Macroscopic type is implicated in the prognostic impact of initial chemotherapy on peritoneal lavage cytology-positive gastric cancer with no other noncurative factors.

BACKGROUND: Initial chemotherapy (Initial-C) followed by surgery is a promising treatment strategy for peritoneal lavage cytology-positive gastric cancer (CY1 GC) with no other noncurative factors. The aim of this study was to investigate the survival advantage of Initial-C compared to initial surgery (Initial-S) for this disease according to the macroscopic type, which was associated with prognosis and the efficacy of chemotherapy in GC. METHODS: One hundred eighty-nine patients who were diagnosed with CY1 GC with no other noncurative factors at four institutions from January 2007 to December 2018 were enrolled. The patients were divided into a macroscopic type 4 group (N = 48) and a non-type 4 group (N = 141). The influence of initial treatment on overall survival (OS) in each group was evaluated. RESULTS: In the type 4 group, the 5-year OS rates of Initial-C (N = 35) and Initial-S (N = 13) were 11.6% and 0%, respectively (P = 0.801). The multivariate analysis could not show the survival advantage of Initial-C. In the non-type 4 group, the 5-year OS rates of Initial-C (N = 41) and Initial-S (N = 100) were 48.4% and 29.0%, respectively (P = 0.020). The multivariate analysis revealed that Initial-C was independently associated with prolonged OS (hazard ratio, 0.591; 95% confidence interval, 0.375-0.933: P = 0.023). CONCLUSIONS: Initial-C improves the prognosis of non-type 4 CY1 GC with no other noncurative factors. On the other hand, further development of effective chemotherapeutic regimens and innovative treatment strategies are required for type 4 CY1 GC.

Risk factors for death from other diseases after curative gastrectomy and lymph node dissection for gastric cancer.

BACKGROUND: Recent advances in treatment are expected to bring a cure to more patients with gastric cancer (GC). Focusing on the risk of death from other diseases (DOD) has become a crucial issue in patients cured of GC. The aim of this study was to elucidate the risk factors for DOD in patients who underwent curative gastrectomy with lymph node dissection for GC. METHODS: We enrolled 810 patients who underwent curative gastrectomy with lymph node dissection for GC from January 1990 to December 2014 and had no recurrence or death of GC until December 2019. We investigated the risk factors for DOD defined as death excluding death from a malignant neoplasm, accident, or suicide after gastrectomy, focusing on the perioperative characteristics at gastrectomy. RESULTS: Among 315 deaths from any cause, 210 died from diseases other than malignancy, accidents and suicide. The leading cause of DOD was pneumonia in 54 patients (25.7%). The actual survival period in 167 patients (79.5%) with DOD was shorter than their estimated life expectancy at gastrectomy. Multivariate analysis revealed that a high Charlson Comorbidity Index score (score 1-2: hazard ratio [HR] 2.192, 95% confidence interval [CI] 1.713-2.804, P < 0.001 and score ≥ 3: HR 4.813, 95% CI 3.022-7.668, P < 0.001), total gastrectomy (HR 1.620, 95% CI 1.195-2.197, P = 0.002) and the presence of postoperative complications (HR 1.402, 95% CI 1.024-1.919, P = 0.035) were significant independent risk factors for DOD after gastrectomy for GC, in addition to age of 70 years or higher, performance status of one or higher and body mass index less than 22.0 at gastrectomy. CONCLUSIONS: Pneumonia is a leading cause of DOD after curative gastrectomy and lymph node dissection for GC. Paying attention to comorbidities, minimizing the choice of total gastrectomy and avoiding postoperative complications are essential to maintain the long-term prognosis after gastrectomy.

[Long-Term Survival after Liver and Pulmonary Metastasectomy Following Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma-A Case Report].

