Long-term nutrition alterations after surgery for gastrointestinal cancers.

As surgical and adjuvant therapies for gastrointestinal (GI) cancers improve in safety and efficacy, extended survival in these diseases is becoming commonplace. Surgically induced nutrition alterations are common side effects of treatment and often debilitating. This review is intended for multidisciplinary teams to better understand the postoperative anatomy, physiology, and nutrition morbidity of GI cancer operations. We have arranged this paper by the anatomic and functional changes to the GI tract intrinsic to common cancer operations. Operation-specific long-term nutrition morbidity is detailed, along with the underlying pathophysiology. We have included the most common and effective interventions for the management of individual nutrition morbidities. Finally, we highlight the importance of a multidisciplinary approach to the evaluation and treatment of these patients over the oncologic surveillance period and beyond.

The Deleterious Effects of Impaired Fibrinolysis on Skeletal Development Are Dependent on Fibrin(ogen), but Independent of Interlukin-6.

Chronic diseases in growing children, such as autoimmune disorders, obesity, and cancer, are hallmarked by musculoskeletal growth disturbances and osteoporosis. Many of the skeletal changes in these children are thought to be secondary to chronic inflammation. Recent studies have likewise suggested that changes in coagulation and fibrinolysis may contribute to musculoskeletal growth disturbances. In prior work, we demonstrated that mice deficient in plasminogen, the principal protease of degrading and clearing fibrin matrices, suffer from inflammation-driven systemic osteoporosis and that elimination of fibrinogen resulted in normalization of IL-6 levels and complete rescue of the skeletal phenotype. Given the intimate link between coagulation, fibrinolysis, and inflammation, here we determined if persistent fibrin deposition, elevated IL-6, or both contribute to early skeletal aging and physeal disruption in chronic inflammatory conditions. Skeletal growth as well as bone quality, physeal development, and vascularity were analyzed in C57BL6/J mice with plasminogen deficiency with and without deficiencies of either fibrinogen or IL-6. Elimination of fibrinogen, but not IL-6, rescued the skeletal phenotype and growth disturbances in this model of chronic disease. Furthermore, the skeletal phenotypes directly correlated with both systemic and local vascular changes in the skeletal environment. In conclusion, these results suggest that fibrinolysis through plasmin is essential for skeletal growth and maintenance, and is multifactorial by limiting inflammation and preserving vasculature.

Evaluation and Management of Colorectal Cancer Hepatic Metastases.

CASE SUMMARY: A 65-year-old man presents with new liver lesions on surveillance imaging 2 years after a right hemicolectomy for cecal adenocarcinoma. The primary tumor was pT3N1, microsatellite stable, and KRAS wild type. He completed adjuvant FOLFOX. His CEA level is 22 ng/mL. There are two 1.5-cm lesions in the right lobe near the dome of the liver and a 4-cm lesion in segment II. No luminal recurrence is detected endoscopically, and there is no evidence of peritoneal or pulmonary disease.

Trends in Antibiotic Duration for Complicated Intra-Abdominal Infections : Adaptation to Current Guidelines.

INTRODUCTION: The 2017 surgical infection society (SIS) guidelines recommend 4 days of antibiotic therapy after source control for complicated intra-abdominal infections (cIAIs). Inappropriate exposure to antibiotics has a negative impact on outcomes in individual patients and populations. The goal of this study was to evaluate our institution's practice patterns and adherence to current antibiotic guidelines. METHODS: Medical records from 2010 to 2018 for cIAIs were examined. Complicated appendicitis and complicated diverticulitis cases were included. Exclusion criteria included other etiologies of IAIs, pediatric cases, and cancer operations. RESULTS: Fifty-nine complicated appendicitis cases and 96 complicated diverticulitis cases were identified. For all cases, antibiotic duration prior to publication of the SIS guidelines was significantly longer than post-SIS duration (appendicitis: 12.6 ± 1.1 days pre-SIS [n = 37] vs 9.0 ± 1.1 days post-SIS [n = 22], P = .01; diverticulitis: 15.1 ± 0.8 days pre-SIS [n = 49] vs 11.2 ± 0.5 post-SIS [n = 47], P = .04). Surgical management (SM) was associated with shorter duration of postsource control antibiotic exposure compared with percutaneous drainage (PD) for both appendicitis (SM 10.0 ± 1.2 days vs PD 13.4 ± 1.0 days, P = .02) and diverticulitis (SM 12.8 ± 1.5 days vs PD 16.0 ± 1.5, P = .07). Patients with complicated appendicitis received shorter duration of antibiotics when managed by acute care surgeons compared to general surgeons (8.4 ± 1.1 vs 11.9 ± 0.8, P = .02). CONCLUSION: Despite improvements after the SIS guidelines' publication, the antibiotic duration is still longer than recommended. Surgical intervention and management by acute care specialists were associated with a shorter duration of antibiotic exposure.

