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Gastrointestinal System Cancers

Digestive and Gastrointestinal System cancers.

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Anal Cancer
Appendix Cancers - including PMP
Colorectal (Bowel) Cancer
Esophageal Cancer
Extra-hepatic Bile Duct Cancer
Gallbladder Cancer
Gastrointestinal Carcinoid Tumours
Gastrointestinal Stromal Tumours
Liver Cancer
Pancreatic Cancer
Stomach (Gastric) Cancer
Small Bowel Cancer
Medical Terminology - Gastrointestinal
General Resources for GI Cancer
Latest Research Publications

General Resources for GI Cancer (9 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Yanagita T, Kusanagi H
Safety and Effectiveness of Enoxaparin as Venous Thromboembolism Prophylaxis after Gastric Cancer Surgery in Japanese Patients.
Am Surg. 2016; 82(12):1232-1237 [PubMed] Related Publications
Routine prophylaxis for venous thromboembolism (VTE) has been recommended after surgery not only in the West but also in Asia recently. The primary objective of this study was to investigate the safety and effectiveness of enoxaparin as a prophylaxis in patients undergoing distal, proximal, or total gastrectomy (TG) for gastric cancers. A total of 565 patients who underwent gastrectomy for gastric cancer were reviewed retrospectively. About 256 patients received postoperative prophylaxis with enoxaparin (2000 international unit twice daily for at least six days) and compression stockings; these patients were assigned to the enoxaparin group. About 257 patients comprised a historical control group, who used only compression stockings as a thromboprophylaxis. All patients underwent the same rehabilitation programs during the perioperative period. None of the patients developed symptomatic venous thromboembolism in either the enoxaparin group or the control group. The complication rate of bleeding was not significantly different between the two groups. Only one patient who used three antiplatelet agents concomitantly with enoxaparin required reoperation for anastomotic site bleeding. The usage of enoxaparin for venous thromboembolism prophylaxis is safe for Japanese patients after gastrectomy. But, cautious application is still needed especially when used concomitantly with other antiplatelet agents.

Uhr A, Singh AP, Munoz J, et al.
Colonic Schwannoma: A Case Study and Literature Review of a Rare Entity and Diagnostic Dilemma.
Am Surg. 2016; 82(12):1183-1186 [PubMed] Related Publications
An asymptomatic 73-year-old woman was found to have a submucosal mass in the descending colon on routine colonoscopy. A CT scan revealed a 31 × 28 × 31 mm lesion in the same location. Previous biopsy proved to be nondiagnostic, and the patient underwent a laparoscopic descending colon resection. Histologic evaluation of the tumor revealed a low grade spindle cell neoplasm with strong, diffuse positivity for S-100 protein by immunohistochemistry, leading to the diagnosis of schwannoma. A review of the literature revealed intestinal schwannoma to be a rare disease entity, with only about 50 cases previously reported.

Hong KD, Um JW, Min BW, et al.
Lymph Node Micrometastasis Cannot Be Considered as Positive Lymph Node in Nonmetastatic Colorectal Cancer.
Am Surg. 2017; 83(2):127-133 [PubMed] Related Publications
The prognostic value of micrometastasis in colorectal cancer (CRC) remains controversial. The study investigated whether lymph node (LN) micrometastasis can have prognostic value in CRC as compared with macrometastasis. The study included 488 patients with curatively resected stage I, II, or III CRC treated between 2004 and 2011. Immuohistochemical staining with monoclonal antibody CAM 5.2 was performed on negative LNs by hematoxylin-eosin staining. The prognostic value of LN micrometastasis was investigated in multivariate analysis. Regression analysis was performed to identify a causal relationship between micro- and macrometastasis. Survival differences were compared between conventional N staging and hypothetic N staging taking micrometastasis in the positive node. A total of 93 patients (19.1%) showed LN micrometastasis. Patients with micrometastasis had more advanced tumor characteristics in terms of tumor size, grade, T stage, N stage, lymphatic invasion, and vascular invasion. In multivariate analysis, micrometastasis was not related with recurrence. Preoperative carcinoembryonic antigen level, neural invasion, and macrometastasis were independent risk factors in the analysis. Regression analysis showed that there was not a causal relationship between micro- and macrometastasis (R2 = 0.004, P = 0.153). When the cumulative numbers of micro- and macrometastatic LNs were calculated together, the discriminative power of survival difference between each node stage became less prominent, compared with conventional N staging. LN micrometastasis is related with advanced tumor characteristics, but does not reflect poor prognosis in nonmetastatic CRC. Micrometastasis cannot be considered as positive LN to predict poor prognosis.

Liu Y, Zuo T, Zhu X, et al.
Differential expression of hENT1 and hENT2 in colon cancer cell lines.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications
Human equilibrative nucleoside transporters (hENT) 1 and 2, encoded by SLC29A1 and SLC29A2, permit the bidirectional passage of nucleoside analogues into cells and may correlate with clinical responses to chemotherapy in patients with colorectal cancer (CRC). The purpose of this study was to evaluate the expression profiles of SLC29A1 and SLC29A2 in human cancer cell lines. Using quantitative real-time polymerase chain reaction, we comprehensively profiled the transcription levels of SLC29A1 and SLC29A2 in 16 colon cancer cell lines. We validated the ubiquitous and heterogeneous distribution of SLC29A1 and SLC29A2 in human colon cancer cell lines and demonstrated that SLC29A1 was highly expressed in 25% of metastatic cell lines (Colo201 and Colo205) and 62.5% of primary cell lines (Caco2, Colo320, HCT116, RKO, and SW48). For the first time, we showed that both SLC29A1 and SLC29A2 were expressed at lower levels in colon cancer cell lines originating from metastatic sites than from primary sites. These findings indicate that most patients with metastatic CRC (mCRC) may have low hENT1 expression, and treatment with nucleoside analogues may be inefficient. However, some patients still show high hENT1 expression and have a high probability of benefiting from these drugs. Therefore, evaluating transporter expression profiles and different drug responses between primary and metastatic tumors in patients with mCRC is important. Further assessment of the association between hENTs and drug-based treatment of mCRC is required to elucidate the mechanisms of chemotherapy resistance.

