HIV-1 infection is associated with a progressive loss of T cell functional capacity and reduced responsiveness to antigenic stimuli. The mechanisms underlying T cell dysfunction in HIV-1/AIDS are not ...completely understood. Multiple studies have shown that binding of program death ligand 1 (PD-L1) on the surface of monocytes and dendritic cells to PD-1 on T cells negatively regulates T cell function. Here we show that neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1. PD-L1 is induced by HIV-1 virions, TLR-7/8 ligand, bacterial lipopolysaccharide (LPS), and IFNα. Neutrophil PD-L1 levels correlate with the expression of PD-1 and CD57 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils (LDNs) expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). Collectively, the accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function.
Abstract Objectives Biliary injuries are frequently accompanied by vascular injuries, which may worsen the bile duct injury and cause liver ischemia. We performed an analytical review with the aim of ...defining vasculobiliary injury and setting out the important issues in this area. Methods A literature search of relevant terms was peformed using OvidSP. Bibliographies of papers were also searched to obtain older literature. Results Vasculobiliary injury was defined as: an injury to both a bile duct and a hepatic artery and/or portal vein; the bile duct injury may be caused by operative trauma, be ischaemic in origin or both, and may or may not be accompanied by various degrees of hepatic ischaemia. Right hepatic artery (RHA) vasculobiliary injury (VBI) is the most common variant. Injury to the RHA likely extends the biliary injury to a higher level than the gross observed mechanical injury. VBI results in slow hepatic infarction in about 10% of patients. Repair of the artery is rarely possible and the overall benefit unclear. Injuries involving the portal vein or common or proper hepatic arteries are much less common, but have more serious effects including rapid infarction of the liver. Conclusions Routine arteriography is recommended in patients with a biliary injury if early repair is contemplated. Consideration should be given to delaying repair of a biliary injury in patients with occlusion of the RHA. Patients with injuries to the portal vein or proper or common hepatic should be emergently referred to tertiary care centers.
Recent observational studies indicate an association between the use of hormonal contraceptives and acquisition and transmission of HIV-1. The biological and immunological mechanisms underlying the ...observed association are unknown. Depot medroxyprogesterone acetate (DMPA) is a progestin-only injectable contraceptive that is commonly used in regions with high HIV-1 prevalence. Here we show that medroxyprogesterone acetate (MPA) suppresses the production of key regulators of cellular and humoral immunity involved in orchestrating the immune response to invading pathogens. MPA inhibited the production of interferon (IFN)-γ, IL-2, IL-4, IL-6, IL-12, TNFα, macrophage inflammatory protein-1α (MIP-1α), and other cytokines and chemokines by peripheral blood cells and activated T cells and reduced the production of IFNα and TNFα by plasmacytoid dendritic cells in response to Toll-like receptor-7, -8, and -9 ligands. Women using DMPA displayed lower levels of IFNα in plasma and genital secretions compared with controls with no hormonal contraception. In addition, MPA prevented the down-regulation of HIV-1 coreceptors CXCR4 and CCR5 on the surface of T cells after activation and increased HIV-1 replication in activated peripheral blood mononuclear cell cultures. The presented results suggest that MPA suppresses both innate and adaptive arms of the immune system resulting in a reduction of host resistance to invading pathogens.
Background
As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions.
...Materials and Methods
A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19‐9 (CA19‐9) were excluded. Serum CA19‐9 response was analyzed as a predictor of disease progression, recurrence, and survival.
Results
One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19‐9 from baseline to minimum value (odds ratio OR 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19‐9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19‐9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1–4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001).
Conclusion
Patients with initially elevated CA19‐9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort.
Implications for Practice
This study identified percent changes in carbohydrate antigen 19‐9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.
Treatment of patients with borderline resectable pancreas cancer is a topic of great debate. This article analyzes serum CA19‐9 response as a predictor of disease progression, recurrence, and survival.
An elevation in serum phosphate-also called hyperphosphatemia-is associated with reduced kidney function in chronic kidney disease (CKD). Reports show CKD patients are more likely to develop lung ...disease and have poorer kidney function that positively correlates with pulmonary obstruction. However, the underlying mechanisms are not well understood. Here, we report that two murine models of CKD, which both exhibit increased serum levels of phosphate and fibroblast growth factor (FGF) 23, a regulator of phosphate homeostasis, develop concomitant airway inflammation. Our in vitro studies point towards a similar increase of phosphate-induced inflammatory markers in human bronchial epithelial cells. FGF23 stimulation alone does not induce a proinflammatory response in the non-COPD bronchial epithelium and phosphate does not cause endogenous FGF23 release. Upregulation of the phosphate-induced proinflammatory cytokines is accompanied by activation of the extracellular-signal regulated kinase (ERK) pathway. Moreover, the addition of cigarette smoke extract (CSE) during phosphate treatments exacerbates inflammation as well as ERK activation, whereas co-treatment with FGF23 attenuates both the phosphate as well as the combined phosphate- and CS-induced inflammatory response, independent of ERK activation. Together, these data demonstrate a novel pathway that potentially explains pathological kidney-lung crosstalk with phosphate as a key mediator.