The patient was a 61-year-old man with a diagnosis of carcinoma of the pancreatic head. Abdominal computed tomography( CT)showed no distant metastasis, and he underwent subtotal stomach-preserving pancreatoduodenectomy. Immediately after surgery, he received liver perfusion chemotherapy with 5-fluorouracil followed by systemic gemcitabine. Eighteen months after surgery, CT revealed liver metastasis in the S6 segment, and partial hepatectomy was performed. The pathological diagnosis was liver metastasis of pancreatic cancer. Postoperatively, the patient was treated with gemcitabine and S-1 therapy for 1 year and then switched to S-1 monotherapy for about 6 months. Four years after the initial surgery, CT showed 2 metastases in the right lung. After 2 months of S-1 monotherapy, wedge resection of the upper and lower lobes of the right lung was performed. Gemcitabine and nab-paclitaxel therapy were administered, after the metastasectomy, but pleural dissemination appeared on CT 5 years after the initial surgery. Modified FOLFIRINOX therapy was started and continued for 8 months, but CT revealed further disseminated lesions in the diaphragm. Palliative irradiation was provided, but the disease gradually progressed. After multidisciplinary treatment, the patient survived for 6 years and 3 months after the initial surgery.

Rational Extent of Regional Lymphadenectomy and the Prognostic Impact of the Number of Positive Lymph Nodes for Perihilar Cholangiocarcinoma.

BACKGROUND: The definition and classification of regional nodes are not standardized for perihilar cholangiocarcinoma. This study aimed to clarify the rational extent of regional lymphadenectomy and to elucidate the impact of number-based regional nodal classification on survival of patients with this disease. METHODS: Data of 136 patients with perihilar cholangiocarcinoma who underwent surgery were reviewed. The incidence of metastasis and the survival of patients with metastasis were calculated for each node group. RESULTS: The incidence of metastasis for the node groups in the hepatoduodenal ligament (denoted as no. 12) ranged from 3.7% to 25.4%, with 5-year disease-specific survival of 12.9% to 33.3% for patients with metastasis. The incidences of metastasis in the common hepatic artery (no. 8) and posterior superior pancreaticoduodenal (no. 13a) node groups were 14.4% and 11.2%, respectively, with 5-year disease-specific survival rates of 16.7% and 20.0% for the patients with metastasis. When these node groups were defined as regional nodes, the 5-year disease-specific survival rates for the patients with pN0 (n = 80), pN1 (1-3 positive nodes, n = 38), and pN2 (≥ 4 positive nodes, n = 18) were 61.4%, 22.9%, and 17.6%, respectively (p < 0.001). The pN classification was independently associated with disease-specific survival (p < 0.001). When only the no. 12 node groups were regarded as regional nodes, pN classification failed to stratify the patients prognostically. CONCLUSIONS: No. 8 and no. 13a node groups should be considered regional nodes in addition to no. 12 node groups and should be dissected. The number-based regional nodal classification allows patients with this disease to be stratified prognostically.

Clinical significance of metastatic tumor deposit foci in rectal cancer in the lateral pelvic lymph node area.

BACKGROUND: Although previous studies have demonstrated that tumor deposits (TDs) are associated with worse prognosis in colon cancer, their clinical significance in rectal cancer has not been fully elucidated, especially in the lateral pelvic lymph node (LPLN) area. This study aimed to clarify the clinical significance of TDs, focusing on the number of metastatic foci, including lymph node metastases (LNMs) and TDs, in the LPLN area. METHODS: This retrospective study involved 226 consecutive patients with cStage II/III low rectal cancer who underwent LPLN dissection. Metastatic foci, including LNM and TD, in the LPLN area were defined as lateral pelvic metastases (LP-M) and were evaluated according to LP-M status: presence (absence vs. presence), histopathological classification (LNM vs. TD), and number (one to three vs. four or more). We evaluated the relapse-free survival of each model and compared them using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). RESULTS: Forty-nine of 226 patients (22%) had LP-M, and 15 patients (7%) had TDs. The median number of LP-M per patient was one (range, 1-9). The best risk stratification power was observed for number (AIC, 758; c-index, 0.668) compared with presence (AIC, 759; c-index, 0.665) and histopathological classification (AIC, 761; c-index, 0.664). The number of LP-M was an independent prognostic factor for both relapse-free and overall survival, and was significantly associated with cumulative local recurrence. CONCLUSION: The number of metastatic foci, including LNMs and TDs, in the LPLN area is useful for risk stratification of patients with low rectal cancer.

Long-term results of minimally invasive transanal surgery for rectal tumors in 249 consecutive patients.