Zekri J, Al-Shehri A, Mahrous M, et al.
Mutations in codons 12 and 13 of K-ras exon 2 in colorectal tumors of Saudi Arabian patients: frequency, clincopathological associations, and clinical outcomes.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications
Mutations in codons 12/13 of K-ras exon 2 are associated with reduced benefit from anti-epidermal growth factor receptor antibody treatment for metastatic colorectal cancer (CRC). Here, we evaluated the frequency of K-ras mutations and their relationship with clinicopathological features and treatment outcomes in Saudi Arabian patients with CRC. The genetic status of K-ras was determined in 300 patients diagnosed with CRC. Clinical information was collected retrospectively. K-ras was wild-type in 58% and mutated in 42% of the tumors. Most mutations were at codon 12 (89%) and were associated with metastasis [odds ratio (OR) = 1.38 (95%CI = 1.14-1.67] and occurrence of >40 µg/L carcinoembryonic antigen (CEA) [OR = 1.33 (1.1-1.74)] during diagnosis. Patients in stages I-III of the disease with wild-type K-ras tumors had a median relapse free survival (RFS) of 29 months in contrast to 22 months for those with the mutated K-ras tumor (P = 0.0357). In multivariate analysis, only the stage of the disease significantly predicted RFS (P = 0.001). Patients in stage IV of CRC with the wild-type K-ras tumor did not reach the median overall survival (OS), whereas patients with the mutated K-ras tumor survived for 23.5 months (P = 0.044). CEA level >40 µg/L (P = 0.004) and status of K-ras (P = 0.044) were independent predictors of OS. This is the largest study investigating K-ras mutations in patients with CRC in the Middle East. Mutations were associated with advanced stage of CRC, higher serum CEA, shorter RFS and OS.

Xiu DH, Chen Y, Liu L, et al.
Tumor-suppressive role of Kruppel-like factor 4 (KLF-4) in colorectal cancer.
Genet Mol Res. 2017; 16(1) [PubMed] Related Publications
Kruppel-like factors (KLFs) are a group of transcriptional regulators that have recently been identified to exhibit tumor-suppressive function against various gastrointestinal cancers. The present study aims to investigate the expression patterns and prognostic value of KLF-4 in colorectal cancers (CRCs). KLF-4 levels in CRC tissues were examined via immunohistochemistry analysis, real-time quantitative polymerase chain reaction, and western blotting. The chi-square test was performed to evaluate the correlation between KLF-4 expression and the clinicopathological characteristics. Kaplan-Meier analysis was performed to assess the prognostic value of KLF-4 in CRC patients. In addition, we evaluated the effect of KLF-4 knockdown on the proliferation of CRC HT-29 cells. Our results showed significant downregulation of KLF-4 in 31 CRC samples, collected from CRC patients showing more malignant characteristics such as lymphatic metastasis, low tumor cell differentiation, and tumor recurrence. CRC patients in the low KLF-4 group were found to have reduced overall survival and decreased disease-free survival time. Moreover, HT-29 cells transfected with siRNA-KLF-4 showed increased proliferation compared to those transfected with control siRNA. In summary, lower KLF-4 expression was correlated with malignant CRC status and poor prognosis in CRC patients. Moreover, KLF-4 suppression promoted the proliferation of CRC cells in vitro. These results provide novel insights into the tumor suppressive role of KLF-4 in CRC.

Abu-Farsakh S, Wu T, Lalonde A, et al.
High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5.
BMC Gastroenterol. 2017; 17(1):33 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression.
METHODS: Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells.
RESULTS: Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC.
CONCLUSIONS: We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.

Khan S, Mikhail S, Xiu J, Salem ME
Molecular biology of gastroesophageal cancers: opportunities and challenges.
Clin Adv Hematol Oncol. 2017; 15(1):75-82 [PubMed] Related Publications
Gastroesophageal (GE) malignancies make up a significant and growing segment of newly diagnosed cancers. Approximately 80% of patients who have GE cancers die within 5 years of diagnosis, which means that effective treatments for these malignancies need to be found. Currently, targeted therapies have a minimal role in this disease group. Intensive study of the molecular biology of GE cancers is a relatively new and ongoing venture, but it has already led to a significant increase in our understanding of these malignancies. This understanding, although still limited, has the potential to enhance our ability to develop targeted therapies in conjunction with the ability to identify actionable gene mutations and perform genomic profiling to predict drug resistance. Several cell surface growth factor receptors have been found to play a prominent role in GE cancer cell signaling. This discovery has led to the approval of 2 agents within the last few years: trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody used in the first-line treatment of HER2-positive GE cancers, and ramucirumab, an anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody that is currently used in later lines of therapy. This review discusses the current state of molecular testing in GE cancers, along with the known molecular biology and current and investigational treatments. The development of trastuzumab and ramucirumab represents a significant advance in our ability to make use of GE tumor molecular profiles. As our understanding of the impact of molecular aberrations on drug effectiveness and disease outcomes increases, we anticipate improved therapy for patients with GE cancers.

