Risk Factors for Rectal Stump Leakage After Discontinuity Resection: Stump Length Matters Most.

BACKGROUND: Discontinuity resection is commonly conducted to avoid anastomotic leakage in high-risk patients but potentially results in rectal stump leakage. Although risk factors for anastomotic leakage have been widely studied, data on rectal stump leakage rates and underlying risk factors are scarce. OBJECTIVE: To determine rectal stump leakage rates following Hartmann's procedure and to identify patient-and surgery-associated risk factors. DESIGN: A retrospective study with univariate and multivariate analyses was performed to identify risk factors of rectal stump leakage. A subgroup analysis of scheduled operations was performed. SETTINGS: The study was conducted at Heidelberg University Hospital, Germany. PATIENTS: Patients were included who underwent discontinuity resection with rectal stump formation between 2010 and 2020. MAIN OUTCOME MEASURES: The main outcome measures included rectal stump leakage rates, 30-day mortality, length of hospitalization, and necessity for further invasive treatment. RESULTS: Rectal stump leakage occurred in 11.78% of patients. Rectal stump leakage rates varied considerably depending on the surgical procedure performed and were highest following subtotal pelvic exenteration (34%). Diagnosis of rectal stump leakage peaked on postoperative day 7. A short rectal stump ( p = 0.001), previous pelvic radiotherapy ( p = 0.04), chemotherapy ( p = 0.004), and previous laparotomy ( p = 0.03) were independent risk factors for rectal stump leakage in the entire patient collective. In patients undergoing scheduled surgery, a short rectal stump was the only independent risk factor ( p = 0.003). Rectal stump leakage was not associated with increased 30-day mortality but prolonged length of hospitalization and frequently necessitated further invasive treatment. LIMITATIONS: Study results are limited by the retrospective design, a high number of emergency operations, and the mere inclusion of symptomatic leakages. CONCLUSIONS: Rectal stump leakage is a relevant complication after discontinuity resection. Risk factors should be considered during surgical decision-making when both discontinuity resection and abdominoperineal resection are feasible. See Video Abstract. FACTORES DE RIESGO PARA LA FUGA DEL MUN RECTAL DESPUS DE UNA RESECCIN POR DISCONTINUIDAD LA LONGITUD DEL MUN ES LO MS IMPORTANTE: ANTECEDENTES:La resección de discontinuidad se realiza comúnmente para evitar la fuga anastomótica en pacientes de alto riesgo, pero potencialmente da como resultado una fuga del muñón rectal. Si bien los factores de riesgo de fuga anastomótica se han estudiado ampliamente, los datos sobre las tasas de fuga del muñón rectal y los factores de riesgo subyacentes son escasos.OBJETIVO:Determinar las tasas de fuga del muñón rectal después del procedimiento de Hartmann e identificar los factores de riesgo asociados con el paciente y la cirugía.DISEÑO:Se realizó un estudio retrospectivo con análisis univariado y multivariado para identificar los factores de riesgo de fuga del muñón rectal. Se llevó a cabo un análisis de subgrupos de las operaciones programadas.AJUSTES:El estudio se realizó en el Hospital Universitario de Heidelberg, Alemania.PACIENTES:Se incluyeron pacientes que se sometieron a resección de discontinuidad con formación de muñón rectal entre 2010 y 2020.MEDIDAS DE RESULTADO PRINCIPALES:Las principales medidas de resultado incluyeron las tasas de fuga del muñón rectal, la mortalidad a los 30 días, la duración de la hospitalización y la necesidad de un tratamiento invasivo adicional.RESULTADOS:La fuga del muñón rectal ocurrió en el 11,78% de los pacientes. Las tasas de fuga del muñón rectal variaron considerablemente según el procedimiento quirúrgico realizado y fueron más altas después de la exenteración pélvica subtotal (34%). El diagnóstico de fuga del muñón rectal alcanzó su punto máximo en el día 7 del postoperatorio. Un muñón rectal corto (p = 0,001), radioterapia pélvica previa (p = 0,04), quimioterapia (p = 0,004) y laparotomía previa (p = 0,03) fueron factores de riesgo independientes de fuga rectal. Fuga del muñón en todo el colectivo de pacientes. En los pacientes sometidos a cirugía programada, el muñón rectal corto fue el único factor de riesgo independiente (p = 0,003). La fuga del muñón rectal no se asoció con un aumento de la mortalidad a los 30 días, pero con una duración prolongada de la hospitalización y con frecuencia requirió un tratamiento invasivo adicional.LIMITACIONES:Los resultados del estudio están limitados por el diseño retrospectivo, un alto número de operaciones de emergencia y la mera inclusión de fugas sintomáticas.CONCLUSIONES:La fuga del muñón rectal es una complicación relevante tras la resección por discontinuidad. Se deben considerar los factores de riesgo durante la toma de decisiones quirúrgicas cuando son factibles tanto la resección por discontinuidad como la resección abdominoperineal. (Traducción-Yesenia Rojas-Khalil ).