PURPOSE: To delineate the long-term results of minimally invasive transanal surgery (MITAS) for selected rectal tumors. METHODS: We analyzed data, retrospectively, on consecutive patients who underwent MITAS between 1995 and 2015, to establish the feasibility, excision quality, and perioperative and oncological outcomes of this procedure. RESULTS: MITAS was performed on 243 patients. The final histology included 142 cancers, 47 adenomas, and 52 neuroendocrine tumors (NET G1). A positive margin of 1.6% and 100% en bloc resection were achieved. The mean operative time was 27.4 min. Postoperative morbidity occurred in 7% of patients, with 0% mortality. The median follow-up was 100 months (up to ≥ 5 years or until death in 91.8% of patients). Recurrence developed in 2.9% of the patients. The 10-year overall survival rate was 100% for patients with NET G1 and 80.3% for those with cancer. The 5-year DFS was 100% for patients with Tis cancer, 90.6% for those with T1 cancer, and 87.5% for those with T2 or deeper cancers. MITAS for rectal tumors ≥ 3 cm resulted in perioperative and oncologic outcomes equivalent to those for tumors < 3 cm. CONCLUSION: MITAS is feasible for the local excision (LE) of selected rectal tumors, including tumors ≥ 3 cm. It reduces operative time and secures excision quality and long-term oncological outcomes.

[Radical Resection Followed by Chemotherapy for Intrahepatic Cholangiocarcinoma with Lymph Node Metastases-Report of a Long-Term Survivor].

We report a case of intrahepatic cholangiocarcinoma(ICC)with lymph node metastases in which long-term survival was achieved after surgery followed by chemotherapy. A 69-year-old man underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection for ICC located mainly in segment 4 of the liver with enlarged lymph nodes in the hepatoduodenal ligament. The histopathologically confirmed diagnosis was ICC(T2N1M0, Stage ⅣA)with 3 positive lymph nodes(No. 12a1, No. 12p1, and No. 12p2). He received chemotherapy with gemcitabine(GEM)plus cisplatin(CDDP)for 9 months, followed by GEM monotherapy for 4 months, and then S-1 monotherapy was started. A right lung nodule was detected 12 months after the initiation of S-1 monotherapy. He received GEM plus S-1 therapy for 28 months, followed by S-1 monotherapy, leading to disappearance of the lung nodule. He remains alive and well without disease 78 months after surgery. Our experience in this case suggests that radical resection followed by chemotherapy may provide a survival benefit in selected patients who have ICC with nodal disease.

[A Case of Appendiceal Carcinoma with BRAF V600E Mutation and Microsatellite Instability-High].

A 75-year-old woman presented to our hospital with abdominal pain and melena. Colonoscopy revealed an ulcer at the appendiceal orifice. Histopathological examination of biopsy specimens revealed adenocarcinoma. Computed tomography showed an appendiceal mass of 11.8×6.7 cm in size involving the cecum and terminal ileum without any distant metastatic findings. Ileocecal resection with regional lymph node dissection to the root of the ileocolonic artery was performed. Histopathological examination of the specimen revealed appendiceal adenocarcinoma. Molecular subtype of the tumor was BRAF V600E mutation and microsatellite instability-high(MSI-H). The pathological stage was pT4bpN1bcM0, pStage ⅢC. She received 8 courses of CapeOX as adjuvant chemotherapy and no recurrence was noted 12 months following the surgery. The establishment of standard treatment strategies including surgery, chemotherapy, and immunotherapy for carcinoma of the appendix with BRAF V600E mutation and/or MSI-H is needed.

[Cancer of the Ascending Colon and Left Breast in an Older Adult Complicated by Thoracic Aortic Aneurysm].

An 87-year-old woman with a gradually enlarging mass in her left breast, diagnosed as having left-sided breast cancer with skin invasion by a local practitioner, was referred to our hospital. Computed tomography revealed ascending colon cancer with abdominal wall invasion and a thoracic aortic aneurysm(Stanford type B), in addition to breast cancer with skin invasion. A thoracic endovascular aortic repair and bypass surgery between the subclavian arteries were both performed for the thoracic aortic aneurysm. After 6 days, a right hemicolectomy and D2 lymphadenectomy were performed for the ascending colon cancer. A postoperative pathological diagnosis of pT3N0M0, pStage Ⅱa, was made. A total left mastectomy with a full-thickness skin graft for left breast cancer was performed after 2 months following the ascending colon cancer surgery. The postoperative pathological diagnosis was pT3N0M0, pStage ⅡB. No evidence of local recurrence or distant metastasis of the ascending colon cancer has been observed at 20 months postoperatively, or of the breast cancer after 18 months following surgery.

