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.

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.

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.

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.

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.

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.

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.

Three-dimensional upper-airway changes with maxillomandibular advancement for obstructive sleep apnea treatment.

INTRODUCTION: Airway size increases are associated with maxillomandibular advancement (MMA) surgery and improvement or elimination of obstructive sleep apnea (OSA). The 3-dimensional morphologic, volumetric, height, cross-sectional surface area, and diameter changes of the upper airway in patients with OSA after MMA, however, are not well understood. METHODS: Patients with moderate or severe OSA who underwent MMA surgery were evaluated by preoperative and postoperative cone-beam computed tomography scans and polysomnograms. The upper airway space was also divided into retropalatal and retroglossal spaces and was analyzed for volumetric, height, cross-sectional surface area, transverse, and anteroposterior diameter changes. RESULTS: Ten consecutive OSA patients with an average preoperative apnea/hypopnea index of 46 and treated with MMA surgery were included in this study. There were 8 men and 2 women, with an average age of 46 years and an average body mass index of 28. There was an average of a 2.5-fold increase in the total volume of the upper airway space. The retropalatal space increased by 3.5-fold. The retroglossal space increased by 1.5-fold. The greatest change in a cross-sectional area occurred in the transverse axis in both the retroglossal and retropalatal spaces. The average apnea/hypopnea index was 4 postoperatively. CONCLUSION: MMA surgery results in a significant increase in the volume and a morphologic airway change from a round to an elliptical f shape in the upper airway space in patients with OSA. The combination of these actions reduces the collapsibility of the upper airway space, hence improving or resolving the OSA.

Wilms tumor presenting with Lambert-Eaton myasthenic syndrome.

Paraneoplastic syndromes may affect the central and peripheral nervous system of adults and children with cancer. Neurological symptoms may resolve with treatment of the underlying neoplasm. We report the case of a child with Wilms tumor who presented with generalized weakness, fatigue, ptosis, hypokinesis, dysarthria, urinary retention, facial diplegia, ophthalmoplegia, and autonomic dysfunction. Routine electrodiagnostic testing, including repetitive nerve stimulation, was normal. Clinical features and stimulation single-fiber electromyogram were consistent with a neuromuscular junction transmission disorder, likely Lambert-Eaton myasthenic syndrome. The child's neurological status returned to normal with successful treatment of the tumor.

3-dimensional facial simulation in orthognathic surgery: is it accurate?

PURPOSE: The purpose of this study was to measure the accuracy of 3D computer simulation of soft tissue changes after orthognathic surgery. MATERIALS AND METHODS: Consecutive patients who underwent orthognathic surgery were studied by photogrammetric facial scanning and cone-beam computed tomography before and after surgery. The photogrammetric scan was then fused to the cone-beam computed tomogram, creating a patient-specific image. The surgery was simulated in 3D form and the simulated soft tissue face was compared with the actual facial scan obtained 6 months postoperatively. Absolute millimeter differences between the simulated and actual postoperative changes in selected cephalometric skin markings were computed. RESULTS: The study was composed of 23 subjects (mean age, 31 yr; 13 women and 10 men). Eighteen different cephalometric landmarks were measured (total, 28). For 15 landmarks, the difference between actual and simulated measurements was smaller than 0.5 mm. Only 3 landmarks had a difference of 0.5 mm, and these were in the region of the labial landmarks. CONCLUSION: Based on the present study, 3-dimensional computer surgical simulation of the soft tissue of the face for routine orthognathic surgery is accurate enough for routine clinical use.

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.

Airway growth and development: a computerized 3-dimensional analysis.

PURPOSE: The present study was undertaken to investigate the changes in the normal upper airway during growth and development using 3-dimensional computer analysis from cone-beam computed tomography (CBCT) data to provide a normative reference. METHODS: The airway size and respiratory mode are known to have a relationship to facial morphology and the development of a malocclusion. The use of CBCT, 3-dimensional imaging, and automated computer analysis in treatment planning allows the upper airway to be precisely evaluated. In the present study, we evaluated the growth of the airway using 3-dimensional analysis and CBCT data from age 6 through old age, in 1300 normal individuals. RESULTS: The airway size and length increase until age 20 at which time a variable period of stability occurs. Next, the airway at first decreases slowly in size and then, after age 40, more rapidly. Normative data are provided in the present study for age groups from 6 to 60 years in relation to the airway total volume, smallest cross-sectional area and vertical length of the airway. CONCLUSIONS: This 3-dimensional data of the upper airway will provide a normative reference as an aid in the early understanding of respiration and dentofacial anatomy, which will help in early treatment planning.

Maxillary, mandibular, and chin advancement: treatment planning based on airway anatomy in obstructive sleep apnea.

Surgical correction of obstructive sleep apnea (OSA) syndrome involves understanding a number of parameters, of which the 3-dimensional airway anatomy is important. Visualization of the upper airway based on cone beam computed tomography scans and automated computer analysis is an aid in understanding normal and abnormal airway conditions and their response to surgery. The goal of surgical treatment of OSA syndrome is to enlarge the velo-oropharyngeal airway by anterior/lateral displacement of the soft tissues and musculature by maxillary, mandibular, and possibly, genioglossus advancement. Knowledge of the specific airway obstruction and characteristics based on 3-dimensional studies permits a directed surgical treatment plan that can successfully address the area or areas of airway obstruction. The end occlusal result can be improved when orthodontic treatment is combined with the surgical plan. The individual with OSA, though, is more complicated than the usual orthognathic patient, and both the medical condition and treatment length need to be judiciously managed when OSA and associated conditions are present. The perioperative management of the patient with OSA is more complex and the margin for error is reduced, and this needs to be taken into consideration and the care altered as indicated.

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.

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.

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.

Three-dimensional imaging and computer simulation for office-based surgery.

PURPOSE: Advancements in computers and imaging, especially over the last 10 years, have permitted the adoption of 3-dimensional imaging protocols in the health care field. In addition, the affordability and ease of use of these modalities allow their widespread adoption and use in diagnosis and treatment planning. This is particularly important when the deformities are complex involving both function and esthetics, such as those in the dentofacial area and with orthognathic surgery. MATERIALS AND METHODS: Image fusion involves combining images from different imaging modalities to create a virtual record of an individual called a patient-specific anatomic reconstruction (PSAR). We describe the system and show its use in 1 case. RESULTS: Image fusion and, more specifically, PSAR permit a more accurate analysis of deformity as an aid to diagnosis and treatment planning. CONCLUSION: Three-dimensional imaging and computer simulation can be effectively used for planning office-based procedures. The PSAR can be used to perform virtual surgery and establish a definitive and objective treatment plan for correction of a facial deformity. The end result is improved patient care and decreased expense.