HIV DNA reservoir and elevated PD-1 expression of CD4 T-cell subsets particularly persist in the terminal ileum of HIV-positive patients despite cART.

OBJECTIVES: Despite its importance as an HIV anatomic sanctuary, little is known about the characteristics of the HIV reservoir in the terminal ileum (TI). In blood, the immune checkpoint inhibitor programmed-death-1 (PD-1) has been linked to the HIV reservoir and T-cell immune dysfunction. We thus evaluated PD-1 expression and cell-associated HIV DNA in memory CD4 T-cell subsets from TI, peripheral blood (PB) and rectum (RE) of untreated and treated HIV-positive patients to identify associations between PD-1 and HIV reservoir in other sites. METHODS: Using mononuclear cells from PB, TI and RE of untreated HIV-positive (N = 6), treated (n = 18) HIV-positive and uninfected individuals (n = 16), we identified and sorted distinct memory CD4 T-cell subsets by flow cytometry, quantified their cell-associated HIV DNA using quantitative PCR and assessed PD-1 expression levels using geometric mean fluorescence intensity. Combined HIV-1 RNA in situ hybridization and immunohistochemistry was performed on ileal biopsy sections. RESULTS: Combined antiretroviral therapy (cART)-treated patients with undetectable HIV RNA and significantly lower levels of HIV DNA in PB showed particularly high PD-1 expression in PB and TI, and high HIV DNA levels in TI, irrespective of clinical characteristics. By contrast, in treatment-naïve patients HIV DNA levels in memory CD4 T-cell subsets were high in PB and TI. CONCLUSION: Elevated PD-1 expression on memory CD4 T-cells in PB and TI despite treatment points to continuous immune dysfunction and underlines the importance of evaluating immunotherapy in reversing HIV latency and T-cell reconstitution. As HIV DNA particularly persists in TI despite cART, investigating samples from TI is crucial in understanding HIV immunopathogenesis.

Predicting ADR from PDR and individual adenoma-to-polyp-detection-rate ratio for screening and surveillance colonoscopies: A new approach to quality assessment.

BACKGROUND AND AIMS: Adenoma detection rate (ADR) has been established as a quality indicator for screening colonoscopy. Because ADR is cumbersome to obtain in routine practice, polyp detection rate (PDR), polypectomy rate (PR) and adenoma-to-polyp-detection-rate-ratio (APDRR) have been proposed to estimate ADR. This study aimed to evaluate APDRR in order to estimate ADR (ADRest) in different settings. METHODS: Average risk screening and surveillance colonoscopies from a community-based private practice and a tertiary academic hospital setting were retrospectively evaluated. APDRR was calculated as averaged group APDRR for all study procedures (APDRR) and for the first half of study procedures of each gastroenterologist (APDRRag) or individually for each gastroenterologist on the basis of his or her first 25, 50 and 100 colonoscopies (APDRRind). ADRest was determined from PDR by using APDRR, APDRRag, and APDRRind, respectively. RESULTS: A total of 2717 individuals were analyzed. Using APDRR, significant correlations between ADR and ADRest were observed for the entire (0.944, p < 0.001), proximal (0.854, p < 0.001), and distal (0.977, p < 0.001) colon. These correlations were lost when APDRRag was used to estimate each gastroenterologist's ADR for the second half of his or her included colonoscopies. However, ADR and ADRest correlated significantly with a root-mean-square-error of 6.8% and 5.8% when APDRRind on the basis of each gastroenterologist's first 50 and 100 colonoscopies was used for subsequent colonoscopies. CONCLUSIONS: ADR for subsequent colonoscopies of an individual endoscopist can be reliably estimated from PDR by using an individually calculated APDRR. Prospective studies are needed to verify this promising approach in different practice settings.

Endosonographic diagnosis of solid pancreatic tumors: a retrospective analysis from a tertiary referral center.

BACKGROUND: The sensitivity of endosonography for pancreatic tumors is good, but differentiation between malignant and benign lesions remains a challenge. We, therefore, analyzed the correlation between endosonographic findings and pancreatic carcinoma in a population with a high prevalence of chronic pancreatitis. METHODS: 171 endosonographic examinations were retrospectively evaluated using 22 dichotomous criteria. Final diagnosis was defined by the results of pancreas resection or by clinical follow-up (median: 41 months). A sum score was established after multivariate analysis. RESULTS: Final diagnosis was carcinoma, chronic pancreatitis, neuroendocrine tumor and normal pancreas in 67, 65, 9, and 38 subjects (prevalence 39 %, 38 %, 5 %, 22 % respectively) After multivariate analysis, carcinoma was significantly correlated with six endosonographic criteria and age, which resulted in the following score (yes = 1, no = 0): (dilated pancreatic duct) + (vascular infiltration) + (suspicious lymph nodes) + (tumor edge with pseudopodia-like extensions) + (age > 50 years) - (increased pancreas parenchyma echogenicity) - (tumor diameter < 10 mm) + 3. After receiver operating characteristic analysis, the area under the curve was 0.85. For score values of 5 (4) or more, sensitivity was 0.63 (0.93), specificity 0.91 (0.55), positive predictive value 0.82 (0.57), negative predictive value 0.79 (0.92), positive likelihood ratio 7.24 (2.05), and negative likelihood ratio 0.41 (0.14). CONCLUSION: A simple and potentially useful score for the prediction of pancreatic cancer based on six endosonographic criteria and patient age was established. Distribution of final diagnoses in the patient population argues for the score's applicability in clinical practice of a tertiary referral center and warrants prospective validation.

Microchimerism in bone marrow-derived CD34(+) cells of patients after liver transplantation.

Lymphoid and dendritic cells of donor origin can be detected in the recipient several years after a solid organ transplantation. This phenomenon is termed microchimerism and could play a role in the induction of tolerance. The fate of other hematopoietic cells transferred by liver transplantation, in particular of stem and progenitor cells, is unknown. For this reason, we studied peripheral blood and bone marrow samples of 12 patients who had received a liver transplant from an HLA-DR mismatched donor. Eight patients were long-term survivors between 2.8 and 10.1 years after allografting. CD34(+) cells from bone marrow were highly enriched with the use of a 2-step method, and a nested polymerase chain reaction was applied to detect donor cells on the basis of allelic differences of the HLA-DRB1 gene. Rigorous controls with DRB1 specificities equal to the donor and host were included. In 5 of 8 long-term liver recipients, donor-specific CD34(+) cells could be detected in bone marrow. Microchimerism in the CD34(+) cell fraction did not correlate to the chimeric status in peripheral blood. In conclusion, our results demonstrate a frequent microchimerism among bone marrow-derived CD34(+) cells after liver transplantation. The functional role of this phenomenon still needs to be defined. (Blood. 2000;96:763-767)