Hashimoto D, Arima K, Chikamoto A, et al.
Limited Resection of the Duodenum for Nonampullary Duodenal Tumors, with Review of the Literature.
Am Surg. 2016; 82(11):1126-1132 [PubMed] Related Publications
The surgical management of duodenal pathology is challenging because of its retroperitoneal position and shared blood supply with the pancreas. We present three types of limited resection of the duodenum for the removal of superficial or small nonampullary duodenal (NADL) lesions, and also a review of the English literature regarding management, such as endoscopic resection and limited duodenal resection. Ten cases underwent limited resections of the duodenum for superficial or small NADL lesions from 2011 to 2015. Pancreas-preserving segmental duodenectomy was performed in three cases, local full-thickness resection was performed in three and transduodenal submucosal dissection was performed in four. One patient experienced pancreatic fistula as a postoperative complication. Postoperative pathological diagnosis were adenoma (n = 2), mucosal adenocarcinomas (n = 5), and neuroendocrine tumor (n = 3). Surgical margin was negative in all cases, and no patient has experienced postoperative recurrence or metastasis. Limited resections of the duodenum were feasible and safe procedures for patients with superficial or small NADL lesions. Laparoscopic surgery may be considered in treatment for these tumors. However, the optimal surgical management for superficial or small nonampullary duodenal lesions remains controversial.

Prabhakaran S, Fulp WJ, Gonzalez RJ, et al.
Resection of Gastrointestinal Metastases in Stage IV Melanoma: Correlation with Outcomes.
Am Surg. 2016; 82(11):1109-1116 [PubMed] Related Publications
The prognosis of patients with gastrointestinal (GI) melanoma metastases is poor. Surgery renders select patients disease free and/or palliates symptoms. We reviewed our single-institution experience of resection with GI melanoma metastases. A retrospective review was performed on patients who underwent surgery for GI melanoma metastases from 2007 to 2013. Fifty-four patients were identified and separated based on completeness of resection into curative 13 (24%) and palliative 41 (75.9%) groups. Thiry-six (63.2%) were symptomatic preoperatively with bleeding and/or obstruction/pain with 91.7 per cent achieving objective symptom relief. Thirty-day operative mortality was 0 per cent. The most common complication was wound infection (n = 5); major complications like anastomotic leak (n = 1) were uncommon. With a median follow-up of 9.5 months (range 0.2-75.8), median overall survival was not reached (curative) versus 9.53 months (palliative group). Median recurrence-free and progression-free survival after resection were 18.89 and 1.97 months in the curative versus palliative groups, respectively. On multivariate analysis, resection to no clinical evidence of disease (P = 0.012) and presence of single metastases (P = 0.031) were associated with improved overall survival. Surgery for GI metastases from melanoma provides symptomatic relief without major morbidity. Fewer metastases and curative resection were associated with improved survival.

Turza KC, Brien T, Porbunderwala S, et al.
The Ferguson Operating Anoscope for Resection of T1 Rectal Cancer.
Am Surg. 2016; 82(11):1105-1108 [PubMed] Related Publications
The Ferguson Operating Anoscope (FOA) is a surgical instrument, which can facilitate transanal excision of appropriate rectal tumors within 15 cm of the anal verge. Previous work showed low recurrence (4.3%) for favorable T1 tumors (no lymphovascular invasion, well/moderate differentiation, negative margins). This follow-up study evaluates outcomes in rectal cancer excised with FOA at a tertiary care center. T1 rectal cancer patients were identified in a prospectively maintained database. Tumor pathology and patient characteristics were reviewed. Primary outcomes include tumor recurrence and patient and disease-free survival. Secondary outcomes are quality of excision (intact specimen). Twenty-eight patients had pathologic stage T1 rectal cancer (average 8 ± 2.6 cm from the anal verge). Final path demonstrated 14 per cent to be well differentiated, 82 per cent moderately differentiated, and 93 per cent without angiolymphatic invasion. All specimens removed were intact. One patient had a true local recurrence and underwent a salvage operation 24 months after her index operation. Patient survival was 96.4 per cent (n = one death from primary lung cancer) at median follow-up 64 ± 35 months. With appropriate tumor selection and quality of initial resection, FOA has demonstrated utility in achieving optimal oncologic resection of T1 rectal tumors.

Kinsinger LA, Garber JC, Whipple O
A Review of Sleeve Gastrectomy Specimen Histopathology.
Am Surg. 2016; 82(11):1101-1104 [PubMed] Related Publications
With the increasing popularity of sleeve gastrectomy, many stomach specimens are being evaluated. Understanding the significance and treatment for unexpected pathology is important. This study examines the incidence of relevant histopathology of sleeve gastrectomy specimens. It evaluates previous data for each histopathology and provides recommendations for treatment. In this study, a retrospective review was performed for 241 patients who underwent sleeve gastrectomy from 2009 to 2014 at a single institution. Of the specimens, 122 had no significant histopathology, 91 had gastritis, 13 had lymphoid aggregates, 5 had hyperplasia, 3 had intestinal metaplasia, 3 had gastrointestinal stromal tumors (GISTs), and 3 had gastric polyps. Of the GISTs all had a low mitotic rate and the size of the tumor ranged from 1.5 to 4.5 cm. The findings of metaplasia may be a marker for increased risk of malignancy and may require additional surveillance. The findings of GIST may warrant interval imaging to survey for recurrence, though the likelihood of recurrence for the tumors in this study is less than 2 per cent based on previous studies.

Gabriel E, Thirunavukarasu P, Al-Sukhni E, et al.
National Disparities in Surgical Approach to T1 Rectal Cancer and Impact on Outcomes.
Am Surg. 2016; 82(11):1080-1091 [PubMed] Related Publications
This study investigated disparities between patients who had local excision versus radical resection for T1 rectal cancer. A retrospective analysis was performed using the National Cancer Data Base, 2004 to 2011. Inclusion criteria consisted of patients with T1, N0 rectal adenocarcinoma that were <3 cm, well or moderately differentiated without perineural invasion. Patients were stratified based on local excision and radical surgery. The primary outcome was overall survival (OS). Secondary outcomes included 30-day mortality, unplanned readmission rates, and postoperative length of stay. A total of 2235 patients were identified; 1335 (59.7%) underwent local excision and 900 (40.3%) had radical surgery. Overall, radical surgery was associated with an improved 5-year OS rate compared to local excision (0.86 vs 0.78, P = 0.009), increased unplanned readmission (6.5% vs 2.7%, P < 0.001), and longer postoperative length of stay (6.9 days vs 3.1 days, P < 0.001). For patients who had local excision, insurance status was an independent predictor of OS. Compared to patients with private insurance, those with government plans or no insurance had poorer OS (hazard ratio = 1.77 and 17.45, respectively, P = 0.006). Further study is warranted to understand the reasons accounting for this disparity in surgical approach to T1 rectal cancer.

