Prospective Multicenter Comprehensive Survey on Male Sexual Dysfunction following Laparoscopic, Robotic, and Transanal Approaches for Rectal Cancer (the LANDMARC Study).

OBJECTIVE: To investigate the incidence of male sexual dysfunction (SD) including erectile dysfunction (ErD) and ejaculatory dysfunction (EjD) after minimally invasive rectal cancer surgery. BACKGROUND: Male SD significantly affects post-rectal cancer surgery quality of life (QOL). Current assessments using the International Index of Erectile Function-5 are unsuitable for patients with reduced postoperative sexual activity, because it assumes sexual intercourse. This study addresses this gap using the Erection Hardness Score (EHS) and custom ejaculatory questionnaires. METHODS: This prospective multicenter open-label phase II trial enrolled 399 patients who underwent laparoscopic (Lap), robotic (Ro), or transanal (Ta) rectal cancer surgery. EHS and custom ejaculatory questionnaires assessed ErD, EjD, and potency impairment at 3, 6, and 12 months postoperatively. The rates were assessed in the full analysis set and compared between the Lap and Ro groups after propensity score matching. RESULTS: At 12 months, the overall incidences of ErD and EjD were 34.7% and 29.8%, respectively. The Ro group showed a significantly lower EjD rate (25.0%) than the Lap group (40.9%), with no significant difference in ErD. Potency impairment was lower in the Ro group at 6 months (32.7% vs. 22.3%) and 12 months (29.0% vs. 17.8%) postoperatively. The Ta group showed relatively high ErD and EjD at 3 months, with some recovery at 12 months. CONCLUSIONS: Minimally invasive rectal cancer surgery commonly results in ErD, EjD, and potency impairment. Robotic surgery provides lower EjD rates and less potency impairment. Comprehensive sexual function assessments are essential to inform patients and improve QOL outcomes.

Colorectal cancer and advanced adenoma characteristics according to causative mismatch repair gene variant in Japanese colorectal surveillance for Lynch syndrome.

BACKGROUND: The optimal interval of colonoscopy (CS) surveillance in cases with Lynch syndrome (LS), and stratification according to the causative mismatch repair gene mutation, has received much attention. To verify a feasible and effective CS surveillance strategy, we investigated the colorectal cancer (CRC) incidence at different intervals and the characteristics of precancerous colorectal lesions of LS cases. METHODS: This retrospective multicenter study was conducted in Japan. CRCs and advanced adenomas (AAs) in 316 LS cases with germline pathogenic variants (path_) were analyzed according to the data of 1,756 registered CS. RESULTS: The mean time interval for advanced CRCs (ACs) detected via CS surveillance was 28.7 months (95% confidence interval: 13.8-43.5). The rate of AC detection within (2.1%) and beyond 2 years (8.7%) differed significantly (p = 0.0003). AAs accounted for 43%, 46%, and 41% of lesions < 10 mm in size in the MLH1-, MSH2-, and MSH6-groups, respectively. The lifetime incidence of metachronous CRCs requiring intestinal resection for path_MLH1, path_MSH2, and path_MSH6 cases was 34%, 23%, and 14% in these cases, respectively. The cumulative CRC incidence showed a trend towards a 10-year delay for path_MSH6 cases as compared with that for path_MLH1 and path_MSH2 cases. CONCLUSIONS: In cases with path_MLH1, path_MSH2, and path_MSH6, maintaining an appropriate CS surveillance interval of within 2 years is advisable to detect of the colorectal lesion amenable to endoscopic treatment. path_MSH6 cases could be stratified with path_MLH1 and MSH2 cases in terms of risk of metachronous CRC and age of onset.

Surgical outcomes of patients with acute cholecystitis treated with gallbladder drainage followed by early cholecystectomy.

