In recurrent head and neck squamous cell carcinoma ineligible for resection or irradiation, treatment aims primarily at symptom control and quality of life enhancement with an expected outcome of 6–12 months.

ABSTRACT Point-of-care tests for tuberculous meningitis (TBM) are needed. We studied the diagnostic accuracy of the lipoarabinomannan (LAM) lateral flow assay (LFA), LAM enzyme-linked immunosorbent assay (ELISA), and Xpert MTB/RIF in cerebrospinal fluid (CSF) in an autopsy cohort of Ugandan HIV-infected adults. We obtained written informed consent postmortem from the next of kin. A complete autopsy was done and CSF obtained. We performed LAM LFA (on unprepared and supernatant CSF after heating and spinning), LAM ELISA, and Xpert MTB/RIF on the CSF samples. Accuracy parameters were calculated for histopathological TBM and also for the composite standard, including Xpert MTB/RIF-positive cases. We tested CSF of 91 patients. LAM LFA had a sensitivity of 75% for definite histopathological TBM, ELISA a sensitivity of 43%, and Xpert MTB/RIF a sensitivity of 100% and specificities of 87%, 91%, and 87%, respectively. LAM LFA had a sensitivity of 50% for definite and probable histopathological TBM, ELISA a sensitivity of 38%, and Xpert MTB/RIF a sensitivity of 86% and specificities of 70%, 91%, and 87%, respectively. LAM LFA had a sensitivity of 68% for the composite standard and ELISA a sensitivity of 48% and specificities of 78% and 98%, respectively. The rapid diagnostic tests detected TBM in 22% to 78% of patients not on anti-TB treatment. Point-of-care tests have high accuracy in diagnosis of TBM in deceased HIV-infected adults. LAM LFA in CSF is a useful additional diagnostic tool.

OBJECTIVE:The detection of urinary lipoarabinomannan (LAM), a mycobacterial cell wall component, is used to diagnose tuberculosis (TB). How LAM enters the urine is not known. To investigate if urinary LAM-positivity is the result of renal TB infection we correlated the outcomes of urinary LAM-antigen testing to renal histology in an autopsy cohort of hospitalized, Ugandan, HIV-infected adults.METHODS:We performed a complete autopsy, including renal sampling, in HIV-infected adults that died during hospitalization after written informed consent was obtained from the next of kin. Urine was collected postmortem through post-mortem catheterisation or by bladder puncture and tested for LAM with both a lateral flow assay (LFA) and an ELISA assay. Two pathologists assessed the kidney histology. We correlated the LAM-assay results and the histology findings.RESULTS:Of the 13/36 (36%) patients with a positive urinary LAM ELISA and/or LFA, 8/13 (62%) had renal TB. The remaining 5 LAM-positive patients had disseminated TB without renal involvement. Of the 23 LAM-negative patients, 3 had disseminated TB without renal involvement. The remaining LAM-negative patients had no TB infection and died mostly of fungal and bacterial infections. LAM LFA had a sensitivity of 81% and specificity of 100% to diagnose TB at any location, and the LAM ELISA a sensitivity of 63% and a specificity of 100%. 54% (7/13) LAM LFA-positive patients were not on anti-TB treatment at the time of death.CONCLUSION:Renal TB infection explained LAM-positivity in the majority of patients. Patients with disseminated TB without renal involvement can also be diagnosed with LAM. This suggests that other mechanisms that lead to urinary LAM-positivity exist in a minority of patients.

Background & Aims: Peroxisome proliferator-activated receptors (PPARs) have been implicated in non-alcoholic steatohepatitis (NASH) pathogenesis, mainly based on animal data. Gene expression data in NASH patients are scarce. We studied liver PPAR alpha, beta/delta, and gamma expression in a large cohort of obese patients assessed for presence of NAFLD at baseline and 1 year follow-up.Methods: Patients presented to the obesity clinic underwent a hepatic work-up. If NAFLD was suspected, liver biopsy was performed. Gene expression was studied by mRNA quantification. Patients were reassessed after 1 year.Results: 125 patients were consecutively included in the study, of which 85 patients had paired liver biopsy taken at 1 year of follow-up. Liver PPAR alpha expression negatively correlated with the presence of NASH (p = 0.001) and with severity of steatosis (p = 0.003), ballooning (p = 0.001), NASH activity score (p = 0.008) and fibrosis (p = 0.003). PPAR alpha expression was positively correlated to adiponectin (R-2 = 0.345, p = 0.010) and inversely correlated to visceral fat (R-2 = -0.343, p < 0.001), HOMA IR (R-2 = -0.411, p < 0.001) and CK18 (R-2 = -0.233, p = 0.012). Liver PPAR beta/delta and PPAR gamma expression did not correlate with any histological feature nor with glucose metabolism or serum lipids. At 1 year, correlation of PPAR alpha expression with liver histology was confirmed. In longitudinal analysis, an increase in expression of PPAR alpha and its target genes was significantly associated with histological improvement (p = 0.008).Conclusion: Human liver PPAR alpha gene expression negatively correlates with NASH severity, visceral adiposity and insulin resistance and positively with adiponectin. Histological improvement is associated with an increase in expression of PPAR alpha and its target genes. These data might suggest that PPAR alpha is a potential therapeutic target in NASH. (C) 2015 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