Dai L, Wang G, Pan W
Andrographolide Inhibits Proliferation and Metastasis of SGC7901 Gastric Cancer Cells.
Biomed Res Int. 2017; 2017:6242103 [PubMed] Free Access to Full Article Related Publications
To explore the mechanisms by which andrographolide inhibits gastric cancer cell proliferation and metastasis, we employed the gastric cell line SGC7901 to investigate the anticancer effects of andrographolide. The cell survival ratio, cell migration and invasion, cell cycle, apoptosis, and matrix metalloproteinase activity were assessed. Moreover, western blotting and real-time PCR were used to examine the protein expression levels and the mRNA expression levels, respectively. The survival ratio of cells decreased with an increasing concentration of andrographolide in a dose-dependent manner. Consistent results were also obtained using an apoptosis assay, as detected by flow cytometry. The cell cycle was blocked at the G2/M2 phase by andrographolide treatment, and the proportion of cells arrested at G1/M was enhanced as the dose increased. Similarly, wound healing and Transwell assays showed reduced migration and invasion of the gastric cancer cells at various concentrations of andrographolide. Andrographolide can inhibit cell proliferation, invasion, and migration, block the cell cycle, and promote apoptosis in SGC7901 cells. The mechanisms may include upregulated expression of Timp-1/2, cyclin B1, p-Cdc2, Bax, and Bik and downregulated expression of MMP-2/9 and antiapoptosis protein Bcl-2.

Ghanbari R, Rezasoltani S, Hashemi J, et al.
Expression Analysis of Previously Verified Fecal and Plasma Dow-regulated MicroRNAs (miR-4478, 1295-3p, 142-3p and 26a-5p), in FFPE Tissue Samples of CRC Patients.
Arch Iran Med. 2017; 20(2):92-95 [PubMed] Related Publications
BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related mortality worldwide. Early diagnosis of this neoplasm is critical and may reduce patients' mortality. MicroRNAs are small non-coding RNA molecules whose expression pattern can be altered in various diseases such as CRC.
METHODS: In this study, we evaluated the expression levels of miR-142-3p, miR-26a-5p (their reduced expression in plasma samples of CRC patients was previously confirmed), miR-4478 and miR-1295-3p (their reduced expression in stool samples of CRC patients was previously confirmed) in tissue samples of CRC patients in comparison to healthy subjects. To achieve this purpose, total RNA including small RNA was extracted from 53 CRC and 35 normal subjects' Formalin-fixed, Paraffin-embedded (FFPE) tissue samples using the miRNeasy FFPE Mini Kit. The expression levels of these four selected miRNAs were measured using quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR).
RESULTS: We found that the expression levels of miR-4478 and miR-1295b-3p (two previously down-regulated fecal miRNAs) were significantly decreased in FFPE samples of CRC patients compared to healthy controls. On the other hand, no significant differences were seen in expression levels of miR-142-3p and miR-26a-5p (two previously down-regulated circulating miRNAs) in FFPE samples between these two groups.
CONCLUSION: Regarding current findings, it may be concluded that to diagnose CRC patients based on the miRNAs approach, stool samples are more likely preferable to plasma samples; nevertheless, additional studies with more samples are needed to confirm the results.

Negovan A, Iancu M, Moldovan V, et al.
The Interaction between GSTT1, GSTM1, and GSTP1 Ile105Val Gene Polymorphisms and Environmental Risk Factors in Premalignant Gastric Lesions Risk.
Biomed Res Int. 2017; 2017:7365080 [PubMed] Free Access to Full Article Related Publications
The study investigated the possible influence of GSTM1, GSTT1, and GSTP1 gene polymorphisms as predisposing factors for premalignant gastric lesions as well as their interaction with H. pylori infection, gastrotoxic drugs, smoking, and alcohol consumption. In this study, 270 patients with a complet set of gastric biopsies and successfully genotyped were finally included. The GSTM1 gene polymorphism had significant contribution in mild/severe endoscopic lesions (p = 0.01) as well as in premalignant lesions (p = 0.01). The GSTM1 null genotype increased the risk for mucosal defects in H. pylori-negative patients (OR = 2.27, 95% CI: 1.20-4.37) and the risk for premalignant lesions in patients with no alcohol consumption (OR = 2.13, 95% CI: 1.19-3.83). The GSTT1 deleted polymorphism did not significantly increase the risk for premalignant lesions in the absence of gastrotoxic drugs (OR = 1.82, 95% CI: 0.72-4.74). The combined GSTT1T1 and GSTM1 null polymorphisms were borderline correlated with an increased risk for premalignant lesions (OR = 1.72, 95% CI: 1.00-2.97). The wild-type GSTP1 Ile/Ile genotype versus the variant genotypes Ile/Val + Val/Val was significantly associated with a decreased risk of gastric atrophy/intestinal metaplasia (OR = 0.60, 95% CI: 0.37-0.98). In conclusion, the GSTM1 and GSTT1 null genotypes increased the risk for premalignant and endoscopic gastric lesions, modulated by H. pylori, alcohol, or gastrotoxic drug consumption, while the presence of the GSTP1Val allele seemed to reduce the risk for premalignant lesions.

