Management of Third and Fourth-Degree Perineal Tears After Vaginal Birth. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/079, December 2020).

Purpose This guideline provides recommendations for the diagnosis, treatment and follow-up care of 3rd and 4th degree perineal tears which occur during vaginal birth. The aim is to improve the management of 3rd and 4th degree perineal tears and reduce the immediate and long-term damage. The guideline is intended for midwives, obstetricians and physicians involved in caring for high-grade perineal tears. Methods A selective search of the literature was carried out. Consensus about the recommendations and statements was achieved as part of a structured process during a consensus conference with neutral moderation. Recommendations After every vaginal birth, a careful inspection and/or palpation by the obstetrician and/or the midwife must be carried out to exclude a 3rd or 4th degree perineal tear. Vaginal and anorectal palpation is essential to assess the extent of birth trauma. The surgical team must also include a specialist physician with the appropriate expertise (preferably an obstetrician or a gynecologist or a specialist for coloproctology) who must be on call. In exceptional cases, treatment may also be delayed for up to 12 hours postpartum to ensure that a specialist is available to treat the individual layers affected by trauma. As neither the end-to-end technique nor the overlapping technique have been found to offer better results for the management of tears of the external anal sphincter, the surgeon must use the method with which he/she is most familiar. Creation of a bowel stoma during primary management of a perineal tear is not indicated. Daily cleaning of the area under running water is recommended, particularly after bowel movements. Cleaning may be carried out either by rinsing or alternate cold and warm water douches. Therapy should also include the postoperative use of laxatives over a period of at least 2 weeks. The patient must be informed about the impact of the injury on subsequent births as well as the possibility of anal incontinence.

Usability evaluation of the Computer-Based Health Evaluation System (CHES) eDiary for patients with faecal incontinence: a pilot study.

BACKGROUND: Faecal incontinence (FI) is prevalent in 15-20% of elderly individuals and is frequently monitored in clinical trials and practice. Bowel diaries are the most common way to document FI, but, in clinical practice, are mainly used as paper-based versions. Electronic diaries (eDiaries) offer many potential benefits over paper-based diaries. The aim of this study was to develop and test an eDiary to document FI. METHODS: We migrated a paper FI diary to an eDiary app based on the Computer-based Health Evaluation System (CHES). To assess usability, we conducted functionality and usability tests at two time points in a sample of patients with FI. In the first assessment, the eDiary functionalities were tested, patients completed the System Usability Scale (SUS, range 0-100) and compared the paper diary with the eDiary. We set a threshold for minimum acceptable average usability at 70 points. Patients were then instructed to use the eDiary for 2 days at home and contacted to report on their usage and completed the SUS a second time. RESULTS: We recruited a sample of N = 14 patients to use the eDiary. All patients were able to use all functionalities of the eDiary and only a few patients with lower technological literacy or access to devices (n = 3) needed initial assistance. The mean usability rating given at the first time point was high with 88 points (SD 18, 95% CI 78.2-96.8) and most patients (n = 10) reported they would prefer the eDiary over the paper-based version. Nine patients (n = 9) participated in the follow-up assessment and the mean SUS rating at the second time point was 97 points (SD 7, 95% CI 92.8-100). CONCLUSION: The eDiary showed excellent usability scores for the assessment of FI at both assessments. Generally, patients preferred the eDiary over the paper-based version. We recommend the eDiary for usage with patients who own and use a smartphone and discuss potential solutions for patients with lower technological literacy or access.

PUFA-Induced Metabolic Enteritis as a Fuel for Crohn's Disease.

BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human inflammatory bowel diseases remains elusive. We aimed to delineate how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, affects gut inflammation and disease course. We hypothesized that the unfolded protein response and antioxidative activity of glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs. METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in 2 mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box binding protein 1 (Xbp1) or Gpx4. We translated the findings to human CD epithelial organoids and correlated PUFA intake, as estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in 2 independent CD cohorts. RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor inositol-requiring enzyme 1α (IRE1α) by toll-like receptor 2 (TLR2) sensing of oxidation-specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression, and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients. CONCLUSIONS: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.

Distal Pancreatic Resection with Splenectomy in the Rat: A Pancreatic Fistula Model to Investigate Postsurgical Damage?