Abstract Background Several observational studies have suggested that radiofrequency ablation (RFA) may have survival benefits similar to hepatic resection (HR) in cirrhotic patients affected by ...hepatocellular carcinoma (HCC) are not candidates for liver transplantation. A small randomized controlled trial confirmed these findings, although underpowered to detect a significant difference at 5-year interval. Methods A Markov model was created to simulate a randomized trial comparing the quality of life–adjusted survival for individuals undergoing HR versus RFA for HCCs less than 5 cm in diameter. Results HR was the best therapeutic option with 5.33 (standard deviation ±.42) versus 3.91 (standard deviation ±.38) quality-adjusted life years except for in individuals older than 75 years of age ( P = .02, log rank test). One-way sensitivity analysis showed that RFA was the preferred strategy if the perioperative mortality of HR was more than 30%, if the percentage of patients with negative margins was less than 60%, and if RFA could be performed at least 60% of the time for recurrent disease after a previous ablation. The quality of life associated with both procedures did not influence the results of this model. Conclusions HR provided better quality of life–adjusted survival as ablation therapy was associated with increased risk of local recurrent disease requiring multiple sessions. For older individuals, RFA appears to be the best therapeutic option. If the probability of ablation for recurrent disease is equal in the 2 arms, survival benefits of RFA is similar to HR.
Background Adhesive small bowel obstruction (ASBO), although a potential surgical emergency, is increasingly being managed by medical hospitalists due to the likelihood these patients will not ...require operation. However, the value of care delivered by medical hospitalists to patients with ASBO has not been reported. Study Design We hypothesized that patients admitted to the medical hospitalist service (MHS) for presumed ASBO have increased length of stay (LOS) and charges compared with patients admitted to the surgical service (SS). There were 555 consecutive admissions with presumed ASBO from 2008 to 2012; these were reviewed and grouped according to admitting service and whether an operation was performed. Group medians were compared and multivariate analysis was performed to identify variables independently associated with increased LOS, time to operation (TTO), and charges. Results Median LOS among patients whose ASBO resolved nonoperatively was similar for those on SS and MHS (2.85 days vs 2.98 days; p = 0.49). In patients without nonoperative resolution of ASBO, those admitted to MHS had longer median LOS when compared with those admitted to SS (9.57 days vs 6.99 days; p = 0.002) and higher median charges ($38,800 vs $30,100; p = 0.025). Patients admitted to MHS who had an operation, had a greater median TTO than operative patients on SS (51.72 hours vs 8.4 hours; p < 0.001). Multivariate analysis did not identify factors independently predictive of increased LOS, TTO, or charges. Conclusions Adhesive small bowel obstruction patients are treated in a heterogeneous fashion in our hospital, causing disparate outcomes depending on admitting service when patients undergo operation. Admitting all suspected ASBO patients to SS has the potential to dramatically decrease LOS and reduce waste in those requiring operation, thereby reducing health care expenditures.
Background
The optimum approach to neoadjuvant therapy for patients with borderline resectable pancreatic cancer is undefined. Herein we report the outcomes of an extended neoadjuvant chemotherapy ...regimen in patients presenting with borderline resectable adenocarcinoma of the pancreatic head.
Methods
Patients identified as having borderline resectable pancreatic head cancer by American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology consensus criteria from 2008 to 2012 were tracked in a prospectively maintained registry. Included patients were initiated on a 24-week course of neoadjuvant chemotherapy. Medically fit patients who completed neoadjuvant treatment without radiographic progression were offered resection with curative intent. Clinicopathologic variables and surgical outcomes were collected retrospectively and analyzed.
Results
Sixty-four patients with borderline resectable pancreatic cancer started neoadjuvant therapy. Thirty-nine (61 %) met resection criteria and underwent operative exploration with curative intent, and 31 (48 %) were resected. Of the resected patients, 18 (58 %) had positive lymph nodes, 15 (48 %) required en-bloc venous resection, 27 (87 %) had a R0 resection, and 3 (10 %) had a complete pathologic response. There were no postoperative deaths at 90 days, 16 % of patients had a severe complication, and the 30-day readmission rate was 10 %. The median overall survival of all 64 patients was 23.6 months, whereas that of unresectable patients was 15.4 months. Twenty-five of the resected patients (81 %) are still alive at a median follow-up of 21.6 months.
Conclusions
Extended neoadjuvant chemotherapy is well tolerated by patients with borderline resectable pancreatic head adenocarcinoma, selects a subset of patients for curative surgery with low perioperative morbidity, and is associated with favorable survival.
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