Backman S, Norlén O, Eriksson B, et al.
Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing.
Anticancer Res. 2017; 37(2):705-712 [PubMed] Related Publications
Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.
PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.
RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.
CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

Hagland HR, Lea D, Watson MM, Søreide K
Correlation of Blood T-Cells to Intratumoural Density and Location of CD3(+) and CD8(+) T-Cells in Colorectal Cancer.
Anticancer Res. 2017; 37(2):675-683 [PubMed] Related Publications
AIM: To test the feasibility of conducting parallel analyses of circulating T-cells in blood and intratumoural T-cells in colorectal cancer. A pre-operative 'liquid biopsy' to determine immune status would facilitate clinical decision-making.
MATERIALS AND METHODS: A total of 18 patients with stage I-III colorectal cancer (CRC) were included. Blood was analyzed for T-cell type (CD3(+), CD4(+) and CD8(+)) and count using flow cytometry. Intratumoural T-cells were stained using immunohistochemistry and quantified by digital pathology. Tumour location was defined as invasive front (IF) or tumour center (TC).
RESULTS: The number of CD3(+) and CD4(+) T-cells in pre-surgical blood samples correlated with the number of CD3(+) T-cells found in the IF (Spearman ϱ=0.558, p<0.05 and 0.598, p<0.01 respectively) and CD3(+) in the TC (ϱ=0.496, p<0.05, and ϱ=0.637, p<0.01, respectively). A strong correlation was found between CD4(+) cells in blood and CD8(+) T-cells found in the TC and IF (ϱ=0.602 and ϱ=0.591, p<0.01).
CONCLUSION: There is a correlation between blood CD3(+) and CD4(+) T-cells and the T-cells found at the TC and IF.

Satoh T, Kaira K, Takahashi K, et al.
Prognostic Significance of the Expression of CD98 (4F2hc) in Gastric Cancer.
Anticancer Res. 2017; 37(2):631-636 [PubMed] Related Publications
BACKGROUND: CD98 expression is high in various human neoplasms. However, the relationship of CD98 expression with the clinicopathological factors of gastric cancer (GC) remains unclear. This study examined CD98 expression and its clinicopathological impact on GC.
PATIENTS AND METHODS: Three hundred and thirty-one patients with surgically resected GC were evaluated. Tumor sections were stained and analyzed using immunohistochemistry to assess CD98 expression.
RESULTS: CD98 was positively expressed in 19% (66/331) of our patient cohort. Increased CD98 expression was significantly associated with advanced GC stage, lymph node metastasis, non-signet histology, lymphatic permeation, and vascular invasion. Positive CD98 expression was also a significant prediction marker for unfavorable prognosis postoperatively. However, CD98 was not identified as GC's independent prognostic predictor.
CONCLUSION: CD98 could be a novel prediction marker for worse prognosis in GC-affected patients. Our data suggests that increased CD98 expression plays an essential role in tumor aggressiveness and metastasis.

Bauer G
Central Signaling Elements of Intercellular Reactive Oxygen/Nitrogen Species-dependent Induction of Apoptosis in Malignant Cells.
Anticancer Res. 2017; 37(2):499-513 [PubMed] Related Publications
Intercellular reactive oxygen/reactive nitrogen species-(ROS/RNS)-dependent induction of apoptosis in malignant cells is discussed as a potential control step during oncogenesis. In previous studies, the mechanism of intercellular apoptosis-inducing signaling was mainly established through the use of specific inhibitors and scavengers. Here, a detailed analysis was carried out based on small interfering ribonucleic acid (siRNA)-mediated knockdown of central players of intercellular ROS/RNS signaling and of the mitochondrial and the FAS receptor-dependent pathway of apoptosis. The data show that transforming growth factor β1, transforming growth factor β receptor, NADPH oxidase-1 (NOX1), NOX1 organizer, and NOX1 activator control the HOCl and the NO/peroxynitrite signaling pathways. Dual oxidase-1 (DUOX1) is specifically involved in HOCl signaling, and NO synthase in NO/peroxynitrite signaling. Both pathways utilize intracellular signal transduction through protein kinase C zeta, sphingomyelinase and central elements of the mitochondrial pathway of apoptosis, whereas the FAS receptor and FAS ligand do not seem to play a role.

Iwata N, Ishikawa T, Okazaki S, et al.
Clinical Significance of Methylation and Reduced Expression of the Quaking Gene in Colorectal Cancer.
Anticancer Res. 2017; 37(2):489-498 [PubMed] Related Publications
BACKGROUND: This study investigated abnormal methylation in colorectal cancer (CRC) and the potential role of the Quaking RNA-binding protein (QKI) gene in tumorigenesis.
MATERIALS AND METHODS: Oligonucleotide microarray expression profiling was carried out on a panel of primary CRC specimens (n=17) and CRC cell lines (n=5), followed by methylation analysis using methylation-specific polymerase chain reaction. QKI expression levels were assessed in 156 primary CRCs by qRT-PCR and immunohistochemistry.
RESULTS: Low QKI expression was observed in 47.7% in CRCs. QKI promoter methylation was detected in 32.1% of patients with CRC, and in these patients mRNA expression in tumor tissue was significantly down-regulated compared to matched normal tissues (p=0.049). There was a significant relationship between low QKI expression and recurrence after surgery (p=0.004). Low QKI expression was an independent risk factor for recurrence after surgery in 153 patients with CRC without distant metastases (p=0.036).
CONCLUSION: Patients with tumors expressing low levels of QKI experienced significantly higher rates of tumor recurrence after curative surgery and worse prognoses. Methylation of the QKI promoter and concomitant reduced expression of QKI mRNA may be important for CRC initiation and progression. Loew QKI expression may be a useful clinical biomarker for predicting recurrence and prognosis.

