur in the genome of all cells, are well accepted to play a critical role in cancer development, as their accumulation in genes could affect cell proliferations and cell cycle.
METHODS: In order to understand the role of somatic mutations in human colorectal cancers, we characterized the mutation spectrum in two colorectal tumor tissues and their matched normal tissues, by analyzing deep-sequenced transcriptome data.
RESULTS: We found a higher mutation rate of somatic variants in tumor tissues in comparison with normal tissues, but no trend was observed for mutation properties. By applying a series of stringent filters, we identified 418 genes with tumor specific disruptive somatic variants. Of these genes, three genes in mucin protein family (MUC2, MUC4, and MU12) are of particular interests. It has been reported that the expression of mucin proteins was correlated with the progression of colorectal cancer therefore somatic variants within those genes can interrupt their normal expression and thus contribute to the tumorigenesis.
CONCLUSIONS: Our findings provide evidence of the utility of RNA-Seq in mutation screening in cancer studies, and suggest a list of candidate genes for future colorectal cancer diagnosis and treatment.

Yanling H, Yuhong Z, Wenwu H, et al.
NQO1 C609T polymorphism and esophageal cancer risk: a HuGE review and meta-analysis.
BMC Med Genet. 2013; 14:31 [PubMed] Free Access to Full Article

BACKGROUND: Many studies have been carried out to test the hypothesis that the NQO1 C609T polymorphism might be associated with the risk of esophageal cancer. However, the results are poorly consistent, partly due to genetic or other sources of heterogeneity. To investigate the association between this polymorphism and the risk of esophageal cancer, a meta-analysis was performed.
METHODS: We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of association. The frequency of the putative risk allele in the controls was estimated by the inverse-variance method. Cochran's Q statistic and the inconsistency index (I2) were used to check heterogeneity. Egger's test and an inverted funnel plot were used to assess the publication bias.
RESULTS: Our study included eight published case-control studies about the NQO1 C609T polymorphism and esophageal cancer, including a total of 1,217 esophageal cancer patients and 1,560 controls. Overall, a significant association was found between the NQO1 C609T variant and esophageal cancer under a recessive model (OR = 1.647; 95% CI = 1.233-2.200). Regarding histological type, more significant evidence was found for esophageal squamous cell carcinoma (ESCC) (OR = 2.03; 95% CI = 1.29-3.19) than esophageal adenocarcinoma (EAC) (OR = 1.61; 95% CI = 1.01-2.56) under a recessive model.
CONCLUSIONS: The meta-analysis suggests that the NQO1 C609T polymorphism considerably increases the risk of esophageal cancer.

Wassira LN, Pinheiro PS, Symanowski J, Hansen A
Racial-ethnic colorectal cancer survival disparities in the mountain west region: the case of Blacks compared to Whites.
Ethn Dis. 2013; 23(1):103-9 [PubMed]

BACKGROUND: Substantial disparities in colorectal cancer (CRC) survival among racial-ethnic groups, especially between Blacks and Whites, have been extensively documented in the Northeast, California and South of the United States. The purpose of this study was to ascertain the determinants of colorectal cancer racial-ethnic survival disparities in a state of the Mountain West region, Nevada.
METHODS: The study population consisted of a cohort of 12,181 men and women with a first primary invasive carcinoma in the colon and rectum diagnosed between 1995 and 2007, identified through the Nevada Central Cancer Registry and followed for vital status until 31 December 2007. Likelihood ratio chi-square statistics were used to compare the sociodemographic and clinical characteristics for race-ethnicity. Cox proportional regression modeling and partial likelihood tests were used to estimate the hazard ratios and assess interaction effects in CRC cause-specific death.
RESULTS: Blacks and Hispanics were more likely to be diagnosed with distant stage disease, 22.4% and 21.5% respectively, compared to 17.9% in Whites. No difference was observed between racial-ethnic groups for diagnoses in regional stage. Univariate analysis yielded a 20.1% higher risk of CRC death for Blacks compared to Whites [95% CI = 1.05-1.37]. Adjustment for tumor stage, sex, age, diagnosis period, tumor sublocation, marital status, and economic status in the multivariate model showed a persistently increased risk of CRC death for Blacks (HR = 1.17, 95% CI = 1.02-1.33) in relation to Whites.
CONCLUSIONS AND IMPLICATIONS: Survival disparities persisted among Blacks in our study even after adjusting for common demographic and tumor factors. Further determinants of survival disparities between race/ethnicities, such as course of treatment, should be investigated. Additionally, more public health intervention programs should tailor CRC screening awareness towards minorities as well as ensuring equal access to health care and quality treatment.