AIM: This study aimed to investigate the impact of preoperative gallbladder drainage and the specific drainage method used on surgical outcomes in patients undergoing surgery for acute cholecystitis. METHODS: This single-center retrospective cohort study included 221 patients who underwent early cholecystectomy between January 2016 and December 2020. Clinical data and outcomes of 140 patients who did not undergo drainage, 22 patients who underwent preoperative percutaneous transhepatic gallbladder drainage (PTGBD), and 59 patients who underwent preoperative endoscopic naso-gallbladder drainage (ENGBD) were compared. RESULTS: There was no difference in the operation time, blood loss, postoperative complications, or length of postoperative hospital stay between patients who did and did not undergo drainage. Among patients who underwent drainage, there was no difference between the ENGBD and PTGBD groups in operation time, blood loss, or postoperative complications; however, more patients in the PTGBD group underwent laparotomy and had a significantly longer postoperative hospital stay. The presence and type of drainage were not risk factors for postoperative complications. CONCLUSION: The presence or absence of preoperative gallbladder drainage for acute cholecystitis and the type of drainage may not significantly affect surgical outcomes.

Preoperative diagnosis and safe surgical approach in gallbladder amyloidosis: a case report.

BACKGROUND: Preoperative diagnosis of gallbladder amyloidosis is usually difficult. In our case, the patient exhibited gallbladder dyskinesia, which led us to suspect cholecystic amyloidosis. We were able to safely perform surgery before cholecystitis onset. CASE PRESENTATION: A 59-year-old male patient with a history of multiple myeloma and cardiac amyloidosis presented to our hospital with a chief complaint of epicardial pain. Abdominal ultrasonography and computed tomography revealed an enlarged gallbladder and biliary sludge without any specific imaging findings of cholecystitis. After percutaneous transhepatic gallbladder aspiration (PTGBA), the patient experienced recurrent bile retention and right upper quadrant pain. Flopropione was effective in relieving these symptoms. Based on his symptoms and laboratory findings, we diagnosed the patient with dyskinesia of the gallbladder. Considering his medical history, we suspected that it was caused by amyloidosis of the gallbladder. A laparoscopic cholecystectomy was performed. The histopathological examination showed amyloid deposits in the gallbladder mucosa, from the intrinsic layer to the submucosa, and in the peripheral nerves of the gallbladder neck. The patient was discharged on postoperative day 5 and has had no recurrence of abdominal pain since then. CONCLUSION: In our case, gallbladder dyskinesia symptoms led us to suspect gallbladder amyloidosis. We safely surgically treated the patient before cholecystitis onset.

Peritoneal dissemination of appendiceal goblet cell adenocarcinoma mimicking white pus caused by peritonitis following appendicitis: an instructive case report.

BACKGROUND: Goblet cell adenocarcinoma is an extremely rare tumor in which the same cells exhibit both mucinous and neuroendocrine differentiation. It is considered more aggressive compared to conventional carcinoids and more likely to cause metastasis. CASE PRESENTATION: We report a case of goblet cell adenocarcinoma with peritoneal metastases. A 62-year-old man underwent appendectomy for acute appendicitis. Intraoperatively, inflammatory white pus and a small amount of dirty ascites were observed in the lower abdomen with severely inflamed appendix. Histopathological examination of the specimen collected during appendectomy revealed goblet cell adenocarcinoma with a positive surgical margin. One month later, additional ileal resection was planned. Laparoscopic examination revealed disseminated nodules throughout the abdominal cavity. Therefore, the patient underwent resection of the peritoneal nodules. The peritoneal specimens confirmed the histopathological findings. Thus we diagnosed the patient with peritoneal dissemination of appendiceal goblet cell adenocarcinoma. CONCLUSIONS: In cases wherein white pus is observed during surgery for acute appendicitis, considering the possibility of dissemination, collecting samples for histopathological examination, and initiating early treatment are crucial.

Weekday Surgery Associated With Short-Term Outcomes in Patients With Colorectal Cancers.