Carbon Dioxide Sensing by Immune Cells Occurs through Carbonic Anhydrase 2-Dependent Changes in Intracellular pH.

CO2, the primary gaseous product of respiration, is a major physiologic gas, the biology of which is poorly understood. Elevated CO2 is a feature of the microenvironment in multiple inflammatory diseases that suppresses immune cell activity. However, little is known about the CO2-sensing mechanisms and downstream pathways involved. We found that elevated CO2 correlates with reduced monocyte and macrophage migration in patients undergoing gastrointestinal surgery and that elevated CO2 reduces migration in vitro. Mechanistically, CO2 reduces autocrine inflammatory gene expression, thereby inhibiting macrophage activation in a manner dependent on decreased intracellular pH. Pharmacologic or genetic inhibition of carbonic anhydrases (CAs) uncouples a CO2-elicited intracellular pH response and attenuates CO2 sensitivity in immune cells. Conversely, CRISPR-driven upregulation of the isoenzyme CA2 confers CO2 sensitivity in nonimmune cells. Of interest, we found that patients with chronic lung diseases associated with elevated systemic CO2 (hypercapnia) display a greater risk of developing anastomotic leakage following gastrointestinal surgery, indicating impaired wound healing. Furthermore, low intraoperative pH levels in these patients correlate with reduced intestinal macrophage infiltration. In conclusion, CO2 is an immunomodulatory gas sensed by immune cells through a CA2-coupled change in intracellular pH.

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses.

Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD deficiency (Phd1-/-, Phd2+/-, and Phd3-/-) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2 haplodeficiency (Phd2+/-) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2+/- (but not PHI or Phd1-/-) protected from sepsis-related mortality. Mechanistically, PHI and Phd2+/- induced immunomodulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by Phd2+/--mediated M2 polarization of macrophages, conferring a favorable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.

Anaesthesia as an influence in tumour progression.

PURPOSE: Tumour growth and the formation of metastases are essential elements in the progression of cancer. The centre of treatment is the surgical resection of primary solid tumours. But even if the tumour can be removed without microscopic residual cells, local recurrences and distant metastases occur and determine the patient's fate. During the operation, tumour cells are shed from the primary tumour and released into the circulation. These circulating tumour cells might play an important role in the formation of new tumour sites. Therefore, a functional innate and adaptive immune system is essential, especially in this perioperative period. Anaesthesia influences consciousness and pain perception and interacts directly with the immune system and tumour cells. METHODS: Review of the current literature concerning intra- and postoperative anaesthetic decisions and tumour progression. RESULTS: There are beneficial aspects for patient survival associated with total intravenous anaesthesia, the use of regional anaesthetics and the avoidance of allogeneic red blood cell transfusions. Alternatives such as irradiated intraoperative blood salvage and preoperative iron supplementation may be advantageous in cases where transfusions are limited or not wanted. The immunosuppressive properties of opioids are theoretical, but strong evidence to avoid them does not exist. The application of nonsteroidal anti-inflammatory drugs and postoperative nausea and vomiting prophylaxis do not impair the patient's survival and may even have a positive effect on tumour regression. CONCLUSION: Anaesthesia does play an important part in the perioperative period in order to improve the cancer-related outcome. Further research is necessary to make more concrete recommendations.

