Local excision versus radical surgery for anal squamous cell carcinoma: a multicenter study in Japan.

BACKGROUND: The standard treatment for anal squamous cell carcinoma is chemoradiation therapy (CRT), but there is a possibility of over-treatment for early-stage disease. cTisN0 and cT1N0 disease is currently indicated for local excision, but it is unclear whether the indication of local excision can be expanded to cT2N0 disease. METHODS: 126 patients with cTis-T2N0 anal cancer treated at 47 centers in Japan between 1991 and 2015 were included. Patients were first classified into the CRT group and surgical therapy group according to the initial therapy, and the latter was further divided into local excision (LE) and radical surgery (RS) groups. We compared prognoses among the groups, and analyzed risk factors for recurrence after local excision. RESULTS: The CRT group (n = 87) and surgical therapy group (n = 39) showed no difference in relapse-free survival (p = 0.29) and overall survival (p = 0.94). Relapse-free survival curves in the LE (n = 23) and RS groups (n = 16) overlapped for the initial 3 years, but the curve for the LE group went lower beyond (p = 0.33). By contrast, there was no difference in overall survival between the two groups (p = 0.98). In the LE group, the majority of recurrences distributed in locoregional areas, which could be managed by salvage treatments. Muscular invasion was associated with recurrence after local excision (hazard ratio: 22.91, p = 0.011). CONCLUSION: LE may be applied to selected patients with anal cancer of cTis-T2N0 stage. Given the high risk of recurrence in cases with muscular invasion, it may be important to consider close surveillance and additional treatment in such patients.

The inguinal lymph nodes as regional lymph nodes in anal canal adenocarcinomas: a nationwide database analysis in Japan.

PURPOSE: To establish if it is appropriate to treat the inguinal lymph node (LN) of anal canal adenocarcinoma (ACA) as the intermediate LN according to the Japanese classification. METHODS: The characteristics of 346 ACA patients were examined from the nationwide registry. The effect of LN dissection was evaluated using the therapeutic value index (TVI). Furthermore, the prognostic classification ability of N factors and stage was evaluated using Akaike's information criterion (AIC), the concordance index (C-index), and the 5-year overall survival (OS) rate. RESULTS: The rate of metastasis of the inguinal LN was 7.5% and the TVI was 3.05. Evaluation using AIC and the C-index showed better results when the inguinal LN was treated as the intermediate LN. The 5-year OS rate for 66 patients with perirectal or intermediate LN metastasis, 7 with inguinal LN metastasis, and 13 with inguinal and perirectal or intermediate LN metastasis were 49.2%, 68.6%, and 47.6%, respectively. When inguinal LN metastases were treated as N3, the 5-year OS rates were 66.7% for those with T1N3 and T2N3 disease, and 49.2% for those with T3N3 disease. CONCLUSIONS: The inguinal LN of ACA was evaluated and staged as the intermediate LN to devise an appropriate treatment strategy.

Characteristics of anal canal squamous cell carcinoma as an HPV-associated cancer in Japan.

The definition of the anal canal was revised in the TNM classification (8th edition). The Japanese Society for Cancer of the Colon and Rectum (JSCCR) conducted a retrospective multi-institutional study to clarify the characteristics of anal canal cancer (ACC) in Japan. The diagnoses of 1781 patients treated for ACC were squamous cell carcimoma (SCC; n = 428; 24.0%), adenosquamous cell carcinoma (n = 7; 0.4%), and adenocarcinoma (n = 1260; 70.7%). Anal carcinoma is associated with human papillomavirus (HPV) infection and is risk factor for anal SCC. Among 40 cases analyzed at Takano Hospital and 47 cases analyzed at National Cancer Center Hospital, 34 cases (85.0%) and 40 cases (85.1%), respectively were infected with HPV; HPV-16 was the most common genotype (79.4% and 82.5%). In the JSCCR retrospective multi-institutional study, the prognosis analysis by stage was performed for anal SCC cases (202 cases treated by CRT and 91 cases treated by surgery). The 5-year overall survival (OS) rates by stage did not differ between the two treatment groups to a statistically significant extent. Regarding the results of cancer treatment of patients who underwent HPV infection tests, although the 5-year OS rates by stage did not differ to a statistically significant extent due to the small number of cases, HPV-positive patients had better survival. While an HPV vaccine for anal canal SCC has already been approved internationally, HPV vaccination has already been implemented in Japan as a national immunization program for young women but not for men at present. An HPV vaccination for men is urgently needed.

Artificial Intelligence System to Determine Risk of T1 Colorectal Cancer Metastasis to Lymph Node.

