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Xiao-Chun Huang,1,2 Fei-Xiong Pang,1,2 Sheng-Song Ou,1,2 Xiao-Jiao Wei,1,2 Yu-Ju Xu,1,2 Yan-Hua Lai1,2 1Department of Transplantation, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of China; 2Guangxi Academy Of Medical Sciences, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Yan-Hua LaiDepartment of transplantation, People’s Hospital of Guangxi Zhuang Autonomous Region, No. 6 Taoyuan Road, Nanning, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of ChinaTel +86 13978798471Email 1379771812@qq.comPurpose: Liver transplantation (LT) currently yields the best outcomes for hepatocellular carcinoma (HCC). However, tumor recurrence still occurs in some patients. Identifying markers that predict HCC recurrence after LT is an unmet medical need.Methods: In this study, differential expression analysis was used to identify differentially expressed microRNAs (DEmiRs) between HCC and liver tissues in the The Cancer Genome Atlas database and in data from patients with recurrent or non-recurrent HCC in the GSE64989 dataset. The expression profiles of the overlap DEmiRs were used to construct an miRNA-based risk score to predict prognosis using Cox regression analysis. The target genes of the miRNAs of interest were predicted, and they were analyzed for functional enrichment. Furthermore, we used the miRNAs of interest to construct a competitive endogenous RNA (ceRNA) network of long non-coding RNAs (lncRNAs), miRs and mRNAs.Results: Four up-regulated and three down-regulated miRNAs in HCC and recurrent HCC after LT were considered as candidate miRs. MiR-3200-3p and miR-3690 were selected to construct the miR-based risk score, which was found to be associated with poor overall survival and progression-free survival. Furthermore, it proved to be an independent prognostic factor after adjusting for other clinicopathological factors. The corresponding ceRNA networks of these two miRs that we constructed may help to understand their regulatory mechanisms in HCC.Conclusion: We propose a risk score based on miR-3200-3p and miR-3690 that may be useful as a prognostic marker to predict HCC recurrence after LT. We generated a ceRNA network involving these miRNAs, which may help reveal their regulatory roles in HCC.Keywords: hepatocellular carcinoma, liver transplantation, microRNA, recurrence, ceRNA network

