[Definition and treatment of superior mesenteric artery revascularization and dissection-associated diarrhea (SMARD syndrome) in Germany]. / Definition und Behandlung der A.-mesenterica-superior-Revaskularisations- und -Dissektions-assoziierten Diarrhö (SMARD-Syndrom) in Deutschland.

BACKGROUND: The superior mesenteric artery (SMA) is exposed and dissected during pancreatic resections (PR) and mesenteric vascular surgery (MVS). The resulting damage of the surrounding extrinsic and intrinsic vegetative nerve plexus can lead to a temporary or treatment refractory diarrhea. OBJECTIVE: This study aimed to provide an overview of the current status of SMA revascularization and dissection-associated diarrhea (SMARD syndrome) in Germany. MATERIAL AND METHODS: After a selective literature search (SLS) on the frequency of newly developed postoperative diarrhea after PR and MVS, an online survey was initiated. RESULTS: The SLS (n = 4) confirmed that newly developed postoperative diarrhea is a frequent complication after preparation for revascularization (RV) or dissection (DIS) of the SMA (incidence approximately 62%). Treatment refractive courses were relatively uncommon with 14%. Out of 159 centers 54 took part in the survey and 63% stated that they carried out an SMA RV/DIS during PR or MVS. The average PR per center was 47 in 2018 and 49 in 2019. The average MVS was 5 per center in both years and on average 3 patients suffered from SMARD syndrome. CONCLUSION: This survey recorded the current status of the SMARD syndrome in Germany for the first time. So far there are no recommendations for the treatment of such a diarrhea. The results show that initially a symptomatic treatment should be carried out. Due to the complexity of the pathophysiology, causal treatment approaches have not yet been developed.

Association of ileocolic pedicle division with postoperative complications after restorative proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis.

BACKGROUND: When performing a restorative proctocolectomy (RPC) with an ileal pouch-anal anastomosis (IPAA), it is common practice to divide the ileocolic artery (ICA) if the patient has a tumor or dysplasia, or in order to gain sufficient length to secure a tension-free anastomosis. However, it is unclear whether there is an association between division of the ICA and the rate of postoperative complications. METHODS: We retrospectively analysed all patients with ulcerative colitis who underwent RPC and IPAA in our department between January 2010 and December 2016. These were divided in two groups, with regard to the ICA being preserved (PRE group) or divided (DIV group). Complications such as stenosis or leakage of the IPAA, perianal fistulas, abscess formation within the lesser pelvis and pouchitis were analysed and compared between both groups. RESULTS: We identified 130 patients meeting the study inclusion criteria, 49 patients in the PRE and 81 patients in the DIV group. No statistical significance was observed in IPAA leakages (p = 0.71), anastomotic strictures (p = 0.33), fistulas (p = 0.19) and pouchitis (p = 0.72). Abscess formation frequency was similar in both groups (p > 0.99). Moreover, short-term (p = 0.53) and long-term complications (p = 0.11) were similar in both groups. A higher conversion rate was observed in obese (p = 0.006) and male (p = 0.02) patients. Within the entire study population, fistulas and IPAA leakages were associated with a higher rate of anastomotic strictures (p = 0.008 and p = 0.02 respectively). CONCLUSION: Our data suggest similar IPAA related complications after either division or preservation of the ICA. Further trials are required in order to examine the trends observed in this study.

Management of colorectal anastomotic leakage using endoscopic negative pressure therapy with or without protective ostomy: a retrospective study.