An independent role of nonalcoholic fatty liver disease (NAFLD) in the development of cardiovascular disease has been suggested, probably mediated through increased levels of prothrombotic factors. Therefore, we examined whether NAFLD is linked to a prothrombotic state, independently of metabolic risk factors in a large single-center cohort of overweight/obese patients. Patients presenting to the obesity clinic underwent a detailed metabolic and liver assessment, including an extensive panel of coagulation factors. If NAFLD was suspected, a liver biopsy was proposed. A series of 273 consecutive patients (65% female) with a liver biopsy were included (age, 44 +/- 0.76 years; body mass index: 39.6 +/- 0.40 kg/m(2)). Increase in fibrinogen, factor VIII, and von Willebrand factor and decrease in antithrombin III correlated with metabolic features, but not with liver histology. Levels of plasminogen activator inhibitor-1 (PAI-1) increased significantly with increasing severity of steatosis (P<0.001), lobular inflammation (P<0.001), ballooning (P=0.002), and fibrosis (P<0.001). Patients with nonalcoholic steatohepatitis had significantly higher PAI-1 values than those with normal liver (P<0.001). In multiple regression, including anthropometric and metabolic parameters, steatosis remained an independent predictor of PAI-1 levels, explaining, together with fasting C-peptide and waist circumference, 21% of the variance in PAI-1. No consistent correlations with histology were found for the other coagulation factors. Conclusion: In obesity, NAFLD severity independently contributes to the increase in PAI-1 levels, whereas other coagulation factors are unaltered. This finding might, in part, explain the increased cardiovascular risk associated with NAFLD. (Hepatology 2014;58:121-129)

BACKGROUND:Percutaneous needle autopsy can overcome a number of barriers that limit the use of complete autopsies. We performed blind-and ultrasound guided needle autopsies in HIV-infected adults in Uganda. In this study we describe in detail the methods we used, the ability of both procedures to obtain sufficient tissue for further examination and the learning curve of the operators over time.METHODS:If written informed consent was granted from the next of kin, we first performed a blind needle autopsy, puncturing brain, heart, lungs, liver, spleen and kidneys using predefined surface marking points. We then performed an ultrasound guided needle autopsy puncturing heart, liver, spleen and kidneys. The number of attempts, expected success and duration of the procedure were noted. A pathologist read the slides and indicated if the target tissue was present and of sufficient quality for pathological review. We report the predicted and true success rates, compare the yield of blind to ultrasound guided needle biopsies and evaluate the failure rate over time.RESULTS:Two operators performed 96 blind needle autopsies and 95 ultrasound guided needle autopsies. For blind needle biopsies true success rates varied from 56-99% and predicted success rates from 89-99%. For ultrasound guided needle biopsies true success rates varied from 72-100% and predicted success rates from 84-98%. Ultrasound guidance led to a significantly higher success rate in heart and left kidney. A learning curve was observed over time with decreasing failure rates with increasing experience and a shorter duration of the needle autopsy.CONCLUSION:Needle autopsy can successfully obtain tissue for further pathological review in the vast majority of cases, with a decrease in failure rate with increasing experience of the operator. The benefit of ultrasound guidance will depend on the population, the disease and organ of interest and the local circumstances. Our results justify further evaluation of needle autopsies as a method to establish a cause of death.

