Erratum forTreatment of Rectovaginal Fistula.

[This corrects the article DOI: 10.23922/jarc.2023-007.].

Treatment of Rectovaginal Fistula.

Rectovaginal fistula (RVF) is a challenging complication with unsatisfactory success and a significant burden for the patients. With insufficient clinical data due to the rare entity, the present state of treatments for RVFs was reviewed especially form the point of factors to determine management, classifications, principle of treatment, conservative and surgical treatments with outcomes. Size, fistula localization and etiology, type of fistula; "simple" or "complex," status of anal sphincter complex and surrounding tissue, presence or absence of inflammation, presence of diverting stoma, previous attempted repair and radiation therapy, patient's condition with co-morbidities, and surgeon's experience are important factors to determine the management of RVF. The inflammation should initially subside in cases with infection. Starting with conservative surgical options and interposing healthy tissue for complex or recurrent fistulas, invasive procedures will be performed if conservative treatment failed. Conservative treatment may be effective in RVFs with minimal symptoms and should be done for small RVFs for a 36 months usual period. Anal sphincter damage might need a repair of sphincter muscles along with RVF repair. Diverting stoma can initially be constructed in patients with severe symptoms and larger RVFs to relief the patient's pain. Simple fistula is usually indicated for local repair. Local repairs to transperineal and transabdominal approaches can be used for complex RVFs. Interposition of healthy, well-vascularized tissue can be required for more complex fistulas and abdominal procedures for high RVFs.

Prognostic Significance of ZKSCAN3 (ZNF306) Expression in Gastric Carcinoma.

BACKGROUND/AIM: Zinc finger protein ZKSCAN3 (ZNF306) is a promising oncogene candidate in colon, bladder, breast, uterine cervical, and prostate cancers. The present study aimed to investigate ZKSCAN3 protein expression in gastric carcinoma patient tissues and to evaluate oncological outcomes in these patients. MATERIALS AND METHODS: ZKSCAN3 was detected using the anti-ZKSCAN3 rabbit polyclonal antibody. For immunohistochemical examination, we used paraffin-embedded specimens from 87 consecutive patients with gastric cancer who underwent gastrectomy. We investigated ZKSCAN3 expression in relation with patient prognosis and clinicopathological factors. RESULTS: ZKSCAN3 was detected in 28 (32.2%) tumour specimens, with significant association with lymphatic system invasion and distant metastasis. Patients with ZKSCAN3-positive tumours had worse overall survival (OS) than those with ZKSCAN3-negative tumours based on log-rank testing. Furthermore, multivariate analysis revealed that ZKSCAN3 was an independent prognostic parameter for OS (hazard ratio: 2.6379, p=0.0164). CONCLUSION: ZKSCAN3 is a potential novel prognostic factor in gastric cancer patients.

Safety profile and oncological outcomes of gastric gastrointestinal stromal tumors (GISTs) robotic resection: Single center experience.

BACKGROUND: Although usefulness of robot assisted surgery has been largely reported and accepted, robot assisted gastrointestinal stromal tumor (GIST) treatment is rare. Hence, the aim of this study is to report a single center evaluation on gastric GIST's robotic resection. METHODS: Six patients were analyzed focusing on safe (conversion/complications rate, hospital stay), oncological (margin resection, recurrence rate), and feasible (operative time, technical tip, and tricks) profile of robotic-assisted GIST surgery. RESULTS: The mean operative time and hospital stay was 173 ± 39 minutes and 3 ± 1 days, respectively. The conversion rate (to open or laparoscopy) was nil, and no intra and postoperative (mean follow-up 12 months) complications were registered. In all cases, the resections were classified as R0. CONCLUSIONS: This study supports the usefulness of robotic-assisted surgery, as the anatomical hand-sewn reconstruction might avoid the stomach distortion, and the oncological (100% R0) and safety profile outcomes encourage its use. However, further studies with larger sample size are recommended to confirm the outcomes of this study.

Sentinel Node Navigation Surgery for Early Gastric Cancer: Analysis of Factors Which Affect Direction of Lymphatic Drainage.