PURPOSE: Management of colorectal anastomotic leakage (AL) is patient-oriented and requires an interdisciplinary approach. We analyzed the management of AL according to its severity and presence of ostomy and proposed a therapy algorithm. METHODS: We identified all patients who underwent colorectal surgery and developed an AL in our clinic between 2012 and 2017. The management of AL was retrospectively analyzed according to the severity grade: asymptomatic (A), requesting interventional or antibiotic therapy (B), undergoing re-operation (C). The groups were compared according to the leakage characteristics, presence of ostomy, and patient clinical conditions. RESULTS: We identified 784 consecutive patients meeting the inclusion criteria. Of these, 10.8% experienced an AL (A = 18%, B = 48%, and C = 34%). The rate of successful ostomy closure was 100% (A), 68% (B), and 62% (C), respectively. Within group B, 91% of the patients were treated solely by endoscopic negative pressure therapy (ENPT), whereas 37% of the patients within group C required ENPT in addition to surgery. Seven cases within group B (17%) required no protective ostomy (nOB) during ENPT which was itself shorter and required less cycles in comparison to group B with ostomy (OB) (p = 0.017 and 0.111, respectively). Moreover, the leakage distance to anal verge was higher in the OB subgroup (p < 0.001). CONCLUSION: ENPT for the treatment of colorectal AL is efficient in combination with operative revision or protective ostomy. In selected patients, it is feasible also in the absence of a protective ostomy.

Less is more-the best test for anastomotic leaks in rectal cancer patients prior to ileostomy reversal.

PURPOSE: No clear consensus exists on how to routinely assess the integrity of the colorectal anastomosis prior to ileostomy reversal. The objective of this study was to evaluate the accuracy of contrast enema, endoscopic procedures, and digital rectal examination in rectal cancer patients in this setting. METHODS: A systematic literature search was performed. Studies assessing at least one index test for which a 2 × 2 table was calculable were included. Hierarchical summary receiver operating characteristic curves were calculated and used for test comparison. Paired data were used where parameters could not be calculated. Methodological quality was assessed with the QUADAS-2 tool. RESULTS: Two prospective and 11 retrospective studies comprising 1903 patients were eligible for inclusion. Paired data analysis showed equal or better results for sensitivity and specificity of both endoscopic procedures and digital rectal examination compared to contrast enema. Subgroup analysis of contrast enema according to methodological quality revealed that studies with higher methodological quality reported poorer sensitivity for equal specificity and vice versa. No case was described where a contrast enema revealed an anastomotic leak that was overseen in digital rectal examination or endoscopic procedures. CONCLUSIONS: Endoscopy and digital rectal examination appear to be the best diagnostic tests to assess the integrity of the colorectal anastomosis prior to ileostomy reversal. Accuracy measures of contrast enema are overestimated by studies with lower methodological quality. Synopsis of existing evidence and risk-benefit considerations justifies omission of contrast enema in favor of endoscopic and clinical assessment. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019107771.

Influence of complete administration of adjuvant chemotherapy cycles on overall and disease-free survival in locally advanced rectal cancer: post hoc analysis of a randomized, multicenter, non-inferiority, phase 3 trial.

BACKGROUND: A randomized trial demonstrated that capecitabine is at least as effective as fluorouracil in the adjuvant treatment of patients with locally advanced rectal cancer. However, not all patients receive all planned cycles of chemotherapy. Therefore it is of interest how complete or partial administration of chemotherapy influences oncological outcome. METHODS: A post hoc analysis of a trial with 401 randomized patients, nine being excluded because of missing data, was performed. 392 patients (197 - capecitabine, 195 - fluorouracil) could be analyzed regarding the number of administered adjuvant chemotherapy cycles. In the subgroup of 361 patients with an overall survival of at least six months, five-year overall and disease-free survival were analyzed in respect to completion (complete vs. incomplete) of chemotherapy cycles. Survival rates and curves were calculated and compared using the log-rank test. The effect of completion of chemotherapy was adjusted for relevant confounding factors. RESULTS: Two hundred fifty-one (64.0%) of analyzed patients received all postoperative scheduled cycles. Five-year overall survival was significantly better in these patients compared to the incomplete group (76.0 vs. 60.6%, p < 0.0001). Of 361 patients with an overall survival of at least six months, 251(69.5%) patients received all cycles. Five-year overall survival was also significantly better than in the incomplete group (76.0 vs. 66.4%, p = 0.0073). Five-year disease free survival was numerically better (64.9 vs. 58.7%, p = 0.0646; HR [not all cycles vs. all cycles] = 1.42 95% CI: [0.98, 2.07]). Cox regression models show a non-significant better OS (p = 0.061) and DFS (p = 0.083), if chemotherapy cycles were administered completely. CONCLUSION: Complete administration of chemotherapy cycles was associated with improved five-year overall and disease-free survival in patients with locally advanced rectal cancer.