Background: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma., Methods: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 10 6 (dose level 1) or 100 × 10 6 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198., Findings: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis)., Interpretation: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable., Funding: Juno Therapeutics, a Bristol-Myers Squibb Company., Competing Interests: Declaration of interests TS discloses institutional support to conduct this study and manuscript writing support for this manuscript from Bristol Myers Squibb (BMS); fees for speakers’ bureaus from BMS, AstraZeneca, and BeiGene; participation on a data safety monitoring board for BeiGene; participation on an advisory board for AbbVie, BeiGene, BMS, Celgene, a BMS Company, AstraZeneca, and Gilead. DGM discloses institutional research funding from Kite, Juno Therapeutics, a BMS Company, Celgene, a BMS Company, Legend Biotech, and BMS; consulting fees from A2 Biotherapeutics, Navan Technologies, Chimeric Therapeutics, Genentech, BMS, ImmPACT Bio, Gilead Sciences, and Interius; rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics, a BMS Company; advisory boards for BMS, Caribou Biosciences, Celgene, a BMS Company, Genentech, Incyte, Janssen, Juno Therapeutics, a BMS Company, Mustang Bio, MorphoSys, Kite, Lilly, Novartis, and Umoja; and stock options from A2 Biotherapeutics and Navan Technologies. SSK discloses grants or contracts from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs; royalties or licences from Novartis, Humanigen, Mettaforge Therapeutics, Sendero, and Mustang Bio; participation on a scientific advisory board for Kite, Juno Therapeutics, a BMS Company, Novartis, Humanigen, Calibr, Torque, Capstan Therapeutics, Lentigen, LEAH Labs, and Luminary Therapeutics; participation on a data safety monitoring board for Humanigen; and research funding from Novartis, Kite/Gilead, Juno Therapeutics, a BMS Company, Lentigen, Humanigen, MorphoSys, Tolero Pharmaceuticals, Sunesis Pharmaceuticals/Viracta Therapeutics, and LEAH Labs. DMB discloses grants paid to their institution (Duke University) and the role of site principal investigator for clinical trials from AbbVie, ArQule/Merck, Ascentage, Acerta, BeiGene, Catapult, DTRM Biopharma, Genentech, Celgene, a BMS Company, Juno Therapeutics, a BMS Company, BMS, MEI Pharma, Newave, Novartis, and TG Therapeutics; consulting fees from Genentech, AbbVie, and Pharmacyclics; participation on a panel of the National Comprehensive Cancer Network for chronic lymphocytic leukaemia or small lymphocytic lymphoma and hairy cell leukaemia, a registry steering committee for informCLL (Pharmacyclics) and CORE (AbbVie), and an expert medical council for Chronic Lymphocytic Leukemia Society (unpaid), and being a leukaemia committee member and trial champion of S1925 for Alliance in Clinical Trials (unpaid); and writing support for abstracts or manuscripts from AbbVie, BeiGene, Pharmacyclics, and TG Therapeutics. KD discloses institutional research funding for this study from BMS; institutional grants or contracts from BMS, Kite/Gilead, and Genmab; consulting fees for participation on an advisory board for BMS; and honoraria for participation in American Society of Hematology Congress Connect. JS discloses consulting fees from AbbVie, AstraZeneca, BeiGene, BMS, Roche, Seattle Genetics, and TG Therapeutics; and research funding paid to their institution from Adaptive Biotechnologies, BeiGene, BostonGene, Genentech/Roche, GlaxoSmithKline, Moderna, Takeda, and TG Therapeutics. PAR discloses consulting fees from AbbVie, BMS, Janssen, Novartis, BeiGene, Kite/Gilead, Intellia Therapeutics, Sana Biotechnology, CVS Caremark, Genmab, Pharmacyclics, Takeda, Karyopharm Therapeutics, Nektar Therapeutics, Nurix Therapeutics, and ADC Therapeutics; honoraria from Kite/Gilead; and support for attending meetings or travel from Nektar Therapeutics. NNS discloses support for this manuscript from Juno Therapeutics, a BMS Company; research funding from Loxo@Lilly and Miltenyi Biotec; consulting fees from Loxo@Lilly and Miltenyi Biotec; participation on a data safety monitoring board for Incyte; participation on an advisory board for Epizyme, Janssen, Kite Pharma, Incyte, Seattle Genetics, Novartis, Juno Therapeutics, a BMS Company, TG Therapeutics, and Umoja Biopharma; travel support from Loxo@Lilly and Miltenyi Biotec; stock or stock options from Tundra Targeted Therapeutics; and is a scientific advisory board member and founder of Tundra Targeted Therapeutics. RN discloses consulting fees from Actinium Pharmaceuticals; consulting fees for participation on an advisory board for Incyte; and stock or stock options from Pfizer. BF discloses research funding from BMS; consulting fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, BMS, Genentech, Genmab, Loxo@Lilly, Pharmacyclics, and TG Therapeutics; honoraria from Curio Science and Medscape; support for attending meetings or travel from AbbVie and Loxo@Lilly; and participation on a guideline panel for chronic lymphocytic leukaemia and hairy cell leukaemia for the National Comprehensive Cancer Network (unpaid). DMS discloses grants or contracts from Celgene, a BMS Company, Novartis, AstraZeneca, Merck, MingSight Pharmaceuticals, and Newave; consulting fees from Lilly, Genentech, Pharmacyclics/Janssen, Karyopharm Therapeutics, BeiGene, Innate Pharma, AstraZeneca, AbbVie, CSL Behring, Celgene, a BMS Company, TG Therapeutics, and Innate Pharma; and research funding from Acerta Pharma, Gilead Sciences, Karyopharm Therapeutics, MingSight Pharmaceuticals, ArQule, Novartis, Verastem Oncology, and Juno Therapeutics, a BMS Company. SM discloses institutional funding from Juno Therapeutics, a BMS Company, BeiGene, Loxo@Lilly, AstraZeneca, and AbbVie; consulting fees from TG Therapeutics; honoraria from AstraZeneca, BeiGene, Janssen, Lilly, and Pharmacyclics; and participation on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, BeiGene, BMS, Genentech, and Janssen. TF discloses consulting fees from Seattle Genetics, BMS, Genmab, ADC Therapeutics, and AstraZeneca; speakers’ bureau fees from Seattle Genetics and Kite; travel expenses from Seattle Genetics and Takeda; honoraria from Seattle Genetics, Pharmacyclics/Janssen, AbbVie, BMS, Kite, Bayer, and Takeda; and research funding from BMS, Seattle Genetics, Portola Pharmaceuticals, Eisai, Kyowa Kirin, Amgen, Viracta Therapeutics, Cell Medica, Roche, Trillium Therapeutics, and Pfizer. SJS discloses consulting fees from Caribou Biosciences, Genentech/Roche, Genmab, Kite Pharma, Incyte, Legend Biotech, MorphoSys, Mustang Bio, Nordic Nanovector, and Novartis; honoraria from Novartis and Takeda; a patent for combination therapies of chimeric antigen receptor and programmed cell death protein-1 inhibitors licensed to Novartis; research funding from Merck and Genentech/Roche; and travel accommodations from Genentech/Roche and Novartis. SKP is an employee of BMS and a shareholder of BMS and Autolus. SAT, S-SO, EP, LP, and YC are employees and shareholders of BMS. WGW discloses travel expenses from AbbVie, Genentech, and Eli Lilly; and research funding from AbbVie, Acerta Pharma, BMS, Cyclacel Pharmaceuticals, Genentech, Gilead Sciences, GlaxoSmithKline, Loxo@Lilly, Novartis, and Oncternal Therapeutics. SRS declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Three-dimensional ultrasound (3D-US) examination is a relatively new modality that can be used for abdominal aortic aneurysm (AAA) surveillance, and may offer improved reproducibility over conventional two-dimensional ultrasound (2D-US) examination. The aim of this study was to evaluate the interoperator reproducibility of maximum anterior-to-posterior diameter by nonphysician ultrasound technicians in a typical vascular laboratory setting, on patients with infrarenal AAAs using 3D-US and 2D-US examination., Methods: A total of 134 consecutive patients with asymptomatic infrarenal AAAs were screened. Of the 134 patients, 28 (21%) were screen failures. From the remaining 106 patients, 3 (2.8%) had missing data and 13 (12.3%) had technically unacceptable image quality. As a result, 90 patients were included for final analysis. Ultrasound image acquisitions were performed during the single visit. The 2D-US images were evaluated at the time of examination by the respective ultrasound technicians who acquired them. All 3D-US images were evaluated offline by both ultrasound technicians after a wash-out period of at least 6 weeks., Results: Excellent interoperator reproducibility was observed for measuring maximum diameter using 3D-US (intraclass correlation coefficient, 0.97), and good agreement among ultrasound technicians (mean difference, -0.08 mm; limits of agreement, -3.17; 3.00 mm). When using 3D-US examination, 74 of the 90 patients (82%) were estimated within 2 mm of interoperator variability. Of 90 patients, 52 (58%) were estimated to be within the same variability by 2D-US examination. Estimating AAA diameter using 3D-US was superior to 2D-US with respect to interoperator reproducibility., Conclusions: Both 3D-US and 2D-US examination demonstrated good reproducibility among two vascular ultrasound technicians with superior agreement from 3D-US examination. The present results support the broader use of 3D-US in standard AAA surveillance programs., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare the effect of powered and manual tooth brushing on plaque and gingivitis following two and six weeks of home use., Methods: This was a randomized, three-arm, parallel-design clinical trial. Eligible participants were manual toothbrush users who were generally healthy non-smokers, aged 18-65 years, with a plaque score of = 1.8 per Lobene and Soparkar Modified Plaque Index (MPI), and mild to moderate gingivitis, defined as a Gingival Bleeding Index (GBI) = 1 on at least 20 sites. Subjects with advanced periodontal disease, excessive gingival recession, and heavy deposits of calculus or rampant decay were excluded. Enrolled participants were randomly dispensed one of three devices: a powered toothbrush (Philips Sonicare DiamondClean Smart with Premium Gum Care brush head) used in either Gum Heath mode (DC-GH) or Clean mode (DC-C), or an ADA reference manual toothbrush (MTB). Efficacy and safety variables were assessed at Baseline, and at two and six weeks following twice-daily product home use., Results: For the primary endpoint, reduction in gingivitis per Modified Gingival Index (MGI) at Week 2, 188 subjects completed and were included in the analysis. Expressed as percent reduction from Baseline, the adjusted mean reduction and Standard Error (SE) estimates were 60.31% (1.95%) for DC-GH, 53.08% (1.95%) for DC-C, and 16.59% (1.96%) for MTB. The difference between each power toothbrush group and the manual toothbrush was statistically significant (p < 0.0001). Statistically significant differences were also observed between DC-GH, DC-C, and manual tooth brushing for MGI at Week 6, as well as for MPI and GBI at Weeks 2 and 6., Conclusions: The powered toothbrush, used in either Gum Health or Clean mode, was statistically significantly superior to a manual tooth brush in reducing gingival inflammation, gingival bleeding, and plaque following two and six weeks of home use., Competing Interests: E.M. Starke, M. Ward, M. Olson, and S-S Ou are employed by Philips Oral Healthcare. K. Milleman and J. Milleman are employed by Salus Research., (Copyright© by the YES Group, Inc.)