Li X, Chu J, Sun C, et al.
Sixty-four-slice computed tomography angiography of perigastric veins with image fusion.
J Comput Assist Tomogr. 2013 Mar-Apr; 37(2):165-70 [PubMed]

OBJECTIVE: The objective of this study was to assess the efficacy and clinical value of 64-slice computed tomography angiography (CTA) with image fusion for demonstrating the perigastric venous anatomy.
METHODS: Twenty-six patients with gastric cancer underwent abdominal CTA examinations. Computed tomography angiography of stomach and perigastric veins and arteries were reconstructed and fused using volume-rendering technique. The inflow and courses of perigastric veins as well as the spatial relationship among the perigastric veins, arteries, and stomach were compared with surgery.
RESULTS: Compared with surgical findings, the visualization rate of the 7 perigastric veins on CTA was 90.9% to 100%. There was a statistically significant decrease in number of short gastric veins identified on CTA compared with surgery (P = 0.004). There was no statistically significant difference between the 2 modalities in detecting other perigastric veins including the left gastric vein, right gastric vein, right gastroepiploic vein, left gastroepiploic vein, posterior gastric vein, and gastrocolic trunk (P = 0.317, P = 0.157, P = 1, P = 1, P = 0.317, P = 1, respectively).
CONCLUSIONS: Sixty-four-slice CTA with image fusion clearly depicts most of perigastric veins and their relationship with the stomach and perigastric arteries. It can facilitate gastrectomy.

Moyes LH, McCaffer CJ, Carter RC, et al.
Cardiopulmonary exercise testing as a predictor of complications in oesophagogastric cancer surgery.
Ann R Coll Surg Engl. 2013; 95(2):125-30 [PubMed]

INTRODUCTION: An anaerobic threshold (AT) of <11 ml/min/kg can identify patients at high risk of cardiopulmonary complications after major surgery. The aim of this study was to assess the value of cardiopulmonary exercise testing (CPET) in predicting cardiopulmonary complications in high risk patients undergoing oesophagogastric cancer resection.
METHODS: Between March 2008 and October 2010, 108 patients (83 men, 25 women) with a median age of 66 years (range: 38-84 years) underwent CPET before potentially curative resections for oesophagogastric cancers. Measured CPET variables included AT and maximum oxygen uptake at peak exercise (VO2 peak). Outcome measures were length of high dependency unit stay, length of hospital stay, unplanned intensive care unit (ICU) admission, and postoperative morbidity and mortality.
RESULTS: The mean AT and VO2 peak were 10.8 ml/min/kg (standard deviation [SD]: 2.8 ml/min/kg, range: 4.6-19.3 ml/min/kg) and 15.2 ml/min/kg (SD: 5.3 ml/min/kg, range: 5.4-33.3 ml/min/kg) respectively; 57 patients (55%) had an AT of <11 ml/min/kg and 26 (12%) had an AT of <9 ml/min/kg. Postoperative complications occurred in 57 patients (29 cardiopulmonary [28%] and 28 non-cardiopulmonary [27%]). Four patients (4%) died in hospital and 21 (20%) required an unplanned ICU admission. Cardiopulmonary complications occurred in 42% of patients with an AT of <9 ml/min/kg compared with 29% of patients with an AT of ≥9 ml/min/kg but <11 ml/min/kg and 20% of patients with an AT of ≥11 ml/min/kg (p = 0.04). There was a trend that those with an AT of <11 ml/min/kg and a low VO2 peak had a higher rate of unplanned ICU admission.
CONCLUSIONS: This study has shown a correlation between AT and the development of cardiopulmonary complications although the discriminatory ability was low.

