Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer.

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .

Exploratory Biomarker Analysis Using Plasma Angiogenesis-Related Factors and Cell-Free DNA in the TRUSTY Study: A Randomized, Phase II/III Study of Trifluridine/Tipiracil Plus Bevacizumab as Second-Line Treatment for Metastatic Colorectal Cancer.

BACKGROUND: The TRUSTY study evaluated the efficacy of second-line trifluridine/tipiracil (FTD/TPI) plus bevacizumab in metastatic colorectal cancer (mCRC). OBJECTIVE: This exploratory biomarker analysis of TRUSTY investigated the relationship between baseline plasma concentrations of angiogenesis-related factors and cell-free DNA (cfDNA), and the efficacy of FTD/TPI plus bevacizumab in patients with mCRC. PATIENTS AND METHODS: The disease control rate (DCR) and progression-free survival (PFS) were compared between baseline plasma samples of patients with high and low plasma concentrations (based on the median value) of angiogenesis-related factors. Correlations between cfDNA concentrations and PFS were assessed. RESULTS: Baseline characteristics (n = 65) were as follows: male/female, 35/30; median age, 64 (range 25-84) years; and RAS status wild-type/mutant, 29/36. Patients in the hepatocyte growth factor (HGF)-low and interleukin (IL)-8-low groups had a significantly higher DCR (risk ratio [95% confidence intervals {CIs}]) than patients in the HGF-high (1.83 [1.12-2.98]) and IL-8-high (1.70 [1.02-2.82]) groups. PFS (hazard ratio {HR} [95% CI]) was significantly longer in patients in the HGF-low (0.33 [0.14-0.79]), IL-8-low (0.31 [0.14-0.70]), IL-6-low (0.19 [0.07-0.50]), osteopontin-low (0.39 [0.17-0.88]), thrombospondin-2-low (0.42 [0.18-0.98]), and tissue inhibitor of metalloproteinase-1-low (0.26 [0.10-0.67]) groups versus those having corresponding high plasma concentrations of these angiogenesis-related factors. No correlation was observed between cfDNA concentration and PFS. CONCLUSION: Low baseline plasma concentrations of HGF and IL-8 may predict better DCR and PFS in patients with mCRC receiving FTD/TPI plus bevacizumab, however further studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs031180122.

Colorectal cancer in adolescent and young adults: epidemiology in Japan and narrative review.

Background and Objective: Although only a small proportion of colorectal cancer (CRC) cases develop in adolescents and young adults (AYAs), its incidence has increased recently. We aimed to conduct a narrative literature review and summarize the epidemiology, clinicopathological features, genetics, and treatments for AYA-CRCs. Methods: We searched the articles published in the PubMed database until November 30, 2022, with keywords, "((adolescent and young adult) OR AYA) AND ((colorectal cancer) OR (colon cancer) OR (rectal cancer))" and "young-onset AND ((colorectal cancer) OR (colon cancer) OR (rectal cancer))". Key Content and Findings: In Japan, the annual incidence of AYA-CRC was approximately 1,200 in the 1970s, but has increased to 2,000 nowadays. An increased incidence of AYA-CRC has also been reported in other countries. AYA-CRC tends to be a more advanced disease at presentation than CRC in older patients, with more adverse histological features and variability in molecular characteristics. Diagnosis of CRC is often delayed in AYAs because they are not invited to undergo cancer screening. Three to five percent of patients with AYA-CRC have hereditary cancer syndromes such as Lynch syndrome and familial adenomatous polyposis (FAP), and a family history should be obtained. Additionally, providing information on fertility preservation and social systems before starting treatment is important for sustainable treatment and life after cancer treatment. Conclusions: The number of AYA-CRC cases is increasing in Japan. Before initiating treatment for AYA-CRC, we should know that these patients may have a hereditary disease and fertility preservation should be explained. More physicians should be aware of the importance of AYA-CRC.

NEXUS trial: a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant colorectal oligometastases.