Objectives: The objective of this study was to compare the effect of two home use oral hygiene regimens on plaque, gingivitis, and gingival bleeding on subjects undergoing orthodontic treatment with fixed appliances., Methods: This was a randomized, parallel, single-center clinical trial. Eligible study subjects fit the following profile: age 12-65 years; nonsmoker; plaque score of = 2.0 per Bonded Bracket Index (BBI) on dentition with fixed orthodontic hardware; minimum of 10 orthodontic brackets in each arch or on all teeth from first molar to first molar; presenting with mild to moderate gingivitis, defined as a score of = 1 on at least 20 sites per Gingival Bleeding Index (GBI). Subjects with advanced periodontal disease or gingival recession were not eligible. Eligible subjects were randomized to one of two home use oral hygiene regimens: manual toothbrush plus string floss (used with a threading device) for interdental cleaning (MTF regimen); or Philips Sonicare EasyClean power toothbrush with InterCare brush head and AirFloss Pro powered device, used with BreathRx mouthrinse for interdental cleaning (Sonicare Orthodontic Regimen or SOR). All subjects brushed twice daily with standard fluoridated dentifrice and performed interdental cleaning once daily. Efficacy and safety examinations were performed at Baseline and following three and six weeks of home use of the study products, and included assessments of BBI, GBI, Modified Gingival Index (MGI), and Modified Plaque Index (MPI)., Results: Of 228 enrolled subjects, 223 were included in the primary analysis. For the primary endpoint, reduction in BBI score following three weeks of product use, the overall least squares (LS) mean (95% CI) reduction was 0.89 (0.84, 0.95) for SOR and 0.06 (0.01, 0.12) for MTF. Expressed as percent reduction (95% CI) from Baseline, this was 33.1% (31.1%, 35.2%) for SOR and 2.01% (-0.06%, 4.07%) for MTF. The differences between regimens were statistically significant, p < 0.0001. Statistically significant differences between regimens were observed in BBI following six weeks of product use, and also for all other efficacy variables (GBI, MGI, MPI) at Week 3 and Week 6., Conclusions: The powered oral hygiene regimen was significantly more effective than a manual regimen in reducing plaque on bracketed and non-bracketed teeth, and in reducing gingival bleeding and gingival inflammation in orthodontic subjects following three weeks of use and persisting following six weeks of use. All products were safe on oral tissues and fixed orthodontic appliances., Competing Interests: K. Nammi, E.M. Starke, S-S Ou, M. Ward, and W. Jenkins are employed by Philips Oral Healthcare. J. Milleman and K. Milleman are employed by Salus Research., (Copyright© by the YES Group, Inc.)

Objectives: To compare the effect of the Philips Sonicare DiamondClean Smart and Oral-B Genius 8000 powered toothbrushes on gingivitis, gingival bleeding, and supragingival plaque reduction following 42 days of home use., Methods: This was a randomized, parallel, examiner-blinded, prospective clinical trial with two treatment groups. Eligible participants were generally healthy volunteers who were manual toothbrush users, non-flossers, 18-65 years of age. The subject panel included non-smokers with = 50 sites of gingival bleeding according to the Gingival Bleeding Index (GBI), and a supragingival plaque score of = 1.8 per Modified Plaque Index (MPI) at 3-6 hours following last tooth brushing encounter. Eligible subjects were randomized to use either a Philips Sonicare DiamondClean Smart with Premium Plaque Control brush head (DCS) or an Oral-B Genius 8000 with FlossAction brush head (OBG) for home use. Each toothbrush was used twice daily for two minutes. All subjects used a standardized fluoride-containing dentifrice. All other oral hygiene measures were prohibited. Subjects returned at Day 14 for an interim compliance and safety assessment, and at Day 42 for the final safety and efficacy assessments., Results: Of 222 enrolled and eligible subjects, 219 completed (112 in the SDC group, 107 in the OBG group) the study. The least squares (LS) mean and 95% confidence interval (CI) estimates for gingivitis reduction and percent reduction per Modified Gingival Index (MGI) following 42 days of product home use were 1.38 (1.30, 1.46) and 51.32% (48.45%, 54.19%) for DCS, and 0.53 (0.45, 0.61) and 20.07% (17.14%, 23.00%) for OBG. The differences, expressed as either reduction or percent reduction, were statistically significant between the two groups, p < 0.001. Statistically significant differences were also observed between products at Day 42 for the gingival bleeding and supragingival plaque reduction endpoints, p < 0.001. There were two reported adverse events., Conclusions: The Philips Sonicare DiamondClean Smart powered toothbrush reduced gingival inflammation, gingival bleeding, and supragingival plaque significantly more than the Oral-B Genius 8000 powered toothbrush following a 42-day home-use period. Both products were safe for use., Competing Interests: F. Mirza, K. Argosino, M. Ward, and San-San Ou are employed by Philips Oral Healthcare. K. Milleman and J. Milleman are employed by Salus Research, (Copyright© by the YES Group, Inc.)

Objective: In liver transplantation, long-time portal vein blocking causes the occurrence of ischemic liver injury. Dexmedetomidine, a widely admired anesthetic, has been reported as a protective agent on organs under ischemic condition. The objective of this study was to reveal the role and underlying mechanism of dexmedetomidine in ischemic liver injury., Materials and Methods: L-02 cells were treated with dexmedetomidine during 6 h of oxygen-glucose deprivation (OGD) exposure. The expression of microRNA-711 (miR-711) in cell was overexpressed by miRNA transfection. Then, the following parameters were observed: cell viability, apoptosis, the expression of apoptosis-related proteins, and the expression and the release of Interleukin 1 beta (IL-1β) and Tumor necrosis factor alpha (TNF-α)., Results: Apoptosis and inflammation were induced following OGD exposure in L-02 cells, as cell viability was impaired, apoptotic cell rate was increased, caspase-3, and caspase-9 was cleaved, and the expression and release of TNF-α and IL-1β were increased. Dexmedetomidine attenuated OGD-induced apoptosis and inflammation, and dexmedetomidine down-regulated the expression of miR-711. Also, dexmedetomidine blocked the activation of p38 mitogen-activated protein kinase (p38MAPK) and Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling upon OGD. Moreover, when miR-711 was overexpressed, dexmedetomidine did not protect L-02 cells against OGD, and did not block p38MAPK and JAK/STAT signaling pathways., Conclusions: Dexmedetomidine ameliorated OGD-induced cell apoptosis and inflammation in L-02 cells, exerting protective activities in ischemic liver injury. The anti-OGD effects of dexmedetomidine might be realized by down-regulation of miR-711 and suppression of p38MAPK and JAK/STAT signaling pathways.

Background: Black men who have sex with men (BMSM) and some who also have sex with women (BMSMW) account for over 70% of new HIV infections in the United States representing an elevated HIV risk in this group, also informing risks of HIV transmission to other BMSM and female sexual partners., Settings: We examined trajectories of self-reported substance use, HIV-related sexual risk behaviors, and psychosocial vulnerabilities among BMSMW versus BMSM over a 1-year study period., Methods: We analyzed baseline, 6-, and 12-month follow-up data from the HIV Prevention Trials Network "BROTHERS" Study (HPTN 061; n = 1126). Categorizing participants by sexual partner type across 3 time points: (1) BMSMO: having male and no female partners across assessments and (2) BMSMW: having sex with male and one or more female partners at least at 1 time point. Using generalized estimating equations, we estimated associations between being BMSMW (versus BMSMO) and changes in psychosocial vulnerability, substance use, and HIV-related sexual risk behaviors., Results: Generalized estimating equation models controlling for sociodemographics, time-varying effects, and intervention status showed that BMSMW versus BMSMO had 50% increased odds of crack use, 71% increased odds of alcohol use during condomless anal intercourse (CAI), 51% greater odds of using drugs at last CAI, and twice the odds of receiving goods at last CAI., Conclusions: Findings show stable and comparatively elevated illicit drugs, alcohol, and exchange sex during last CAI among BMSMW. Future intervention research should focus on ways to address changes in substance-related HIV-transmission behaviors over time in this population of men.