Yacob M, Raju RS, Vyas FL, et al.
Management of colorectal cancer liver metastasis in a patient with immune thrombocytopaenia.
Ann R Coll Surg Engl. 2013; 95(2):e50-1 [PubMed]

Immune thrombocytopaenia (ITP) was referred to previously as idiopathic thrombocytopaenic purpura and is usually of autoimmune or viral aetiology. Colorectal cancer liver metastasis with concomitant ITP is rare and only three cases have been reported in the English literature. Adverse effects of adjuvant chemotherapy may aggravate ITP. The sequencing of chemotherapy, operation for the primary and liver metastasis, and a decision on splenectomy is important. We present our experience in the management of a 52-year-old man who, having undergone anterior resection one year earlier for carcinoma of the rectum, presented with liver metastasis and ITP. He underwent splenectomy with hepatectomy prior to chemotherapy.

Somasundaram SK, Akritidis G, Alagaratnam S, et al.
Extraluminal colonic arteriovenous haemangioma: an unusual cause of chronic lower gastrointestinal bleeding.
Ann R Coll Surg Engl. 2013; 95(2):e44-6 [PubMed]

Lower gastrointestinal bleeding is a common general surgical presentation in acute and chronic settings. Vascular anomalies account for 2% of such cases and can therefore be missed. We discuss a rare vascular anomaly in one of our patients where the diagnosis was not established for a ten-year period. We describe the subsequent management and a brief review of the literature of this uncommon condition.

Masrur M, Gheza F, Raimondi P, et al.
Robot-assisted subtotal pancreas-preserving duodenectomy.
JSLS. 2012 Oct-Dec; 16(4):654-9 [PubMed] Free Access to Full Article

BACKGROUND: Angiodysplasia of the duodenum is a rare disorder, often requiring surgical resection. Technical difficulties have made the use of the minimally invasive approach uncommon. Herein, we present a subtotal pancreas-preserving duodenectomy using robotic assistance.
METHODS: The patient is a 60-y-old female with a long medical history including chronic gastrointestinal bleeding due to angiodysplasia with intermittent melena, and requiring multiples blood transfusions. A capsule endoscopy and double-balloon upper endoscopy showed angiectasis, which appeared to be limited to the third and fourth portion of the duodenum and the proximal loops of the jejunum. Despite multiple endoscopic cauterizations, the patient continued to require blood transfusion for several years. The patient underwent a robot-assisted subtotal pancreas-preserving duodenectomy.
RESULTS: The operation lasted 420 min with minimal blood loss. The postoperative course was uneventful. The pathology report showed multiple small bowel mucosal and submucosal distorted and dilated vasculature, consistent with angiodysplasia. At 2-mo follow-up, the patient was totally asymptomatic. A barium swallow study showed contrast passed antegrade through the duodenojejunostomy with no evidence of obstruction, stricture, or leakage.
CONCLUSION: The use of robotic assistance to perform a subtotal pancreas-preserving duodenectomy for the treatment of benign duodenal disease, such as angiodysplasia, is feasible and safe. The technical advantages include a high degree of freedom offered by the robotic instruments, as well as enhanced visualization, which allows for precise microdissection and microsuture, thereby preserving the benefits of minimally invasive surgery. The use of robotic technology allows for a wider range of indications for minimally invasive surgery.

Syrios J, Kechagias G, Agrogiannis G, et al.
DNA ploidy: a prognostic factor of response to chemotherapy and survival in metastatic gastric adenocarcinoma.
Anticancer Res. 2013; 33(3):1209-14 [PubMed]

BACKGROUND: Metastatic gastric adenocarcinoma confers a dismal prognosis. Several prognostic factors are needed to distinguish patients that will benefit from chemotherapy. In this setting, the prognostic impact of DNA ploidy is still unclear.
MATERIALS AND METHODS: The records of 61 patients with metastatic gastric adenocarcinoma were retrospectively reviewed. Response to chemotherapy and overall survival (OS) were assessed and correlated to tumour DNA ploidy index, which was calculated by cytometric image analysis.
RESULTS: The median value of DNA ploidy index was 2.3. Patients with a low index responded better to chemotherapy than those with a higher index (p<0.01). Nevertheless, when the median value was used as a cut-off, no significant correlation of DNA ploidy index with response to chemotherapy (p=0.41) or OS (p=0.09) was observed.
CONCLUSION: The prognostic role of DNA ploidy in metastatic gastric adenocarcinoma is still debatable. In this study, a low DNA ploidy index was associated with favorable prognosis; however, a suitable cut-off value is not yet available.