[Surgery for Cholangiocarcinoma with Superficial Spread and Lymph Node Metastasis-Report of a Long-Term Survivor Who Had Positive Proximal Ductal Resection Margins with Carcinoma In Situ].

A 66-year-old man was referred to our hospital with fever and abdominal pain. CT showed a mass in the intrapancreatic bile duct but no wall thickness in the perihilar bile ducts. Neither regional lymphadenopathy nor distant metastasis was observed. Biliary cytology showed adenocarcinoma. The diagnosis was distal cholangiocarcinoma, and pancreatoduodenectomy was performed. Intraoperative frozen section examination of the ductal resection margins at the right and left hepatic ducts was positive for carcinoma in situ, and the operation ultimately completed with R1 resection. Histological examination confirmed a diagnosis of cholangiocarcinoma with superficial spread and a single positive lymph node. Adjuvant chemotherapy with S-1 was administered for 1 year. Anastomotic recurrence at the hepaticojejunostomy was found 5 years after resection; biopsy specimens revealed adenocarcinoma. Thereafter, S-1 chemotherapy was resumed, and the patient remains alive and well 9 years and 1 month after resection.

[A Case of Intraductal Papillary Mucinous Adenocarcinoma with Hepatic Dysfunction Due to Tumor Perforation into the Bile Duct].

A 58-year-old woman presented with a complaint of weight loss. Abdominal computed tomography showed dilatation of the biliary and pancreatic ducts and a mural nodule in the pancreatic duct. The diagnosis was intraductal papillary mucinous neoplasm(IPMN). Endoscopic retrograde cholangiopancreatography(ERCP)and cholangioscopy revealed a fistula between the common bile duct and the IPMN. A sudden increase in hepatobiliary enzymes was noted preoperatively. ERCP showed that the common bile duct was obstructed by mucus. A nasobiliary drainage tube was inserted into the bile duct endoscopically and kept open by daily tube washing, and the liver dysfunction improved. Total pancreatectomy, splenectomy, and regional lymph node dissection were performed. Histological examination confirmed that the primary tumor was mixed invasive intraductal papillary mucinous adenocarcinoma. The patient remains alive and well with no evidence of recurrence 18 months after resection.

[Two Operations for Intrahepatic Recurrence of Biliary Cystadenocarcinoma-A Long-Term Survivor].

We report a case of biliary cystadenocarcinoma in which long-term survival was achieved after 2 operations for intrahepatic recurrence. A 72-year-old man with biliary cystadenocarcinoma located mainly in segment 3 of the liver underwent left hepatectomy, extrahepatic bile duct resection, and lymph node dissection. Seven years and 9 months after the initial resection, he underwent partial liver resection(segment 5)for intrahepatic recurrence detected by computed tomography. Fifteen years and 7 months after the initial resection, he underwent repeat partial resection of the liver(segment 5)for intrahepatic recurrence. Histologically, these tumors were confirmed to be recurrence of biliary cystadenocarcinoma. He remains alive and well with no further recurrence 21 years and 6 months after the initial resection. This case and a literature review suggest that hepatic resection is a useful treatment option for intrahepatic recurrence of biliary cystadenocarcinoma.

[A Case of Esophageal Carcinoma with Tracheal Invasion after Preoperative Treatment with Docetaxel, Cisplatin, and 5-Fluorouracil in Which Definitive Chemoradiotherapy and Salvage Esophagectomy Prolonged Survival].

A 57-year-old man was diagnosed as having resectable advanced esophageal carcinoma adjacent to the trachea(Ut, cT3N0M0)and received preoperative docetaxel, cisplatin, and 5-fluorouracil therapy. Due to tracheal tumor invasion and upstaging to cT4bN0M0 after 1 course of chemotherapy, the treatment was converted to definitive chemoradiotherapy (CRT). A remarkable response with no evidence of tracheal invasion was observed on computed tomography following definitive CRT. He underwent successful curative resection with salvage esophagectomy, and the resected tumor was staged as pT1bN0M0. No adjuvant therapy was administered, and the patient was alive with no evidence of disease at the 5-year postoperative follow-up. The response to preoperative treatment should be meticulously assessed and appropriate treatment modalities used to avoid overlooking the potential for cure, even if the response to preoperative treatment with docetaxel, cisplatin, and 5-fluorouracil is poor.