Objective: Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(-)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052)., Method: HBV infection status at enrollment was compared between HIV(+) (N = 1241) and HIV(-) (N = 1232) from 7 HBV-endemic countries. Hepatitis B e antigen and plasma HBV DNA were determined in cHB. Median CD4, median plasma HIV RNA, and prevalence of transaminase elevation were compared in HIV(+) with and without cHB. Significance was assessed with χ, Fisher exact, and median tests., Results: Among all participants, 33.6% had HBV exposure without cHB (8.9% isolated HBV core antibody, "HBcAb"; 24.7% HBcAb and anti-HB surface antibody positive, "recovered"), 4.3% had cHB, 8.9% were vaccinated, and 53.5% were uninfected. Data were similar among HIV(+) and HIV(-) except for isolated HBcAb, which was more prevalent in HIV(+) than HIV(-) [10.1% vs. 7.7%, P = 0.046]. Median HBV DNA trended higher in HIV(+) than in HIV(-). In HIV(+) with cHB versus those without cHB, transaminase elevations were more prevalent (alanine aminotransferase ≤ grade 2, 12% vs. 5.2%, P = 0.037; aspartate aminotransferase ≤ grade 2, 26% vs. 6.0%, P < 0.001), CD4 trended lower, and HIV RNA was similar., Conclusions: HBV infection status did not differ by HIV infection status. HIV co-infection was associated with isolated HBcAb and a trend of increased HBV DNA. In HIV, cHB was associated with mild transaminase elevations and a trend toward lower CD4.

Introduction: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked infections were observed shortly after ART initiation or after virologic failure., Objective: To evaluate factors associated with time to viral suppression and virologic failure in participants who initiated ART in HPTN 052., Methods: 1566 participants who had a viral load (VL) > 400 copies/mL at enrollment were included in the analyses. This included 832 in the early ART arm (CD4 350-550 cells/mm 3 at ART initiation) and 734 in the delayed ART arm (204 with a CD4 < 250 cells/mm 3 at ART initiation; 530 with any CD4 at ART initiation). Viral suppression was defined as two consecutive VLs ≤ 400 copies/mL after ART initiation; virologic failure was defined as two consecutive VLs > 1000 copies/mL > 24 weeks after ART initiation., Results: Overall, 93% of participants achieved viral suppression by 12 months. The annual incidence of virologic failure was 3.6%. Virologic outcomes were similar in the two study arms. Longer time to viral suppression was associated with younger age, higher VL at ART initiation, and region (Africa vs. Asia). Virologic failure was strongly associated with younger age, lower educational level, and lack of suppression by three months; lower VL and higher CD4 at ART initiation were also associated with virologic failure., Conclusions: Several clinical and demographic factors were identified that were associated with longer time to viral suppression and virologic failure. Recognition of these factors may help optimize ART for HIV treatment and prevention.

HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART., Competing Interests: Conflict of Interests None of the authors has a financial or personal relationship with other people or organizations that could inappropriately influence (bias) their work. The following relationship is noted: SHE has collaborated with Abbott Diagnostics (distributor of the ViroSeq HIV Genotyping System) on evaluation of HIV-related assays.

Early initiation of antiretroviral treatment (ART) reduces HIV transmission and has health benefits. HIV drug resistance can limit treatment options and compromise use of ART for HIV prevention. We evaluated drug resistance in 85 participants in the HIV Prevention Trials Network 052 trial who started ART at CD4 counts of 350-550 cells per cubic millimeter and failed ART by May 2011; 8.2% had baseline resistance and 35.3% had resistance at ART failure. High baseline viral load and less education were associated with emergence of resistance at ART failure. Resistance at ART failure was observed in 7 of 8 (87.5%) participants who started ART at lower CD4 cell counts.

Antiretroviral (ARV) drug use was analyzed in HIV-uninfected women in an observational cohort study conducted in 10 urban and periurban communities in the United States with high rates of poverty and HIV infection. Plasma samples collected in 2009-2010 were tested for the presence of 16 ARV drugs. ARV drugs were detected in samples from 39 (2%) of 1,806 participants: 27/181 (15%) in Baltimore, MD and 12/179 (7%) in Bronx, NY. The ARV drugs detected included different combinations of non-nucleoside reverse transcriptase inhibitors and protease inhibitors (1-4 drugs/sample). These data were analyzed in the context of self-reported data on ARV drug use. None of the 39 women who had ARV drugs detected reported ARV drug use at any study visit. Further research is needed to evaluate ARV drug use by HIV-uninfected individuals.

Controlled trials of HIV prevention and care interventions are susceptible to contamination. In a randomized controlled trial of a social network peer education intervention among people who inject drugs and their risk partners in Philadelphia, PA and Chiang Mai, Thailand, we tested a contamination measure based on recall of intervention terms. We assessed the recall of test, negative and positive control terms among intervention and control arm participants and compared the relative odds of recall of test versus negative control terms between study arms. The contamination measures showed good discriminant ability among participants in Chiang Mai. In Philadelphia there was no evidence of contamination and little evidence of diffusion. In Chiang Mai there was strong evidence of diffusion and contamination. Network structure and peer education in Chiang Mai likely led to contamination. Recall of intervention materials can be a useful method to detect contamination in experimental interventions.

Background: Combination antiretroviral therapy (ART) for HIV-1-infected individuals prevents sexual transmission if viral load is suppressed., Methods: Participants were HIV-1-infected partners randomized to early ART (CD4 350-550) in HPTN052 (n = 886, median follow-up = 2.1 years), a clinical trial of early ART to prevent sexual transmission of HIV-1 in serodiscordant couples at 13 sites in 9 countries. Adherence was assessed through pill count (dichotomized at <95%) and through self-report items. Predictors of adherence were mental health and general health perceptions, substance use, binge drinking, social support, sexual behaviors, and demographics. Viral suppression was defined as HIV plasma viral load <400 copies per milliliter. Adherence counseling and couples' counseling about safer sex were provided. Logistic and linear regression models using generalized estimating equation for repeated measurements were used., Findings: Through pill count, 82% of participants were adherent at 1 month and 83.3% at 1 year. Mental health was the only psychosocial variable associated with adherence [pill count, odds ratios (OR) = 1.05, 95% confidence intervals (CIs): 1.00 to 1.11; self-report parameter estimate, OR = 0.02, 95% CI: 0.01 to 0.04], although regional differences emerged. Pill count (OR = 1.19, 95% CI: 1.10 to 1.30) and self-report (OR = 1.42, 95% CI: 1.14 to 1.77) adherence were associated with viral suppression., Interpretation: Although adherence was high among individuals in stable relationships taking ART for prevention, mental health and adherence covaried. Assessing and intervening on mental health in the context of promoting adherence to ART as prevention should be explored. Adherence and couples' counseling, feedback about viral suppression, and/or altruism may also help explain the magnitude of adherence observed.

Objective: We pilot tested a Motivational Interviewing (MI) -based counseling intervention for individuals with Acute HIV Infection (AHI) to reduce risky sexual behavior in Lilongwe, Malawi., Methods: Twenty-eight individuals diagnosed with AHI were randomized to receive either brief education alone, or the brief education plus the MI-based intervention, called Uphungu Wanga. Participants in Uphungu Wanga received four sessions delivered on the day of diagnosis, three days later and at weeks 1 and 2 with a booster session at week 8; participants were followed for 24 weeks from diagnosis. An interviewer administered quantitative questionnaire was conducted at baseline and at weeks 2, 4, 8, 12, 16, 20 and 24. Semi-structured qualitative interviews (SSI) were conducted at weeks 2, 8, 12, and 24., Results: The majority of participants in both arms reported rapid and sustained behavior change following diagnosis with AHI. Very few participants reported having sex without a condom after diagnosis. Participants reported a trend towards fewer sex partners and abstaining from sex during study follow-up. Participants in the MI-based arm provided concrete examples of risk reduction strategies in the SSIs while those in the brief education arm primarily described reducing risk behavior, suggesting that the MI-based group may have acquired more risk reduction skills., Conclusions: Individuals in both study arms reduced risky sexual behaviors after diagnosis with AHI. We found few major differences between study arms during the 6-month follow up period in self-reported sexual behaviors therefore a MI-based intervention may not be needed to trigger behavior change following AHI. However, comparing the MI-based intervention to repeated brief education sessions made it difficult to assess the potential benefit of an MI-based intervention in a setting where standard counseling often consists of one post-test session. Nevertheless, provision of counseling immediately following diagnosis with HIV to support behavior change should remain a priority., Trial Registration: ClinicalTrials.gov NCT01197027.