Chung SS, Adekoya D, Enenmoh I, et al.
Salinomycin Abolished STAT3 and STAT1 Interactions and Reduced Telomerase Activity in Colorectal Cancer Cells.
Anticancer Res. 2017; 37(2):445-453 [PubMed] Related Publications
BACKGROUND: Colorectal cancer is the third leading cause of cancer-related mortality in most developed countries. This mortality is mainly due to the metastatic progression to the liver with frequent recurrence. Colorectal cancer remains a therapeutic challenge and this has intensified the search for new drug targets. In an effort to establish a novel targeted-therapy, we studied the molecular mechanisms of cancer stem cell inhibitor salinomycin.
MATERIALS AND METHODS: Co-immunoprecipitation was performed to examine STAT3-STAT1 protein interactions. Telomerase activity was measured by polymerase chain reaction (PCR) and ELISA assays. Apoptosis and cell stress arrays were analyzed to identify key proteins responding to salinomycin treatments.
RESULTS: IL-6 and TNF-α induced STAT3 and STAT1 interactions, however the interactions were abolished by salinomycin challenge. Salinomycin reduced cancer stem cell phenotype and decreased telomerase activity of colorectal cancer cells.
CONCLUSION: Our work uncovers a new mechanism through which salinomycin inhibits cancer stemness suggesting a novel targeted-therapy for metastatic colorectal cancer.

Vrana D, Matzenauer M, Aujesky R, et al.
Potential Predictive Role of MicroRNAs in the Neoadjuvant Treatment of Esophageal Cancer.
Anticancer Res. 2017; 37(2):403-412 [PubMed] Related Publications
Esophageal cancer is a disease with disappointing prognosis. Currently, there are no predictive factors that can identify patients who on the one hand would likely benefit from tri-modality management and, on the other hand, would not be significantly affected by the morbidity accompanying the treatment. MicroRNAs are short non-coding RNAs responsible for post-transcriptional modification of gene expression by binding to 3'-UTR of messenger RNA and represent emerging potential predictive biomarkers of treatment (chemotherapy and radiotherapy) efficacy and toxicity. We reviewed the current literature, addressing the potential predictive role of microRNAs for efficacy of chemotherapy (specifically cisplatin, 5-fluorouracil, doxorubicin and paclitaxel) and radiotherapy, including predicted targets in the cell. Altogether 82 articles were identified and included in this review. This may be the first review on this topic specifically focusing on neoadjuvant treatment of esophageal cancer.

Sasikumar A, Bhan C, Jenkins JT, et al.
Systematic Review of Pelvic Exenteration With En Bloc Sacrectomy for Recurrent Rectal Adenocarcinoma: R0 Resection Predicts Disease-free Survival.
Dis Colon Rectum. 2017; 60(3):346-352 [PubMed] Related Publications
BACKGROUND: The management of recurrent rectal cancer is challenging. At the present time, pelvic exenteration with en bloc sacrectomy offers the only hope of a lasting cure.
OBJECTIVE: The purpose of this study was to evaluate clinical outcome measures and complication rates following sacrectomy for recurrent rectal cancer.
DATA SOURCES: A search was conducted on Pub Med for English language articles relevant to sacrectomy for recurrent rectal cancer with no time limitations.
STUDY SELECTION: Studies reported sacrectomy with survival data for recurrent rectal adenocarcinoma.
MAIN OUTCOME MEASURE: Disease-free survival following sacrectomy for recurrent rectal cancer was the main outcome measured.
RESULTS: A total of 220 patients with recurrent rectal cancer were included from 7 studies, of which 160 were men and 60 were women. Overall median operative time was 717 (570-992) minutes and blood loss was 3.7 (1.7-6.2) L. An R0 (>1-mm resection margin) resection was achieved in 78% of patients. Disease-free survival associated with R0 resection was 55% at a median follow-up period of 33 (17-60) months; however, none of the patients with R1 (<1-mm resection margin) survived this period. Postoperative complication rates and median length of stay were found to decrease with more distal sacral transection levels. In contrast, R1 resection rates increased with more distal transection.
LIMITATION: The studies assessed by this review were retrospective case series and thus are subject to significant bias.
CONCLUSION: Sacrectomy performed for patients with recurrent rectal cancer is associated with significant postoperative morbidity. Morbidity and postoperative length of stay increase with the level of sacral transection. Nevertheless, approximately half of patients eligible for rectal excision with en bloc sacrectomy may benefit from disease-free survival for up to 33 months, with R0 resection predicting disease-free survival in the medium term.

Kong JC, Guerra GR, Warrier SK, et al.
Outcome and Salvage Surgery Following "Watch and Wait" for Rectal Cancer after Neoadjuvant Therapy: A Systematic Review.
Dis Colon Rectum. 2017; 60(3):335-345 [PubMed] Related Publications
BACKGROUND: Currently there is no reliable test to predict pathological complete response following neoadjuvant chemoradiotherapy for rectal cancer. However, there is increasing interest in using clinical complete response as a surrogate marker, allowing a subset of patients with locally advanced rectal cancer to be allocated into a "watch and wait" pathway. Little is known about the oncological safety of the "watch and wait" approach or the rate of salvage surgery in cases of tumor regrowth. This information is critical for the implementation of this approach.
OBJECTIVE: The aim of this study is to assess the rate of salvage surgery and associated oncological outcomes for patients who develop a tumor regrowth with the "watch and wait" approach.
DATA SOURCES: Relevant studies were identified through PubMed, Embase, and Google Scholar search.
STUDY SELECTION: A systematic review was undertaken of studies assessing patients selected for the "watch and wait" approach according to PRISMA guidelines.
MAIN OUTCOME MEASURES: The associated tumor regrowth, salvage surgery, and disease-free and overall survival rates were assessed.
RESULTS: Five retrospective and 4 prospective observational studies were included into the analysis, with a total of 370 patients in the "watch and wait" group, of which 256 (69.2%) had persistent clinical complete response. Of those who had tumor regrowth, salvage surgery was possible in 83.8%. There was no difference in overall survival and disease-free survival between patients who received immediate surgery and the "watch and wait" group.
LIMITATIONS: The limitations of this study include its retrospective nature and small sample size. Furthermore, there is significant heterogeneity between study protocols, including the short median follow-up, given that tumor regrowth and distant metastasis may manifest at a later time point.
CONCLUSION: The majority of patients with tumor regrowth can be salvaged with definite surgery after "watch and wait." However, there is insufficient evidence to draw firm conclusions on the oncological safety of this approach; therefore, it is currently not the standard of care for locally advanced rectal cancer.