[Resectable Pancreatic Cancer Successfully Treated with Neoadjuvant Chemotherapy Regimen Change to Modified FOLFIRINOX-A Case Report].

A 72-year-old woman presented with obstructive jaundice. Computed tomography revealed a 12-mm low-density mass in the head of the pancreas. She was diagnosed as having pancreatic cancer by endoscopic ultrasound-guided fine-needle aspiration. She received gemcitabine plus nab-paclitaxel as preoperative chemotherapy. After 2 courses, hepatoduodenal lymph node metastasis appeared and was accompanied by increased tumor marker levels. The regimen was changed to modified FOLFIRINOX. After 5 courses, the lymph node metastasis was reduced in size and the tumor marker levels were decreased, so subtotal stomach-preserving pancreaticoduodenectomy was performed. Adjuvant chemotherapy was administered postoperatively. The patient was alive and well without recurrence 2 years and 9 months after the surgery, but died of sepsis. Nevertheless, this case highlights that when preoperative chemotherapy for resectable pancreatic cancer appears to be ineffective, a change in regimen may be useful.

[A Case of Unresectable Advanced Gastric Cancer Resected by Conversion Surgery after Trastuzumab Combination Chemotherapy].

A 74-year-old man presented to our hospital with a mass in the left supraclavicular fossa. He was diagnosed with advanced gastric cancer with liver metastasis and left supraclavicular and para-aortic lymph node metastasis, cT3N2M1 (LYM, HEP), cStage Ⅳ(the Union for International Cancer Control, TNM 7th edition). He received a total of 3 courses of S- 1 plus cisplatin therapy. Since he developed adverse reactions such as anorexia, renal dysfunction, and thrombocytopenia and the tumor was HER2-positive, he received 25 courses of capecitabine, cisplatin, and trastuzumab chemotherapy. Three years and 2 months after the first chemotherapy, remarkable tumor reduction was observed. The patient then underwent radical distal gastrectomy with D2 lymphadenectomy, and R0 resection was achieved. The histopathological diagnosis was ypT1aN0M0, ypStage ⅠA. Chemotherapy with trastuzumab may improve the long-term prognosis of HER2-positive Stage Ⅳ gastric cancer if the disease is controlled and radical resection can be achieved.

[A Case of Long-Term Survival with Multidisciplinary Treatment after Surgery for Duodenal Cancer with Left Supraclavicular Lymph Node Metastasis].

The patient was a 71-year-old man with a diagnosis of duodenal carcinoma. Abdominal computed tomography(CT) showed no distant metastasis, and he underwent subtotal stomach-preserving pancreaticoduodenectomy. Postoperative adjuvant chemotherapy was not administered. A left supraclavicular lymph node recurrence was detected on CT 15 months after surgery. Capecitabine and oxaliplatin(CAPOX)therapy was administered and the metastatic lesion shrank. Positron emission tomography(PET)-CT showed no lesions at other sites and left cervical lymph node dissection was performed 5 months after the recurrence. Postoperative adjuvant therapy with S-1 was administered for 6 months. However, 2 years and 10 months after the first recurrence, CT showed recurrence in the left supraclavicular lymph node. CAPOX therapy was resumed, but due to an allergic reaction to oxaliplatin, the patient was treated with capecitabine alone. The recurrent lesion was gradually increased in size, and FOLFIRI therapy was introduced. One year and 5 months after secondary recurrence, PET-CT showed that the second recurrent lesion had grown but was confined to the left supraclavicular lymph node, so radiation therapy(60 Gy)to the left neck was performed. The disease was stable for about 10 months and chemotherapy could be discontinued. The lesion increased in size thereafter, and the patient died 7 years after initial surgery.

[Total Pancreatectomy for Remnant Pancreatic Cancer with Positive Washing Cytology after Conversion to Negative Cytology Following Gemcitabine plus Nab-Paclitaxel Therapy-A Case Report].