BACKGROUND: Postoperative pancreatic fistula (POPF) is a major complication in pancreatic surgery and can cause considerable postoperative morbidity. Advanced surgical-technical approaches to prevent POPF did not yield a substantial improvement. To investigate innovative treatments, experimental animal models of distal pancreatic resection and pancreaticoduodenectomy are of fundamental importance. After a failed attempt to replicate a previously described rat model for pancreatic fistula induction, we proceeded to distal pancreatic resection with splenectomy to provoke pancreatic leakage and generate a suitable animal model. METHODS: Distal pancreatic resection with splenectomy was performed in 40 rats. The rats were sacrificed on postoperative day (POD) 1, 2, 4, 6, 8, or 10, and the abdominal cavity was explored. Ascites probes were collected pre- and postoperatively for the detection of pancreas amylase and lipase. Tissue samples from the naïve pancreas (POD 0) and the postoperatively harvested remnant were evaluated histologically. The extent of necrosis was determined, and samples were examined for neutrophil infiltration. TUNEL staining served for the verification of necrosis in distinct cases. Immunohistochemistry of Ki67, von Willebrand factor, and CD68 was performed to evaluate proliferation, blood-vessel sprouting, and macrophage invasion. RESULTS: The rats showed no clinical symptoms or severe complications in the postoperative course up to 10 days. Abdominal exploration revealed adhesions in the upper abdomen, but no intra-abdominal fluid accumulations were found. Signs of inflammation and tissue damage were evident at the pancreatic resection margin on histological examination whereas the naïve pancreatic tissue was widely unaffected. Statistically significant differences were seen between the preoperative and postoperative extent of necrosis, the presence of neutrophil infiltrate, and levels of ascitic amylase and lipase. Immunohistochemical staining on Ki67, von Willebrand factor, and CD68 did not reveal any workable results on nonstatistical examination, and it was therefore not considered for further analyses. CONCLUSION: Creating a functional animal model of pancreatic fistula that reflects the clinical and pathophysiological impact of pancreatic leakage in humans has not been achieved. Our approach of left pancreatic resection recapitulated inflammation and tissue damage, early events in the development of fistulas, and it could be suitable for the experimental testing of novel targeting methods.

Low anterior resection syndrome (LARS) in ovarian cancer patients - A multi-centre comparative cohort study.

BACKGROUND: Low anterior resection syndrome (LARS) is a common functional disorder after low anterior resection impacting the quality of life. Data on LARS derives nearly exclusively from rectal cancer studies. Therefore, the study was designed to assess LARS in advanced epithelial ovarian cancer (EOC) patients, who underwent rectal resection and to compare it with a female rectal cancer cohort. MATERIAL AND METHODS: A cross-sectional multi-centre analysis was performed on female patients suffering from either rectal or EOC who received a low anterior resection as part of their therapy regimen. None of the patients received pre- or postoperative radiotherapy. LARS was defined by using the validated LARS score and its severity was divided into "no", "minor" and "major LARS". RESULTS: In total, 125 female patients (44.8% (n = 56) EOC vs. 55.2% (n = 69) rectal cancer patients) met the final inclusion criteria and were retrospectively analyzed. Baseline characteristics were comparable between the groups. Median follow-up was 22 (IQR 12-56) months. In total, 30.4% (n = 38) of the patient group reported bowel dysfunction after surgery. Rates of LARS were not significantly different between EOC and rectal cancer patients (major LARS 16.1% (n = 9) vs. 15.9% (n = 11); minor LARS 17.9% (n = 10) vs. 11.6% (n = 8); p = 0.984). The time interval between surgery and final assessment had no impact on the postoperative bowel function (p = 0.820). CONCLUSION: LARS is a frequent and highly underreported postoperative disorder in EOC patients who require cytoreductive surgery with rectal resection. The functional outcome is comparable to female patients with rectal cancer who underwent low anterior resection without receiving radiotherapy.

Is Duplex-Ultrasound a useful tool in defining rejection episodes in composite tissue allograft transplants?

Immunologic reactions in transplanted organs are in more or less all allograft patients detectable: clear parameters exist as e.g. in renal transplants where the clearance power reduces by rejection. On the contrary, in composite tissue allografts clear and objective indicators stating a rejection episode lack. We present the case of a hand-transplanted subject with signs of acute transplant rejection diagnosed by means of Duplex Ultrasound and confirmed by biopsy.

High expression of prostate-specific membrane antigen in the tumor-associated neo-vasculature is associated with worse prognosis in squamous cell carcinoma of the oral cavity.

Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in prostate cancer as well as in the neo-vasculature of nonprostatic solid tumors. Here, we determined the expression pattern of PSMA in the vasculature of oral squamous cell carcinoma. Using a previously validated antibody, PSMA staining distribution and cyclooxygenase 2 (COX2) expression status was evaluated in a cohort of patients with squamous cell carcinoma of the oral cavity (n=96) using immunohistochemistry and was correlated with clinicopathological features as well as outcome. Twenty-four (25%) cases showed no detectable PSMA staining, 48 (50%) demonstrated positive immunoreactivity for PSMA in less than 50% of microvessels and 24 (25%) cases showed strong endothelial PSMA expression in more than 50% of tumor-associated microvessels. High endothelial PSMA expression was associated with greatly reduced survival (18.2 vs 77.3 months; P=0.0001) and maintained prognostic significance after adjusting for grade and stage in multivariate analysis (hazard ratio=2.19, P=0.007). Furthermore, we observed a strong association between endothelial PSMA and cancer cell-specific COX2 expression. In conclusion, we provide the first evidence for the prognostic significance of endothelial PSMA expression in oral squamous cell carcinoma and, suggest a potential interaction between arachidonic acid metabolites and endothelial PSMA expression in the tumor neo-vasculature.

