Endoscopic ultrasound acquired portal venous circulating tumor cells predict progression free survival and overall survival in patients with pancreaticobiliary cancers.

BACKGROUND AND AIMS: Despite recent advances, patients with pancreaticobiliary cancers have a poor prognosis. We previously demonstrated the efficacy of endoscopic ultrasound (EUS) guided acquisition of portal vein (PV) blood for enumeration of circulating tumor cells (CTCs). The aim of this study was to assess PV-CTCs as potential biomarkers for the assessment of progression-free (PFS) and overall survival (OS) in patients with pancreaticobiliary cancers. METHODS: 17 patients with biopsy-proven pancreaticobiliary malignancy were enrolled. CTCs were enumerated from both peripheral and PV blood. All patients were followed until death. PFS and OS were evaluated with the log-rank test and summarized with the use of Kaplan-Meier methods. Unadjusted and adjusted Cox-proportional hazards models were fitted to study the relationship between PV-CTCs and PFS and OS. RESULTS: After 3.5 years of follow-up, all patients had expired. PV-CTCs were detected in all patients (median PV-CTCs 62.0/7.5 mL (interquartile range [IQR] 17-132). The mean PFS in patients with PV-CTCs <185/7.5 mL was significantly longer than patients with PV-CTCs ≥185/7.5 mL (43.3 weeks vs. 12.8 weeks, log-rank p = 0.002). The mean OS in patients with PV-CTCs <185/7.5 mL was significantly longer than patients with PV-CTCs ≥185/7.5 mL (75.8 weeks vs. 29.5 weeks, log-rank p = 0.021). In an adjusted Cox-proportional hazards model, PV-CTCs were significant predictors of both PFS and OS (HR 1.004, p = 0.037; HR 1.004, p = 0.044 respectively). CONCLUSION: In this pilot and feasibility study, EUS-acquired PV-CTCs predicted PFS and OS. Our findings suggest that PV-CTCs can help provide important prognostic data for both providers and patients.

The obesity paradox and survivors of ischemic stroke.

BACKGROUND: Although obesity is a risk factor for stroke and achieving normal weight is advocated to decrease stroke risk, the risk associated with obesity and weight loss after stroke has not been well established. The aim of this study was to assess the association of obesity at the time of stroke admission and weight loss after stroke with total mortality. METHODS: We analyzed 736 consecutive patients (mean age, 66 ± 11 years; 58% men) hospitalized for their first ischemic stroke. Body weight at hospital admission and at the outpatient visit during follow-up was used in the analysis. RESULTS: After multivariate adjustment, obesity at admission was associated with lower mortality risk as compared with normal weight (hazard ratio [HR], .50, P = .03). At the outpatient visit, with a median follow-up time of 16 months, 21% of patients had lost more than 3 kg of weight. Stroke severity, heart failure, transient ischemic attack, and depression after stroke were independently associated with significant weight loss. Weight loss of more than 3 kg was associated with increased mortality risk (HR, 5.87; P = .001) independently of other factors. Similar results were seen when weight loss was defined as losing more than 3% of baseline weight (HR, 4.97; P = .004). Weight gain of more than 5% of the baseline weight tended to be associated with better survival when compared with no weight change (log-rank test, P = .07). CONCLUSIONS: Normal weight at hospital admission and weight loss after ischemic stroke are independently associated with increased mortality. Overweight and obesity at baseline do not decrease the risk associated with weight loss.

How Drug Shortages Affect Clinical Care: The Case of the Surgical Anesthetic Propofol.

BACKGROUND: Periodic drug shortages have become a reality in clinical practice. In 2010, in the context of a nationwide drug shortage, our hospital experienced an abrupt 3-month shortage of the surgical anesthetic propofol. The purpose of this retrospective study was to survey the clinical impact of the abrupt propofol shortage at our hospital and to survey for any change in perioperative mortality. METHODS: A retrospective before-and-after analysis, comparing May through July 2010 (group A, prior to the propofol shortage) to August through October 2010 (group B, during the propofol shortage). RESULTS: In May through July 2010, before the propofol shortage, a majority of patients (80%) received propofol (group A, n = 2,830). In August through October 2010, during the propofol shortage, a majority of patients (81%) received etomidate (group B, n = 3,066). We observed that net usage of etomidate increased by more than 600% in our hospital. Baseline health characteristics and type of surgery were similar between groups A and B. Thirty-day and 2-year mortality were similar between groups A and B. The reported causes and frequency of mortality in groups A and B were also similar. CONCLUSION: The propofol shortage led to an increased usage of etomidate by more than 600%. In spite of that, we did not detect an increase in mortality associated with the increased use of etomidate during a 3-month propofol shortage.

Normal-weight obesity: implications for cardiovascular health.

We sought to review the epidemiological features and clinical implications of normal-weight obesity. The concept of normal-weight obesity has been recently reported as an important risk factor for cardiovascular disease, metabolic dysregulation, and poor functional outcomes. However, in clinical practice, normal-weight obesity is not commonly recognized. In this review, we examine the clinical significance and important epidemiological outcomes of normal-weight obesity and describe other variants of adiposity and adiposity-related metabolic status. The incorporation of measures of body fat content and distribution in the clinical setting could allow more accurate identification of adiposity-related long-term risk. This could in turn lead to early lifestyle changes and behavioral modifications that are essential to the treatment of obesity.

Cancer Cachexia in STK11/LKB1 -mutated NSCLC is Dependent on Tumor-secreted GDF15.

Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in STK11/LKB1 , a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered STK11/LKB1 -mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived STK11/LKB1 -mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived STK11/LKB1 -mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of GDF15 in multiple human NSCLC lines was also sufficient to eliminate in vivo circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type STK11/LKB1 in a human STK11/LKB1 loss-of-function NSCLC line that normally induces cachexia in vivo correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with STK11/LKB1 loss-of-function mutations promote cachexia-associated wasting.

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.

Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

Colonocyte-derived lactate promotes E. coli fitness in the context of inflammation-associated gut microbiota dysbiosis.

BACKGROUND: Intestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology. RESULTS: We investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis. CONCLUSIONS: The release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract.

Favorable Outcomes Combining Vedolizumab With Other Biologics or Tofacitinib for Treatment of Inflammatory Bowel Disease.

Background: Combining advanced therapies may improve outcomes in inflammatory bowel disease (IBD), but there are little data on the effectiveness and safety of this approach. Methods: We examined outcomes of patients who received vedolizumab in combination with another biologic or tofacitinib between 2016 and 2020. Results: Fourteen patients (10 ulcerative colitis [UC], 3 Crohn disease, 1 indeterminate colitis) received a combination of advanced therapies. Vedolizumab was combined with tofacitinib in 9 patients, ustekinumab in 3, and adalimumab in 2. Median follow-up on combination therapy was 31 weeks. Normalization of C-reactive protein (CRP) or fecal calprotectin (<5 mg/L and <150 µg/g, respectively) was achieved in 56% (5/9) and 50% (4/8) of patients. Paired median CRP decreased from 14 mg/L to <5 mg/L with combination therapy (n = 9, P = 0.02), and paired median calprotectin from 594 µg/g to 113 µg/g (n = 8, P = 0.12). Among patients with UC, paired median Lichtiger score decreased from 9 to 3 (n = 7, P = 0.02). Prednisone discontinuation was achieved in 67% (4/6) of prednisone-dependent patients. There were 4 infections: 2 required hospitalization (rotavirus, Clostridium difficile), and 2 did not (pneumonia, sinusitis). During follow-up, 5/14 patients discontinued combination therapy (2 nonresponse; 1 improvement and de-escalation; 1 noninfectious adverse effect; 1 loss of coverage). Conclusions: In this retrospective case series of a cohort with refractory IBD, combining vedolizumab with other biologics or tofacitinib improved inflammatory markers, reduced clinical disease activity and steroid use, and was well tolerated.

Complete response of metastatic melanoma in a patient with Crohn's disease simultaneously receiving anti-α4ß7 and anti-PD1 antibodies.

BACKGROUND: Immune checkpoint inhibitors (ICPIs) are increasingly being used in the treatment of a variety of malignancies. The original studies that demonstrated the efficacy of ICPIs excluded patients actively being treated for autoimmune conditions, and there is only limited evidence that these treatments are safe and effective in this population of patients. CASE PRESENTATION: We present a case of a man with Crohn's disease actively requiring immunosuppressive therapy who subsequently received pembrolizumab for metastatic melanoma. He had no further progression of metastatic disease and had resolution of his pulmonary nodule while he experienced no Crohn's disease flares or immune related adverse events. We surveyed the existing literature for studies examining the use of ICPIs in patients with autoimmune disorders and reviewed the unique mechanism of action of the α4ß7 inhibitor, vedolizumab. CONCLUSION: Patients with autoimmune conditions should be considered candidates for immune checkpoint inhibition even in the setting of active immunosuppressive therapy. The mechanism of action of immunosuppressive therapy should be considered with the most targeted form of treatment being used when possible. Further prospective studies investigating immunotherapy in patients with autoimmune conditions are warranted.

Outcomes of endoscopic treatment of leaks and fistulae after sleeve gastrectomy: results from a large multicenter U.S. cohort.

BACKGROUND: Sleeve gastrectomy is the most commonly performed bariatric surgery in the United States. Leaks after sleeve gastrectomy (SGL) occur in 1% to 3% of patients. Endoscopic therapies are increasingly used for treatment of SGLs, but few data exist on their outcomes. OBJECTIVES: The aim of this study was to assess technical success, leak resolution, and reoperation rates of patients undergoing endoscopic therapy for repair SGLs. SETTING: Eight high-volume academic endoscopy centers. METHODS: Patients undergoing endoscopic therapy for SGLs from 2007 to 2017 were identified. Patients were excluded if the index endoscopic therapy for SGL was performed elsewhere or if no follow-up data were available. Leaks were classified as acute (≤7 d of SG), early (1-6 wk), late (7-12 wk), and chronic (>12 wk). Leak resolution was defined as lack of extraluminal air, extravasation on oral contrast radiography, cross-sectional imaging, or resolution of percutaneous drain output. Demographic and procedural data were recorded as rates of additional therapy, adverse events, and surgical revision. RESULTS: A total of 85 patients met criteria for analysis (70 women, age 42.6 ± 10.8 yr). A total of 295 endoscopic sessions (median 3, range 1-14) were performed across the cohort. SGLs resolved after index endoscopic therapy in 43 (50.1%) patients. The primary outcome of endoscopic resolution of SGL was observed in 62 patients (72.9%). There were 34 (11.5%) PRAE (the majority occurring with self-expandable metal stents), all but 1 of which were managed endoscopically. Surgical revision was required in 23 (21.7%) patients. On univariate analyses independent variables associated with the need for surgical revision included both acute and chronic SGLs (P = .028), loculated subphrenic collections/abscesses (P = .03), and intraabdominal sepsis (P = .03). On multivariable logistic regression using statistically significant predictors from the univariate analyses, acute SGLs were significantly associated with a need for surgical revision (odds ratio 4.8, 95% confidence interval 1.2-18.9, P = .025). CONCLUSION: Endoscopic therapy for SGLs is associated with good clinical success, avoiding the need for surgical revision in 73% of patients, with an acceptable adverse event profile. Patients with acute or chronic SGLs and those with loculated abscesses or intraabdominal sepsis are more likely to undergo surgical revision. Endoscopic therapy is an appropriate first-line modality for the management of SGLs, especially those not classified as acute or chronic.