BACKGROUND AND PURPOSE: We started performing sentinel node navigation surgery (SNNS) for patients with early gastric cancer (EGC) using infrared ray electronic endoscopy (IREE) with indocyanine green injection from year 2000. The EGCs usually have complex lymphatic drainage, unidirectional or multidirectional lymphatic flow. In this study, we investigated and clarified factors that affect the direction of gastric lymphatic drainage. PATIENTS AND METHOD: Consecutive 60 patients with EGC who underwent SNNS by IREE from year 2006 to 2014 were enrolled to this study. Patients' age, gender, location of tumors, operative method, previous treatment by endoscopic submucosal dissection (ESD), presence of pathological ulcerative scar and maximum tumor diameter were enrolled as parameters which may affect direction of lymphatic drainage and analyzed. RESULT: Bivariate analysis demonstrated that the presence of pathological ulcerative scar (P = 0.01), tumor location (g.c vs. a.w vs. p.w vs. l.c, P = 0.01), and maxim tumor diameter (P = 0.0003) were relevant to direction of gastric lymphatic drainage. Multivariate analysis showed that tumor location (g.c/a.w/p.w vs. l.c, odds ratio 8.227, P = 0.011) and the maximum tumor diameter (odds ratio 1.057, P = 0.037) are independent factors that affect direction of gastric lymphatic flow. Of tumors, 78% located at lesser curvature had unidirectional lymphatic drainage, and 93% of tumors whose diameter was 40 mm and more had multidirectional lymphatic drainage. CONCLUSION: Our investigation revealed that the tumor location and tumor diameter were the key factors which affect the direction of lymphatic drainage, which is useful fact to understand the complexity of gastric lymphatic drainage.

Prediction of lymph node metastasis and sentinel node navigation surgery for patients with early-stage gastric cancer.

Accurate prediction of lymph node (LN) status is crucially important for appropriate treatment planning in patients with early gastric cancer (EGC). However, consensus on patient and tumor characteristics associated with LN metastasis are yet to be reached. Through systematic search, we identified several independent variables associated with LN metastasis in EGC, which should be included in future research to assess which of these variables remain as significant predictors of LN metastasis. On the other hand, even if we use these promising parameters, we should realize the limitation and the difficulty of predicting LN metastasis accurately. The sentinel LN (SLN) is defined as first possible site to receive cancer cells along the route of lymphatic drainage from the primary tumor. The absence of metastasis in SLN is believed to correlate with the absence of metastasis in downstream LNs. In this review, we have attempted to focus on several independent parameters which have close relationship between tumor and LN metastasis in EGC. In addition, we evaluated the history of sentinel node navigation surgery and the usefulness for EGC.

Comparison of Short-term and Long-term Clinical Outcomes Between Laparoscopic and Open Total Gastrectomy for Patients With Gastric Cancer.

BACKGROUND AND PURPOSE: Validation of laparoscopic total gastrectomy (LTG) for patients with gastric cancer has not been fully investigated. In particular, the technique for esophagojejunostomy remains controversial. We performed 103 cases of LTG for patients with gastric cancer between 2007 and 2013, in which all esophagojejunostomy reconstruction was performed with intracorporeal circular stapling esophagojejunostomy using the OrVil system except for the first 3 cases. The purpose of this study is to retrospectively analyze the clinical usefulness of LTG with intracorporeal circular stapling esophagojejunostomy using the OrVil system and oncological feasibility of LTG as compared with open total gastrectomy (OTG). PATIENTS AND METHOD: We retrospectively analyzed clinical course of consecutive 100 operations with LTG in comparison with consecutive 53 operations with OTG for patients with gastric cancer. As an estimation of short-term outcome, operative time, blood loss, postoperative hospital days and postoperative data of blood and drain examination were included. Moreover, relapse-free survival time and overall survival time stratified by each stage were calculated by log-rank test as an estimation of prognostic relevance. RESULTS: Blood loss and postoperative hospital stay of LTG were significantly less than that of OTG. Postoperative complications were equivalent between the 2 groups and no patient died within 1 month post-LTG. Only 1 patient had recurrence and died for carcinomatosa peritonitis 50 months after LTG (median follow-up period: 44 mo). CONCLUSIONS: Our experience revealed that LTG with intracorporeal circular stapling esophagojejunostomy using the OrVil system could be performed safely and with acceptable oncological outcome for patients with gastric cancer.

Prognostic significance of ZNF217 expression in gastric carcinoma.