INTRODUCTION: The "weekday effect" on elective surgery remains controversial. We aimed to examine the association between the day of surgery and short-term outcomes after elective surgery for stage I-III colorectal cancer (CRC). METHODS: We performed a multicenter retrospective analysis of 2574 patients who underwent primary colorectal resection for CRC between January 2017 and December 2019 at 15 institutions belonging to the Hiroshima Surgical Study Group of Clinical Oncology. Patients were divided into two groups according to the day of surgery: Friday and non-Friday (Monday to Thursday). After propensity score matching (PSM), we compared 30-day mortality and postoperative outcomes. RESULTS: Out of the total, 368 patients underwent surgery on Fridays, and the remaining 2206 underwent surgery on non-Fridays. The overall mortality rate was 0.04% (n = 1). In 1685 patients with colon cancer, the proportion of American Society of Anesthesiologists scores was significantly lower in the Friday group than in the non-Friday group before PSM. After PSM of patient, tumor, and operative characteristics, operative time was slightly more prolonged and blood loss was slightly greater in the Friday group; however, these differences were not clinically meaningful. In the 889 patients with rectal cancer, the proportion of patients with abnormal respiratory patterns was significantly lower in the Friday group than in the non-Friday group before PSM. After PSM, the Friday group had a higher incidence of morbidity (≥ Clavien-Dindo 3a), higher incidence of digestive complications, and prolonged postoperative hospital stay. CONCLUSIONS: The results may be useful in determining the day of the week for CRC surgery, which requires more advanced techniques and higher skills.

Predictive factors associated with anastomotic leakage after resection of rectal cancer: a multicenter study with the Hiroshima Surgical study group of Clinical Oncology.

PURPOSE: Several factors have been reported as risk factors for anastomotic leakage after resection of rectal cancer. This study aimed to evaluate the risk factors for anastomotic leakage, including nutritional and immunological indices, following rectal cancer resection. METHODS: This study used a multicenter database of 803 patients from the Hiroshima Surgical study group of Clinical Oncology who underwent rectal resection with stapled anastomosis for rectal cancer between October 2016 and April 2020. RESULTS: In total, 64 patients (8.0%) developed postoperative anastomotic leakage. Five factors were significantly associated with the development of anastomotic leakage after rectal cancer resection with stapled anastomosis: male sex, diabetes mellitus, C-reactive protein/albumin ratio ≥ 0.07, prognostic nutritional index < 40, and low anastomosis under peritoneal reflection. The incidence of anastomotic leakage was correlated with the number of risk factors. The novel predictive formula based on odds ratios in the multivariate analysis was useful for identifying patients at high risk for anastomotic leakage. Diverting ileostomy reduced the ratio of anastomotic leakage ≥ grade III after rectal cancer resection. CONCLUSIONS: Male sex, diabetes mellitus, C-reactive protein/albumin ratio ≥ 0.07, prognostic nutritional index < 40, and low anastomosis under peritoneal reflection are possible risk factors for developing anastomotic leakage after rectal cancer resection with the stapled anastomosis. Patients at high risk of anastomotic leakage should be assessed for the potential benefits of diverting stoma.

A prospective feasibility study of uracil-tegafur and leucovorin as adjuvant chemotherapy for patients aged ≥ 80 years after curative resection of colorectal cancer, the HiSCO-03 study.

PURPOSE: There is no consensus on the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥ 80 years. We conducted a prospective multi-institutional phase II study of uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy in this population. PATIENTS AND METHODS: Patients with stage III CRC aged ≥ 80 years who underwent curative resection were enrolled. Eligible patients received UFT/LV therapy (UFT, 300 mg/m2 per day as tegafur; LV, 75 mg/day on days 1-28, every 35 days for five courses). Primary endpoint was feasibility, and secondary endpoints were safety and relative dose intensity. RESULTS: Sixty-nine patients were enrolled between 2013 and 2021. Of the 69 patients, 65 were included in the analysis. There were 32 males and 33 females with a median age of 82 years (range 80-88 years). In the primary endpoint, administration completion rate was 67.3% (95% confidence interval 54.9-77.6%), and the lower limit of the 95% confidence interval was below the threshold of 60%. 21 patients discontinued treatment because of adverse events (AEs) and refused treatment. The median relative dose intensities were 84% (range 4-100%) for UFT, and 100% (range 4-100%) for LV. Incidence of grade three or higher AEs were neutropenia (1.5%), aspartate transaminase elevation (3%), alanine transaminase elevation (1.5%), oral mucositis (3%), anemia (1.5%), and diarrhea (4.6%). CONCLUSIONS: The indications for adjuvant UFT/LV therapy for elderly CRC aged ≥ 80 years were considered limited. It is necessary to clarify the background of patients in whom drug administration is discontinued and investigate their impact on long-term prognosis.

Current practice of colonoscopy surveillance in patients with lynch syndrome: A multicenter retrospective cohort study in Japan.