Acute HIV infection (AHI) is a relatively brief period of time when individuals are highly infectious and the opportunity to intervene to prevent forward transmission is extremely limited. HPTN 062 partnered with CHAVI 001 to evaluate the feasibility and acceptability of a motivational interviewing (MI)-based counseling intervention to reduce HIV-transmission risk behaviors among individuals with acute and early HIV infection in Lilongwe, Malawi. Participants were randomized to receive either (1) brief education sessions about HIV and AHI; or (2) the same brief education sessions plus an MI-based counseling intervention called Uphungu Wanga. Although Uphungu Wanga was determined to be feasible and acceptable, few major differences existed between the two arms with regard to acceptability, feasibility, and self-reported sexual behaviors. We therefore conclude that an additional MI-based counseling intervention may not be needed during the short period of AHI. Instead, we recommend that individuals with AHI receive frequent, but brief, counseling immediately after diagnosis and then transition to receiving counseling at less frequent intervals until they can initiate antiretroviral therapy. Other recommendations are provided.

Background: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes., Methods: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581., Findings: 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per μL in patients assigned to the early treatment group and 428 (357-522) cells per μL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group., Interpretation: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment., Funding: US National Institute of Allergy and Infectious Diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: Maternal-to-child-transmission of HIV-1 infection remains a significant cause of HIV-1 infection despite successful prevention strategies. Testing protective HIV-1 vaccines remains a critical priority. The immunogenicity of ALVAC-HIV vCP1521 (ALVAC) in infants born to HIV-1-infected women in Uganda was evaluated in the first pediatric HIV-1 vaccine study in Africa., Design: HIV Prevention Trials Network 027 was a randomized, double-blind, placebo-controlled phase I trial to evaluate the safety and immunogenicity of ALVAC in 60 infants born to HIV-1-infected mothers with CD4 counts of >500 cells per microliter, which were randomized to the ALVAC vaccine or placebo. ALVAC-HIV vCP1521 is an attenuated recombinant canarypox virus expressing HIV-1 clade E env, clade B gag, and protease gene products., Methods: Infants were vaccinated at birth and 4, 8, and 12 weeks of age with ALVAC or placebo. Cellular and humoral immune responses were evaluated using interferon-γ enzyme-linked immunosorbent spot, carboxyfluorescein diacetate succinimidyl ester proliferation, intracellular cytokine staining, and binding and neutralizing antibody assays. Fisher exact test was used to compare positive responses between the study arms., Results: Low levels of antigen-specific CD4 and CD8 T-cell responses (intracellular cytokine assay) were detected at 24 months (CD4-6/36 vaccine vs. 1/9 placebo; CD8-5/36 vaccine vs. 0/9 placebo) of age. There was a nonsignificant trend toward higher cellular immune response rates in vaccine recipients compared with placebo. There were minimal binding antibody responses and no neutralizing antibodies detected., Conclusions: HIV-1-exposed infants are capable of generating low levels of cellular immune responses to ALVAC vaccine, similar to responses seen in adults.

Walking speed is shown to be an important indicator of the health status and function in older adults and part of the comprehensive geriatric assessment in clinical practice. The present study aimed to assess the influence of different assessment methods on walking speed and its association with the key aspects of poor health status, i.e., the presence of low cognitive performance and cardiopulmonary disease. In 288 community-dwelling elderly (mean age 82.2 ± 7.1 years) referred to a geriatric outpatient clinic, walking speed was assessed with the 4-m, 10-m, and 6-min walking tests. The mean walking speed assessed with the 10-m walking test was higher compared to the 4-m and 6-min walking tests (mean difference (95% CI) 0.11 m/s (0.10; 0.13) and 0.08 m/s (0.04; 0.13), respectively). No significant difference was found in the walking speed assessed with the 4-m compared to the 6-min walking test (mean difference (95% CI) -0.03 m/s (-0.08; 0.03)). ICCs showed excellent agreement of the 4-m with the 10-m walking test and fair to good agreement of the 6-min with the 4-m as well as 10-m walking test. The presence of low cognitive performance was negatively associated with walking speed, with the highest effect size for the 4-m walking test. The presence of cardiopulmonary disease was negatively associated with walking speed as well, with the highest effect size for the 6-min walking test. In conclusion, in the clinically relevant population of elderly outpatients, walking speed and its interpretation depends on the assessment method, which therefore cannot be used interchangeably in clinical practice.

We assessed associations in substance use, psychosocial characteristics, and HIV-related sexual risk behaviors, comparing characteristics of Black men who only have sex with other men only (BMSMO; n = 839) to Black men who have sex with men and women (BMSMW; n = 590). The study analyzed baseline data from the HIV Prevention Trials Network Brothers Study (HPTN 061), a feasibility study of a multi-component intervention for Black MSM in six US cities. Bivariate analyses compared BMSMO to BMSMW along demographics, substance use, psychosocial characteristics, and HIV-related sexual risk behaviors. Logistic regression models then assessed multivariable associations between being BMSMW and the odds of engaging in HIV-related sexual risk behaviors. Adjusted analyses revealed that BMSMW remained more likely to have unprotected anal intercourse while under the influence of alcohol (AOR: 1.45; 95 % CI:1.11-1.90) and were more likely to receive money/drugs for sex (AOR: 2.11; 95 % CI:1.48-3.03), compared to BMSMO. Substance use is an important factor to be considered when developing risk-reduction interventions for BMSMW. Structural interventions that address factors that may contribute to exchange sex among these men are also warranted.

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings.

Background: The development of a safe and effective vaccine against HIV type 1 for the prevention of mother-to-child transmission of HIV would significantly advance the goal of eliminating HIV infection in children. Safety and feasibility results from phase 1, randomized, double-blind, placebo-controlled trial of ALVAC-HIV vCP1521 in infants born to HIV type 1-infected women in Uganda are reported., Methods: HIV-exposed infants were enrolled at birth and randomized (4:1) to receive vaccine or saline placebo intramuscular injections at birth, 4, 8, and 12 weeks of age. Vaccine reactogenicity was assessed at vaccination and days 1 and 2 postvaccination. Infants were followed until 24 months of age. HIV infection status was determined by HIV DNA polymerase chain reaction., Results: From October 2006 to May 2007, 60 infants (48 vaccine and 12 placebo) were enrolled with 98% retention at 24 months. One infant was withdrawn, but there were no missed visits or vaccinations among the 59 infants retained. Immune responses elicited by diphtheria, polio, hepatitis B, haemophilus influenzae type B, and measles vaccination were similar in the 2 arms. The vaccine was well tolerated with no severe or life-threatening reactogenicity events. Adverse events were equally distributed across both study arms. Four infants were diagnosed as HIV infected [3 at birth (2 vaccine and 1 placebo) and 1 in vaccine arm at 2 weeks of age]., Conclusion: The ALVAC-HIV vCP1521 vaccination was feasible and safe in infants born to HIV-infected women in Uganda. The conduct of high-quality infant HIV vaccine trials is achievable in Africa.