Prevention of Anastomotic Leak Via Local Application of Tranexamic Acid to Target Bacterial-mediated Plasminogen Activation: A Practical Solution to a Complex Problem.

OBJECTIVE: To investigate the role of bacterial- mediated plasminogen (PLG) activation in the pathogenesis of anastomotic leak (AL) and its mitigation by tranexamic acid (TXA). BACKGROUND: AL is the most feared complication of colorectal resections. The pathobiology of AL in the setting of a technically optimal procedure involves excessive submucosal collagen degradation by resident microbes. We hypothesized that activation of the host PLG system by pathogens is a central and targetable pathway in AL. METHODS: We employed kinetic analysis of binding and activation of human PLG by microbes known to cause AL, and collagen degradation assays to test the impact of PLG on bacterial collagenolysis. Further, we measured the ability of the antifibrinolytic drug TXA to inhibit this process. Finally, using mouse models of pathogen-induced AL, we locally applied TXA via enema and measured its ability to prevent a clinically relevant AL. RESULTS: PLG is deposited rapidly and specifically at the site of colorectal anastomoses. TXA inhibited PLG activation and downstream collagenolysis by pathogens known to have a causal role in AL. TXA enema reduced collagenolytic bacteria counts and PLG deposition at anastomotic sites. Postoperative PLG inhibition with TXA enema prevented clinically and pathologically apparent pathogen-mediated AL in mice. CONCLUSIONS: Bacterial activation of host PLG is central to collagenolysis and pathogen-mediated AL. TXA inhibits this process both in vitro and in vivo. TXA enema represents a promising method to prevent AL in high-risk sites such as the colorectal anastomoses.

Current Status of Circulating Tumor DNA Liquid Biopsy in Pancreatic Cancer.

Pancreatic cancer is a challenging disease with a low 5-year survival rate. There are areas for improvement in the tools used for screening, diagnosis, prognosis, treatment selection, and assessing treatment response. Liquid biopsy, particularly cell free DNA liquid biopsy, has shown promise as an adjunct to our standard care for pancreatic cancer patients, but has not yet been universally adopted into regular use by clinicians. In this publication, we aim to review cfDNA liquid biopsy in pancreatic cancer with an emphasis on current techniques, clinical utility, and areas of active investigation. We feel that researchers and clinicians alike should be familiar with this exciting modality as it gains increasing importance in the care of cancer patients.

The Impact of Perioperative Antibiotic Prophylaxis on Weight Loss Following Laparoscopic Sleeve Gastrectomy.

Although >10% of surgical patients receive alternative antibiotic prophylaxis for reported penicillin allergies, it is estimated that <20% of such cases represent true allergies that preclude standard prophylaxis. Each antibiotic class has a distinct impact on the intestinal microbiota and on postoperative metabolomics. The community structure and function of the microbiota are linked to the ability to lose weight after bariatric surgery. This study demonstrates differential weight loss after laparoscopic sleeve gastrectomy between patients who received standard (cefoxitin) and alternative (levofloxacin and metronidazole) perioperative prophylaxis. Multivariate analysis demonstrates that alternative prophylaxis is significantly and independently associated with diminished postoperative weight loss.

Western Diet Promotes Intestinal Colonization by Collagenolytic Microbes and Promotes Tumor Formation After Colorectal Surgery.

