Completely Responsive Multiple Liver Recurrence of Colon Cancer Treated Using Chemotherapy with Oral S-1 and Oxaliplatin Plus Bevacizumab : A Case Report.

The aim of this study was to evaluate the efficacy and safety of co-administration of oral S-1 and oxaliplatin (SOX) in combination with bevacizumab (bev) in patients with advanced recurrent colorectal cancer. A retrospective study of 36 patients with advanced recurrent colorectal cancer was performed, of whom 27 received first-line and 9 received second-line SOX+bev chemotherapy between 2010 and 2013 at the Hachioji Digestive Disease Hospital (Hachioji, Japan). The SOX+bev regimen consisted of administration of intravenous oxaliplatin (85 mg/m2) on days 1 and 14, bevacizumab (5 mg/kg) on day 1, and co-administration of oral S-1 twice daily on days 1-14. The drug regimen was repeated every 4 weeks. SOX+bev treatment was associated with a response rate of 45.2%, a disease control rate of 71%, and a median progression-free survival (PFS) and overall survival (OS) of 9.9 and 21.9 months, respectively. Patients who received first-line chemotherapy benefited from treatment in terms of prolonged PFS (13.8 months) and OS (28.2 months). Grade 3/4 adverse events were infrequent and included anaemia, thrombocytopenia, anorexia, diarrhea, sensory neuropathy, increased aspartate aminotransferase level and skin rash. In conclusion, SOX+bev therapy was found to be feasible and safe for patients with advanced and recurrent colorectal cancer.

Selecting the appropriate preoperative neoadjuvant chemotherapy (NACT) regimen for patients with advanced gastric cancer (GC) is critical to effective treatment. The aim of this study was to develop nomograms based on pretherapeutic computed tomography (CT) features to predict response to NACT with S-1 and oxaliplatin (SOX) or that with docetaxel and SOX (DOS) in patients with advanced GC. This study enrolled 311 consecutive patients with confirmed advanced GC undergoing contrast-enhanced CT before and after the three cycles of NACT with DOS (n=152) or SOX (n=159), who were randomized into a training cohort (TC) (NACT with DOS: n=111; NACT with SOX: n=120) and validation cohort (VC) (NACT with DOS: n=41; NACT with SOX: n=39). The objective response rate (ORR) was used to evaluate the response to NACT. In the TC, ORR was compared between the DOS and SOX regimens, and independent predictors including CT features and tumor differentiation were determined by univariate and binary logistic regression analyses. Individual nomograms were constructed for the SOX and DOS regimens in the TC, and the predictive accuracy was validated in the VC. After NACT, the percentage of ORR was higher in patients receiving DOS than in those receiving SOX in TC (P value <0.05). The independent predictors after DOS and SOX were pretherapeutic cT stage [odds ratio (OR) =7.364; OR =8.848], cN stage (OR =1.027; OR =1.345), degree of differentiation (OR =7.127; OR =7.835), and gross tumor volume (OR =8.960; OR =8.161) (all P values <0.05). The concordance indexes of the individual nomograms developed using these predictors were 0.940 and 0.932 after DOS or SOX in the TC, respectively, which was validated by calibration plots with a slope close to 45° in the TC and VC. Despite there being a superior response to DOS compared with SOX, nomograms for predicting response to both NACT regimens were similar, with each demonstrating good predictive performance.

147 Background: Perioperative chemotherapy could improve the prognosis compared with surgery alone. This study is to compare the efficacy and safety of S-1 and oxaliplatin (SOX) with fluorouracil, leucovorin and oxaliplatin (FOLFOX) as neoadjuvant chemotherapy for locally advanced gastric carcinoma. Methods: Patients with histologically confirmed locally advanced gastric carcinoma were enrolled and divided into two groups. Preoperative staging and response evaluation was achieved mainly by gastroscopy and abdominal computer tomography. Neoajuvant chemotherapy consisted of 2-6 cycles of S-1 80mg/m2 (2-week administration and 1-week rest) plus oxaliplatin 130mg/m2 on Day1 in SOX group, or 2 h infusion of 130mg/m2 oxaliplatin plus 2h infusion of 400 mg/m2 leucovorin, followed by infusion of 400 mg/m2 5-fluorouracil on Day 1 and 46 h 2.4 g/m2 bolus in FOLFOX group. The clinical response was evaluated after 2 cycles of chemotherapy, and surgery was attempted. Results: From 2009.9 to 2011.5, 88 patients were enrolled in this study(56 in SOX and 32 in FOLFOX). The clinical response rate was significant higher in the SOX compared with FOLFOX (54.7% vs. 31.2%, p=0.03). 68 patients received surgery(45 in SOX and 23 in FOLFOX), R0 resection rate was similar in both group (SOX: 93.3% vs. FOLFOX: 82.6%, p=0.22). Pathological complete response was observed in 3 patients in SOX group. All enrolled patients were evaluated for the adverse events (AE). The most common non-hematological AE was nausea (57.1% in SOX and 50% in FOLFOX) and vomiting (41.1% in SOX and 40.6% in FOLFOX). The major hematological AE included thrombocytopenia (37.5% in SOX and 21.9% in FOLFOX), neutropenia (33.9% in SOX and 53.1% in FOLFOX) and leukocytopenia (32.1% in SOX and 40.6% in FOLFOX). Conclusions: SOX had higher response rate and acceptable toxicity compared with FOLFOX as neoadjuvant chemotherapy.