The HIV Prevention Trial Network (HPTN) 052 Study is a Phase III, two-arm, controlled, open-labeled, randomized clinical trial designed to determine whether early antiretroviral therapy (ART) can prevent the sexual transmission of human immunodeficiency virus type 1 (HIV-1). A total of 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative were enrolled in four continents, nine countries and thirteen study sites. The HIV-1-positive partner was randomly assigned to either of the two arms: "immediate" (early) therapy with ART initiated upon enrollment plus HIV primary care, or "delayed" therapy with HIV primary care but ART initiated when the index case would have two consecutive measurements of a CD4+ cell count within or below the range of 200-250 cells/mm(3), or develop an AIDS-defining illness. In this paper, we describe several key statistical considerations for the design of this landmark study. Despite that the observed event rates were lower than expected, which might have compromised the study power, an early release of the trial results in May 2011 showed an overwhelming 96% risk reduction for the immediate therapy in the prevention of genetically linked HIV-1 incident transmissions. Nevertheless, the durability of its long-term effectiveness is yet to be assessed. The HPTN 052 Study is still ongoing and will not complete till 2015., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Next-generation sequencing (NGS) has recently been used for analysis of HIV diversity, but this method is labor-intensive, costly, and requires complex protocols for data analysis. We compared diversity measures obtained using NGS data to those obtained using a diversity assay based on high-resolution melting (HRM) of DNA duplexes. The HRM diversity assay provides a single numeric score that reflects the level of diversity in the region analyzed. HIV gag and env from individuals in Rakai, Uganda, were analyzed in a previous study using NGS (n = 220 samples from 110 individuals). Three sequence-based diversity measures were calculated from the NGS sequence data (percent diversity, percent complexity, and Shannon entropy). The amplicon pools used for NGS were analyzed with the HRM diversity assay. HRM scores were significantly associated with sequence-based measures of HIV diversity for both gag and env (P < 0.001 for all measures). The level of diversity measured by the HRM diversity assay and NGS increased over time in both regions analyzed (P < 0.001 for all measures except for percent complexity in gag), and similar amounts of diversification were observed with both methods (P < 0.001 for all measures except for percent complexity in gag). Diversity measures obtained using the HRM diversity assay were significantly associated with those from NGS, and similar increases in diversity over time were detected by both methods. The HRM diversity assay is faster and less expensive than NGS, facilitating rapid analysis of large studies of HIV diversity and evolution.

Purpose: This analysis was undertaken to determine the cumulative risk of and risk factors for portal hypertension (PHTN) in patients with Wilms' tumor (WT)., Methods and Materials: Medical records were reviewed to identify cases of PHTN identified with late liver/spleen/gastric toxicities in a cohort of 5,195 patients treated with National Wilms' Tumor Studies (NWTS) protocols 1 to 4. A nested case control study (5 controls/case) was conducted to determine relationships among doxorubicin, radiation therapy (RT) dose to the liver, patient gender, and PHTN. Conditional logistic regression was used to estimate adjusted hazard ratios (HR) of PHTN associated with these factors., Results: Cumulative risk of PHTN at 6 years from WT diagnosis was 0.7% for patients with right-sided tumors vs. 0.1% for those with left-sided tumors (p = 0.002). Seventeen of 19 cases were evaluable for RT. The majority of cases (16/17 [94%]) received right-flank RT either alone or as part of whole-abdomen RT and received >15 Gy to the liver. Fifteen of 17 (88%) patients received a higher dose to the liver than they would have with modern WT protocols. Controlling for RT dose, the HR was 3.0 for patients who received doxorubicin (p = 0.32) and 2.8 for females (p = 0.15). Controlling for doxorubicin, the 95% lower confidence bound on the HR associating PHTN with a minimum liver RT dose of >15 Gy vs. 15 Gy vs. 15 Gy) and the development of PHTN among WT patients.

We undertook a new approach to investigate the aerosol indirect effect of the first kind on ice cloud formation by using available data products from the Moderate-Resolution Imaging Spectrometer (MODIS) and obtained physical understanding about the interaction between aerosols and ice clouds. Our analysis focused on the examination of the variability in the correlation between ice cloud parameters (optical depth, effective particle size, cloud water path, and cloud particle number concentration) and aerosol optical depth and number concentration that were inferred from available satellite cloud and aerosol data products. Correlation results for a number of selected scenes containing dust and ice clouds are presented, and dust aerosol indirect effects on ice clouds are directly demonstrated from satellite observations.

Background: A multicenter phase 2 trial was conducted to evaluate the safety and feasibility of radiotherapy after paclitaxel, estramustine phosphate, and carboplatin (TEC) plus androgen deprivation therapy in previously untreated unfavorable-risk localized prostate cancer patients., Methods: Patients with localized high-risk prostate cancer were treated with 4 cycles (16 weeks) of continuous weekly paclitaxel at 80 mg/m(2) intravenously with estramustine at 280 mg orally 3 times a day for 5 days a week and carboplatin (area under the curve of 6) on Day 1 of every cycle followed by 3-dimensional conformal or intensity-modulated radiotherapy (total dose of 77.4 gray [Gy] in 1.8-Gy fractions). All patients received androgen deprivation therapy with either goserelin acetate at 3.6 mg subcutaneously or leuprolide acetate at 7.5 mg intramuscularly monthly for 6 months starting at Day 1 of therapy. Patients were evaluated for acute and late toxicities along with progression-free survival and time to prostate-specific antigen (PSA) failure associated with the multimodality therapy., Results: Twenty-seven of 34 patients completed therapy and were evaluable for safety and feasibility. There was 1 patient with grade 3 nausea during chemotherapy. No other grade 3 or 4 gastrointestinal, cardiovascular, or genitourinary acute or late toxicities were reported. The most common grade 1 to 2 late toxicities were proctitis (11%), dysuria (11%), and urinary frequency/urgency (33%). Two deaths due to prostate cancer were observed. Median follow-up was 38 months among 24 surviving patients; median PSA progression-free survival was 12.1 months (95% confidence interval, 13.3-25.9)., Conclusions: Neoadjuvant chemohormonal therapy with TEC followed by high-dose radiation therapy is safe and feasible in a multicenter setting., ((c) 2008 American Cancer Society)

Purpose: Bevacizumab is an antibody that binds to vascular endothelial growth factor (VEGF) and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN) is a historic standard first-line treatment for RCC. A prospective, randomized phase III trial of bevacizumab plus IFN versus IFN monotherapy was conducted., Patients and Methods: Patients with previously untreated, metastatic clear-cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN (9 million U subcutaneously three times weekly) or the same dose and schedule of IFN monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety., Results: Between October 2003 and July 2005, 732 patients were enrolled. The prespecified stopping rule for OS has not yet been reached. The median PFS was 8.5 months in patients receiving bevacizumab plus IFN (95% CI, 7.5 to 9.7 months) versus 5.2 months (95% CI, 3.1 to 5.6 months) in patients receiving IFN monotherapy (log-rank P < .0001). The adjusted hazard ratio was 0.71 (95% CI, 0.61 to 0.83; P < .0001). Bevacizumab plus IFN had a higher ORR as compared with IFN (25.5% [95% CI, 20.9% to 30.6%] v 13.1% [95% CI, 9.5% to 17.3%]; P < .0001). Overall toxicity was greater for bevacizumab plus IFN, including significantly more grade 3 hypertension (9% v 0%), anorexia (17% v 8%), fatigue (35% v 28%), and proteinuria (13% v 0%)., Conclusion: Bevacizumab plus IFN produces a superior PFS and ORR in untreated patients with metastatic RCC as compared with IFN monotherapy. Toxicity is greater in the combination therapy arm.