Kobayashi N, Nakayama H, Osaka Y, et al.
Tumor response after low-dose preoperative radiotherapy combined with chemotherapy for squamous cell esophageal carcinoma.
Anticancer Res. 2013; 33(3):1157-61 [PubMed]

AIM: Patients with T3 or more squamous cell esophageal cancer underwent low-dose preoperative radiotherapy with chemotherapy, to reduce local recurrence, followed by surgery. The aim was to ascertain tumor response and assess prognostic factors.
PATIENTS AND METHODS: Between May 2002 and June 2011, 37 consecutive patients with esophageal cancer underwent chemoradiotherapy followed by surgery. The numbers of patients in clinical stages IIA/IIIA/IIIB/IIIC were 2/24/7/4, respectively. All were given a dose of 30 Gy in 15 fractions, with concurrent chemotherapy using cisplatin and fluorouracil. Curative surgery was performed a median of 1.2 months after completion of chemoradiotherapy.
RESULTS: Based on the findings from surgery, 26 patients (70%) achieved a stage reduction and six patients (16%) had a complete pathological response. The numbers of patients undergoing resections microscopically complete, with microscopically positive margins, and macroscopically positive margins were 33, 3, and 1, respectively. During a median follow-up period of 22.5 months, the two-year progression-free survival and overall survival were 62.1% [95% confidence interval (CI)=45.8 to 78.4%] and 71.9% [95% CI=55.1 to 88.7%], respectively. Statistically significant prognostic factors for overall survival were age [hazard ratio=6.6; 95% CI=1.1 to 38; p=0.04] and pathological T factor [hazard ratio=10.2; 95% CI=1.4 to 77; p=0.02]. No patients died as a result of surgery.
CONCLUSION: Seventy percent of patients with esophageal cancer who received radiotherapy dose of 30 Gy in 15 fractions combined with chemotherapy achieved a stage reduction with low toxicity.

Komori K, Kanemitsu Y, Kimura K, et al.
Tumor necrosis in patients with TNM stage IV colorectal cancer without residual disease (R0 Status) is associated with a poor prognosis.
Anticancer Res. 2013; 33(3):1099-105 [PubMed]

AIM: To examine the usefulness of the histopathological finding of tumor necrosis for stratifying TNM stage IV colorectal cancer in R0 status.
PATIENTS AND METHODS: We enrolled 98 patients with stage IV colorectal cancer, without residual disease after resection. The extent of necrosis was assessed using published thresholds, the extent was graded as "absent", "moderate" (<30% of tumor area), or "severe" (≥30%) in each section.
RESULTS: In multivariate analysis, the only significant difference in the disease-free survival rate was related to tumor necrosis (p=0.01) and the significant differences in the overall survival rates were related to the maximum tumor size and the degree of tumor necrosis (p=0.02 and p=0.001, respectively).
CONCLUSION: Tumor necrosis is associated with a poor prognosis in colorectal cancer and may allow the stratification of TNM stage IV patients without residual disease after surgery.

Preusser M, Berghoff AS, Ilhan-Mutlu A, et al.
Brain metastases of gastro-oesophageal cancer: evaluation of molecules with relevance for targeted therapies.
Anticancer Res. 2013; 33(3):1065-71 [PubMed]