Standard of Care and Outcomes of Primary Laparotomy Versus Laparotomy in Patients with Prior Open Abdominal Surgery (ReLap Study; DRKS00013001).

BACKGROUND: Patients undergoing relaparotomy are generally underrepresented in trials, despite how common the procedure is in clinical practice. The aim of this trial was to determine standard of care and gain evidence of intra- and postoperative outcomes for patients undergoing relaparotomy compared to primary laparotomy. METHODS: In this single-center controlled clinical trial, adult patients scheduled for elective abdominal surgery via relaparotomy or primary laparotomy were consecutively screened for eligibility. The perioperative course was monitored prospectively in five study visits during hospital stay and one study visit 1 year after surgery. Intraoperative standards, short and long-term outcomes were statistically explored at a level of significance of 5%. RESULTS: A total of 131 patients with relaparotomy and 50 patients with primary laparotomy were analyzed. In the relaparotomy group, the access to the abdomen took longer (23.5 min vs. 8.8 min; p = < 0.001) and the peritoneal adhesion index was higher (10.8 vs. 0.4; p = < 0.001). Inadvertent enterotomies were more frequent in the relaparotomy group (relaparotomy 0.3 versus primary laparotomy: 0.0; p = 0.002). The overall comprehensive complication index and rates of surgical site infection and wound dehiscence with evisceration were not different between the two groups. At long-term follow-up, rates of incisional hernia did not differ (relaparotomy: n = 12/104 (11.5%); primary laparotomy: n = 7/35 (20.0%); p = 0.208). DISCUSSION: In this first prospective comparison of relaparotomy with primary laparotomy, inadvertent enterotomies were more frequent in the relaparotomy group. However, contrary to previous retrospective studies, the risk of complications and incisional hernias was not increased compared to primary laparotomy. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( www.germanctr.de ): DRKS00013001.

Randomised-controlled feasibility trial on abdominal wall closure techniques in patients undergoing relaparotomy (ReLap study; DRKS00013001).

BACKGROUND: Patients undergoing relaparotomy are generally underrepresented in clinical trials, despite how common the procedure is in clinical practice. Specifically, techniques for re-do abdominal wall closure have never been evaluated in a randomised-controlled trial. The aim of this trial was to identify the optimal abdominal wall closure technique in patients undergoing relaparotomy. METHODS: In this monocentric, randomised feasibility trial, patients scheduled for elective relaparotomy were randomised to abdominal wall closure with either the small stitches technique, using Monomax® 2-0, or the large stitches technique, using PDS II® 1 loop. Patients' postoperative courses were followed for 1 year after the index operation. Effectiveness and safety outcomes were compared at a level of significance of 5% between the two techniques. RESULTS: A total of 100 out of 131 patients (76.3%) were evenly randomised to the small stitches and large stitches groups. The time for abdominal wall closure did not differ between the two techniques (small stitches 27.5 ± 9.5 min versus large stitches 25.3 ± 12.4 min; p = 0.334). The overall comprehensive complication index was 14.4 ± 15.5 in the small stitches group and 19.9 ± 23.4 in the large stitches group (p = 0.168). Specifically, rates of surgical site infection (small stitches 30.0% versus large stitches 36.0%; p = 0.524) and burst abdomen (small stitches 4.0% versus large stitches 0.0%; p = 0.495) did not differ. After 1 year, incisional hernia rate was 7.5% in the small stitches group and 10.0% in the large stitches group (p > 0.999). DISCUSSION: Both abdominal wall closure techniques investigated in this trial were feasible in relaparotomy patients. This exploratory trial revealed no noticeable difference in the effectiveness or safety of the small stitches technique with Monomax® 2-0 versus the large stitches technique with PDS II® 1 loop. Therefore, surgeons should stay with their preferred suture technique in relaparotomy patients. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( www.germanctr.de ): DRKS00013001.