BackgroundSynchronous double cancer of the colon and stomach accompanied by liver metastasis is rare. It is often difficult to determine an appropriate treatment strategy for multiple liver metastases of synchronous gastric cancer and colorectal cancer. Multidisciplinary treatment is required based on the progression and location of each tumor and chemotherapy for complete resection.Case presentationA 57-year-old male who complained of acute abdominal pain and fever visited his local hospital. He underwent emergent surgery for peritonitis caused by a gastric perforation. The cytodiagnosis of ascites did not show any tumor cells. There was a liver metastasis in the lateral segment of the liver. We performed a primary closure of the defect and then applied an omentum flap. After surgery, the patient was diagnosed as having synchronous cStage IV transverse colon cancer with multiple liver metastases and cStage IIB gastric cancer. The [18F]-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed 18F-FDG uptake by the colon tumor and multiple liver metastases, but there was no uptake in the gastric tumor or lymph nodes. We retrospectively reevaluated the CT findings from a local hospital and detected a liver nodule in segment 2/3 (from 35 to 60 mm) and segment 6 (from 26 to 57 mm), and the tumors had dramatically grown in size in only 2 months. Because complete tumor resection would be difficult, S-1 and oxaliplatin (SOX) plus bevacizumab therapy was started to control tumor progression. After 20 courses of chemotherapy, the clinical diagnosis was ycStage IV transverse colon cancer and ycStage IIa gastric cancer. We planned a two-step procedure to completely resect the primary tumors and multiple liver metastases. We first performed a laparoscopic right-colon resection+D3 lymphadenectomy and open distal gastrectomy+D2 lymphadenectomy. The patient was discharged home on postoperative day 18. After 1 month, we performed open liver resection. The pathological findings showed that the transverse colon was ypT2 (MP) with grade 2 therapeutic effects and that there were no atypical cells in the gastric tumor and multiple liver nodules (pathological complete response).ConclusionThe SOX plus bevacizumab regimen could be an option for controlling tumor progression in synchronous double cancer of the colon and stomach with liver metastasis and led to the complete resection of such tumors.

136 Background: Although clinical outcomes of chemotherapy in patients with locally advanced or metastatic colorectal cancer (CRC) have improved over the last decade, the standard-of-care chemotherapy regimens for patients with unresectable RAS wild-type CRC remain to be discussed. The aim of this study was to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Methods: This phase II, randomized, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Forty-five patients were enrolled in this study between February 2012 and October 2016. Results: The overall response rate (ORR) for the SOX+B-mab group was 59.1%, whereas that for the SOX+C-mab group was 43.5% (p = 0.29). The disease control rate (DCR) for the SOX+B-mab group was 90.9%, whereas that of the SOX+C-mab group was 91.3% (p = 0.96). For all patients, median OS were 25.3 months (95% CI: 16.5–39.4 months) in the SOX+B-mab group and 15.5 months (95% CI: 7.30–30.4 months, p = 0.167) in the SOX+C-mab group. Median PFS were 11.7 months (95% CI: 7.37–18.2 months) in the SOX+B-mab group and 5.5 months (95% CI: 3.36–10.1 months, p = 0.077) in the SOX+C-mab group. In the SOX+B-mab group, OS and PFS were not significantly different with and without early tumor shrinkage (ETS). However, in the SOX+C-mab group, patients with ETS had significantly better OS (30.4 months [95% CI: 8.0–44.3 months, p = 0.032]) and PFS (12.0 months [95% CI: 5.1–19.7 months, p = 0.003]) than those without ETS. Conclusions: The safety and efficacy of SOX+B-mab and SOX+C-mab as initial treatment for unresectable CRC with wild-type KRAS were almost the same. ETS was more correlated with PFS in the SOX+C-mab group than in the SOX+B-mab group, suggesting consideration of treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Clinical trial information: UMIN000006706 .

Pathological complete response to systemic chemotherapy is associated with more favorable survival in patients with colorectal cancer liver metastases. We present a case of a 63-year-old man with multiple liver metastases from descending colon cancer. Following surgical resection of the primary tumor, the patient received systemic chemotherapy with S-1 and oxaliplatin in combination with bevacizumab. On achievement of a markedly favorable response to chemotherapy, surgical treatment of liver metastases was performed, and the liver tumors were successfully resected without any macroscopic residue. Histopathological analyses showed necrotic tissue in the complete absence of residual viable tumor cells. This is the first reported case of a patient with multiple liver metastases from descending colorectal cancer to achieve a pathological complete response following systemic chemotherapy with S-1 and oxaliplatin in combination with bevacizumab. This regimen is a systemic chemotherapy option to 'cure' liver metastasis from colorectal cancer.