BACKGROUND: The zinc finger protein ZNF217 is a candidate oncogene in breast cancer and ovarian clear cell cancer. The purpose of the present study was to clarify the significance of this protein's expression in gastric carcinoma and to evaluate the outcome of these patients. MATERIALS AND METHODS: Using paraffin-embedded specimens from 84 patients with gastric cancer, ZNF217 protein was detected using an anti-ZNF217 goat polyclonal antibody. We evaluated the ZNF217 protein expression in relation to patient outcome and clinicopathological parameters. RESULTS: The ZNF217 protein was expressed in 34 (40.5%) tumor sections. Patients with ZNF217-negative tumors had better relapse-free survival (RFS) and overall survival (OS) than those with ZNF217-positive tumors by the log-rank test. Notably, multivariate analysis indicated that ZNF217 was an independent prognostic factor for RFS. CONCLUSION: ZNF217 expression seems to be a novel prognostic biomarker in gastric cancer.

Prediction of lymph node metastasis in patients with submucosa-invading early gastric cancer.

BACKGROUND AND AIM: Early gastric cancer (EGC), with wall invasion limited to the submucosa, has approximately 15 to 20% chance of lymph node metastasis. The purpose of this study is to clarify the parameters which affect lymph node metastasis and survey whether lymph node metastasis can be predicted preoperatively. PATIENTS AND METHODS: We retrospectively analyzed 145 consecutive patients with EGC using multivariate analysis and developed a formula which predicts lymph node metastasis by linear discriminant analysis. In addition, we prospectively validated this formula in another subset of 106 consecutive patients with EGC and compared the predicted with the actual pathological lymph node metastasis. RESULTS: Multivariate analyses revealed that independent factors, which affect lymph node metastasis for EGC, were lymphatic system invasion (p=0.00002, odds ratio 3.11) and venous system invasion (p=0.039, odds ratio 2.44). In addition, we developed the lymph node metastasis-predicting formula using these two factors by linear discriminant analysis. The formula is as follows: Y=0.12 × (venous system invasion: 0, 1, 2 or 3) + 0.19 × (lymphatic system invasion: 0, 1, 2, or 3) - 0.14. If Y>0, we judge that a patient with gastric cancer is susceptible lymph node metastasis. The result of this prospective study showed that the sensitivity and specificity rates were 70% and 61.6%, respectively. CONCLUSION: We developed a formula which can predict lymph node metastasis using linear discriminant analysis. This formula seems useful in predicting for lymph node metastasis in patients with EGC.

Sentinel lymph node navigation surgery for early stage gastric cancer.

We attempted to evaluate the history of sentinel node navigation surgery (SNNS), technical aspects, tracers, and clinical applications of SNNS using Infrared Ray Electronic Endoscopes (IREE) combined with Indocyanine Green (ICG). The sentinel lymph node (SLN) is defined as a first lymph node (LN) which receives cancer cells from a primary tumor. Reports on clinical application of SNNS for gastric cancers started to appear since early 2000s. Two prospective multicenter trials of SNNS for gastric cancer have also been accomplished in Japan. Kitagawa et al reported that the endoscopic dual (dye and radioisotope) tracer method for SN biopsy was confirmed acceptable and effective when applied to the early-stage gastric cancer (EGC). We have previously reported the usefulness of SNNS in gastrointestinal cancer using ICG as a tracer, combined with IREE (Olympus Optical, Tokyo, Japan) to detect SLN. LN metastasis rate of EGC is low. Hence, clinical application of SNNS for EGC might lead us to avoid unnecessary LN dissection, which could preserve the patient's quality of life after operation. The most ideal method of SNNS should allow secure and accurate detection of SLN, and real time observation of lymphatic flow during operation.

High UBCH10 protein expression as a marker of poor prognosis in esophageal squamous cell carcinoma.

BACKGROUND/AIM: Ubiquitin-conjugating enzyme H10 (UBCH10) is required in the cell-cycle transition from metaphase to anaphase. Therefore, we investigated whether its expression level in cancerous esophageal lesions affected prognosis of patients with esophageal squamous-cell carcinoma. MATERIALS AND METHODS: Paraffin-embedded tissue samples from 121 patients with esophageal squamous cell carcinoma were stained with antibody to UBCH10 for immunohistochemical analysis. RESULTS: UBCH10 was expressed in cancerous and dysplastic lesions, but not in normal tissue. Patients were grouped according to expression: High (N=33) or low (N=88), depending on the staining pattern. There were significant differences between the groups in terms of invasion into lymphatic vessels, number of metastatic lymph nodes, TNM classification, and stages, as well as in survival: the 50% survival rate in the high expression group was 2.3 years, whereas it was 9.9 years for the low-expression group (p<0.0001). Even with multivariate adjusting for stage 0 to stage IV using the Cox proportional hazard model, patients belonging to the high-expression group had a poor prognosis (Hazard ratio=2.5; 95% Confidence Interval=1.3-4.5; p=0.004). CONCLUSION: High protein expression of UBCH10 is a marker of poor prognosis in esophageal squamous cell carcinoma.