BACKGROUND: The optimal treatment strategy for resectable BRAF V600E mutant colorectal oligometastases (CRM) has not been established due to the rarity and rapid progression of the disease. Since the unresectable recurrence rate is high, development of novel perioperative therapies are warranted. On December 2020, the BEACON CRC triplet regimen of encorafenib, binimetinib, and cetuximab was approved for unresectable metastatic colorectal cancer in Japan. METHODS: The NEXUS trial is a multicenter phase II clinical study evaluating the efficacy and safety of the perioperative use of encorafenib, binimetinib, and cetuximab in patients with previously untreated surgically resectable BRAF V600E mutant CRM. The key inclusion criteria are as follows: histologically diagnosed with colorectal adeno/adenosquamous carcinoma; RAS wild-type and BRAF V600E mutation by tissue or blood; and previously untreated resectable distant metastases. The triplet regimen (encorafenib: 300 mg daily; binimetinib: 45 mg twice daily; cetuximab: 400 mg/m2, then 250 mg/m2 weekly, 28 days/cycle) is administered for 3 cycles each before and after curative resection. The primary endpoint of the study is the 1-year progression-free survival (PFS) rate and the secondary end points are the PFS, disease-free survival, overall survival, and objective response rate. The sample size is 32 patients. Endpoints in the NEXUS trial as well as integrated analysis with the nationwide registry data will be considered for seeking regulatory approval for the perioperative use of the triplet regimen. DISCUSSION: The use of the triplet regimen in the perioperative period is expected to be safe and effective in patients with resectable BRAF V600E mutant CRM. TRIAL REGISTRATION: jRCT2031220025, April. 16, 2022.

Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer.

The extent of tumor spread influences on the clinical outcome, and which determine T stage of colorectal cancer. However, pathologic discrimination between pT3 and pT4a in the eighth edition of the American Joint Committee on Cancer (AJCC)-TNM stage is subjective, and more objective discrimination method for deeply invasive advanced colon cancer is mandatory for standardized patient management. Peritoneal elastic laminal invasion (ELI) detected using elastic staining may increase the objective discrimination of deeply invasive advanced colon cancer. In this study, we constructed ELI study group to investigate feasibility, objectivity, and prognostic utility of ELI. Furthermore, pT classification using ELI was investigated based on these data. At first, concordance study investigated objectivity using 60 pT3 and pT4a colon cancers. Simultaneously, a multi-institutional retrospective study was performed to assess ELI's prognostic utility in 1202 colon cancer cases from 6 institutions. In the concordance study, objectivity, represented by κ, was higher in the ELI assessment than in pT classification. In the multi-institutional retrospective study, elastic staining revealed that ELI was a strong prognostic factor. The clinical outcome of pT3 cases with ELI was significantly and consistently worse than that of those without ELI. pT classification into pT3 without ELI, pT3 with ELI, and pT4a was an independent prognostic factor. In this study, we revealed that ELI is an objective method for discriminating deeply invasive advanced colon cancer. Based on its feasibility, objectivity, and prognostic utility, ELI can subdivide pT3 lesions into pT3a (without ELI) and pT3b (with ELI).

Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined. Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer. Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022). Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate. Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%). Conclusions and Relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population. Trial Registration: ClinicalTrials.gov Identifier: NCT02394795.

Is frequent measurement of tumor markers beneficial for postoperative surveillance of colorectal cancer?

PURPOSE: To determine whether frequent measurement of tumor markers triggers early detection of colorectal cancer recurrence. METHODS: Of 1,651 consecutive patients undergoing colorectal cancer surgery between 2010 and 2016, 1,050 were included. CEA and CA 19-9 were considered to be postoperative tumor markers and were measured every 3 months for 3 years, and then every 6 months for 2 years. Sensitivity analysis of elevated CEA and CA19-9 levels and multivariate analysis of factors associated with elevated CEA and CA19-9 levels were performed. The proportion of triggers for detecting recurrence was determined. RESULTS: The median follow-up period was 5.3 years. After applying the exclusion criteria, 1,050 patients were analyzed, 176 (16.8%) of whom were found to have recurrence. After excluding patients with persistently elevated CEA and CA19-9 levels before and after surgery from the 176 patients, 71 (43.6%) of 163 patients had elevated CEA levels and 35 (20.2%) of 173 patients had elevated CA19-9 levels. Sensitivity/positive predictive values for elevated CEA and CA19-9 levels at recurrence were 43.6%/32.3% and 20.2%/32.4%, respectively. Lymph node metastasis was a factor associated with both elevated CEA and CA19-9 levels at recurrence. Of the 176 patients, computed tomography triggered the detection of recurrence in 137 (78%) and elevated tumor marker levels in 13 (7%); the diagnostic lead interval in the latter 13 patients was 1.7 months. CONCLUSION: Tumor marker measurements in surveillance after radical colorectal cancer resection contribute little to early detection, and frequent measurements are unnecessary for stage I patients with low risk of recurrence.