Background: The SOFT study was a phase III trial designed to validate the non-inferiority of S-1 and oxaliplatin (SOX) plus bevacizumab to mFOLFOX6 plus bevacizumab in terms of PFS in patients with metastatic colorectal cancer (mCRC) who had not previously received chemotherapy. In this study, we retrospectively reviewed cases in which S-1 plus bevacizumab as maintenance therapy after induction of S-1 and Oxaliplatin (SOX) plus bevacizumab as first-line chemotherapy in patients with metastatic colorectal cancer was applied in order to evaluate its efficacy and safety in clinical practice. Material and method: Among the 40 patients with mCRC at the Fuchu Hospital who received SOX plus bevacizumab as a first line treatment between August 2013 and December 2018. The eligible patients had histologically confirmed mCRC. On day 1 of each 3-week period during the study, patients in the SOX plus bevacizumab received a 7.5 mg/kg intravenous infusion of bevacizumab, followed by an intravenous infusion of 130 mg/m2 oxaliplatin. S-1 (40 - 60 mg) was administered orally two times per day from after dinner on day 1 to after breakfast on day 15, followed by a 7-day rest. Results: The median PFS was 15.0 months and median OS was 36.0 months. The response rate (RR: complete pus partial response) was 85.0%, and the disease control rate (DCR: RR plus stable disease) was 92.5%. The most common adverse events with SOX plus bevacizumab were hypertension (50%), neurosensory toxicity (50%), anorexia (32.5%), fatigue (45%), pigmentation (39%), Neutrophil count decreased (30%), and platelet count decreased (40%). The most common grade 3/4 adverse events were neurosensory toxicity (5%) and fatigue (9%). Conclusion: This study revealed that the survival benefit of S-1 and oxaliplatin (SOX) plus bevacizumab in Japanese patients with mCRC was like that observed in previous clinical trials. Therefore, S-1 and oxaliplatin (SOX) plus bevacizumab can be considered as routine first-line treatment option for patients with mCRC.

BackgroundAlthough patients with stage IV gastric cancer who respond well to systemic chemotherapy can be treated with gastrectomy, the prognosis of patients with unresectable gastric cancer with para-aortic lymph node metastasis is poor. We herein report a case of remnant gastric cancer with para-aortic lymph node metastasis that was treated with potentially curative conversion surgery after showing a complete response to chemotherapy with S-1 and oxaliplatin (SOX).Case presentationAn 81-year-old man was diagnosed with type 3 remnant gastric cancer with giant para-aortic lymph node metastasis, and he received SOX chemotherapy. After three courses of SOX chemotherapy, the primary tumor and para-aortic lymph node metastases markedly reduced in size, indicating a partial response. Because conversion surgery was possible, the patient underwent total remnant gastrectomy with D2 and para-aortic lymph node dissection. Histological examination revealed no residual cancer cells in the resected stomach and lymph nodes. The patient was diagnosed with a complete pathological response and was discharged on postoperative day 24. Currently, 1 year after surgery, the patient is alive and has not shown any tumor recurrence.ConclusionTo the best of our knowledge, this is the first case of advanced remnant gastric cancer with giant para-aortic lymph node metastasis that showed a pathological complete response and favorable outcome after SOX chemotherapy.

PURPOSEThis multicenter, randomized phase III trial evaluated the efficacy and safety of perioperative camrelizumab (an anti–PD-1 antibody) plus low-dose rivoceranib (a VEGFR-2 inhibitor) and S-1 and oxaliplatin (SOX) (SOXRC), high-dose rivoceranib plus SOX (SOXR), and SOX alone (SOX) for locally advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.METHODSPatients with T3-4aN + M0 G/GEJ adenocarcinoma were randomly assigned (1:1:1) to receive perioperative treatment with SOXRC, SOXR, or SOX. The primary end points were pathologic complete response (pCR) and event-free survival. The Independent Data Monitoring Committee recommended stopping enrollment in the SOXR group on the basis of the safety data of the first 103 randomly assigned patients in the three groups. The patients were then randomly assigned 1:1 to the SOXRC or SOX groups. This report presents the pCR results obtained per protocol for the first 360 randomly assigned patients who had the opportunity for surgery in the SOXRC and SOX groups.RESULTSIn the SOXRC and SOX groups, of the 180 patients in each group, 99% and 98% of patients received neoadjuvant therapy, 91% and 94% completed planned neoadjuvant therapy, and 86% and 87% underwent surgery, respectively. The pCR was significantly higher in the SOXRC group at 18.3% (95% CI, 13.0 to 24.8) compared with 5.0% (95% CI, 2.3 to 9.3) in the SOX group (difference of 13.7%; 95% CI, 7.2 to 20.1; odds ratio of 4.5 [95% CI, 2.1 to 9.9]). The one-sided P value was <.0001, crossing the prespecified statistical significance threshold of P = .005. Surgical complications and grade ≥3 neoadjuvant treatment-related adverse events were 27% versus 33% and 34% versus 17% for SOXRC and SOX, respectively.CONCLUSIONThe SOXRC regimen significantly improved pCR compared with SOX alone in patients with G/GEJ adenocarcinoma with a tolerable safety profile.