BACKGROUND & AIMS: In accordance with guidelines, most patients with T1 colorectal cancers (CRC) undergo surgical resection with lymph node dissection, despite the low incidence (∼10%) of metastasis to lymph nodes. To reduce unnecessary surgical resections, we used artificial intelligence to build a model to identify T1 colorectal tumors at risk for metastasis to lymph node and validated the model in a separate set of patients. METHODS: We collected data from 3134 patients with T1 CRC treated at 6 hospitals in Japan from April 1997 through September 2017 (training cohort). We developed a machine-learning artificial neural network (ANN) using data on patients' age and sex, as well as tumor size, location, morphology, lymphatic and vascular invasion, and histologic grade. We then conducted the external validation on the ANN model using independent 939 patients at another hospital during the same period (validation cohort). We calculated areas under the receiver operator characteristics curves (AUCs) for the ability of the model and US guidelines to identify patients with lymph node metastases. RESULTS: Lymph node metastases were found in 319 (10.2%) of 3134 patients in the training cohort and 79 (8.4%) of /939 patients in the validation cohort. In the validation cohort, the ANN model identified patients with lymph node metastases with an AUC of 0.83, whereas the guidelines identified patients with lymph node metastases with an AUC of 0.73 (P < .001). When the analysis was limited to patients with initial endoscopic resection (n = 517), the ANN model identified patients with lymph node metastases with an AUC of 0.84 and the guidelines identified these patients with an AUC of 0.77 (P = .005). CONCLUSIONS: The ANN model outperformed guidelines in identifying patients with T1 CRCs who had lymph node metastases. This model might be used to determine which patients require additional surgery after endoscopic resection of T1 CRCs. UMIN Clinical Trials Registry no: UMIN000038609.

Prognosis of anal canal adenocarcinoma versus lower rectal adenocarcinoma in Japan: a propensity score matching study.

PURPOSE: Anal canal adenocarcinoma (AC) is rare and its surgical outcomes and prognostic factors (PFs) are not well understood. The aim of this retrospective study was to identify the characteristics and PFs of AC, using population-based data in Japan. METHODS: Patients with AC (n = 390) or lower rectal adenocarcinoma (LR) (n = 12,477) diagnosed between1991 and 2006 were enrolled in this study. We compared the clinical- and patient-related factors of the two diseases and then examined propensity score matching, overall survival (OS), and PFs. RESULTS: AC tended to develop more often in women and in patients of advanced age. Macroscopically, AC was of an unclassified type and microscopically, it was of high-grade histological types such as mucinous adenocarcinoma, poorly differentiated adenocarcinoma (por), or signet-ring cell carcinoma (sig), with a high frequency of inguinal node metastasis (P < 0.05). The 5 year OS rates were 56.9% for AC and 67.9% for LR (P = 0.002). The PFs of AC were a high-grade histological type (por/sig), T, N, and M. CONCLUSIONS: AC has a significantly worse prognosis than LR. Moreover, the AC lymph node metastatic sites for AC, especially the inguinal nodes, are different from those for LR.

Diffuse large B-cell lymphoma originating from the rectum and diagnosed after rectal perforation during the treatment of ulcerative colitis: a case report.

BACKGROUND: Gastrointestinal lymphomas like diffuse large B-cell lymphoma (DLBCL) are rare complications of ulcerative colitis (UC), and only a few studies have reported intestinal ulcers caused by DLBCL, which got perforated during the treatment of UC. CASE PRESENTATION: A 43-year-old man with severe lower abdominal pain and an 8-year history of UC was admitted in our hospital. He was diagnosed UC since 8 years and received a maintenance oral dose of 5-aminosalicylic acid, and no other immunosuppressive drugs. A deep rectal ulcer was endoscopically diagnosed 10 months before admission, no malignancy or cytomegalovirus infection was detected on biopsy. After 7 months a further endoscopy with biopsies confirmed the finding and the absence of malignancy. Three months later the patient developed sudden abdominal pain and was admitted in our hospital. Rectal perforation was suspected on X-ray and computed tomography imaging, and an emergency surgery was performed. Surgical exploration revealed a perforation on the anterior wall of the rectum. A subtotal colectomy with temporary ileostomy was performed. Pathology examinations showed lymphocyte infiltration of all of the layers of the perforated site and an immunohistochemical evaluation revealed DLBCL. Clinical staging was stage IV, and the patient received a 6-months regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Positron emission tomography restaging revealed disappearance of distant uptake and a slight uptake in the residual rectum, and completion proctectomy with ileal pouch-anal anastomosis was performed. No residual tumor in the specimen was found, and the patient was disease-free at 2 years follow-up. CONCLUSIONS: DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. This case study emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies during the treatment of UC.

Long-term results of intersphincteric resection for low rectal cancer in Japan.

Intersphincteric resection (ISR) is the ultimate sphincter-preserving procedure for low rectal cancer. A questionnaire about the standardization of ISR was given to 2125 patients who underwent curative ISR for low rectal cancer between 2005 and 2012 at 127 affiliated institutions of the Japanese Society for Cancer of the Colon and Rectum (JSCCR), and the results were compared with the results of a systematic review. The findings revealed that although mortality and morbidity were relatively low and the survival rate after ISR was good, the rates of local recurrence and postoperative fecal incontinence were relatively high. The radicality of ISR was compared with that of abdominoperineal resection and low anterior resection using the propensity score matching prognosis analysis of patients in the JSCCR nationwide registry. The local recurrence rate was significantly higher after ISR, and especially high in patients with T3 (invasion into the external anal sphincter) and T4 disease. These results provide evidence about the factors related to fecal incontinence after ISR. As measures for the standardization of ISR, it is important to reconfirm that ISR is not indicated for patients with cT3 and cT4 disease and those with poor preoperative defecatory function, based on the ISR indication criteria.