IDO and regulatory T cell support are critical for cytotoxic T lymphocyte-associated Ag-4 Ig-mediated long-term solid organ allograft survival.

Costimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig upregulates expression of the immunoregulatory enzyme IDO in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. In this study, we studied whether concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor-specific transfusion showed indefinite graft survival (>100 d) without signs of chronic rejection or donor specific Ab formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared with rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-dl-tryptophan, either at transplant or at postoperative day 50, abrogated CTLA4Ig + DST-induced long-term graft survival. Importantly, IDO1 knockout recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of regulatory T cells (Tregs) resulted in decreased IDO activity and again prevented CTLA4Ig + DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this costimulatory blocker.

Immunohistochemically detectable dickkopf-3 expression in tumor vessels predicts survival in gastric cancer.

Dickkopf-3 (Dkk-3) may act as a tumor suppressor as it is downregulated in various types of cancer. Moreover, a putative role in tumor neovascularization is discussed. Here, we investigated the expression of Dkk-3 protein in gastric cancer and its potential value as a prognostic marker. Dkk-3 expression was analyzed by immunohistochemistry in 136 tumor samples and was correlated with microvessel density (MVD), tumor stage, and grading as well as the clinical outcome of the patients. Dkk-3 expression was detected in endothelial cells of the tumor vessels in 129/136 (94.9%) and in tumor cells in 85/136 (62.5%) samples. MVD was high and low in 57 (42.9%) and 76 (57.1%) specimens respectively. In tumor cells, overexpression of Dkk-3 was found in 41 (30.1%) of all cases and was correlated significantly to pT-stage (p < 0.05) and UICC stage (p < 0.05). Survival analysis regarding Dkk-3 expression in tumor endothelial cells showed that Dkk-3 is an independent predictor of disease-free survival (p < 0.05). Dkk-3 expression in tumor vessels of patients with gastric cancer identifies a population of patients with relatively favorable prognosis.

Prostate-specific membrane antigen expression in the neovasculature of gastric and colorectal cancers.

Prostate-specific membrane antigen (PSMA), a type II transmembrane metallo-peptidase highly overexpressed in prostate cancer cells, has been studied as a targeting molecule in prostate cancer. Recently, PSMA has also been found to be expressed in the neovasculature of multiple nonprostatic solid tumors. Because of its unique expression pattern limited to tumor-associated endothelial cells, PSMA may also be an interesting molecule for vascular targeting. In this study, PSMA expression was determined by immunohistochemistry in 119 cases of primary gastric adenocarcinoma, 130 cases of primary colorectal adenocarcinoma, and 24 metastasis of colorectal adenocarcinoma. Expression data were correlated with clinicopathologic information. PSMA expression was detected in tumor-associated neovasculature of 79 (66%) of 119 gastric and 110 (85%) of 130 colorectal carcinomas. Furthermore, the neovasculatures of 16 (84%) of 19 liver and 4 (80%) of 5 nodal metastases from colorectal carcinomas were prostate-specific membrane antigen positive. There was a trend for high-grade tumors to higher PSMA expression (Spearman r = 0.18, P = .046) in colorectal cancers. No association between PSMA expression and overall- or disease-free survival was observed in gastric or colorectal cancers. This study provides the first in-depth look at PSMA expression in gastric and colorectal cancer. Because of its highly tumor-restricted expression and its accessibility to targeted therapy, PSMA represents a promising therapeutic and diagnostic target in colorectal and gastric cancer.

Small bowel adenocarcinoma in Crohn's disease: a case report and review of literature.

Small bowel adenocarcinomas are remarkable for their rarity, difficult diagnosis and poor prognosis. Here we report an unusual case of a 33-year-old patient in whom infiltrative adenocarcinoma of the small bowel was diagnosed after a 10-year history of Crohn's disease. In most previously reported cases, detection of Crohn's disease was subsequent to that of carcinoma of the small bowel or the patients involved had an even longer history of the disease. Our literature review suggests that the risk of small bowel adenocarcinoma is higher in patients with Crohn's disease than in the overall population. We present details on epidemiology as well as clinical and diagnostic aspects of this rare disease entity.