BACKGROUND & AIMS: The Western diet, which is high in fat, is a modifiable risk factor for colorectal recurrence after curative resection. We investigated the mechanisms by which the Western diet promotes tumor recurrence, including changes in the microbiome, in mice that underwent colorectal resection. METHODS: BALB/c male mice were fed either standard chow diet or Western-type diet (characterized by high fat, no fiber, and decreased minerals and vitamins) for 4 weeks; some mice were given antibiotics or ABA-PEG20k-Pi20 (Pi-PEG), which inhibits collagenase production by bacteria, but not bacterial growth, in drinking water. Colorectal resections and anastomoses were then performed. The first day after surgery, mice were given enemas containing a collagenolytic rodent-derived strain of Enterococcus faecalis (strain E2), and on the second day they were given mouse colon carcinoma cells (CT26). Twenty-one days later, distal colons were removed, and colon contents (feces, distal colon, and tumor) were collected. Colon tissues were analyzed by histology for the presence of collagenolytic colonies and by 16S ribosomal RNA sequencing, which determined the anatomic distribution of E faecalis at the site of the anastomosis and within tumors using in situ hybridization. Mouse imaging analyses were used to identify metastases. RESULTS: Colorectal tumors were found in 88% of mice fed the Western diet and given antibiotics, surgery, and E faecalis compared with only 30% of mice fed the standard diet followed by the same procedures. Colon tumor formation correlated with the presence of collagenolytic E faecalis and Proteus mirabilis. Antibiotics eliminated collagenolytic E faecalis and P mirabilis but did not reduce tumor formation. However, antibiotics promoted emergence of Candida parapsilosis, a collagenase-producing microorganism. Administration of a Pi-PEG reduced tumor formation and maintained diversity of the colon microbiome. CONCLUSIONS: We identified a mechanisms by which diet and antibiotic use can promote tumorigenesis by colon cancer cells at the anastomosis after colorectal surgery. Strategies to prevent emergence of these microbe communities or their enzymatic activities might be used to reduce the risk of tumor recurrence in patients undergoing colorectal cancer surgery.

Enterococcus faecalis exploits the human fibrinolytic system to drive excess collagenolysis: implications in gut healing and identification of druggable targets.

Perforations, anastomotic leak, and subsequent intra-abdominal sepsis are among the most common and feared complications of invasive interventions in the colon and remaining intestinal tract. During physiological healing, tissue protease activity is finely orchestrated to maintain the strength and integrity of the submucosa collagen layer in the wound. We (Shogan, BD et al. Sci Trans Med 7: 286ra68, 2015.) have previously demonstrated in both mice and humans that the commensal microbe Enterococcus faecalis selectively colonizes wounded colonic tissues and disrupts the healing process by amplifying collagenolytic matrix-metalloprotease activity toward excessive degradation. Here, we demonstrate for the first time, to our knowledge, a novel collagenolytic virulence mechanism by which E. faecalis is able to bind and locally activate the human fibrinolytic protease plasminogen (PLG), a protein present in high concentrations in healing colonic tissue. E. faecalis-mediated PLG activation leads to supraphysiological collagen degradation; in this study, we demonstrate this concept both in vitro and in vivo. This pathoadaptive response can be mitigated with the PLG inhibitor tranexamic acid (TXA) in a fashion that prevents clinically significant complications in validated murine models of both E. faecalis- and Pseudomonas aeruginosa-mediated colonic perforation. TXA has a proven clinical safety record and is Food and Drug Administration approved for topical application in invasive procedures, albeit for the prevention of bleeding rather than infection. As such, the novel pharmacological effect described in this study may be translatable to clinical trials for the prevention of infectious complications in colonic healing.NEW & NOTEWORTHY This paper presents a novel mechanism for virulence in a commensal gut microbe that exploits the human fibrinolytic system and its principle protease, plasminogen. This mechanism is targetable by safe and effective nonantibiotic small molecules for the prevention of infectious complications in the healing gut.

Evolving Clinical Utility of Liquid Biopsy in Gastrointestinal Cancers.

Room for improvement exists regarding recommendations for screening, staging, therapy selection, and frequency of surveillance of gastrointestinal cancers. Screening is costly and invasive, improved staging demands increased sensitivity and specificity to better guide therapy selection. Surveillance requires increased sensitivity for earlier detection and precise management of recurrences. Peripherally collected blood-based liquid biopsies enrich and analyze circulating tumor cells and/or somatic genomic material, including circulating tumor DNA along with various subclasses of RNA. Such assays have the potential to impact clinical practice at multiple stages of management in gastrointestinal cancers. This review summarizes current basic and clinical evidence for the utilization of liquid biopsy in cancers of the esophagus, pancreas, stomach, colon, and rectum. Technical aspects of various liquid biopsy methodologies and targets are reviewed and evidence supporting current commercially available assays is examined. Finally, current clinical applicability, potential future uses, and pitfalls of applying liquid biopsy to the screening, staging and therapeutic management of these diseases are discussed.

Correction to: Peritoneal Metastases in Colorectal Cancer.

In the original article Fadi Dahdaleh's last name was spelled incorrectly. It is correct as reflected here.

Successful non-operative management of intraabdominal hypertension and abdominal compartment syndrome after complex ventral hernia repair: a case series.