Multicenter, single-arm, phase II study of the continuous use of panitumumab in combination with FOLFIRI after FOLFOX for RAS wild-type metastatic colorectal cancer: Exploratory sequential examination of acquired mutations in circulating cell-free DNA.

This multicenter single-arm, phase II study evaluated the efficacy and safety of uninterrupted panitumumab usage combined with cytotoxic doublets for unresectable/metastatic colorectal cancer (mCRC). Additionally, clinical value of the RAS/BRAF mutation status in circulating cell-free DNA (ccfDNA) was evaluated; this evaluation was measured independently of the protocol treatment. Eligible patients with RAS wild-type mCRC who had received the first-line panitumumab plus FOLFOX treatment were recruited and administered continuous panitumumab combined with FOLFIRI. Progression-free survival (PFS) at 6 months was the primary endpoint, with threshold and expected values of 35% and 50%, respectively. In total, 54 patients were enrolled between October 2017 and October 2019. The crude 6-month PFS rate was 37.0%, with a 4.8-month median PFS. The response rate and disease control rate were 16.7% and 50.0%, respectively. Notably, of the 54 participants, 17 showed RAS/BRAF mutations until the end of the protocol treatment and of the 22 patients with progressive disease as their best response, 10 possessed RAS/BRAF mutations in their plasma ccfDNA at baseline. The median PFS significantly differed among patients harboring tumors with BRAF and RAS mutations and those with wild-type tumors. In conclusion, our study failed to show the expected efficacy of the continuous panitumumab use in the second-line treatment. Liquid biopsy discriminated the duration of PFS according to the mutation status. The effectiveness of continuous treatment with panitumumab should be evaluated in patients with RAS/BRAF wild-type mCRC determined by liquid biopsy at the start of the second-line treatment.

The necessity of intensive surveillance colonoscopy for patients with a remaining right colon after resection of colorectal cancer: a retrospective cohort study.

PURPOSE: To clarify how often postoperative surveillance colonoscopy should be undertaken based on the risk factors for the development of metachronous cancer (MC) and advanced adenoma (AA) after surgery for colorectal cancer. METHODS: We collected data of consecutive patients who underwent curative resection for primary colorectal cancer between 2005 and 2012, with preoperative colonoscopy and surveillance colonoscopy at 1 year after surgery (406 patients, mean age: 69 years, 59% male). The detection rates of AA (with villous features, > 10 mm or high-grade dysplasia) and MC by surveillance colonoscopy were the primary outcomes. RESULTS: At 5 years, colonoscopy was performed as postoperative surveillance an average of 3.2 times. AA and MC were detected in 57 (14.0%) and 18 patients (4.4%), respectively. Both lesions were more common in the right colon (n = 43) than in the left colon (n = 28). The detection rate did not differ to a statistically significant extent according to the number of colonoscopies performed for surveillance (p = 0.21). However, after left-sided colectomy, both types of lesions were more commonly detected in those who received ≥ 3 colonoscopies than in those with one or two colonoscopies (p = 0.04). CONCLUSION: A remaining right colon after left-sided colectomy was associated with a higher risk of developing AA and MC. Physicians should consider performing surveillance colonoscopy more frequently if the right colon remains after surgery.

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study).

LESSONS LEARNED: A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. BACKGROUND: TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2 /day on days 1-5 and 8-12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. METHODS: Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1-5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). RESULTS: From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2 /day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%-56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). CONCLUSION: Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

[Appendiceal Goblet Cell Carcinoid Successfully Treated with Bevacizumab plus mFOLFOX6 Regimen-A Case Report].

A 67-year-old man presented with abdominal distention and vomiting.Computed tomography revealed bowel obstruction due to a cecal tumor.We performed laparoscopic ileocecal resection after decompression with an ileus tube. Intraoperative findings included multiple disseminated nodules on the mesenterium surrounding the cecal tumor.The histopathologic diagnosis was poorly differentiated adenocarcinoma, which consisted of glandular proliferation of atypical epithelial cells and dispersed infiltration of goblet cells. Immunohistochemistry showed positively stained neuroendocrine markers, such as CD56, chromogranin, and synaptophysin.The patient was diagnosed with goblet cell carcinoid of the appendix and treated with combination chemotherapy of bevacizumab, fluorouracil, folinic acid, and oxaliplatin.He remained free from progression for over 1 and half years with this treatment.Subsequent chemotherapy was ineffective, and he passed away.There is no established chemotherapy regimen for goblet cell carcinoid, which has the aspects of both adenocarcinoma and neuroendocrine tumors.However, the present case suggested the efficacy of the mFOLFOX6 regimen in combination with bevacizumab for appendiceal goblet cell carcinoid.