INTRODUCTION:Minimal invasive but accurate methods to establish the cause of death in HIV-infected patients are needed. We studied the agreement in cause of death between blind and ultrasound-guided needle autopsy and complete autopsy in HIV-infected patients in Uganda.METHODS:We subsequently performed a blind and ultrasound-guided needle autopsy followed by a complete autopsy in HIV-infected adults who died during hospitalization. Two teams of pathologists reviewed the tissue from either the needle autopsies or the complete autopsy and formulated the major diagnoses, that is, diseases directly contributing to death. The primary outcome was concordance in major diagnosis between needle and complete autopsies.RESULTS:We performed 96 blind needle and complete autopsies and 95 ultrasound-guided needle autopsies. Concordance in major diagnosis between blind needle and complete autopsy was 50%. For the main major diagnosis, tuberculosis (TB) concordance was higher (71%; P < 0.01). Blind needle autopsy identified at least 1 major diagnosis in 60% of patients; and in 46%, there was complete concordance for all major diagnoses. The main reason for discordance was sampling error of the lesion. Concordance with the addition of ultrasound guidance was 52% for all major diagnoses and 79% for TB. Major diagnoses were mainly identified in tissue cores from the liver (76%) and the spleen (82%).DISCUSSION:Blind needle autopsy identified half of the major diagnosis. The addition of ultrasound guidance did not significantly improve the performance of needle autopsy. Needle autopsy is a valuable method to confirm causes of death in HIV-infected patients, especially for highly prevalent diseases like TB.

Background Information on causes of death in HIV-infected patients in Sub-Saharan Africa is mainly derived from observational cohort and verbal autopsy studies. Autopsy is the gold standard to ascertain cause of death. We conducted an autopsy study to describe and compare the clinical and autopsy causes of death and contributory findings in hospitalized HIV-infected and HIV-uninfected patients in Uganda. Methods Between May and September 2009 a complete autopsy was performed on patients that died on a combined infectious diseases gastroenterology ward in Mulago Hospital in Kampala, Uganda. Autopsy cause of death and contributing findings were based on the macro- and microscopic post-mortem findings combined with clinical information. Clinical diagnoses were reported by the ward doctor and classified as confirmed, highly suspected, considered or not considered, based on information derived from the medical chart. Results are reported according to HIV serostatus. Results Fifty-three complete autopsies were performed in 66% HIV-positive, 21% HIV-negative and 13% patients with an unknown HIV serological status. Infectious diseases caused death in 83% of HIV-positive patients, with disseminated TB as the main diagnosis causing 37% of deaths. The spectrum of illness and causes of death were substantially different between HIV-positive and HIV-negative patients. In HIV-positive patients 12% of postmortem diagnoses were clinically confirmed, 27% highly suspected, 16% considered and 45% not considered. In HIV-negative patients 17% of postmortem diagnoses were clinically highly suspected, 42% considered and 42% not considered. Conclusion Autopsy examination remains an important tool to ascertain causes of death particularly in settings with limited access to diagnostic testing during life. HIV-positive patients continue to die from treatable and clinically undiagnosed infectious diseases. Until rapid-point of care testing is available to confirm common infections, empiric treatment should be further investigated.

Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n=30) or a methionine–choline-deficient (MCD) diet (n=30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-α, IL-1β and interferon-γ, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-α smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636±0.0605 mm Hg/ml/min in controls vs 0.7270±0.0408 mm Hg/ml/min in MCD-fed rats, P<0.001), indicating an increased intrahepatic resistance, which was haemodynamically significant (portocaval pressure gradient 2.2±1.1 vs 8.2±1.3 mm Hg in controls vs MCD, P<0.001). Dose-response curves to acetylcholine were significantly reduced in MCD-fed rats (P<0.001) as was the responsiveness to methoxamine (P<0.001). Vascular corrosion casts showed a replacement of the regular sinusoidal anatomy by a disorganized pattern with multiple interconnections and vascular extensions. Liver phosphorylated endothelial NO synthase (eNOS)/eNOS and serum nitrite/nitrate were not increased in severe steatosis, whereas liver thromboxane synthase expression, liver endothelin-1 (ET-1) expression and serum andothelin-1 concentration were significantly increased. Severe steatosis induces a haemodynamically significant increase in intrahepatic resistance, which precedes inflammation and fibrogenesis. Both functional (endothelial dysfunction and increased thromboxane and ET-1 synthesis) and structural factors are involved. This phenomenon might significantly contribute to steatosis-related disease.