Hypoxia-adaptive pathways: A pharmacological target in fibrotic disease?

Wound healing responses are physiological reactions to injuries and share common characteristics and phases independently of the injured organ or tissue. A major hallmark of wound healing responses is the formation of extra-cellular matrix (ECM), mainly consisting of collagen fibers, to restore the initial organ architecture and function. Overshooting wound healing responses result in unphysiological accumulation of ECM and collagen deposition, a process called fibrosis. Importantly, hypoxia (oxygen demand exceeds supply) plays a significant role during wound healing responses and fibrotic diseases. Under hypoxic conditions, cells activate a gene program, including the stabilization of hypoxia-inducible factors (HIFs), which induces the expression of HIF target genes counteracting hypoxia. In contrast, in normoxia, so-called HIF-prolyl hydroxylases (PHDs) oxygen-dependently hydroxylate HIF-α, which marks it for proteasomal degradation. Importantly, PHDs can be pharmacologically inhibited (PHI) by so-called PHD inhibitors. There is mounting evidence that the HIF-pathway is continuously up-regulated during the development of tissue fibrosis, and that pharmacological (HIFI) or genetic inhibition of HIF can prevent organ fibrosis. By contrast, initial (short-term) activation of the HIF pathway via PHI during wound healing seems to be beneficial in several models of inflammation or acute organ injury. Thus, timing and duration of PHI and HIFI treatment seem to be crucial. In this review, we will highlight the role of hypoxia-adaptive pathways during wound healing responses and development of fibrotic disease. Moreover, we will discuss whether PHI and HIFI might be a promising treatment option in fibrotic disease, and consider putative pitfalls that might result from this approach.

High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases.

BACKGROUND: Patients with borderline resectable colorectal liver metastases (CRLM) frequently receive neoadjuvant chemotherapy (NC) to reduce tumour burden, thus making surgical resection feasible. Even though NC can induce severe liver injury, most studies investigating tissue-based prognostic markers focus on tumour tissue. Here, we assessed the prognostic significance of pyruvate-dehydrogenase-kinase isoenzyme 4 (PDK4) within liver tissue of patients undergoing surgical resection due to CRLM. METHODS: Transcript levels of hypoxia-adaptive genes (such as PDK isoenzymes) were assessed in the tissue of healthy liver, corresponding CRLM, healthy colon mucosa and corresponding tumour. Uni- and multivariate analyses were performed. Responses to chemotherapy upon up- or down-regulation of PDK4 were studied in vitro. RESULTS: PDK4 expression within healthy liver tissue was associated with increased overall survival and liver function following surgical resection of CRLM. This association was enhanced in patients with NC. PDK4 expression in CRLM tissue did not correlate with overall survival. Up-regulation of PDK4 increased the resistance of hepatocytes and colon cancer cells against chemotherapy-induced toxicity, whereas knockdown of PDK4 enhanced chemotherapy-associated cell damage. CONCLUSION: Our findings suggest that up-regulated PDK4 expression reduces hepatic chemotherapy-induced oxidative stress and is associated with improved postoperative liver function in patients undergoing multimodal treatment and resection of CRLM.

Loss of Prolyl-Hydroxylase 1 Protects against Biliary Fibrosis via Attenuated Activation of Hepatic Stellate Cells.