Correction to: Long-term results of intersphincteric resection for low rectal cancer in Japan.

In the original publication Fig. 2 and Table 4 were incorrectly published. The corrected figure and table are given in this Correction.

Characteristics of anal canal cancer in Japan.

Anal canal cancer (ACC) has been reported to be an uncommon cancer in Japan, as in the USA, Europe, and Australia. This retrospective multi-institutional study was conducted to clarify the characteristics of ACC in Japan. First, the histological ACC type cases treated between 1991 and 2015 were collected. A detailed analysis of the characteristics of anal canal squamous cell carcinoma (SCC) cases was then conducted. The results of the histological types revealed that of the 1781 ACC cases, 435 cases (24.4%) including seven cases of adenosquamous cell carcinomas were SCC and 1260 cases (70.7%) were adenocarcinoma. However, the most common histological type reported in the USA, Europe, and Australia is SCC. Most ACC cases are adenocarcinomas and there is a low incidence of SCC in Japan which is different from the above-mentioned countries. Moreover, we reclassified T4 into the following two groups based on tumor size: T4a (tumor diameter of 5 cm or less) and T4b (tumor diameter of more than 5 cm). The results of the TNM classification of SCC revealed that the hazard ratio (HR) to T1 of T2, T3, T4a, and T4b was 2.45, 2.28, 2.89, and 4.97, respectively. As T4b cases had a worse prognosis than T4a cases, we propose that T4 for anal canal SCC in Japan be subclassified into T4a and T4b.

Comprehensive analysis of the clinical significance of inducing pluripotent stemness-related gene expression in colorectal cancer cells.

BACKGROUND: We previously determined that cancer stem-like cells may influence the susceptibility of colorectal cancer (CRC) cells to chemotherapeutic agents. Although Takahashi and Park identified a set of induced pluripotent stem cell (iPS)-related genes required for normal stem cell maintenance, the precise role of iPS-related gene expression in CRC pathogenesis remains to be determined. The purpose of this study was to clarify the clinical relevance of "stemness"-regulating gene expression in CRC cases. MATERIALS AND METHODS: Cancer cells were excised from tissues of 79 CRC cases by laser microdissection (LMD), and quantitative RT-PCR was used to evaluate expression levels of the iPS-related genes c-MYC, SOX2, OCT3/4, LIN28, KLF4, and NANOG, and to identify any associations between their expression and clinicopathological CRC progression. RESULTS: We found that LIN28 expression is significantly associated with lymph node metastasis (p = 0.018) and Dukes stage (p = 0.0319). SOX2expression is also correlated with lymph node metastasis. Furthermore, the ten cases with Dukes D disease expressed significantly higher levels of SOX2transcript than the other 69 cases (p = 0.0136). In contrast, KLF4 expression was inversely related to Dukes stage. Expression of c-MYC, OCT3/4, and NANOG did not appear to have clinical relevance in CRC cases. CONCLUSION: The present analysis strongly suggests that altered expression of several iPS-related genes plays a role in CRC pathogenesis.

Long-term results of intersphincteric resection for low rectal cancer.

PURPOSE: Intersphincteric resection has been performed as an alternative to abdominoperineal resection for low rectal cancer. The purpose of this study was to assess the long-term results after intersphincteric resection in terms of the morbidity, oncologic safety, and defecatory function. METHODS: Between 1994 and 2006, 107 consecutive patients with low rectal cancer had curative intersphincteric resection, categorized as total, subtotal, or partial resection of the internal anal sphincter. RESULTS: There were no mortalities. Neorectal mucosal prolapse in patients with total intersphincteric resection and coloanal anastomotic stenosis in patients with subtotal or partial intersphincteric resection were observed as characteristic late complications. The five-year disease-free survival rates classified according to the TNM stage were 100 percent for stage I, 83.5 percent for stage II, and 72.0 percent for stage III cases. The five-year cumulative local recurrence rate after intersphincteric resection was 2.5 percent. Defecatory function, which was evaluated by bowel movement in a 24-hour period, and continence after intersphincteric resection were objectively good. The results of the multivariate analysis revealed that age was the only factor associated with a risk of fecal incontinence. CONCLUSION: Provided strict selection criteria are used, intersphincteric resection may be the optimal sphincter-preserving surgery for low rectal cancer.

Changes in expression levels of ERCC1, DPYD, and VEGFA mRNA after first-line chemotherapy of metastatic colorectal cancer: results of a multicenter study.

Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1, DPYD, and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group (P = 0.033), and were significantly correlated (Spearman's correlation coefficient = 0.42; P < 0.0001). VEGFA expression level was higher in patients receiving bevacizumab (n = 51) than in those who did not (n = 251) (P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression.