Risk-adjustment in hepatobiliary pancreatic surgery

AIM: The present study evaluates the performance of the POSSUM, the American Society of Anesthetists (ASA), APACHE and Childs classification in predicting mortality and morbidity in hepatopancreaticobiliary (HPB) surgery. We describe especially the limitations and advantages of risk in stratifying the patients. METHODS: We investigated 177 randomly chosen patients undergoing elective complex HPB surgery in a single institution with a total of 71 pre-operative and intra-operative risk factors. Primary endpoint was in-hospital mortality and morbidity. Ordered logistic regression analysis was used to identify individual predictors of operative morbidity and mortality. RESULTS: The operative mortality in the series was 3.95%. This compared well with the p-POSSUM and APACHE predicted mortality of 4.31% and 4.29% respectively. Postoperative complications amounted to 45% with 24 (13.6%) patients having a major adverse event. On multrvariate analysis the pre-operative POSSUM physiological score (OR = 1.18, P = 0.009) was superior in predicting complications compared to the ASA (P= 0.108), APACHE (P= 0.117) or Childs classification (P= 0.136). In addition, serum sodium, creatinine, international normalized ratio (INR), pulse rate, and intra-operative blood loss were independent risk factors. A combination of the POSSUM variables and INR offered the optimal combination of risk factors for risk prognostication in HPB surgery. CONCLUSION: Morbidity for elective HPB surgery can be accurately predicted and applied in everyday surgical practice as an adjunct in the process of informed consent and for effective allocation of resources for intensive and high-dependency care facilities.     

Microsatellite Analysis of Sporadic Flat and Depressed Lesions of the Colon

Prior studies of molecular and genetic derangements in flat and depressed lesions of the colon have revealed lower frequencies in a number of markers commonly present in exophytic lesions. These and other differences suggest that flat lesions are driven by alternative pathways. We reviewed a database of patients who had undergone endoscopic mucosal resection (EMR) for flat and depressed lesions at the University of Chicago from January 2001 to April 2003. Formalin-fixed and paraffin-embedded colonic samples were retrieved from the tissue bank, and five standardized mononucleotide and dinucleotide microsatellite regions were analyzed for instability (MSI) using fluorescently labeled forward primers in nonmultiplex reactions. Sixteen patients were identified with flat or depressed lesions who had adequate tissue specimens available for MSI analysis. Of these specimens, eight were tubular adenomas, three were tubulovillous adenomas, and five were carcinomas in situ. Four of the lesions were microsatellite unstable, each at a single locus, and one lesion showed probable instability at a second locus. Eleven lesions were microsatellite stable. Aberrations in DNA repair mechanisms do not appear to significantly contribute to the molecular derangements underlying sporadic flat or depressed colonic lesions. The molecular bases that underlie the aggressive behavior of sporadic flat and depressed lesions remain to be determined, and further investigation is warranted.     

Baroreflex dysfunction in patients with adult-onset diabetes and hypertension

Ten patients with adult-onset diabetes in whom diabetes antedated the appearance of hypertension were evaluated. These patients had evidence of diabetic autonomic neuropathy, including significant orthostatic hypotension (four patients), impotence (three patients), and evidence of diabetic peripheral sensorimotor neuropathy (nine patients) in clinical testing and nerve conduction study results. Baroreflex function was evaluated by multiple hemodynamic tests, including inhalation of amyl nitrite and intravenous administration of phenylephrine, before and after parasympathetic blockade with atropine, and the cold presser test; results were compared with results in normal control subjects, patients with essential hypertension, and two subgroups of uremie patients undergoing maintenance hemodialysis. Baroreflex function was significantly abnormal in the diabetic patients and was consistent with combined parasympathetic and sympathetic motor nerve (efferent) dysfunction in the baroreflex arc. There was a significant inverse correlation between the degree of orthostatic hypotension in the diabetic patients and their baroreflex responsc to phenylephrine (r = ?0.680, p < 0.05). There was no significant correlation between supine hypertension in the patients with diabetes and any of the hemodynamic or biochemical parameters examined. The results suggest that orthostatic hypotension in these patients is related to baroreflex dysfunction. However, baroreflex dysfunction does not appear to be a factor in the development of hypertension in these patients, although more studies with normotensive diabetic patients are needed to confirm this point.     

Mechanisms of intestinal failure in Crohn's disease

PURPOSE: The purpose of this study was to determine the mechanisms by which patients with Crohn's disease develop intestinal failure and, in particular, to assess the relative importance of severe primary disease, repeated uncomplicated elective small intestine resection, and resection performed as a consequence of intra-abdominal septic surgical complications. METHODS: This was a retrospective analysis of 41 patients with Crohn's disease referred to a specialized intestinal failure unit between January 1987 and September 1998 for permanent home parenteral nutrition. To compare the surgical activity in patient groups, a resection index was calculated by dividing the number of intestinal resections by the interval in years between the first resection for Crohn's disease and referral for management of intestinal failure. RESULTS: Extensive primary Crohn's disease was responsible for intestinal failure in 7 cases (17 percent). The remainder (n=34, 83 percent) developed intestinal failure after intestinal resection. Nine of the surgical Crohn's patients developed intestinal failure after uncomplicated sequential resection, (median small-bowel length 65 (range, 60–120) cm) after a median of 3 (range, 2–8) operations over a median of 17 (range, 3–27) years. By contrast, the other 25 surgical Crohn's patients developed intestinal failure after multiple unplanned laparotomies for intra-abdominal sepsis (median small-bowel length 70 (range, 60–200) cm), with a median of 4 (range, 2–7) laparotomies performed over a median of 0.5 (range, 0.1 to 1.5) years (P<0.001). The resection index for the 25 Crohn's patients undergoing laparotomies for intra-abdominal sepsis was significantly greater than that of the 9 patients who had planned sequential resections (2.1 (0.27–25)vs. 0.23 (0.1–1.0);P < 0.002, Mann-WhitneyU test). CONCLUSION: Intestinal failure develops in Crohn's disease primarily as a result of complications of surgical treatment. The largest group of patients at risk consists of those who are undergoing multiple unplanned laparotomies to control intra-abdominal sepsis.     

Milky Spots Promote Ovarian Cancer Metastatic Colonization of Peritoneal Adipose in Experimental Models

The goal of controlling ovarian cancer metastasis formation has elicited considerable interest in identifying the tissue microenvironments involved in cancer cell colonization of the omentum. Omental adipose is a site of prodigious metastasis in both ovarian cancer models and clinical disease. This tissue is unusual for its milky spots, comprised of immune cells, stromal cells, and structural elements surrounding glomerulus-like capillary beds. The present study shows the novel finding that milky spots and adipocytes play distinct and complementary roles in omental metastatic colonization. In vivo assays showed that ID8, CaOV3, HeyA8, and SKOV3ip.1 cancer cells preferentially lodge and grow within omental and splenoportal fat, which contain milky spots, rather than in peritoneal fat depots. Similarly, medium conditioned by milky spot–containing adipose tissue caused 75% more cell migration than did medium conditioned by milky spot–deficient adipose. Studies with immunodeficient mice showed that the mouse genetic background does not alter omental milky spot number and size, nor does it affect ovarian cancer colonization. Finally, consistent with the role of lipids as an energy source for cancer cell growth, in vivo time-course studies revealed an inverse relationship between metastatic burden and omental adipocyte content. Our findings support a two-step model in which both milky spots and adipose have specific roles in colonization of the omentum by ovarian cancer cells.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.It is estimated that 22,240 women will be diagnosed with and 14,030 women will die of cancer of the ovary in 2013 (http://seer.cancer.gov/csr/1975_2009_pops09, last accessed June 18, 2013). The majority of patients present with metastases or eventually die of metastatic disease within the abdominal cavity. After escape from the primary tumor, ovarian cancer cells in the peritoneal fluid have access to and can potentially lodge within a variety of tissues.^1,2 In both clinical disease and experimental models, however, the omentum is the site of prodigious metastasis formation.^3–6 Thus, attachment of ovarian cancer cells to the omentum represents an early step in the development of widespread peritoneal disease.^7,8 Although the importance of the omentum is widely acknowledged, there still is no consensus on its role in metastasis formation. This raises the question of what components of the omental tissue microenvironment participate in, or facilitate, ovarian cancer metastatic colonization.Studies of omental function date back to the early 19th century. Jobert de Lamballe, a 19th-century surgeon in France, was reportedly the first to recognize the curious ability of this organ to fight infection and form adhesions to help control injuries.⁹ After nearly two centuries of investigation, a great deal is known about the physiology and surgical applications of the omentum.^9–12 As the central regulator of peritoneal homeostasis, its functions include regulating fluid and solute transport, sensing and repairing injuries, promoting angiogenesis, fighting infection, serving as a source of stem cells, producing regulatory molecules, and storing and supplying lipids. These diverse functions are conferred by the cellular composition and architecture characteristic of human omenta.Aside from the clear collagenous membrane that acts as a scaffold for the organ, the majority of the omentum is composed of bands of adipose tissue that contain adipocytes, blood and lymph vessels, immune cells, stromal cells, and connective matrix components that lie beneath an irregular mesothelium.¹³ In general, adipocytes have a variety of functions, ranging from lipid storage to production of endocrine molecules, and can serve as an integrating hub for inflammation, metabolism, and immunity.^2,14–23 A distinctive feature of the omental vasculature is the presence of numerous branching blood vessels ending in tortuous glomerulus-like capillary beds near the tissue periphery.^24–28 Immune cells aggregate around and within these capillary beds to form milky spots, which are the major immune structure for host defense of the peritoneal cavity.^24,29–36 In milky spots, both the endothelial lining of the capillaries and the overlying mesothelium are specially adapted to facilitate transmigration of immune cells.^24,37,38 Additional structural elements include plasmocytes, fibroblasts, and mesenchymal cells, as well as collagen and reticular and elastic fibers.^29,34,37,39A comprehensive literature review showed that studies examining the role of the omentum in metastasis focus on the contribution of its individual components, and not on the tissue as a whole. In our view, results from the majority of studies support models in which ovarian cancer metastatic colonization is driven either purely by milky spots or purely by adipocytes. The milky spot–driven model is based on a large body of in vivo data showing that, on intraperitoneal injection, cancer cells rapidly and specifically localize, invade, and proliferate within omental milky spots.^{3,6,24,28,40–44} In contrast, the adipocyte-driven model is based on the observation that, in its resting state, the omentum is composed predominantly of adipose and that cultured adipocytes can produce adipokines capable of promoting ovarian cancer cell migration and invasion in vitro.⁴⁵ Adipocytes can also provide a proliferative advantage by transferring fatty acids to ovarian cancer cells.⁴⁵ Although both models have clear strengths, neither addresses the intimate and dynamic interaction among milky spots, surrounding adipocytes, and other components of omental tissues.Taking tissue architecture and function as a guide, we propose that an alternative, more fully integrated model of metastatic colonization is needed. To test this idea, we identified peritoneal fat depots (omentum, mesentery, and uterine, gonadal, and splenoportal fat) that are accessible to ovarian cancer cells after intraperitoneal injection.² Of these, the omentum and splenoportal fat are reported to contain milky spot structures.^24,46 We reasoned that a comparison of peritoneal adipose that either contains or lacks milky spots could be used to determine the contributions of adipocytes and milky spots to the lodging and progressive growth of ovarian cancer cells in physiologically relevant tissues. In vivo studies using a panel of ovarian cancer cell lines showed that milky spots dramatically enhance early cancer cell lodging on peritoneal adipose tissues. Consistent with this finding, conditioned medium from milky spot–containing adipose tissue had a significantly increased ability to direct cell migration, compared with conditioned medium from milky spot–deficient adipose tissue. Studies using a panel of immunodeficient mice showed that the number and size of omental milky spots is not dependent on the mouse genetic background and, similarly, that ovarian cancer cell colonization does not depend on the immune composition of the milky spot. Finally, consistent with the role for lipids as an energy source for ovarian cancer cell growth, in vivo time-course studies revealed an inverse relationship between metastatic burden and adipocyte content in the omentum. Our findings support a two-step model in which both milky spots and adipose have specific roles in colonization of the omentum by ovarian cancer cells.     

Using Natural Language Processing on Electronic Health Records to Enhance Detection and Prediction of Psychosis Risk

BackgroundUsing novel data mining methods such as natural language processing (NLP) on electronic health records (EHRs) for screening and detecting individuals at risk for psychosis. MethodThe study included all patients receiving a first index diagnosis of nonorganic and nonpsychotic mental disorder within the South London and Maudsley (SLaM) NHS Foundation Trust between January 1, 2008, and July 28, 2018. Least Absolute Shrinkage and Selection Operator (LASSO)-regularized Cox regression was used to refine and externally validate a refined version of a five-item individualized, transdiagnostic, clinically based risk calculator previously developed (Harrell’s C = 0.79) and piloted for implementation. The refined version included 14 additional NLP-predictors: tearfulness, poor appetite, weight loss, insomnia, cannabis, cocaine, guilt, irritability, delusions, hopelessness, disturbed sleep, poor insight, agitation, and paranoia. ResultsA total of 92 151 patients with a first index diagnosis of nonorganic and nonpsychotic mental disorder within the SLaM Trust were included in the derivation (n = 28 297) or external validation (n = 63 854) data sets. Mean age was 33.6 years, 50.7% were women, and 67.0% were of white race/ethnicity. Mean follow-up was 1590 days. The overall 6-year risk of psychosis in secondary mental health care was 3.4 (95% CI, 3.3–3.6). External validation indicated strong performance on unseen data (Harrell’s C 0.85, 95% CI 0.84–0.86), an increase of 0.06 from the original model. ConclusionsUsing NLP on EHRs can considerably enhance the prognostic accuracy of psychosis risk calculators. This can help identify patients at risk of psychosis who require assessment and specialized care, facilitating earlier detection and potentially improving patient outcomes.     

Defects in Mitochondrial Efficiency and H2O2 Emissions in Obese Women Are Restored to a Lean Phenotype With Aerobic Exercise Training

The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m²), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m²). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H₂O₂ (mtH₂O₂) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH₂O₂ production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH₂O₂ emissions were refractory to a high-fat meal at baseline, but after exercise, mtH₂O₂ emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH₂O₂ emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.