BACKGROUND: Intraabdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are devastating complications of surgery. Patients who undergo complex ventral hernia repair (CVHR) may be at risk for IAH and ACS. METHODS: We performed a retrospective review of 175 patients who underwent CVHR by a single surgeon. Body mass index (BMI), prior hernia repair, operative time, bladder pressure, serum creatinine, sedation, paralytic therapy, and ventilator support were reviewed. RESULTS: IAH was identified in 33 patients; 11 patients developed ACS. Paralytic therapy was employed in 29 patients for an average of 1.4 days. Elevated BMI was independently associated with an increased risk of IAH (p = 0.006) and ACS (p = 0.02). CONCLUSION: Patients who undergo CVHR are at risk of developing IAH and ACS in the postoperative period. Elevated BMI and longer operative time are independent risk factors for the development of IAH. IAH and ACS can be successfully managed with surgical critical care.

Outcomes in complex ventral hernia repair with anterior component separation in class III obesity patients.

BACKGROUND: Consensus guidelines recommend against elective ventral hernia repair (VHR) in patients with BMI >30 kg/m2 without preoperative weight loss intervention. We aim to compare hernia recurrence and perioperative complications in VHR utilizing anterior component separation (CS) in patients with class III obesity (BMI >40 kg/m2). METHODS: A retrospective review of patients undergoing VHR with CS was performed. The primary endpoint was hernia recurrence; secondary endpoints were wound complications, postoperative medical complications, mortality and length of stay. RESULTS: 185 consecutive patients were identified from 2008 to 2016. There were no significant differences between groups: hernia recurrence (6.9% BMI >40 kg/m2, 2.4% BMI <39.9 kg/m2, p = 0.21), wound complications (58.6% BMI >40 kg/m2, 47.2% BMI <39.9 kg/m2, p = 0.16), postoperative complications (39.7% BMI >40 kg/m2, 26% BMI <39.9 kg/m2, p = 0.08), mortality (1.6% BMI >40 kg/m2, 3.4% BMI <39.9 kg/m2, p = 0.59), and length of stay (10.6 days BMI >40 kg/m2, 11.2 days BMI <39.9 kg/m2, p = 0.5). CONCLUSION: This study demonstrates similar outcomes in class III obesity patients undergoing elective VHR compared to patients with BMI <39.9 kg/m2.

Characterizing the Acute Phase Response in Healthy Patients Following Total Joint Arthroplasty: Predictable and Consistent.

BACKGROUND: During surgery, trauma to musculoskeletal tissue induces a systemic reaction known as the acute phase response (APR). When excessive or prolonged, the APR has been implicated as an underlying cause of surgical complications. The purpose of this study was to determine the typical APR following total joint arthroplasty in a healthy population defined by the Charlson Comorbidity Index (CCI). METHODS: This retrospective study identified 180 healthy patients (CCI < 2) who underwent total joint arthroplasty by a single surgeon for primary osteoarthritis from 2013 to 2015. Serial measurements of C-reactive protein (CRP) and fibrinogen were obtained preoperative, perioperative, and at 2 and 6 weeks postoperative. RESULTS: Postoperative CRP peaked during the inpatient period and returned to baseline by 2 weeks. Fibrinogen peaked after CRP and returned to baseline by 6 weeks. Elevated preoperative CRP correlated with a more robust postoperative APR for both total hip arthroplasty and total knee arthroplasty, suggesting that a patient's preoperative inflammatory state correlates with the magnitude of the postoperative APR. CONCLUSION: Measurement of preoperative acute phase reactants may provide an objective means to predict a patient's risk of postoperative dysregulation of the APR and complications.

The impact of visiting student electives on surgical Match outcomes.

BACKGROUND: Residency applicants commonly complete visiting student electives (VSEs) hoping to increase their odds of matching at host institutions. Existing evidence on Match outcomes for applicants who complete VSEs is limited. As VSEs involve monetary and opportunity costs to students and administrators, data on their utility are vital for student well-being, preparedness for residency, and, ultimately, success in the Match. We investigated the utilization and impact of VSEs for all applicants. We hypothesized that completion of VSEs would increase the likelihood of matching at a host institution. MATERIALS AND METHODS: A retrospective review was conducted of academic records and National Resident Matching Program outcomes for the graduates of one institution and visiting students to that institution over the course of 7 y. RESULTS: Utilization of VSEs varied significantly among specialties. Across all specialties and in general surgery, applicants were more likely to match into host programs than others. The size of the effect of VSEs on outcomes varied by specialty. Host programs were applicants' top choice for residency in 48% of cases. CONCLUSIONS: Completion of VSEs may give surgical applicants increased control over Match outcomes. Our findings may assist future students in strategic decision making when determining whether and where to use VSEs.

Outcomes and Use of Laparoscopic Versus Open Gastric Resection.