Ge X, Dai X, Ding C, et al.
Early Postoperative Decrease of Serum Albumin Predicts Surgical Outcome in Patients Undergoing Colorectal Resection.
Dis Colon Rectum. 2017; 60(3):326-334 [PubMed] Related Publications
BACKGROUND: A simple and accurate predictor of postoperative complications is needed for early and safe discharge after surgery. A decrease in serum albumin is commonly observed early after surgery, even in patients with normal preoperative levels. However, whether it predicts patient postoperative outcome is unknown.
OBJECTIVE: The purpose of this study was to evaluate whether the reduction in serum albumin within 2 postoperative days compared with the preoperative level could serve as an independent predictor of postoperative complications after colorectal surgery.
DESIGN: This was a retrospective study from a single institution.
SETTINGS: The study was conducted in a tertiary referral hospital.
PATIENTS: A total of 626 patients undergoing major colorectal surgery between December 2012 and January 2016 were eligible for this study.
MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify risk factors for postoperative complications and to identify the factors associated with Δalbumin. Receiver operating characteristic curves were developed to examine the cutoff value of the change in albumin in predicting postoperative complications.
RESULTS: Among all of the patients, the median Δalbumin after surgery was 15%. ΔAlbumin was an independent risk factor for overall complications (p < 0.01). The cutoff value was 15%, and an increased area under the curve compared with C-reactive protein occurred on postoperative day 3 or 4. Patients with a Δalbumin ≥15% experienced more postoperative major complications, a higher comprehensive complication index, a longer postoperative stay, and increased surgical site infections (p < 0.05) than those <15%. ΔAlbumin correlated with sex, type of surgery, stoma creation, C-reactive protein on postoperative day 3 or 4, and intraoperative blood transfusion. Postoperative C-reactive protein remained independently associated with Δalbumin (p < 0.01).
LIMITATIONS: The study was limited by its retrospective nature.
CONCLUSIONS: A cutoff value of a 15% reduction in serum albumin within 2 postoperative days could help to identify patients with a high probability of postoperative complications and permit safe and early discharge after colorectal surgery.

Takatsu Y, Fukunaga Y, Nagasaki T, et al.
Short- and Long-term Outcomes of Laparoscopic Total Mesenteric Excision for Neuroendocrine Tumors of the Rectum.
Dis Colon Rectum. 2017; 60(3):284-289 [PubMed] Related Publications
BACKGROUND: To our knowledge, no studies to date have assessed the short- and long-term outcomes of laparoscopic total mesenteric excision in patients with neuroendocrine tumors of the rectum.
OBJECTIVE: The purpose of this study was to investigate the short- and long-term outcomes of patients who underwent laparoscopic rectal resection plus total mesenteric excision for rectal neuroendocrine tumors at our institution.
DESIGN: This was a single center, retrospective study.
SETTINGS: The study was conducted at a tertiary care facility.
PATIENTS: Eight-two patients with neuroendocrine tumors who underwent rectal resection with total mesenteric excision, 77 laparoscopically, between June 2005 and August 2015 were included.
INTERVENTIONS: Laparoscopic rectal resection and total mesenteric excision were the study interventions.
MAIN OUTCOME MEASURES: Demographic characteristics and surgical and postoperative outcomes were measured.
RESULTS: Median tumor size was 8.8 mm (range, 3.0-35.0 mm); 63.6% of tumors were located in the lower rectum, with the median distance from the tumor to the anal verge being 50.0 mm (range, 20.0-130.0 mm). Anal preservation was achieved in all of the patients. Anastomotic leakage occurred in 5 patients (6.5%), but there were no deaths. Seventy-one patients (92.2%) had tumor invasion confined to the submucosa. Lymph node metastasis was present in 29 patients (37.7%), including 26 (33.8%) with perirectal and 5 (6.5%) with lateral lymph node metastasis. The median follow-up period in 59 patients was 42 months (range, 11-113 months), and the 3-year overall survival rate was 97.8%.
LIMITATIONS: The study was limited by its single-center, retrospective analysis.
CONCLUSIONS: Laparoscopic rectal resection with total mesenteric excision is safe in patients with rectal neuroendocrine tumors, with good short- and long-term outcomes. Because rectal neuroendocrine tumors are smaller and show superficial invasion, the rate of anal preservation may be high.