BACKGROUND: Brain metastases (BM) of gastro-oesophageal cancer are exceedingly rare and only limited data exist on their pathobiology.
MATERIALS AND METHODS: We identified tissue samples of BM of gastro-oesophageal cancer and analyzed the expression of human epidermal growth factor receptor-2 (HER2), phosphorylated signal transducer and activator of transcription-3 (pSTAT3), epithelial growth factor receptor (EGFR), V600E point mutation of the v-raf murine sarcoma viral oncogene homolog-B1 (BRAF V600E), cluster of differentiation molecule-34 (CD34), hypoxia inducible factor-1α (HIF 1-α) and Ki-67 by immunohistochemical methods.
RESULTS: Our series comprised of twenty adenocarcinomas and one oesophageal squamous cell carcinoma. Three (14%), 7 (33%), 9 (43%), 18 (86%) and 0 BM specimens were scored positively for HER2, EGFR, pSTAT3, HIF1-α and BRAF V600E expression. The median Ki-67 index was 59%. The microvascular density was moderate-to-high and active intratumoral microvascular sprouting was evident in 20/21 (95%) of BMs. The HER2 and EGFR expression status were consistent between primary tumors and BM in all three assessable cases. HIF1-α and pSTAT3 expression were significantly higher in HER2-positive cases.
CONCLUSION: Therapeutic use of agents targeting HER2, pSTAT3, EGFR and angiogenesis may be feasible for selected BM of gastro-esophageal cancer. HER2 positivity does not seem to predispose to brain colonization in gastro-esophageal cancer.

Healey E, Stillfried GE, Eckermann S, et al.
Comparative effectiveness of 5-fluorouracil with and without oxaliplatin in the treatment of colorectal cancer in clinical practice.
Anticancer Res. 2013; 33(3):1053-60 [PubMed]

BACKGROUND: First-line chemotherapeutic treatment of colorectal cancer (CRC) typically comprises oral (capecitabine) or intravenous 5-fluorouracil (5-FU) plus leucovorin (LV), in combination with oxaliplatin (XELOX or FOLFOX, respectively), although debate exists regarding the best course of treatment by modality in clinical practice. Evidence from practice comparisons is important in considering the net benefit of alternative chemotherapy regimens, given expected differences in survival associated with compliance and age of patients treated in real life versus controlled trial settings.
PATIENTS AND METHODS: Practice variation in 5-FU treatment (i.e. 5-FU/leucovorin, FOLFOX, capecitabine and XELOX) of patients with CRC from an Australian area health service (n=636) was analyzed between modalities by patient age, tumour stage and site using non-parametric tests. Survival analyses (n=434) were conducted over a three-year follow-up period using Cox regression, adjusting for observed confounders.
RESULTS: FOLFOX was the most commonly administered regimen. 5-FU modality was significantly associated with patient age (p<0.001), tumour stage (p<0.001) and site (p<0.001). Cox regression analyses found no significant difference in survival with the addition of oxaliplatin to 5-FU regimens.
CONCLUSION: Our findings suggested no survival benefit with the addition of oxaliplatin to 5-FU modalities in treating CRC in practice. This raises questions as to the net benefit of oxaliplatin, given its known toxicity profile and expense.

Pluschnig U, Schoppmann SF, Preusser M, et al.
Modified EOX (Epirubicin, Oxaliplatin and Capecitabine) as palliative first-line chemotherapy for gastroesophageal adenocarcinoma.
Anticancer Res. 2013; 33(3):1035-9 [PubMed]

BACKGROUND: The efficacy of triple-drug combination regimens such as epirubicin, oxaliplatin and capecitabine (EOX) is superior to standard cisplatin/5-fluorouracil, but considerable toxicity needs to be taken into account in patients with upper gastrointestinal adenocarcinoma. Therefore, we aimed to establish a modified version of the EOX regimen with improved tolerability for these patients.
PATIENTS AND METHODS: Patients received palliative first-line chemotherapy with a modified EOX regimen repeated every three weeks (epirubicin 50 mg/m(2) i.v., day 1; oxaliplatin 130 mg/m(2) i.v., day 1; capecitabine at a twice-daily dose of 1000 mg/m(2) p.o. for two weeks).
RESULTS: Out of 51 patients, partial remission was observed in five (10.2%) and stable disease in 31 (60.8%). Progression-free survival was four months, and overall survival twelve months.
CONCLUSION: Modified EOX was generally well-tolerated and, therefore, further investigation within prospective clinical trials is warranted.