BACKGROUND AND OBJECTIVES: The advantages of laparoscopy over open surgery are well established. Laparoscopic resection for gastric cancer is safe and results in equivalent oncologic outcomes when compared with open resection. The purpose of this study was to assess the use of laparoscopy to treat gastric cancer and the associated outcomes. METHODS: The American College of Surgeons National Surgical Quality Improvement Project (NSQIP) dataset was queried for patients with gastric cancer (ICD-9 Code 151.0-151.9) from January 2005 through December 2012. Logistic regression was used to evaluate the 30-day morbidity and mortality of open gastrectomy (CPT code 43620-2, 43631-4) versus that of the laparoscopic procedure on the stomach (CPT code 43650), while adjusting for preoperative risk factors. RESULTS: A total of 4116 patients with gastric cancer were identified and divided by surgical approach into 2 groups: open gastrectomy (n = 3725; 90.5%) and laparoscopic procedure on the stomach (n = 391; 9.5%). After adjustment for preoperative risk factors, complications were significantly fewer in laparoscopic versus open gastric resection (odds ratio [OR] 0.61, 95% confidence interval [CI] = 0.45-0.82; P = .001). After adjusting for preoperative risk factors, there was no statistically significant difference in mortality with laparoscopic compared to open gastric resection (OR 0.74; 95% CI = 0.32-1.72; P = .481). CONCLUSIONS: Laparoscopy is underused in the treatment of gastric cancer. Given that laparoscopic gastric resection has a lower morbidity in comparison to open resection, steps should be made toward advancing the use of laparoscopy for gastric cancer.

The hyperglycemic byproduct methylglyoxal impairs anticoagulant activity through covalent adduction of antithrombin III.

INTRODUCTION: The blood coagulation system is a tightly regulated balance of procoagulant and anticoagulant factors, disruption of which can cause clinical complications. Diabetics are known to have a hypercoagulable phenotype, along with increased circulating levels of methylglyoxal (MGO) and decreased activity of the anticoagulant plasma protein antithrombin III (ATIII). MGO has been shown to inhibit ATIII activity in vitro, however the mechanism of inhibition is incompletely understood. As such, we designed this study to investigate the kinetics and mechanism of MGO-mediated ATIII inhibition. METHODS: MGO-mediated ATIII inhibition was confirmed using inverse experiments detecting activity of the ATIII targets thrombin and factor Xa. Fluorogenic assays were performed in both PBS and plasma after incubation of ATIII with MGO, at molar ratios comparable to those observed in the plasma of diabetic patients. LC-coupled tandem mass spectrometry was utilized to investigate the exact mechanism of MGO-mediated ATIII inhibition. RESULTS AND CONCLUSIONS: MGO concentration-dependently attenuated inhibition of thrombin and factor Xa by ATIII in PBS-based assays, both in the presence and absence of heparin. In addition, MGO concentration-dependently inhibited ATIII activity in a plasma-based system, to the level of plasma completely deficient in ATIII, again both in the presence and absence of heparin. Results from LC-MS/MS experiments revealed that MGO covalently adducts the active site Arg 393 of ATIII through two distinct glyoxalation mechanisms. We posit that active site adduction is the mechanism of MGO-mediated inhibition of ATIII, and thus contributes to the underlying pathophysiology of the diabetic hypercoagulable state and complications thereof.

High molecular weight hyaluronic acid increases the differentiation potential of the murine chondrocytic ATDC5 cell line.

Osteoarthritis (OA) is a group of common, chronic, and painful inflammatory joint diseases. One important finding in OA patients is a remarkable decrease in the molecular weight of hyaluronic acid (HA) in the synovial fluid of affected joints. Therapeutic HA is available to patients in most parts of the world as a viscosupplementation product for the treatment of OA. Previous clinical reports show that high molecular weight HA (HMWHA) more effectively relieves pain than low molecular weight HA (LMWHA). However, the mechanism behind this finding remains unclear. In this study, we investigated whether a LMWHA (Low-0.9 MDa) and two types of HMWHA (High-1.9 MDa and 6 MDa) differentially affected chondroregulatory action. We tested this using ATDC5 cell, a murine chondrocytic cell line widely used in culture systems to study chondrogenic differentiation. We found that HMWHA, especially hylan G-F 20 (High-6 MDa), significantly induced aggrecan and proteoglycan accumulation, nodule formation, and mRNA expression of chondrogenic differentiation markers in a time- and dose-dependent manner. In addition, we showed that HMWHA prevented TNF-α induced inhibition of chondrogenic differentiation, with no effect on cell proliferation or viability. These results reveal that HMWHA significantly promotes chondrogenic differentiation of ATDC5 cells in vitro, and suggest that HMWHA plays a significant chondroregulatory role in vivo.