Purpose: Transperineal prostate brachytherapy (TPPB) can be used with external beam radiation therapy (EBRT) to provide a high-dose conformal boost to the prostate. The results of a multicenter Phase II trial assessing safety of combination of EBRT and TPPB boost with androgen suppression (AST) in treatment of intermediate-risk prostate cancer are present here., Materials and Methods: Patients had intermediate-risk prostate cancer. Six months of AST was administered. EBRT to the prostate and seminal vesicles was administered to 45Gy followed by TPPB using either (125)I or (103)Pd to deliver an additional 100Gy or 90Gy. Toxicity was graded using the National Cancer Institute CTC version 2 and the Radiation Therapy Oncology Group late radiation morbidity scoring systems., Results: Sixty-three patients were enrolled. Median follow-up was 38 months. Side effects of AST including sexual dysfunction and vasomotor symptoms were commonly observed. Apart from erectile dysfunction, short-term Grade 2 and 3 toxicity was noted in 21% and 7%, primarily genitourinary related. Long-term Grade 2 and 3 toxicities were noted in 13% and 3%. Two patients had Grade 3 dysuria that resolved with longer follow-up. The most common Grade 2 long-term toxicity was urinary frequency (5%). No biochemical or clinical evidence of progression was noted for the entire cohort., Conclusions: In a cooperative group setting, combination EBRT and TPPB boost with 6 months of AST was generally well tolerated with expected genitourinary and gastrointestinal toxicities. Further follow-up will be required to fully assess long-term toxicity and cancer control.

Purpose: Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug., Patients and Methods: Eighty men with chemotherapy-naive HRPC were enrolled in a multicenter, cooperative group study. The treatment regimen consisted of oral estramustine (280 mg 3 times daily for 5 days), docetaxel 70 mg/m2, oral exisulind (250 mg twice daily), oral dexamethasone (8 mg twice daily for 3 days), and oral warfarin (2 mg daily)., Results: Seventy-five eligible patients were treated with a median of 6 cycles of therapy. Fortyseven patients (62.7%; 95% CI, 50.7%-73.6%) had a > or = 50% decline in prostate-specific antigen levels. Forty-six patients had measurable disease with 6 partial responses (13%; 95% CI, 4.9%-26.3%). The main grade 3/4 toxicities were neutrophils (79%), fatigue (15%), and thrombosis/embolism (10%). The median time to first progression was 5.1 months (95% CI, 4.4-6.3 months) and the median survival time was 17.8 months (95% CI, 14.7-20.1 months)., Conclusion: The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine.

Purpose: Pain from castration-refractory prostate cancer (CRPC) bone metastases is a common event. Although it is assumed that pain represents an adverse prognostic factor, this variable has not been extensively evaluated. The objective of this study was to determine whether men with CRPC who had higher pain interference scores at baseline had worse clinical outcomes compared with men who had lower pain scores., Patients and Methods: Data from three randomized phase III multicenter trials conducted by the Cancer and Leukemia Group B from 1992 to 1998 were combined. Eligible patients had progressive CRPC adenocarcinoma of the prostate, an Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate hematologic, renal, and hepatic functions. Seven items from the Brief Pain Inventory were used to assess the impact of pain on a range of daily activities and quality of life, each rated on a scale from 0 to 10., Results: In 599 men, the median pain interference scores was 17 (interquartile range, 4 to 34), and 38% of the men had opioid analgesic use at baseline. There was a statistically significant association between pain interference scores and risk of death. The median survival times were 17.6 months (95% CI, 16.1 to 19.1 months) and 10.2 months (95% CI, 8.6 to 11.3 months; P < .001) in men with low (< 17) and high (>or= 17) pain scores, respectively. Pain was inversely associated with likelihood of prostate-specific antigen decline, objective response, and time to bone progression., Conclusion: This analysis demonstrates that pain is a statistically significant predictor of overall survival in men with metastatic CRPC. These results need to be validated prospectively in future phase III trials.

Background: Obesity has a variety of adverse health outcomes, but to the authors' knowledge, the effect of obesity on outcome in patients with advanced prostate cancer is not known. For this reason, the correlation between an elevated body mass index (BMI) and clinical outcomes in patients with metastatic, castration-recurrent prostate cancer (CRPC) was evaluated., Methods: A total of 1226 men with CRPC who were enrolled in 9 prospective clinical trials conducted by the Cancer and Leukemia Group B (CALGB) for the treatment of metastatic disease were considered. Eligible patients had progressive prostate cancer during androgen deprivation therapy (with documented castrate levels of testosterone); an Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate hematologic, renal, and hepatic function. Patients were classified based on BMI as normal (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and mildly to severely obese (> or =30 kg/m(2))., Results: Approximately 24% of the patients had a normal BMI, 43% were overweight, and 33% were mildly to severely obese. On multivariable analysis, BMI was found to be a statistically significant predictor of overall survival and prostate cancer-specific mortality. Compared with men with normal BMIs, the hazard ratios for death for overweight men and mildly to severely obese men were 0.80 (95% confidence interval [95% CI], 0.68-0.93; P = .001) and 0.80 (95% CI, 0.68-0.94; P = .010), respectively., Conclusions: In patients with metastatic CRPC, obesity (as defined by an elevated BMI) appears to have a protective effect against overall mortality and prostate cancer-specific mortality. Alternatively, a higher BMI may reflect different cancer biology (ie, the lack of cachexia-producing substances). Further studies to gain a more comprehensive understanding of the mechanisms behind these clinical observations are needed.

Purpose: Adrenal androgens activate the androgen receptor and stimulate prostate cancer growth. Ketoconazole is used as an inhibitor of adrenal androgen synthesis in men with androgen-independent prostate cancer. This study analyzes the relationship between pretreatment androgen levels and outcome following ketoconazole treatment., Experimental Design: Baseline levels of three adrenal androgens (androstenedione, dehydroepiandrostenedione, and dehydroepiandrostenedione-sulfate) and testosterone were measured. Regression models (logistic and proportional hazard) were used to assess the prognostic significance of these levels in predicting overall survival and prostate-specific antigen (PSA) response defined by Consensus Criteria., Results: In 103 patients with available levels, PSA response rate was 28% and median response duration was 4.8 months. The median baseline androstenedione level was 0.64 ng/mL and was 0.88 ng/mL versus 0.53 ng/mL for those with and without a PSA response, respectively (P = 0.034). In univariate analysis, elevation of baseline androstenedione levels was predictive of PSA response [odds ratio, 2.26; 95% confidence interval (95% CI), 1.03-4.96; P = 0.043]. In multivariate analysis, both the uppermost and the middle tertile of baseline androstenedione level were associated with an improved overall survival compared with those in the lower tertile (hazard ratio, 0.59; 95% CI, 0.36-0.98; P = 0.40; hazard ratio, 0.53; 95% CI, 0.32-0.90; P = 0.018, respectively). A linear correlation was observed among all androgen levels., Conclusions: Higher androstenedione levels predict likelihood of response to ketoconazole and improved survival compared with patients with lower levels. These data suggest that therapy with ketoconazole is less effective in patients with low levels of androgen at baseline.