Reduced expression of Rho GDP dissociation inhibitor 2 mRNA is associated with lymph node metastasis in gastric carcinoma.

Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1 and cdc42, are molecules that have significant roles in linking cell shape and cell cycle progression in cytoskeletal arrangements and mitogenic signaling. Rho GDP dissociation inhibitor 2 (RhoGDI2) has recently been identified as a metastasis suppressor gene in models of bladder cancer. RhoGDI2 has also been identified as a potential regulator of tumorigenesis and cancer progression. The present study aimed to clarify the significance of RhoGDI2 gene expression in gastric carcinoma and to evaluate the outcome of affected patients. A total of 46 pairs of normal mucosa and cancer specimens were obtained from patients who had undergone a gastrectomy for primary gastric carcinoma and were subjected to semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) for RhoGDI2. The expression of RhoGDI2 mRNA was significantly higher in early-stage gastric cancer specimens compared with the normal gastric epithelium samples. By contrast, the depth of the tumor was negatively correlated with RhoGDI2 mRNA expression. In addition, a reduced expression of RhoGDI2 mRNA was associated with venous system invasion and lymph node metastasis. RhoGDI2 mRNA was more frequently expressed in differentiated adenocarcinoma compared with poorly-differentiated adenocarcinoma. Although the statistical significance was not established, RhoGDI2-positive patients tended to have a superior oncological outcome compared with RhoGDI2-negative patients. The reduced expression of RhoGDI2 mRNA in gastric carcinoma is associated with venous system invasion and lymph node metastasis.

Preoperative determination of appropriate cutting line for proximal gastrectomy to avoid postoperative jejunal ulcer.

BACKGROUND/AIMS: Although proximal gastrectomy has become a procedure of choice for patients' early cancer in the upper third of stomach, no clinical guide for optimal gastric resection in order to avoid postoperative jejunal ulcer is available. The aim of this study was to investigate whether determining the distribution of parietal and chief cells of the stomach using Congo red test is clinically relevant. METHODOLOGY: The F-line was defined as a boundary line between fundic and intermediate area of the stomach according to the pathological findings in 29 patients who underwent total gastrectomy for early gastric cancer, whereas the f-line was regarded as a boundary line between intermediate and pyloric area. In the additional 6 patients undergoing vagus-preserving proximal gastrectomy with jejunal pouch interposition, endoscopic Congo red test was preoperatively performed to determine the F-f-line. RESULTS: The distances from the pyloric ring to f-line on the lesser and greater curvatures were variable. Long-term outcomes of proximal gastrectomy guided by preoperative endoscopic Congo red test were favorable. CONCLUSIONS: It is suggested that preoperative endoscopic Congo red test is useful to determine the appropriate cutting line in order to avoid postoperative jejunal ulcer after proximal gastrectomy.

Clinical significance of Rho GDP dissociation inhibitor 2 in colorectal carcinoma.

BACKGROUND: Small GTPase proteins, including RhoA, RhoB, RhoC, Rac1, and cdc42, are important molecules for linking cell shape and cell-cycle progression because of their role in both cytoskeletal arrangements and mitogenic signaling. Over-expression of wild-type or constitutively active forms of RhoA has been shown to induce invasive behavior in non-invasive rat hepatoma cells in vitro. In addition, over-expression of RhoC has been found in melanoma cells with increasing metastatic activity as well as inflammatory breast cancer. These results indicate that overexpression of Rho proteins contributes to cancer cell invasion and metastasis. Rho GDP dissociation inhibitor 2 (RhoGDI2) was recently shown to act as a metastasis suppressor gene in bladder cancer. The purpose of this study was to clarify the clinical significance of this gene expression in patients with colorectal carcinoma. METHODS: Fifty pairs of normal mucosa and cancer specimens obtained at the time of surgery from patients with colorectal cancer (CRC) were subjected to reverse transcription-polymerase chain reaction for RhoGDI2. RESULTS: No patients with RhoGDI2-higher expression tumors had liver metastasis (0 in 8 cases); however, 33.3% (14 in 42 cases) of patients with RhoGDI2-lower expression tumors had liver metastasis. With regard to outcome in relation to RhoGDI2-positivity, RhoGDI2-higher expression tumors had a significant correlation with superior relapse-free survival (RFS) time as compared to RhoGDI2-lower expression tumors in stage III CRC (log-rank test, P < 0.05). Moreover, multivariate analysis indicated that RhoGDI2 was an independent prognostic factor for RFS. CONCLUSION: RhoGDI2 is a novel predictor of RFS in patients with colorectal carcinoma.