Liver fibrosis, eventually progressing to cirrhosis necessitating liver transplantation, poses a significant clinical problem. Oxygen shortage (hypoxia) and hypoxia-inducible transcription factors (HIFs) have been acknowledged as important drivers of liver fibrosis. The significance of oxygen-sensing HIF prolyl-hydroxylase (PHD) enzymes in this context has, however, remained elusive. In this study, we demonstrate that loss of PHD1 (PHD1-/-) attenuates the development of liver fibrosis in mice subjected to chronic bile duct injury, induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. This effect was accompanied with reduced recruitment of inflammatory leukocytes and attenuated occurrence of profibrotic myofibroblasts in PHD1-/- livers. Further analyses focused on the significance of PHD1 in the activation of hepatic stellate cells (HSCs), which represent the driving force in liver fibrosis. Primary HSCs isolated from PHD1-/- mice displayed significantly attenuated myofibroblast differentiation and profibrogenic properties compared with HSCs isolated from wild-type mice. Consistently, the expression of various profibrogenic and promitogenic factors was reduced in PHD1-/- HSCs, without alterations in HIF-1α protein levels. Of importance, PHD1 protein was expressed in HSCs within human livers, and PHD1 transcript expression was significantly increased with disease severity in hepatic tissue from patients with liver fibrosis. Collectively, these findings indicate that PHD1 deficiency protects against liver fibrosis and that these effects are partly due to attenuated activation of HSCs. PHD1 may represent a therapeutic target to alleviate liver fibrosis.

Pharmacological HIF-inhibition attenuates postoperative adhesion formation.

Peritoneal adhesions represent a common complication of abdominal surgery, and tissue hypoxia is a main determinant in adhesion formation. Reliable therapeutic options to reduce peritoneal adhesions are scarce. We investigated whether the formation of postsurgical adhesions can be affected by pharmacological interference with hypoxia-inducible factors (HIFs). Mice were treated with a small molecule HIF-inhibitor, YC-1 (3-[5'-Hydroxymethyl-2'-furyl]-1-benzyl-indazole), or vehicle three days before and seven days after induction of peritoneal adhesions or, alternatively, once during induction of peritoneal adhesions. Pretreatment or single intraperitoneal lavage with YC-1 significantly reduced postoperative adhesion formation without prompting systemic adverse effects. Expression analyses of cytokines in peritoneal tissue and fluid and in vitro assays applying macrophages and peritoneal fibroblasts indicated that this effect was cooperatively mediated by various putatively HIF-1α-dependent mechanisms, comprising attenuated pro-inflammatory activation of macrophages, impaired recruitment and activation of peritoneal fibroblasts, mitigated epithelial-mesenchymal-transition (EMT), as well as enhanced fibrinolysis and impaired angiogenesis. Thus, this study identifies prevention of postsurgical peritoneal adhesions as a novel and promising field for the application of HIF inhibitors in clinical practice.

Influence of neoadjuvant chemotherapy on resection of primary colorectal liver metastases: A propensity score analysis.

BACKGROUND AND OBJECTIVES: There is ongoing debate about whether patients planned for liver resection of colorectal liver metastases (CRLM) benefit from neoadjuvant chemotherapy (NC). Therefore, we performed a retrospective survival analysis of patients with and without NC prior to surgery. METHODS: Data prospectively collected from 468 consecutive patients were analyzed in a retrospective design. We performed a survival analysis and added propensity score matching (PSM). Univariate and multivariate analysis was performed to determine independent prognostic risk factors. RESULTS: NC was performed in 145/468 patients. NC did not have a significant influence on overall survival (OS) either before or after PSM. Patients receiving NC showed increased complication rates, especially concerning non-surgical complications after primary resection (P = 0.025) of CRLM. Multivariate analysis before and after PSM revealed that the Memorial Sloan Kettering Cancer Center (MSKCC) score and CEA values are strong predictors for OS in patients with CRLM. CONCLUSIONS: NC was not associated with increased OS in patients suffering from CRLM. Additionally, potentially harmful chemotherapy prior to surgery increases the risk of postoperative complications in these patients.