Objectives: Colonoscopy surveillance reduces the incidence of colorectal cancer through the detection and endoscopic removal of adenomas. Current guidelines recommend that patients with Lynch syndrome should have colonoscopy surveillance every 1-2 years starting at the age of 20-25. However, insufficient data are available to evaluate the quality and safety of colonoscopy surveillance for patients with Lynch syndrome nationwide in Japan. Methods: Patients with Lynch syndrome (n = 309) from 13 institutions who underwent one or more colonoscopy procedures were enrolled in this retrospective analysis. Colonoscopy completion rate, colonoscopy-related complication rate, proportion with an adequate colonoscopy interval, and adenoma detection rate were reviewed. Results: The colonoscopy completion rate was 98.8% and a history of previous colorectal cancer surgery was significantly associated with a higher completion rate. All complications were associated with endoscopic treatment and the rate of bleeding needing hemostasis and perforation needing surgical repair were both 0.16% after colonoscopy with polypectomy. The adenoma detection rate at the first colonoscopy was 25%. Although there was no difference in the completion and complication rates based on differences in the colonoscopy experience of the endoscopist, the detection rate of adenomas and intramucosal cancers was significantly higher with more experienced endoscopists. The proportion of patients developing cancer was significantly higher with a >24 months than a ≤24 months interval. Conclusion: High-volume experienced endoscopists and appropriate surveillance intervals may minimize the risk of developing colorectal cancers in patients with Lynch syndrome.

Comparison of Three Clinical Trials of Preoperative Predictors for Complicated Appendicitis.

BACKGROUND/AIM: We previously reported three items that preoperatively predicted complicated appendicitis (body temperature, C-reactive protein, and fluid retention around the appendix). In this study, we aimed to compare other predictors to confirm the usefulness of our predictors with those of previous reports on the items as predictors of complicated appendicitis preoperatively (criteria A which consist of 8 items, criteria B which consist of 7 items). PATIENTS AND METHODS: We retrospectively evaluated 417 adult patients who underwent surgery for acute appendicitis between January 2013 and December 2019 and compared our items with criteria A and criteria B according to the results of the area under the receiver operating characteristic curve (AUC), homogeneity, discriminatory ability, and Akaike information criterion (AIC). RESULTS: The AUC for the sensitivity to diagnose complicated appendicitis according to according to our criteria, as well as criteria A, and criteria B was 0.823, 0.839, and 0.856, respectively. The discriminatory ability linear trend χ2 of our criteria and those of criteria A and B were 128.9, 121.1, and 142.5, respectively. The homogeneity likelihood ratios χ2 calculated using the Cox regression model, which indicate homogeneity, were 146.4, 143.6, and 172.8, respectively. The AIC of each criterion was 397.0, 345.8, and 369.0, respectively. CONCLUSION: Although the criteria B were the best, it was possible to predict complicated appendicitis preoperatively by all criteria. Above all, our criteria have only three items, therefore they have the advantage of making it possible to make decisions quickly with a certain degree of accuracy, regardless of the degree of experience.

Risk of first onset of colorectal cancer associated with alcohol consumption in Lynch syndrome: a multicenter cohort study.

BACKGROUND: Complex interactions among endogenous and exogenous factors influence the incidence of colorectal cancer (CRC). Germline mutations in mismatch repair (MMR) genes causing Lynch syndrome (LS) are major endogenous factors. The exogenous factor, alcohol consumption, is potentially associated with CRC incidence among patients with LS. However, insufficient data are available to determine whether alcohol consumption influences the time of the first onset of CRC associated with sex, MMR gene mutations, and anatomical tumor site. METHODS: Among 316 patients with LS identified in a Japanese LS cohort, we included 288 with data on age, sex, proband status, alcohol status, smoking status, tumor location, and MMR gene mutations. Multivariable analysis assessed the association of alcohol consumption with earlier onset of the first CRC. RESULTS: Ever drinkers were associated with higher risk of the first onset of CRC than never drinkers (HR 1.54, 95%CI 1.14-2.07, P = 0.004). The association of the first onset of CRC with alcohol consumption was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations (vs those with pathogenic MSH6, PMS2 and EPCAM mutations), and tumors in the proximal colon cancer (vs distal colon and rectal cancer). CONCLUSIONS: Alcohol consumption was associated with earlier onset of the first CRC in Japanese LS cohort. The association was stronger in men, carriers of pathogenic MLH1 and MSH2 mutations, and tumors located in the proximal colon. Our findings illuminate the mechanism of LS-associated carcinogenesis and serve as a recommendation for discontinuing or ceasing alcohol consumption.