Purpose: A prior report suggested that radical prostatectomy may confer a survival advantage to patients with metastatic castration recurrent prostate cancer. Therefore, a pooled analysis of 9 trials performed by Cancer and Leukemia Group B was done to determine if men with metastatic castration recurrent prostate cancer who underwent prior prostatectomy had improved clinical outcomes, such as overall, prostate specific, progression-free and PSA progression-free survival, than men who did not undergo prior prostatectomy., Materials and Methods: Data from 9 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer during androgen deprivation therapy, Eastern Cooperative Oncology Group performance status 0-2, and adequate hematological, renal and hepatic functions. The proportional hazards model was used to assess the prognostic importance of radical prostatectomy for predicting clinical outcomes., Results: Of 1,238 men 310 (25%) underwent prostatectomy. Median survival was 14.7 (95% CI 12.9-16.7) and 14.5 months (95% CI 13.5-15.7) in men who did and did not undergo prostatectomy, respectively. The HR for death was 1.03 (95% CI 0.90-1.19, p = 0.65) in men with vs without prostatectomy., Conclusions: Prior prostatectomy in men with metastatic castration recurrent prostate cancer who were subsequently enrolled on clinical trials for cancer treatment had similar survival compared to men who did not undergo prior prostatectomy. These data do not support another report suggesting that prior prostatectomy confers a subsequent survival advantage in men with castration recurrent prostate cancer.

Purpose: We determined if age is a prognostic factor of clinical outcomes, specifically overall survival, disease-free survival and progression-free survival in men with hormone refractory prostate cancer., Materials and Methods: Data from 8 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive adenocarcinoma of the prostate after androgen ablation, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate hematological, renal and hepatic function. The proportional hazards model stratified by study was used to assess the prognostic importance of age for predicting clinical outcomes., Results: Of 1,194 men 132 (11%) were 50 to 60 years old and 120 (10%) were 80 to 89 years old. Median survival was 12.2 months (95% CI 10.6 to 13.8) in men 50 to 59 years old, 15.9 months (95% CI 14.2 to 17.6) in men 60 to 69 years old, 15.6 months (95% CI 13.8 to 16.9) in men 70 to 79 years old and 8.9 months (95% CI 6.6 to 12.1) in men 80 to 89 years old. Compared to 70 to 79-year-old men the HR for death in octogenarians was 1.3 (95% CI 1.0 to 1.6, p = 0.015). Furthermore, the HR for prostate cancer death in octogenarians was 1.3 (95% CI 1.1 to 1.7, p = 0.010) and in 50 to 59-year-old men it was 1.3 (95% CI 1.0 to 1.6, p = 0.042) compared to men 70 to 79 years old. Black men were at lower risk for death than white men (HR 0.77, 95 CI% 0.65 to 0.92, p = 0.004)., Conclusions: Octogenarians and white men are at increased risk for death compared to other men with hormone refractory prostate cancer.

Purpose: Analyzing metastatic prostate cancer tissue is of considerable importance in evaluating new targeted agents, yet acquiring such tissue presents a challenge due to the predominance of bone metastases. We assessed factors predicting a successful tumor harvest from bone marrow biopsies (BMBx) in castration-resistant metastatic prostate cancer patients., Material and Methods: Data from Cancer and Leukemia Group B study 9663 were reviewed. Bone marrow biopsies were obtained from 184 patients who underwent an office-based, unguided bone marrow biopsy of the posterior iliac crest., Results: Forty-seven of the 184 patients (25.5%) had a positive bone marrow biopsy. When considered in a multivariate logistic regression analysis, lower hemoglobin levels, higher alkaline phosphatase, and higher lactate dehydrogenase levels were associated with a higher likelihood of a positive BMBx. The median survival time was 11 months (95% confidence interval, 8.0-14) among patients with a positive BMBx compared with 23 months (95% confidence interval, 19-27) with a negative BMBx. The median time to progression and time to prostate-specific antigen progression-free survival were also significantly decreased among positive BMBx patients. No patients with a positive BMBx survived beyond 3 years, whereas 11 of the 137 patients with a negative BMBx survived beyond 5 years., Discussion: Using common laboratory values, a specific patient cohort can be defined from whom the yield of a nonguided BMBx would be high enough to justify this approach. For studies that require broader entry criteria, a more directed approach with image guidance is recommended.

Polymerase chain reaction (PCR) based tests are commonly used to diagnose various infections. Such tests are assumed to be highly 'sensitive', however, no consensus definition of, or method for estimating, sensitivity exists. Hughes and Totten proposed that sensitivity be defined as a function of the number of target DNA molecules in the sample with specificity corresponding to the case where there is no target DNA molecule present. They then developed parametric, non-parametric and semi-parametric models for estimating the sensitivity curve. In this paper a general model is proposed that yields their three models as special cases when specificity is assumed to be 1.0. We also extend the general model to incorporate covariates. Simulation studies are used to compare the different estimators. The methods are applied to data from a PCR-based test for Mycoplasma genitalium., (Copyright 2005 John Wiley & Sons, Ltd)

Background: After randomized trials in the 1980s, doxorubicin (DOX) was added to dactinomycin plus vincristine as standard chemotherapy for patients who had Stage III Wilms tumor (WT) of favorable histology (FH). Double-agent chemotherapy was retained for patients with Stage II disease. In this study, the authors reevaluated the efficacy of DOX using extended follow-up and additional patients., Methods: The relative risks (RR) (DOX vs. no DOX) of disease recurrence and mortality were estimated for patients with Stage II-III/FH WT who were enrolled in the third and fourth National Wilms Tumor Studies (NWTS-3 and NWTS-4). The risk of congestive heart failure (CHF) was estimated for all patients who received DOX., Results: No statistically significant effects of DOX were found for patients with Stage II tumors. For patients with Stage III tumors, the 8 year recurrence-free survival (RFS) and overall survival (OS) rates for randomized patients on NWTS-3 were 84% and 89%, respectively, for patients who received DOX (n = 130) and 74% and 83%, respectively, for patients who did not receive DOX (n = 118). Including all patients with Stage III disease who received DOX (n = 678) and did not receive DOX (n = 138), the RRs of recurrence were 0.47 (P = 0.007) and 0.40 (P = 0.011), and local recurrence respectively, after adjustment for radiation therapy (RT) dose, whereas the RR of mortality adjusted for RT and study was 0.68 (P = 0.17). The 20-year risk of CHF after primary DOX treatment on NWTS-3 and NWTS-4 was 1.2%., Conclusions: The inclusion of data from nonrandomized patients yielded estimates of DOX treatment effects for Stage III/FH WT that were stronger, albeit more susceptible to bias, than reported previously. Despite a lower reported risk of CHF, conclusive evidence that frontline therapy with DOX definitively improves survival remains elusive., (Copyright 2004 American Cancer Society.)