BackgroundAlthough chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS.MethodsThis randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled.ResultsOverall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively).ConclusionsThe efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen.Trial registrationUMIN Clinical Trials Registry (UMIN000006706).Date of registration: NOV/11/2011.URL of trial registry record:https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920

Carving Out a Place for Endoscopic Submucosal Dissection

The incidence, morbidity, and mortality of colorectal cancer are increasing, largely owing to an increasingly aging population. Additionally, along with the increasing age of cancer patients, the number of patients with various comorbidities such as membranous nephropathy is also rising, and problems associated with the administration of chemotherapy to elderly patients with these conditions are becoming more common. Herein, we describe a case involving an 80-year-old woman who presented with general malaise, edematous limbs, and pleural effusion. An abdominal CT revealed multiple, relatively large, metastatic lesions in a wide area of the liver and left pleural effusion, and she was accordingly diagnosed with membranous nephropathy secondary to ascending colon cancer and multiple liver metastases. Despite her advanced age and the presence of membranous nephropathy, her general condition was favorable and chemotherapy was hence administered. Taking the toxicity profiles and the patient's preference into consideration, S-1 and oxaliplatin (SOX) therapy was selected, which showed a good tolerability. An abdominal CT after 8 cycles of SOX therapy revealed a marked reduction in the metastatic lesions in the liver and a decrease in the left pleural effusion, and the levels of tumor markers also decreased (partial response). At the latest follow-up, after the completion of 16 cycles, the condition of the patient remained stable, without any apparent signs of progressive disease. Based on this case, we conclude that, even for elderly patients with systemic complications or comorbid diseases, standard treatments should be considered after their general conditions, and therapeutic regimens have been sufficiently examined.