A 53-year-old woman underwent subtotal stomach-preserving pancreaticoduodenectomy(SSPPD)for resectable pancreatic cancer after neoadjuvant chemotherapy. Postoperatively, she received hepatic arterial infusion of 5-FU and S-1 chemotherapy. Two years after SSPPD, abdominal computed tomography showed a 2-cm mass in the remnant pancreas, which was diagnosed as recurrence of cancer by endoscopic ultrasound-guided fine-needle aspiration. Staging laparoscopy was performed and peritoneal washing cytology(CY)was positive. She then received gemcitabine plus nab-paclitaxel chemotherapy for 8 months. After that, staging laparoscopy was performed again and negative CY was confirmed. A total remnant pancreatectomy with splenectomy was performed. She received chemotherapy after pancreatectomy and is now alive and well without recurrence 2 years and 1 month after the second surgery. Although positive CY is a poor prognostic factor, surgery combined with perioperative chemotherapy may contribute to prolonged survival for some patients who have recurrence in the remnant pancreas with positive CY.

[A Case of Granulocyte Colony-Stimulating Factor-Associated Aortitis during Neoadjuvant Chemotherapy for Esophageal Cancer].

A 71-year-old man with middle thoracic esophageal cancer was treated with neoadjuvant chemotherapy using docetaxel plus 5-FU plus cisplatin therapy and was also administered pegfilgrastim. Blood tests showed elevated white blood cell counts and C-reactive protein levels before the start of the third course. Contrast-enhanced computed tomography revealed wall thickening of the aortic arch. We diagnosed this as aortitis due to pegfilgrastim. Inflammation was improved with conservative treatment. We then performed video-assisted thoracoscopic esophagectomy. Drug-induced vasculitis should be included in the differential diagnosis of patients with elevated inflammation markers of unknown cause following the administration of granulocyte colony-stimulating factor preparations.

[Laparoscopic Abdominoperineal Resection for Anal Canal Cancer with Pagetoid Spread].

A woman in her 60s had been aware of perianal erosions for 1 month. Skin biopsy showed Paget's cells in the stratified squamous epithelium, and immunohistochemistry showed negative staining for CK7 and positive staining for CK20. Colonoscopy revealed well-differentiated adenocarcinoma in the anal canal. Computed tomography showed neither regional lymph node metastasis nor distant metastasis. Hence, she was diagnosed with anal canal carcinoma with pagetoid spread. We determined the extent of resection of the skin lesion preoperatively by mapping biopsy, and performed laparoscopic abdominoperineal resection. The pathological findings revealed adenocarcinoma(tub1, tub2), and the skin resection margin was negative. Immunohistochemistry for Paget's cells in the stratified squamous epithelium showed negative staining for GCDFP-15 and CK7, and positive staining for CK20. Twenty-four months after surgery, we detected right inguinal lymph node metastasis and performed right inguinal lymphadenectomy. As of 4 months after the lymphadenectomy, no local recurrence or distant metastasis has been detected during follow-up examinations.

Robotic low anterior resection for rectal cancer with side-to-end anastomosis in a patient with anal stenosis.

BACKGROUND: Colorectal anastomosis using the double stapling technique (DST) has become a standard procedure. However, DST is difficult to perform in patients with anal stenosis because a circular stapler cannot be inserted into the rectum through the anus. Thus, an alternative procedure is required for colorectal anastomosis. CASE PRESENTATION: A 78-year-old woman presented with bloody stool. Colonoscopy and computed tomography revealed advanced low rectal cancer without lymph node or distant metastasis. We initially planned to perform low anterior resection using a double stapling technique or transanal hand-sewn anastomosis, but this would have been too difficult due to anal stenosis and fibrosis caused by a Milligan-Morgan hemorrhoidectomy performed 20 years earlier. The patient had never experienced defecation problems and declined a stoma. Therefore, we inserted an anvil into the rectal stump and fixed it robotically with a purse-string suture followed by insertion of the shaft of the circular stapler from the sigmoidal side. In this way, side-to-end anastomosis was accomplished laparoscopically. The distance from the anus to the anastomosis was 5 cm. The patient was discharged with no anastomotic leakage. Robotic assistance proved extremely useful for low anterior resection with side-to-end anastomosis. CONCLUSION: Performing side-to-end anastomosis with robotic assistance was extremely useful in this patient with rectal cancer and anal stenosis.