[Sigmoid Colon Cancer with Lateral Lymph Node Metastasis That Presented with Gastric Perforation].

A 74-year-old man visited his local clinic complaining of abdominal pain that persisted for three days. He was diagnosed with diffuse peritonitis and was transported to our hospital. Contrast computed tomography(CT)showed gastric perforation and a tumor in the sigmoid colon with left obturator lymph node metastasis. He was diagnosed with diffuse peritonitis resulting from gastric perforation and performed emergent surgery. As the size of the gastric perforation was large, we performed distal gastrectomy and transverse colostomy. He was discharged without any complications, and a total of 6 courses of SOX with a bevacizumab regimen were administered postoperatively. CT following chemotherapy showed shrinkage of the lesion. He was admitted again for sigmoidectomy with left lateral lymph node resection and discharged from the hospital on postoperative day 8. We administered 2 courses of SOX regimen after the surgery. He remains alive with no recurrence 27months after the first surgery.

The utility of longitudinal slicing method for rectal specimen: pathological analysis of circumferential resection margin of intersphincteric resection for low-lying rectal cancer.

The pathological assessment of the resection margin of rectal cancer is important to predict clinical outcome. The transverse slicing method of rectal specimens is recommended in Western countries. However, in Japan the longitudinal slicing method is traditionally advocated. The aim of this study was to assess the advantages of the longitudinal slicing method. The subjects were 197 consecutive patients with primary rectal cancer who underwent curative intersphincteric resection from 2000 to 2013. The resected rectal specimens were cut into 12 slices in the direction of the long axis. Resection margin was considered positive when it was less than or equal to 1 mm. Resection margin was positive in 23 patients (12%). They were classified into two groups, namely the DEEP group (n = 16, 70%), when the resection margin corresponded to the deepest tumor invasion area, and the ENTRY group (n = 7, 30%), when resection margin was around the initial cutting point of the anal canal. It was shown that resection margin tends to be positive not only in the deepest tumor invasion area but also in the entry area of the anal canal. The longitudinal slicing method may have some advantages for accurate assessment of resection margin especially in low-lying rectal cancer.

The safety and efficacy of laparoscopic hepatectomy in obese patients.

BACKGROUND: Obesity is generally reported to increase the risk of surgical complications. There have been few reports of laparoscopic hepatectomy (LH) in obese patients. The purpose of this study was to compare the safety and efficacy of (1) LH versus open hepatectomy (OH) in obese patients and (2) LH in obese patients versus LH in non-obese patients. METHODS: We introduced LH at our institution in April 2014. LH was performed in 63 obese patients and 108 non-obese patients from April 2014 to May 2017. OH was performed in 79 obese patients from January 2010 to May 2017. This study retrospectively compared the short-term outcomes of the LH obese group with those of the OH obese group and the LH non-obese group. RESULTS: In patient characteristics, the LH obese group included a significantly higher percentage of patients with liver cirrhosis than the OH obese group. The LH obese group had fewer patients with a history of abdominal surgery but more with liver cirrhosis than the LH non-obese group. For short-term outcomes, the LH obese group had significantly less blood loss, fewer intraoperative transfusions, fewer positive surgical margins, and shorter postoperative hospital stays than the OH obese group. In contrast, only operation time was significantly different (longer) in the LH obese group than in the LH non-obese group. There were no significant differences in morbidity or mortality between the LH obese group and either the OH obese or the LH non-obese groups. CONCLUSION: LH in obese patients is safe and effective.

Strangulated Hernia Can Be a Risk Factor of Seroma following Laparoscopic Transabdominal Preperitoneal Repair.