This Month in Gastroenterology

Colorectal polyps are the precursors for most colorectal cancers (CRCs). Some colorectal polyps accumulate enough mutations to develop high-grade dysplasia and eventual invasion of dysplastic elements into the submucosa (1). The invasion of dysplastic elements into the submucosa constitutes the clinical definition of CRC (Figure 1).Figure 1.: Cancer depth and AJCC classification.The term malignant polyp specifically refers to a colorectal lesion with cancer invading the submucosa but not extending into the muscularis propria. These lesions are classified as pT1 in the TNM classification system (2). A synonymous and more modern term is submucosally invasive lesion. We will use the nomenclature of submucosal invasion throughout this document interchangeably when referring to a malignant polyp. The prevalence of cancer in colorectal polyps ranges from 0.2% to 5% (3–5). Malignant polyps represent the earliest form of clinically relevant CRC in most patients because neoplastic invasion of the submucosa allows for possible lymphatic and vascular metastasis. The risk of metastasis depends on several endoscopic and histologic features. The clinical issue most often raised by malignant polyps is whether a patient with an endoscopically resected colorectal lesion with submucosal invasion requires surgical resection of the colorectal segment from which the lesion was removed. Some malignant polyps can be managed endoscopically because the risk of residual cancer in the bowel wall and/or adjacent lymph nodes is very low. Other endoscopically resected malignant polyps are best managed by surgical resection because endoscopic resection alone is accompanied by a very high risk of residual cancer and/or lymph node metastases. Optimal selection of patients with malignant polyps for endoscopic surveillance vs surgical treatment is important to minimize both the risk of residual cancer and the risk of surgery (6,7). The purpose of this document is to guide endoscopists on how to assess lesions for endoscopic features associated with cancer, discuss how these factors guide endoscopic management, and to outline the factors that frame whether to advise surgery after a malignant polyp has been endoscopically resected. The approach in the document is formulated around several specific key questions with relevant data from the literature that inform the recommendations. Specifically, we will discuss 6 key questions that address the following 3 tasks: endoscopic recognition of colorectal polyps with deep submucosal invasion that should be referred directly to surgery; optimal endoscopic resection techniques and specimen handling when an increased risk of superficial submucosally invasive polyp is identified; and weighing the risks and benefits of surgery when an endoscopically removed polyp is found to have submucosal invasion. Another document by the US Multi-Society Task Force (Kaltenbach, unpublished data) discusses optimal resection techniques for large and malignant polyps. This document excludes management of polyps associated with inflammatory bowel disease. Methods Literature Review The English language medical literature was searched using MEDLINE, EMBASE, and Cochrane Database of Systematic reviews from January 1980 to December 31, 2018. A combination of key words and Medical Subject Headings were used and are summarized in Appendix 1, https://links.lww.com/AJG/B748. Review articles, meta-analyses, and editorials were reviewed for additional references. Grading of Evidence The US Multi-Society Task Force on Colorectal Cancer (USMSTF) consists of gastroenterologists with expertise in colorectal neoplasia (ie, CRC and precursor lesions, such as polyps). The American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy are represented. Summary tables and a draft document were circulated to members of the USMSTF and final guidelines were developed by consensus during several joint teleconferences. The document underwent committee review and governing board approval by all 3 societies. The USMSTF grades the quality of evidence and strength of recommendations using an adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (8). The GRADE process categorizes the quality of the evidence as high, moderate, low, or very low (Table 1). This categorization is based on an assessment of the study design (eg, randomized controlled trial or observational study), study limitations, inconsistency of results, indirectness of evidence, imprecision, and publication bias. The USMSTF members conduct literature searches to identify published articles that address the key issues discussed within these recommendations. These publications are supplemented both by review of citations from the identified articles, as well as other key references elicited from the subject matter experts on the Task Force. The GRADE process involves the collection of literature, analysis, summary, and a separate review of the quality of evidence and strength of recommendations. The USMSTF members employed a modified, qualitative approach for this assessment based on exhaustive and critical review of evidence, without a traditional meta-analysis. The GRADE process separates evaluation of the quality of the evidence to support a recommendation from the strength of that recommendation. This is done in recognition of the fact that, although the quality of the evidence impacts the strength of the recommendation, other factors can influence a recommendation, such as side effects, patient preferences, values, and cost. Strong recommendations mean that most informed patients would choose the recommended management and that clinicians can structure their interactions with patients accordingly. Weak recommendations mean that patients' choices will vary per their values and preferences, and clinicians must ensure that patient care is in keeping with their values and preferences. Weaker recommendations are indicated by phrases such as “we suggest,” and stronger recommendations are stated as “we recommend.”Table 1.: Grading of Recommendations Assessment, Development and Evaluation Ratings of EvidenceDefinitions Definition of Malignant Polyp The term malignant polyp refers to a colorectal polyp including flat lesions with neoplastic invasion of the submucosa without extension into the muscularis propria (2,9). Another term for such lesions is submucosally invasive polyps. The Vienna classification system is a consensus between Western and Japanese pathologists for classifying gastrointestinal epithelial neoplasia into 5 categories (Table 2) (10). According to this classification, malignant polyps would fall under category 5.2 (submucosal carcinoma and beyond).Table 2.: Vienna Classification of Gastrointestinal Epithelial NeoplasiaMalignant colorectal polyps are classified as pT1 in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system (Figure 1) (2). This clinical definition of CRC excludes lesions with high-grade dysplasia, in which dysplastic changes are solely confined to the epithelium, lamina propria, or muscularis mucosa. Such lesions are classified as “Tis” in the AJCC staging system and National Comprehensive Cancer Network guidelines (2,9). Pathologists sometimes use the term cancer or carcinoma in situ or intramucosal carcinoma to describe such lesions. However, the use of terms such as carcinoma or cancer in describing lesions confined to the mucosa may cause undue alarm to endoscopists, surgeons, patients, or primary care providers, and can lead to unnecessary surgery. Although lesions confined to the mucosa, lamina propria, and the muscularis mucosa, are precancerous, they should not be confused with invasive colon cancer. The recommended management of adenomas with high-grade dysplasia should be endoscopic resection alone, because these lesions have no risk of residual neoplasia in the bowel wall or lymph nodes after complete endoscopic resection. We encourage endoscopists to discuss appropriate terminology with their pathologists and for pathologists to avoid the terms carcinoma and cancer in describing lesions confined to the mucosa, in order to reduce errors in understanding and clinical management. Endoscopic and Histologic Classification Systems Used in This Document The optimal management of malignant polyps in modern colonoscopy is based on the endoscopic diagnosis. Before endoscopic resection, every colorectal lesion detected at colonoscopy should undergo complete assessment of the lesion morphology, surface, and vessel pattern. A skilled assessment, often accompanied by dye-based chromoendoscopy or electronic-based image enhancement, will identify lesions with endoscopic features that are specific for deep submucosal invasion of cancer (see below). Deep submucosal invasion of a colorectal lesion is defined as ≥1 mm (1000 μm) of submucosal invasion, and is associated with a high risk of residual cancer after endoscopic resection, specifically a high risk of lymph node metastases (11). When endoscopic features of deep submucosal invasion are present, areas exhibiting these features should be biopsied and the patient scheduled for staging studies in anticipation of surgical resection. Absent the endoscopic features of deep submucosal invasion, most colorectal lesions are candidates for endoscopic resection. There are no endoscopic signs with high sensitivity or specificity for superficial (<1 mm) invasion, however, there are certain endoscopic features associated with a higher risk of superficial submucosal invasion, including large size (≥2 cm), depressed or sessile morphology in nongranular lateral spreading tumors (LST-NG), and discrete nodules in granular lateral spreading tumors (LST-G) (see below). Some lesions with these features should be considered for en bloc endoscopic resection because en bloc resection optimizes the pathologic assessment of any lesion, particularly with regard to the depth of invasion. These points emphasize that optimal management of potentially malignant lesions includes careful endoscopic evaluation and estimation of the degree of invasiveness before resection. Once resection has occurred and cancer is identified by pathology, then the more traditionally discussed issues of whether to proceed with surgery must be addressed. The post-resection management of submucosally invasive lesions optimally utilizes a multidisciplinary approach, with input from the pathologist, surgeon, and sometimes an oncologist and/or radiation oncologist. However, the endoscopist often plays the central role in informed decision-making, frequently serving as the point of contact for the patient and their family. Endoscopic Surface Pattern Classifications Endoscopic assessment of colorectal polyps and lesions to predict the histologic class (ie, adenoma vs serrated class) and determine the presence of features associated with deep submucosal invasion are important skills for the modern colonoscopist. Endoscopic assessment can be assisted by illumination with wavelengths that enhance blood vessels and delineate surface features (eg, narrow band imaging [NBI]; Olympus, Center Valley, PA and Fujinon Blue Light Imaging; Fujinon, Valhalla, NY) or by post-processing techniques that enhance these elements (eg, Fujinon Linked Color Imaging and Pentax iscan; Pentax Medical, Montvale, NJ). Optical magnification can assist with characterization, if available. Classification systems associating endoscopically visualized surface features with specific histology facilitate prediction of histology by the endoscopist. The descriptions of the polyp and endoscopic classification systems used in the document are provided below. Narrow Band Imaging International Colorectal Endoscopic Classification. In 2009, the Colon Tumor NBI Interest Group proposed the NBI International Colorectal Endoscopic (NICE) classification system, which has been validated in subsequent studies as an accurate system to classify polyps as type 1 (serrated class: either hyperplastic or sessile serrated polyp) or type 2 (conventional adenoma) (12). Lesions with disruption of the surface pattern and vessel structure are type 3, which is specific (although not sensitive) for deep submucosal invasive cancer (13). The NICE classification system can be used with or without magnification, and does not require use of dye spray (14,15) (Table 3 and Figure 2).Table 3.: Narrow Band Imaging International Colorectal Endoscopic ClassificationFigure 2.: NICE classification Kudo pit pattern classification.Japanese Narrow Band Imaging Expert Team Classification (Modified Narrow Band Imaging International Colorectal Endoscopic Classification). One limitation of the NICE classification is that it is difficult to distinguish among low-grade dysplasia, high-grade dysplasia, and superficial submucosal invasion in type 2 lesions. To address this limitation, the Japanese Narrow Band Imaging Expert Team (JNET) published a new NBI colorectal magnification classification in 2014 (16), which requires magnification endoscopy. JNET maintains NICE types 1 and 3 but divides NICE type 2 into JNET 2a and 2b, with 2b features associated with high-grade dysplasia and superficial submucosal invasion. The classification system is presented in Table 4 and Figure 3.Table 4.: Japanese Narrow Band Imaging Expert Team ClassificationFigure 3.: JNET classification.Kudo Pit Pattern Classification. Used extensively in the East, the Kudo pit pattern classification system has been adopted in the Western world as well (17–20). It requires magnification colonoscopy with dye spray (although many Western endoscopists use it without dye spray), and allows for evaluation of malignant polyps through characterization of the pits, which are openings for crypts (21–23). As described by Kudo and colleagues (18), pits are classified into 6 patterns: type I, II, IIIL, IIIS, IV and V. Type I pits appear as roundish pits; type II pits appear as stellar or papillary pits; type III-s pits are small roundish, tubular pits (smaller than type I), and type III-L are roundish and tubular pits (larger than type I); type IV pits appear as branch-like or gyrus-like pits and type V pits appear as nonstructured pits. Pit pattern type V is further classified as VN (nonstructural) and VI (irregular). Type I and II are characteristic of normal, serrated or inflammatory polyps, whereas pit pattern classes III–V are considered to indicate dysplastic and malignant changes. The classification system is presented in Table 5 and Figure 2.Table 5.: Kudo's Classification of Polyp Pit Pattern (18)Other Classification Systems. Using magnification endoscopy and NBI, there are several colorectal NBI magnifying classifications, such as the Hiroshima classification (24), Sano classification (25), Showa classification (26), and Jikei classification (27) used mainly in Asian countries. The BASIC system (for FUJI Blue Light Imaging) (28), is similar to the NICE classification. Irregular and thickened microvessels, when using NBI, is another way to assess for risk of submucosal invasion with Sano class III A and B, being highly sensitive and specific for estimating depth of submucosal invasion (29). However, several of these systems are not commonly used in the United States. Endoscopic Morphologic Classification Systems Paris Classification. Proposed in 2002 at the Paris collaborative meeting (30), the Paris classification is an endoscopic classification of superficial colorectal lesion morphology, whereby a lesion is superficial when its endoscopic appearance suggests that the depth of penetration in the digestive wall is not more than into the submucosa, that is, there is no infiltration of the muscularis propria. The Paris classification describes 3 major superficial morphologies with subtypes. Lesions are classified as polyps (type 0–I), which include both pedunculated (0–Ip) and sessile (0–Is) morphologies; or flat lesions (type 0–II), which consist of slightly elevated (0–IIa), flat (0–IIb), and slightly depressed (0–IIc) morphologies. Lesions with the third major morphology, excavated (0–III), are rarely seen in the colon. The classification system is presented in Figure 4. We present differences in management and outcomes based on morphologies in the key questions, where applicable. It is important to acknowledge that interobserver agreement of the Paris classification among expert endoscopist is modest (31).Figure 4.: Paris classification of polyp morphology.Laterally Spreading Tumor (Lesion). Okamoto et al (32) described polyps in the colorectum that are > 10 mm, flat (0–II), or sessile (0–Is) shape, and extend laterally (in contrast to vertically) along the colonic wall, as LSTs or lateral spreading lesions. These lesions are further classified into 2 distinct phenotypes, LST-G, which has a nodular surface, and LST-NG, which have a smooth surface (Figures 5 and 6). LST-G can be subtyped by the nodular surface and are comprised of lesions with homogeneous even-sized nodules and lesions with nodules of mixed sizes known as mixed LST-G. LST-NG have a smooth surface and are comprised of the flat elevated and pseudodepressed subtypes.Figure 5.: Granular laterally spreading tumors (LST-G). (A, B) Nodular surface. (C, D) mixed nodular morphology.Figure 6.: Nongranular laterally spreading tumors (LST-NG). (A, B) Smooth surface. (C, D) Pseudodepressed.The morphologic sub-classifications of LSTs facilitate the endoscopic removal plan, as they inform about the risks of