Laparoscopic repair of sciatic hernia recognizing the ureterohypogastric nerve fascia and vesicohypogastric fascia: a case report.

BACKGROUND: Sciatic hernias are rare pelvic floor hernias that occur through the sciatic foramen and often present as abdominal or pelvic pain, particularly in women. Historically, they were repaired using an open approach, with limited reports on their laparoscopic treatment. CASE PRESENTATION: Here we present the case of an 85-year-old woman who had repeated abdominal pain and was referred to our hospital for sciatic hernia surgery after conservative treatment. We laparoscopically observed the deep pelvis and identified the right sciatic hernia. When an extraperitoneal space was dissected, an ureterohypogastric nerve fascia (UNF) and a vesicohypogastric fascia (VF) were identified. Moreover, the maneuver to mobilize the fasciae inside from the pelvic wall made it possible to separate the ureter and urinary bladder, which might have otherwise incarcerated in the hernia. We repaired the defect of the sciatic foramen with a mesh plug and patch. The patient had an uneventful recovery, and the absence of sciatic herniation recurrence was confirmed 1 year after surgery. CONCLUSION: A laparoscopic repair of a sciatic hernia could permit detailed non-invasive observations of the deep pelvis and be performed effectively by recognizing an UNF and a VF located near the sciatic foramen.

Retroperitoneal Bronchogenic Cyst Resected by Single-Incision Laparoscopic Surgery in an Adolescent Female: A Case Report.

A 16-y-old Japanese female was referred to our hospital with a suspicion of infected retroperitoneal cyst. Abdominal CT MRI revealed a 38-mm diameter retroperitoneal cyst under the left diaphragm. Because a retroperitoneal bronchogenic cyst was suspected, total resection was planned. In addition, preoperative 3D reconstruction using multidetector CT provided a detailed location of the lesion. Based on the anatomical position, we decided that single-incision laparoscopic surgery with an anterior approach through the umbilicus would be the optimal choice. The lesion was completely resected without intraoperative complications. Histopathological examination confirmed the diagnosis of bronchogenic cyst. Postoperatively, the surgical wound became completely unnoticeable, and there was no incisional hernia or cyst recurrence at the 2-y follow-up.

[A Case of Extranodal NK/T-Cell Lymphoma with Perforation of the Small Intestine].

A rare case of extranodal NK/T-cell lymphoma(ENKL)with small intestinal perforation is reported. A 92-year-old man was admitted for a loss of consciousness. Computed tomography(CT)scan revealed the presence of an intraperitoneal abscess that was drained. Two days later, the drained fluid changed to intestinal juice, and intestinal perforation was suspected. The patient underwent surgery which revealed a 1 cm perforation site in the ileum. A high fever continued after surgery, and malignant lymphoma was diagnosed from pathological findings; however, further treatment could not be performed. He died 24 days after the operation. Pathological dissection revealed metastasis of ENKL at the systemic lymph nodes.

Laparoscopic anterior resection for rectal stenosis caused by ALTA injection for internal hemorrhoids: A case report.

We herein report the first case of rectal stenosis that developed after internal hemorrhoid treatment with aluminum potassium sulfate and tannic acid (ALTA) therapy that was successfully treated by laparoscopic surgery. A 72-year-old man suffered from a fever and rectal stenosis after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA at a previous clinic. Three months after ALTA therapy, he developed frequent mucous and bloody stools. Lower intestinal tract endoscopy revealed circumferential severe rectal stenosis. He was therefore referred to our hospital. The patient suffered from frequent stool build-up and difficulty defecating. We performed balloon-dilatation intervention. The stenosis was not improved at all. Five months after ALTA therapy, we performed laparoscopic low anterior resection with diverting ileostomy. Three months after the operation, ileostomy takedown was performed. The patient has experienced no rectal stenosis in the 2 years since his radical operation.