Pre-pyloric site gastric cancer after pylorus-preserving gastrectomy (PPG): a case report.

Pylorus-preserving gastrectomy (PPG) is a function-preserving surgical procedure which is now applied to treat early gastric cancer in the mid-portion of the stomach. We report a patient who developed a pre-pyloric site gastric cancer after PPG. To our knowledge, this is the first report on the development of pre-pyloric site gastric cancer after PPG in the English literature using PubMed.

Frequent splicing aberration of the base excision repair gene hMYH in human gastric cancer.

BACKGROUND: Missense mutation of hMYH, which prevents transversion mutations induced by oxidative DNA damage, is reportedly associated with the development of gastric and colon cancer. We investigated whether deficiency or mutation of hMYH is associated with gastric carcinogenesis. PATIENTS AND METHODS: Thirty patients with gastric carcinoma, three gastric cancer cell lines and lymphocytes from three healthy volunteers were investigated. Reverse transcription-polymerase chain reaction (RT-PCR) was performed for hMYH, and the full-length sequence of hMYH mRNA was analysed. RESULTS: A silent mutation at codon 473 was seen in two tumours. Single nucleotide polymorphism at codon 345 was observed in 14 patients. These two base substitutions had no pathogenic effect. Seven splice variants were observed and two aberrant transcripts were detected more frequently in cancer specimens (67%) than in normal mucosa (10%). CONCLUSION: The high frequency of splicing aberration in cancer tissues suggests that aberrant transcripts may be involved in gastric carcinogenesis and cancer development.

Expression of vascular endothelial growth factor (VEGF)-C and -D in gastric carcinoma.

BACKGROUND: Both vascular endothelial growth factor (VEGF)-C and (VEGF)-D are ligands of VEGF receptor (VEGFR)-3 (Flt-4) and VEGFR-2 (KDR/FLK-1) and are supposed to participate in lymphangiogenesis. The purpose of this study was to clarify the clinical significance of the expression of these factors and to evaluate their relationship with prognosis in patients with gastric carcinoma. METHODS: Fifty pairs of normal mucosa and cancer specimens were obtained from patients who had undergone gastrectomy for primary gastric carcinoma and subjected to reverse transcriptase-polymerase chain reaction for VEGF-C, VEGF-D, and VEGFR-3. RESULTS: Both VEGF-C and VEGF-D mRNA expression significantly correlated with lymphatic invasion (P < 0.05). Although VEGF-C and -D were concomitantly expressed in most cases, only VEGF-C expression was related to lymph node metastasis. VEGFR-3 expression was associated both with VEGF-C and VEGF-D expression, but not with lymph node metastasis. Tumors expressing these mRNAs tended to correlate with poorer prognosis, but the relationships were not statistically significant. CONCLUSION: Our study suggests that both VEGF-C and VEGF-D are involved in lymphatic spreading of gastric cancer cells, which is clinically useful for the evaluation of lymphatic invasion in patients with gastric carcinoma.

Prognostic significance of vascular endothelial growth factor D in gastric carcinoma.

The angiogenic factor called vascular endothelial growth factor (VEGF)-D is a ligand for VEGF receptor-2 (VEGFR-2/KDR) and receptor-3 (VEGFR-3/Flt-4). It is implicated in the development of lymphatic vessels and promotion of lymphatic metastasis. The purpose of this study was to investigate the prognostic significance of VEGF-D expression in patients with gastric carcinoma. We assessed the expression of VEGF-D in gastric carcinoma by immunohistochemistry on 143 consecutive patients' stored sections and evaluated the lymphatic vessel count (LVC) in tumors using the novel selective lymphatic endothelium marker D2-40. VEGF-D expression was observed in 55 (39%) tumor sections. The expression of VEGF-D correlated significantly with tumor size, T of the TNM classification, lymphatic and venous system invasion, LVC, lymph node metastasis, M of TNM, and pTNM stage. Multivariate analysis indicated that VEGF-D expression was an independent prognostic factor for both relapse-free survival (RFS) and overall survival (OS). Our data indicate the involvement of VEGF-D in tumor progression via lymphoangiogenic pathways. Practically, VEGF-D expression can be useful for predicting RFS and OS in patients with gastric carcinoma.