PURPOSES: Seroma is a postoperative complication following laparoscopic transabdominal preperitoneal repair (TAPP) for inguinal hernioplasty. Seroma naturally resolves in most cases, but it can lead to an increased amount of visits to the outpatient clinic and can result in anxiety of the patient. Local inflammation of the inguinal area is etiology of seroma formation. Strangulated hernia involves severe inguinal pain and can lead to severe inflammation and subsequent seroma. There have been no reports demonstrating the links of seroma and strangulated hernia. This study aimed to retrospectively evaluate the risk of seroma after TAPP and to identify the association between strangulated hernia and seroma. METHODS: We treated 300 inguinal hernias by TAPP between 2013 and 2016 at Kurashiki Central Hospital. We used the Chi-square test. Factors significant in each association were further examined using multiple subsequent logistic regressions. RESULTS: A total of 222 hernias were eligible for analysis. The incidence of seroma was 11% (n=25). There were nine cases of strangulated hernias, and three (33%) resulted in seroma. The ratio of strangulated hernia of seroma group is significantly high (p<0.03). Multiple subsequent logistic regressions showed that strangulated hernia was associated with a significantly increased risk for seroma formation (p = 0.023; OR 6.564; 95% CI 1.29-33.3). CONCLUSION: This study shows that strangulated hernia can be a risk factor in seroma formation. This risk should be incorporated into a management plan of TAPP for strangulated hernia, with careful consideration of patients' concerns.

The feasibility and efficacy of pure laparoscopic repeat hepatectomy.

BACKGROUND: Repeat hepatectomy is often required for hepatocellular carcinoma and metastatic tumors. However, this procedure is technically challenging, so laparoscopic repeat hepatectomy (LRH) has not been widely adopted. The aim of this study was to evaluate the feasibility and efficacy of LRH compared with open repeat hepatectomy (ORH) and laparoscopic primary hepatectomy (LPH). METHODS: We introduced laparoscopic hepatectomy at our institution in April 2014. We performed 127 LPH (LPH group) and 33 LRH procedures (LRH group) from April 2014 to April 2017; 37 patients underwent ORH from January 2010 to April 2017 (ORH group). This study retrospectively compared the patient characteristics and short-term outcomes of the LRH and ORH groups as well as the LRH and LPH groups. RESULTS: There were no conversions to open surgery in the LRH group. In comparing the LRH and ORH groups, there were no significant differences in patient characteristics except for the type of approach to the previous hepatectomy (p = 0.004) and indocyanine green retention rate at 15 min (median 12.5 vs. 8.75%, p = 0.026). The LRH group had less blood loss (median 30 mL vs. 652 mL; p < 0.001), less intraoperative transfusion (6.1 vs. 32.4%; p = 0.006), and shorter postoperative hospital stays (median 6.5 days vs. 9.0 days; p < 0.001). There were no differences with regard to operation time, severe postoperative complications, and mortality. In comparing the LRH and LPH groups, there was a significant difference only in past history of abdominal surgery (100 vs. 61.4%; p < 0.001). In the short-term outcomes, the postoperative hospital stay was significantly shorter in the LRH group (median 6.5 days vs. 7 days; p = 0.033), and the other results were comparable between the two groups. CONCLUSIONS: LRH is feasible and useful for repeat hepatectomy, achieving good short-term outcomes.

Laparoscopic approach to suspected T1 and T2 gallbladder carcinoma.

AIM: To evaluate a laparoscopic approach to gallbladder lesions including polyps, wall-thickening lesions, and suspected T1 and T2 gallbladder cancer (GBC). METHODS: We performed 50 cases of laparoscopic whole-layer cholecystectomy (LCWL) and 13 cases of laparoscopic gallbladder bed resection (LCGB) for those gallbladder lesions from April 2010 to November 2016. We analyzed the short-term and long-term results of our laparoscopic approach. RESULTS: The median operation time was 108 min for LCWL and 211 min for LCGB. The median blood loss was minimal for LCWL and 28 ml for LCGB. No severe morbidity occurred in either procedure. Nine patients who underwent LCWL and 7 who underwent LCGB were postoperatively diagnosed with GBC. One of these patients had undergone LCGB for pathologically diagnosed T2 GBC after LCWL. All of the final surgical margins were negative. Three of these 15 patients underwent additional open surgery. The mean follow-up period was 26 mo, and only one patient developed recurrence. CONCLUSION: LCWL and LCGB are safe and useful procedures that allow complete resection of highly suspected or early-stage cancer and achieve good short-term and long-term results.

Anal Function after Surgery for Low-Lying Rectal Cancer: Comparison of Mechanical and Hand-Sewn Coloanal Anastomosis.

BACKGROUND/AIMS: Mechanical coloanal anastomosis (MCAA) or hand-sewn coloanal anastomosis (HCAA) are used in anus-preserving surgery for low-lying rectal cancer. Either method can be used if the lower edge of the tumor is 4-6 cm from the anal verge. The goal of this study was to evaluate differences in the anal function after MCAA or HCAA. METHODS: The subjects were 305 consecutive patients with primary rectal cancer tumors situated 4-6 cm from the anal verge who underwent curative anus-preserving surgery between 2004 and 2013. Functional assessment was performed using a questionnaire at 3, 6, 12, and 24 months after stoma closure. RESULTS: Of the 305 patients, 145 underwent MCAA and 160 underwent HCAA. The median distance of the tumor from the anal verge was 6.0 cm (range 4.0-6.0) in the MCAA group and 4.5 cm (range 4.0-6.0) in the HCAA group (p < 0.001). A total of 192 patients (73%) responded to the 1-year questionnaire. The median Wexner score was 6 (range 0-17) in the MCAA group and 11 (range 0-20) in the HCAA group (p < 0.001). CONCLUSIONS: Retention of anal function is feasible after both MCAA and HCAA. MCAA may contribute to better postoperative anal function compared to HCAA.

Laparoscopic radical antegrade modular pancreatosplenectomy for left-sided pancreatic cancer using the ligament of Treitz approach.

BACKGROUND: Laparoscopic distal pancreatectomy (Lap-DP) for benign lesions or those with low malignant potential has been proven safe and effective, and its performance is now widespread [1-3]. Lap-DP for left-sided pancreatic cancer (PC) is also being increasingly performed. According to some reports, Lap-DP has superior short-term outcomes (blood loss, postoperative hospital stay) and comparable oncological outcomes and overall survival with those of open distal pancreatectomy (Op-DP) [4-6]. PC has highly malignant potential; thus, complete resection and sufficient regional lymphadenectomy with tumor-free margins are very important. Radical antegrade modular pancreatosplenectomy (RAMPS) is an accepted standard Op-DP technique for PC and is reportedly useful for achieving R0 resection and radical lymphadenectomy [7-10]. However, laparoscopic RAMPS (Lap-RAMPS) is not yet popular because of its technical difficulty and lack of adequate evidence. Few reports have described the detailed surgical technique of Lap-RAMPS [11-13]. We employ Lap-RAMPS using the ligament of Treitz approach with the benefit of a laparoscopic view and herein describe the usability of this laparoscopic procedure with a video. METHODS: Our indication for Lap-RAMPS is left-sided PC located ≥1 cm away from the origin of the splenic artery (SPA) without invasion of the superior mesenteric artery (SMA), celiac artery (CA), common hepatic artery (CHA), or portal vein (PV). We apply either anterior or posterior RAMPS to achieve tumor-free margins. Therefore, the left adrenal gland and the nerve plexus around the SMA and CA are resected depending on the extent of the cancer. Three patients underwent Lap-RAMPS for left-sided PC using the ligament of Treitz approach from April to December 2016. This video shows our Lap-RAMPS procedure performed in a 67-year-old man with pancreatic body cancer who was being followed up for autoimmune pancreatitis. The tumor was suspected to have invaded the SPA, splenic vein, and retroperitoneum but was not close to the SMA, CA, CHA, or PV. The patient was put in the supine position with his legs opened, and the operation was performed using five trocars. Early in the operation, we incised the retroperitoneum just beside the ligament of Treitz, and the inferior vena cava and left renal vein (LRV) were exposed with resection of Gerota's fascia under a good laparoscopic view. The left adrenal gland was resected in this case to obtain sufficient tumor-free margins. The origin of the SMA was easily identified above the LRV. The most posterior dissection was carried out early in the operation, making it easy and safe to determine the resected margin and enabling curative resection with sufficient regional lymphadenectomy. After division of the pancreas with a linear stapler, the lymph nodes around the SMA and CA were safely removed. RESULTS: The operative time was 358 min, and the estimated blood loss was 1 ml. The postoperative course was uneventful, and the patient was discharged on postoperative day 10. Pathological examination revealed invasive ductal carcinoma (stage III, T3N1M0 according to the 7th edition of the Union for International Cancer Control system) with tumor-free margins. In all three patients, the median operative time and blood loss were 358 (328-451) min and minimal (minimal to 1 ml). One patient underwent anterior RAMPS and the other two patients, including the case mentioned above, underwent posterior RAMPS. One patient developed a grade B pancreatic fistula according to the International Study Group for Pancreatic Fistula (ISGPF) classification, but he recovered promptly with conservative treatment. No life-threatening complications occurred. The median postoperative hospital stay was 14 (10-16) days. CONCLUSIONS: Lap-RAMPS using the ligament of Treitz approach is feasible and extremely helpful in performing minimally invasive, curative resection for well-selected left-sided PC.