Cell therapeutic approaches to immunosuppression after clinical kidney transplantation.

Refinement of immunosuppressive strategies has led to further improvement of kidney graft survival in recent years. Currently, the main limitations to long-term graft survival are life-threatening side effects of immunosuppression and chronic allograft injury, emphasizing the need for innovative immunosuppressive regimens that resolve this therapeutic dilemma. Several cell therapeutic approaches to immunosuppression and donor-specific unresponsiveness have been tested in early phase I and phase II clinical trials in kidney transplantation. The aim of this overview is to summarize current cell therapeutic approaches to immunosuppression in clinical kidney transplantation with a focus on myeloid suppressor cell therapy by mitomycin C-induced cells (MICs). MICs show great promise as a therapeutic agent to achieve the rapid and durable establishment of donor-unresponsiveness in living-donor kidney transplantation. Cell-based therapeutic approaches may eventually revolutionize immunosuppression in kidney transplantation in the near future.

Quality of Life and Timing of Stoma Closure in Patients With Rectal Cancer Undergoing Low Anterior Resection With Diverting Stoma: A Multicenter Longitudinal Observational Study.

BACKGROUND: After low anterior resection for rectal cancer, creation of a diverting stoma is recommended. Data on the impact of a diverting stoma on quality of life are conflicting. Optimal timing of stoma closure in the setting of adjuvant chemotherapy is unclear. OBJECTIVE: The purpose of this study was to investigate the impact of a diverting stoma on quality of life in patients undergoing rectal cancer resection before and after stoma closure. Furthermore, the study was conducted to look at the timing of stoma reversal and the potential influence of factors such as adjuvant chemotherapy. DESIGN: This was a longitudinal, observational, multicenter study. SETTINGS: The study was conducted at 17 German colorectal centers. PATIENTS: Patients with rectal cancer who planned for elective curative surgery with creation of temporary diverting stoma were included. MAIN OUTCOME MEASURES: This longitudinal observational study assessed quality of life at 3 occasions using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire/Colorectal Cancer Module before cancer resection, before stoma closure, and 6 months after stoma closure. Furthermore, the timing of stoma closure and continence were evaluated. RESULTS: A total of 120 patients (64% men; mean age, 63.2 ± 11.5 years) were analyzed. Longitudinal global quality of life was not influenced by the presence of a stoma. Several functional and GI symptom scales were markedly impaired after stoma creation. Physical, role functioning, and sexual interest recovered after stoma closure. Social functioning stayed impaired (p < 0.0001). Median time to stoma closure was 5 months (range, 17 days to 18 months). A total of 3.4% of patients had very early stoma closure (within 30 days). Adjuvant chemotherapy delayed stoma closure (median, 5.6 vs 3.4 months without chemotherapy; p = 0.0001). LIMITATIONS: The study was limited by its missing quality-of-life data for sexual function. CONCLUSIONS: The presence of a stoma had a negative impact on social functioning and GI symptoms. However, this had no clinically relevant influence on global quality of life. Time to stoma closure was nearly doubled when patients underwent adjuvant chemotherapy.

CoCStom trial: study protocol for a randomised trial comparing completeness of adjuvant chemotherapy after early versus late diverting stoma closure in low anterior resection for rectal cancer.