submucosal invasion and submucosal fibrosis. For example, LST-G with even-sized nodules tend to grow laterally to very large diameters with a low risk of developing submucosal invasion (<2%) or significant fibrosis regardless of size (33), whereas LST-G with mixed-sized nodules have a higher risk of submucosal invasion (7.1% for lesions <20 mm and 38% for those >20 mm) (34), with the point of invasion usually located under the largest nodule. In such lesions, it is preferable to remove the largest nodule (and any nodule suspicious to harbor more advanced pathology) in one piece when feasible, in order to optimize histologic assessment. LST-NG have a high risk of submucosal invasion: 27.8% and 41.4% in nongranular pseudodepressed LSTs 10–19 mm and 20–29 mm, respectively, and 6.4% and 10.4% in nongranular flat elevated LSTs 10–19 mm and 20–29 mm, respectively (35). In such lesions, the points of invasion are typically multifocal. In addition, LST-NG lesions often have submucosal fibrosis that can make their removal with simple snare resection or even standard endoscopic mucosal resection (EMR) more technically challenging. Nonlifting Sign. The nonlifting sign for sessile polyps was described by Uno et al, (36) whereby fluid injected under the polyp fails to lift it. The nonlifting sign may be due to deep submucosal invasion (37) in lesions without prior endoscopic manipulation or attempted resection. The nonlifting sign may also be the result of fibrosis from prior biopsy, cautery, or tattoo, in which case it does not reflect deep submucosal invasion and is not a contraindication to endoscopic resection (38). Histologic Classification Systems for Depth of Cancer Invasion Kikuchi and Kitajima Classification Systems for Depth of Submucosal Invasion. Accurate measurement of the depth of invasion in malignant polyps generally requires specific handling of the pathology specimen, that is, pinning the cut surface of the specimen to a stiff material before immersion into formalin. Pinning the specimen enables the cut sections to be properly oriented for evaluation by the pathologist (ie, at right angles to the plane of the resection). For sessile malignant polyps, the Kikuchi classification describes the depth of invasion by dividing the submucosa into three levels (SM1–3). SM1, 2, and 3 denote invasion of cancer into the first one-third, second one-third, and the deepest one-third of the submucosa, respectively (39). The Kikuchi classification system is presented in Figure 7. The difficulty in implementing the Kikuchi system is that the entire submucosa is not typically present in endoscopic resection specimens. For that reason, the Kikuchi system has been largely replaced by measuring the depth of submucosal invasion with an optical micrometer. An invasion depth of < 1 mm is called “superficial submucosal invasion” and is associated with a very low risk of lymph node metastasis (0%–4%), provided that other adverse histologic features are An invasion depth of ≥1 mm submucosal is associated with a risk of residual in the bowel wall or lymph nodes after endoscopic resection and is generally an for surgical Kikuchi Classification of Depth of Submucosal Invasion. In et al proposed a classification system for depth of cancer invasion in polyps. The classification is in Figure This system is most for pedunculated polyps. within pedunculated polyps are classified as levels In dysplastic elements are to the mucosa. have submucosal invasion but are based on the invasive in the and of the pedunculated polyp. 1 cancer invasion into the submucosa, but is to the of the pedunculated polyp. 2 cancer the of the pedunculated polyp in 3, cancer the 4 cancer invading the submucosa the but not the muscularis propria of the pedunculated polyp. malignant lesions that by definition have submucosal invasion are classified as 4. endoscopists pedunculated polyps through the it the clinical of the classification in assessment of malignant polyps resected and endoscopic features in a colorectal polyp predict deep submucosal When deep submucosal cancer is how should and pedunculated polyps be We that both pedunculated and polyps with the following features be considered to have deep submucosal invasion: NICE classification type 3 or Kudo classification of type V and Strong evidence lesions with these features should be biopsied (in the of surface in or the and referred to surgery. polyps with features of deep submucosal invasion should undergo endoscopic Weak evidence and lesions Endoscopic features of deep submucosal invasion are highly et al a of the NICE 3 features for prediction of deep submucosal invasion using and a of 5 expert endoscopists, and that presence of any 1 of the 3 deep submucosal invasive carcinoma or surface and (13). type VN pit pattern in the Kudo classification deep submucosal invasion. A observational study by the Endoscopic resection study patients with large mm) polyps and found invasion of the deep submucosa in of of polyps with pit pattern type V to in lesions with other pit In their study lesions, pit pattern V was the associated with submucosal invasive cancer and cancer with and A of studies of Kudo pit a of colorectal lesions from 4 studies that the of lesions in pit pattern by pathology results, and a sensitivity of and specificity of When lesions with NICE 3 or Kudo VN features are should be to the of surface if not in or the and the patient to surgery. NICE 3 and Kudo VN features are often associated with surface and In 1 the risk of deep submucosal invasion in lesions that were LST-NG with was and for lesions of size 10–19 mm, 20–29 mm, and mm, respectively (35). The nonlifting sign for sessile polyps is also associated with deep submucosal invasion with of However, lesions may also not lift because of submucosal fibrosis from prior biopsy, cautery, or (0–Ip) lesions polyps with features of deep submucosal invasion are candidates for endoscopic resection, as the features may be pedunculated lesions should be resected en bloc through the and the polyp and by An accurate histologic is key to accurate staging and management (see Figure an for recognition and management of malignant for approach to malignant polyp assessment and endoscopic features predict risk of superficial submucosal invasion in a sessile is the optimal endoscopic of resection for sessile and pedunculated malignant polyps with superficial submucosal LST-NG morphology with sessile or and LST-G with a nodule predict a higher risk of submucosally invasive cancer. Weak evidence We that such lesions be considered for en bloc endoscopic resection, of resection, when and based on In the case of LST-G with a at the nodular should be considered for en bloc resection. pedunculated polyps, even if should be resected en Weak evidence In a lesion, if endoscopic features of deep submucosal invasion are the is to the polyp for other morphologic features that predict an increased risk of superficial submucosal invasion. should be to the lesion en bloc for pathologic assessment if the morphologic features discussed are with depressed (0–IIc) morphology are often associated with invasive cancer even when small One study found that of lesions, of lesions submucosal the morphology of mm lesions, et al that with lesions with and morphology were associated with submucosal invasive cancer. The also that lesions with a a high specificity and for submucosal invasive cancers but low sensitivity In Paris classification and morphology, the were to the prediction of or submucosal invasive cancer as endoscopic features of submucosally invasive cancer, such as a depressed or or an of surface pit such that nongranular and nongranular lesions a higher risk of submucosal invasive cancer and Type lesions in the JNET classification have a higher risk of superficial submucosal invasion, where en bloc resection should be if JNET can be without optical magnification on of the JNET classification are and studies lesion size alone have enough to predict risk of submucosal invasion, but with other endoscopic features (see these factors may studies have that risk of submucosal invasion is higher with lesions In their et al lesions and invasive carcinoma was found in The of submucosal invasion was in lesions mm, to an of 10 in lesions mm in size to polyps mm in which no cancer was et al also found a between in lesion size and risk of reviewed invasive carcinoma and of the invasive were >20 mm in size Some of the largest lesions in the colon are the LST-G. These lesions have a low risk of submucosal invasion, which allows to grow laterally for large et al published a of that were removed with that LST-NG were more to be present in the right colon and have submucosal invasion with LST-G.