Laparoscopic repair of traumatic diaphragmatic hernia with colon incarceration: A case report.

Traumatic diaphragmatic hernia is a serious complication of blunt trauma to the abdomen or thorax. Although traumatic diaphragmatic hernia is treated with surgical repair, a laparoscopic approach is infrequently employed. Here we present the case of a 66-year-old man with a bruise on the left side of his back. CT revealed a left pneumothorax and left rib fractures. He was urgently hospitalized and relieved with conservative treatment. However, on day 4 of hospitalization, an incarcerated diaphragmatic hernia containing the transverse colon was observed on CT. The herniated viscera of the abdominal cavity were reduced laparoscopically, and the hernial orifice was repaired with direct closure. One-lung ventilation was used to limit the movement of the affected diaphragm, enabling effective laparoscopic suturing. The patient had an uneventful recovery period and was discharged 8 days postoperatively. The absence of diaphragmatic herniation recurrence was confirmed 6 months after surgery.

Long-term outcomes of laparoscopic surgery in elderly patients with colorectal cancer: A single institutional matched case-control study.

INTRODUCTION: The number of elderly patients with colorectal cancer has gradually increased. Laparoscopic colorectal surgery is widely used to approach colorectal cancer. The aim of this study was to evaluate long-term outcomes in octogenarians who underwent laparoscopic colorectal surgery for colorectal cancer. METHODS: This study included 158 patients aged 80 or over who underwent surgery for colorectal cancer between 2010 and 2015. We compared long-term outcomes of a laparoscopic colorectal surgery group with those of an open colorectal surgery group by propensity score matching equalizing factors that could affect prognosis such as prognostic nutritional index and Charlson comorbidity index score. RESULTS: Forty-eight pairs were selected after propensity score matching. The cancer-specific 5-year survival rate was 97.1% in the laparoscopic colorectal surgery group and 87.6% in the open colorectal surgery group (P = .17). The overall 5-year survival rate was 77.3% in the laparoscopic colorectal surgery group and 73.9% in the open colorectal surgery group (P = .32). The 5-year recurrence-free survival rate was 95.1% in the laparoscopic colorectal surgery group and 85.4% in the open colorectal surgery group (P = .14). CONCLUSION: Laparoscopic colorectal surgery for octogenarians with colorectal cancer achieves similar oncological outcomes to open colorectal surgery and should be considered as a treatment option.

A phase II study of FOLFOXIRI plus bevacizumab as initial chemotherapy for patients with untreated metastatic colorectal cancer: TRICC1414 (BeTRI).

PURPOSE: FOLFOXIRI plus bevacizumab is regarded as a first-line therapeutic option for selected patients with metastatic colorectal cancer (mCRC). Our aim was to assess the efficacy and safety of induction treatment with FOLFOXIRI plus bevacizumab in patients with untreated mCRC harboring UGT1A1 wild (*1/*1), or single-hetero (*1/*6 or *1/*28) genotypes. METHODS: Twelve cycles of FOLFOXIRI plus bevacizumab were administered to patients with untreated mCRC. The primary endpoint was the overall response rate (ORR) assessed by central independent reviewers. Secondary endpoints included time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), relative dose intensity (RDI), R0 resection rate, and safety. The exploratory objectives were early tumor shrinkage (ETS) and depth of response (DoR). RESULTS: Of the 47 patients enrolled, 46 and 44 patients were eligible for the safety and efficacy analysis, respectively. The primary endpoint was met. The ORR was 63.6% (95% CI 47.8-77.6). At a median follow-up of 25.4 months, median TTF, PFS, and OS was 8.1, 15.5, and 34.4 months, respectively. The median RDI of 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab was 72, 69, 62, and 71%, respectively. R0 resection rate was 22.7%. Grade 3 or higher adverse events (≥ 10%) included neutropenia (65.2%), febrile neutropenia (26.1%), leukopenia (23.9%), anorexia (10.9%), nausea (10.9%), and diarrhoea (10.9%). No treatment-related deaths were observed. ETS and DoR were 70.5 and 45.4%, respectively. CONCLUSIONS: FOLFOXIRI plus bevacizumab induction treatment of Japanese patients was shown to be beneficial and manageable, although caution is required since the treatment causes febrile neutropenia.