BACKGROUND: Current evidence supports a diverting stoma in patients undergoing low anterior resection with total mesorectal excision for rectal cancer as it reduces clinical severity of anastomotic leakage. However, relevant stoma morbidity after rectal cancer surgery exists and has a significant impact on quality of life. Moreover, a diverting stoma has an influence on completeness of chemotherapy but it remains unclear in which way. There is no evidence regarding optimal timing for stoma closure in relation to adjuvant chemotherapy. Two randomised controlled trials have studied early stoma closure after low anterior resection in patients with rectal cancer, one of them showing that early closure around day 8 after resection is possible without increasing morbidity. METHODS/DESIGN: CoCStom is a randomised multicentre trial comparing completeness of adjuvant chemotherapy as primary endpoint after early (8-10 days after resection, before starting adjuvant therapy) versus late (~26 weeks after resection and completion of adjuvant therapy) stoma closure in patients with locally advanced rectal cancer undergoing low anterior resection after neoadjuvant therapy. After exclusion of post-operative anastomotic leakage 257 patients from 30 German hospitals are planned to be included in order to assure a power of 80% for the confirmatory analysis of at least 214 evaluable cases. An absolute increase of 20% for the rate of completely administered adjuvant chemotherapy is regarded as a clinically meaningful step forward and serves as basis for sample size calculation. Quality of life, stoma-related complications, individual completeness of chemotherapy rate, percentage of patients stopping adjuvant therapy or undergoing dose modifications or delay, oncological outcomes, cumulative days of hospitalisation and number of readmissions, rate of symptomatic anastomotic leaks after stoma closure, mortality, post-operative complications and toxicity of adjuvant chemotherapy are secondary endpoints. DISCUSSION: The CoCStom trial aims to clarify optimal timing of stoma closure in the context of adjuvant chemotherapy. Depending on the results of the trial, patients could benefit either from early or late stoma closure in regard to long term oncological survival due to a higher rate of completeness of adjuvant chemotherapy treatment and thus better effectiveness. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00005113. Registered 28 August 2013.

Immunosuppressive properties of mitomycin C-incubated human myeloid blood cells (MIC) in vitro.

Previous animal studies showed that donor-derived blood cells treated with mitomycin C (MMC) prolong allograft survival when injected into recipients. This model was effective with whole blood, peripheral blood mononuclear cells (PBMC) (monocytes being the active cell subpopulation) or dendritic cells. In view of a potential clinical application, we study now the immunosuppressive properties of human myeloid cells in vitro. Mature dendritic cells (generated from naïve monocytes) or monocytes treated with mitomycin C do not or only weakly inhibit allogeneic T cells in vitro, whereas cells in an early differentiation state between monocytes and DC exert suppressive activity when treated with MMC. In contrast, DC generated from MMC-treated monocytes show the morphology and phenotype of early immature DC (iDC) and suppress T-cell responses. It is known that untreated monocytes injected into a recipient encounter a cytokine milieu which differentiates them to stimulatory DC. In our in vitro experiment MMC-treated monocytes cultured in a DC-maturing milieu transform themselves into suppressive early iDC. This reproduces a process which takes place when administering MMC-monocytes to a recipient. In conclusion, human MMC-DC or MMC-monocytes are not or only weakly suppressive in vitro. When MMC-monocytes are differentiated to DC the resulting cells become suppressive.

Cell therapy for immunosuppression after kidney transplantation.

PURPOSE: To give an overview over cell therapeutic approaches to immunosuppression in clinical kidney transplantation. A focus is on myeloid suppressor cell therapy by mitomycin C-induced cells (MICs). METHODS: Literature review with an emphasis on already existing therapies. RESULTS: Several cell therapeutic approaches to immunosuppression and donor-specific unresponsiveness are now being tested in early phase I and phase II trials in clinical kidney transplantation. Cell products such as regulatory T cells or regulatory macrophages, or other myeloid suppressor cell therapies, may either consist of donor-specific, third-party, or autologous cell preparations. Major problems are the identification of the suppressive cell populations and their expansion to have sufficient amount of cells to achieve donor unresponsiveness (e.g., with regulatory T cells). We show a simple and safe way to establish donor unresponsiveness in living-donor kidney transplantation by MIC therapy. A phase I clinical trial is now under way to test the safety and efficacy of this cell therapeutic approach. CONCLUSIONS: Cell therapeutic approaches to immunosuppression after kidney transplantation may revolutionize clinical transplantation in the future.

Generation of suppressive blood cells for control of allograft rejection.

Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers CD4 and CD25 and forkhead box protein 3 (FoxP3). Tolerance could be transferred to syngeneic recipients with blood or spleen cells. Depletion of Tregs from tolerogenic cells abrogated their suppressive effect, arguing for mediation of immunosuppression by CD4⁺CD25⁺FoxP3⁺ Tregs. Donor-derived MICs also prolonged kidney allograft survival in pigs. MICs generated from donor monocytes were applied for the first time in humans in a patient suffering from therapy-resistant rejection of a haploidentical stem cell transplant. We describe, in the present paper, a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans.

Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis.

BACKGROUND: The Model for End-Stage Liver Disease (MELD) score is a tool for assessment of the degree of hepatic insufficiency/failure. Quinolinic acid (QuinA) is a tryptophan metabolite produced by activated macrophages. Here we investigate whether the degree of systemic inflammation (QuinA, neopterin, CRP and IL-6) correlates with clinical liver dysfunction according to the MELD Score. METHOD: Ninety-four patients with liver cirrhosis were categorized into 2 groups according to baseline MELD score (group I, MELD <20, n = 61, and group II, MELD ≥20, n = 33). RESULTS: Serum levels of QuinA, neopterin, CRP, and IL-6 significantly correlated with MELD score (r = 0.77, 0.75, 0.57, and 0.50; p < 0.0001, respectively). Patients of group II had significantly higher serum levels of QuinA, neopterin, CRP, and IL-6 than group I (p0.0001). ROC curve analysis showed that QuinA and neopterin are more sensitive markers for severity of liver disease than established markers of inflammation such as CRP and IL-6 (sensitivity = 86% and 79%, respectively) (AUC=0.89 and 0.89, respectively). QuinA provided the most sensitive index with regard to the identification of patients with hepatic encephalopathy. CONCLUSION: Serum levels of QuinA reflect the degree of liver dysfunction. Moreover, high levels of QuinA may serve as a sensitive indicator of hepatic encephalopathy.

Mitomycin C-treated antigen-presenting cells as a tool for control of allograft rejection and autoimmunity: from bench to bedside.

Cells have been previously used in experimental models for tolerance induction in organ transplantation and autoimmune diseases. One problem with the therapeutic use of cells is standardization of their preparation. We discuss an immunosuppressive strategy relying on cells irreversibly transformed by a chemotherapeutic drug. Dendritic cells (DCs) of transplant donors pretreated with mitomycin C (MMC) strongly prolonged rat heart allograft survival when injected into recipients before transplantation. Likewise, MMC-DCs loaded with myelin basic protein suppressed autoreactive T cells of MS patients in vitro and prevented experimental autoimmune encephalitis in mice. Comprehensive gene microarray analysis identified genes that possibly make up the suppressive phenotype, comprising glucocorticoid leucine zipper, immunoglobulin-like transcript 3, CD80, CD83, CD86, and apoptotic genes. Based on these findings, a hypothetical model of tolerance induction by MMC-treated DCs is delineated. Finally, we describe the first clinical application of MMC-treated monocyte-enriched donor cells in an attempt to control the rejection of a haploidentical stem cell transplant in a sensitized recipient and discuss the pros and cons of using MMC-treated antigen-presenting cells for tolerance induction. Although many questions remain, MMC-treated cells are a promising clinical tool for controlling allograft rejection and deleterious immune responses in autoimmune diseases.

Suppressive dendritic cells as a tool for controlling allograft rejection in organ transplantation: promises and difficulties.

The most important antigen-presenting cells are dendritic cells (DCs), which play a central role in the initiation of immunity and tolerance. Their immunoregulatory properties offer the potential of donor-specific control of graft rejection after organ transplantation. It has not been clarified which DC subpopulations mediate tolerance, and the use of natural DCs for therapeutic applications is therefore problematic. Suppressive DCs can be generated in vitro by treating the cells with biologic, pharmacologic, or genetic agents. Here we discuss approaches for generating inhibitory DCs and present DC-based animal models for control of allograft rejection. A prerequisite of suppressive DCs for therapeutic application in clinical transplantation is a reproducible method for their generation as well as the induction of irreversible suppressive function. Based on lessons learned from the use of DCs as tools in clinical vaccine trials in cancer, we discuss the unknown aspects and risks of DC therapy in transplantation.