The prognosis of locally advanced gastric cancer is poor even if radical gastrectomy with D2 lymphadenectomy is followed by adjuvant chemotherapy. Hence, neoadjuvant chemotherapy is performed to try to improve the prognosis, as it can significantly downstage the tumor and safely improve the R0 resection rate of patients. Herein, we report a case of locally advanced gastric cancer with pancreatic invasion and gastric outlet obstruction that showed a pathological complete response after neoadjuvant chemotherapy with S-1 and oxaliplatin (SOX). A 74-year-old man presented to our hospital with abdominal pain and pyloric stenosis. CT images revealed a cStage IVb, cT4b tumor in the pancreas, cN1, cM0. Therefore, we performed laparoscopic gastrojejunostomy, and the patient’s oral intake improved after surgery; we then administered neoadjuvant chemotherapy with SOX on postoperative day 18, without any surgical complications. After 3 courses of neoadjuvant chemotherapy, the patient underwent radical distal gastrectomy, thereby avoiding pancreatoduodenectomy. Histopathological examination of the resected sample revealed no residual cancer cells, indicating a pathological complete response. No recurrence has occurred for 1 year after surgery. Thus, neoadjuvant chemotherapy with SOX can help in tumor downstaging and may be a multipotent option for the treatment of locally advanced gastric cancer, such as cases with the invasion of other organs; this treatment can result in improved curability and avoid overinvasive surgery.