BACKGROUND & AIMS: Reliable noninvasive tools are needed for staging nonalcoholic fatty liver disease (NAFLD). Published scoring systems have not been validated in prospective assessments of unselected patients. We aimed to identify factors that predicted development of nonalcoholic steatohepatitis (NASH) in a large group of overweight or obese patients and compared these with established factors. METHODS: We performed a prospective analysis of factors associated with the development and severity of NAFLD in patients at a single obesity center. We evaluated liver involvement in 542 patients by a large set of routine and non-routine parameters, including ultrasound and genetic testing. Those suspected of having NAFLD underwent liver biopsy (57.7%). Patients were divided into design cohort (n = 200) and validation cohort (n = 113) to identify factors associated with the presence and severity of NAFLD and NASH. RESULTS: Factors independently associated with development of NASH included increased levels of alanine aminotransferase (ALT), fasting levels of C-peptide, and ultrasound steatosis scores (USSs), with area under the receiver operating curve (AUROC) values of 0.854 in the design cohort and 0.823 in the validation cohort. NASH activity scores also correlated with level of ALT, USS, and fasting level of C-peptide (R-2 = 0.491). Independent predictors of advanced fibrosis included waist circumference and level of aspartate aminotransferase (AUROC values of 0.839 and 0.846 for design and validation cohorts, respectively; negative predictive values of 98% and 97%, respectively, for a cutoff of -2.14). Previously published scoring systems had significantly lower AUROC values. Levels of CK18 and PNPLA3 polymorphisms correlated with development of NASH but did not add value. CONCLUSIONS: Parameters routinely analyzed in assessing obese patients can be used to determine the presence of NASH and advanced fibrosis. Non-routine tests do not increase diagnostic accuracy. Previously published scores are significantly less accurate.

Ductal carcinoma in situ (DCIS) represents a heterogenous group of lesions with variable malignant potential. Although it is clearly pre-invasive, not all lesions progress to an invasive malignant disease. The significant increase in the frequency of diagnosis is the result of both widespread use of screening mammography and better recognition among pathologists. Treatment is controversial, but for several decades total mastectomy has been considered as the appropriate treatment. The tendency to be less aggressive in terms of surgery has followed the pattern of events observed in the treatment of invasive breast carcinomas. More recently, it has become clear that breastconserving procedures could be applied and selected on the basis of diagnostics and risk factors. When all patients with DCIS are considered, the overall mortality is extremely low, only about 1–2%. On the other hand, breast-conserving surgery is only curative in 75–85%; 50% of the local recurrences have proven to be invasive with a mortality rate of 12–15%. There is no place for axillary node dissection, adjuvant hormonal treatment or chemotherapy in the treatment. Important factors in predicting local recurrence are age, family history, nuclear grade, comedo-type necrosis, tumor size and margin width. With the addition of radiation therapy to excisional surgery, there is a 50% reduction in the overall local recurrence rate. The Van Nuys Prognostic Index (VNPI), recently updated, is a tool that quantifies measurable prognostic factors that can be used in the decision-making process of treatment. Recent data from large cohort studies and randomized trials have emerged to guide treatment. DCIS is now understood to have diverse malignant potential and it is unlikely that there will be a single treatment for this wide range of lesions. Advances in molecular biology and gene expression profiling of human breast tumors have been providing important insights into the relationship between DCIS and invasive breast cancer.

Abstract:  Ductal carcinoma in situ (DCIS) is considered a heterogeneous premalignant condition of the breast with a certain probability for progressing to malignancy. There is no standard of care. The updated Van Nuys Prognostic Index (VNPI) 2003 is a clinical tool in treatment decision making. This study assessed the prognostic value of the VNPI after integration of proliferative biomarkers (GGI and Ki‐67). DCIS samples were divided into three VNPI subgroups (low risk [score 4–6], intermediate risk [score 7–9], high risk [score 10–12]) based on nuclear grade ± necrosis, tumor size, margin width, and age. Nuclear grade was substituted by the genomic grade index (GGI) to generate the VNPI‐GGI and combined with the Ki‐67 to generate the VNPI‐Ki67. Disease‐free survival was calculated by Kaplan–Meier survival plots with log‐rank significance. Multiple regression analysis was carried out using Cox proportional hazard regression analysis. A total of 88 cases (median age 54 years) with representative tissue were identified out of 168 DCIS patients. Median follow‐up was more than 5 years. Ten patients developed an ipsilateral recurrence of whom nine were invasive: six patients were classified in the VNPI subgroup 2 and three patients in the VNPI subgroup 3. One non‐invasive recurrence (DCIS) was classified in the VNPI subgroup III. A statistical association was observed between a high VNPI score and a higher risk of recurrence (HR = 7.72 [95% CI 1.01–58.91], p = 0.049). Ki‐67 did not improve the prognostic value of VNPI (HR = 6.5, [95% CI 0.80–53.33], p = 0.08). In contrast, the VNPI‐GGI could identify more accurately high‐risk DCIS patients with early relapses within 5 years (HR = 18.14 [95% CI 1.75–188], p = 0.015). GGI incorporated into the VNPI improved its prognostic value for DCIS, especially for identifying early relapses. This method should be validated and incorporated in future prospective clinical DCIS trials.