van den Broek JJ, van der Wolf FS, Lahaye MJ, et al.
Accuracy of MRI in Restaging Locally Advanced Rectal Cancer After Preoperative Chemoradiation.
Dis Colon Rectum. 2017; 60(3):274-283 [PubMed] Related Publications
BACKGROUND: Patients with a locally advanced rectal carcinoma benefit from preoperative chemoradiotherapy. MRI is considered the first choice imaging modality after preoperative chemoradiation, although its reliability for restaging is debatable.
OBJECTIVE: The purpose of this study was to determine the accuracy of MRI in restaging locally advanced rectal cancer after preoperative chemoradiation.
DESIGN: This was a retrospective study.
SETTINGS: The study was conducted in a Dutch high-volume rectal cancer center.
PATIENTS: A consecutive cohort of 48 patients with locally advanced rectal cancer treated with a curative intent was identified.
MAIN OUTCOME MEASURES: Three readers independently evaluated the MRI both for primary staging and for restaging after preoperative chemoradiation and were blinded to results from the other readers as well as histological results. Interobserver variability was determined. Accuracy of the restaging MRI was assessed through the comparison of tumor characteristics on MRI with histopathologic outcomes.
RESULTS: T stage was correctly predicted by the 3 readers in 47% to 68% and N stage in 68% to 70%. Overstaging was more common than understaging. Positive predictive values (PPV) among the 3 readers for T0 were 0%, and negative predictive values (NPVs) varied from 84% to 85%. For T1/2, PPVs and NPVs were 50% to 67% and 72% to 90%, and for T3/4 they were 54% to 62% and 33% to 78%. PPVs and NPVs for N0 stage were 81% to 95% and 58% to 73%. Tumor regression grade on MRI did not correspond with histopathologic tumor regression grade; PPVs for good response (tumor regression grade on MRI 1-2) were 48% to 61%, and NPVs were 42% to 58%. Interobserver agreement was fair to moderate for T stage, N stage, and tumor response (κ = 0.20-0.41) and fair to substantial for the relation with the mesorectal fascia (κ = 0.33-0.77). In none of the patients was the surgical plan changed after the restaging MRI.
LIMITATIONS: This study was limited by its small sample size and retrospective nature.
CONCLUSIONS: MRI has low accuracy for restaging locally advanced rectal cancer after preoperative chemoradiation, and the interobserver variability is significant.

Kim J, Baek SJ, Kang DW, et al.
Robotic Resection is a Good Prognostic Factor in Rectal Cancer Compared with Laparoscopic Resection: Long-term Survival Analysis Using Propensity Score Matching.
Dis Colon Rectum. 2017; 60(3):266-273 [PubMed] Related Publications
BACKGROUND: Robotic total mesorectal excision for rectal cancer has rapidly increased and has shown short-term outcomes comparable to conventional laparoscopic total mesorectal excision. However, data for long-term oncologic outcomes are limited.
OBJECTIVE: The aim of this study is to evaluate long-term oncologic outcomes of robotic total mesorectal excision compared with laparoscopic total mesorectal excision.
DESIGN: This was a retrospective study.
SETTINGS: This study was conducted in a tertiary referral hospital.
PATIENTS: A total of 732 patients who underwent totally robotic (n = 272) and laparoscopic (n = 460) total mesorectal excision for rectal cancer were included in this study.
MAIN OUTCOME MEASURES: We compared clinicopathologic outcomes of patients. In addition, short- and long-term outcomes and prognostic factors for survival were evaluated in the matched robotic and laparoscopic total mesorectal excision groups (224 matched pairs by propensity score).
RESULTS: Before case matching, patients in the robotic group were younger, more likely to have undergone preoperative chemoradiation, and had a lower tumor location than those in the laparoscopic group. After case matching most clinicopathologic outcomes were similar between the groups, but operative time was longer and postoperative ileus was more frequent in the robotic group. In the matched patients excluding stage IV, the overall survival, cancer-specific survival, and disease-free survival were better in the robotic group, but did not reach statistical significance. The 5-year survival rates for robotic and laparoscopic total mesorectal excision were 90.5% and 78.0% for overall survival, 90.5% and 79.5% for cancer-specific survival, and 72.6% and 68.0% for disease-free survival. In multivariate analysis, robotic surgery was a significant prognostic factor for overall survival and cancer-specific survival (p = 0.0040, HR = 0.333; p = 0.0161, HR = 0.367).
LIMITATIONS: This study has the potential for selection bias and limited generalizability.
CONCLUSIONS: Robotic total mesorectal excision for rectal cancer showed long-term survival comparable to laparoscopic total mesorectal excision in this study. Robotic surgery was a good prognostic factor for overall survival and cancer-specific survival, suggesting potential oncologic benefits.

Marks JH, Salem JF, Valsdottir EB, et al.
Quality of Life and Functional Outcome After Transanal Abdominal Transanal Proctectomy for Low Rectal Cancer.
Dis Colon Rectum. 2017; 60(3):258-265 [PubMed] Related Publications
BACKGROUND: Transanal abdominal transanal proctectomy is a sphincter-preserving procedure designed to avoid colostomy in patients with cancer in the distal third of the rectum. Oncologic outcomes of this procedure have been established. However, data regarding patient satisfaction and quality of life are scant.
OBJECTIVE: The purpose of this study was to evaluate the quality of life and functional outcomes of patients after transanal abdominal transanal proctectomy.
DESIGN: This is a cross-sectional study.
SETTINGS: The study was conducted at a tertiary referral colorectal center.
PATIENTS: Patients who underwent transanal abdominal transanal proctectomy were included and surveyed using the Fecal Incontinence Quality of Life Scale, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, the Quality of Life Questionnaire CR38 module, and a questionnaire designed by the authors to assess satisfaction with quality of life.
MAIN OUTCOME MEASURES: Quality of life, functional outcomes, and patient satisfaction were measured and compared by age, tumor level, and stage of the disease.
RESULTS: A total of 133 surveys were mailed, and 90 patients responded and were included in the study. Patient quality of life was not significantly different after surgery. Patients with more proximal tumors had better lifestyle, physical, and emotional scores. Older patients performed better on multiple levels, including coping, emotional, body image, future perspective, and digestive. Stage of disease had no impact on quality of life. Compared with reference values, patients who underwent transanal abdominal transanal proctectomy performed better on most of the components. All of patients preferred transanal abdominal transanal proctectomy over having a stoma based on their current anal sphincter function, and >97% of patients preferred transanal abdominal transanal proctectomy based on their current quality of life, sexual function, and level of activities.
LIMITATIONS: This study is limited by the lack of a comparison group and a potential selection bias.
CONCLUSIONS: Satisfaction with quality of life and functional outcomes is high after transanal abdominal transanal proctectomy. Older patients and those with more proximal tumors performed better. This patient population clearly preferred a sphincter-preserving option for treatment of their rectal cancer.

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