Characterizing tumor shrinkage as a measure of clinical benefit for immune checkpoint inhibitors.

BACKGROUND: We explored whether the effectiveness of immune checkpoint inhibitors (ICIs) can be characterized by incorporating a composite of duration of response (DOR) to complement traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria for objective response rate (ORR) in an intent-to-treat (ITT) population. Furthermore, the correlation of this novel endpoint, characterized by the restricted mean time in response (RMTR), with overall survival (OS) will be examined. METHODS: We analyzed ORR alone or in combination with DOR (RMTR) in available phase I, II, and III trials evaluating nivolumab monotherapy or in combination with ipilimumab across solid tumor types. ORR was evaluated per RECIST V.1.1. DOR was estimated using individual patient data in ITT populations regardless of RECIST response, with non-responders imputed as zero. Associations between ORR alone or RMTR and OS were evaluated in the ITT population. DOR curves were generated using the Kaplan-Meier product limit method, and 6-month RMTR, a measure of response durability, was derived from the area under the curves. For ORR and RMTR in the ITT population, the strength of association with OS was analyzed using Pearson correlation coefficients (r). RESULTS: Nivolumab treatment was associated with longer response durations than active control in responder and ITT populations. Similarly, ORR and RMTR were both significantly correlated with OS (ORR vs OS: r=0.684, p=0.02; RMTR vs OS: r=0.695, p=0.018). CONCLUSIONS: Combining ORR and DOR (RMTR) to objectively characterize tumor shrinkage in an ITT patient population is a novel approach that appears to correlate well with OS in patients treated with nivolumab monotherapy or in combination with ipilimumab. This endpoint may provide a more complete characterization of tumor shrinkage to incorporate into the design of future ICI clinical trials. However, confirmation of this approach will require further research.

A Case Report of Basilar Artery Occlusion in a Healthy 36-Year-Old Female.

Basilar artery occlusion is rare, accounting for approximately 1% of strokes. Symptoms range from paresthesia and oculomotor symptoms to locked-in syndrome. Intervention can lead to complete neurological recovery despite the severity of initial deficits. We report a case of basilar artery occlusion in a healthy 36-year-old female with minimal risk factors. The patient underwent interventional thrombectomy within eight hours of onset of symptoms and made a significant recovery. Due to the variation in severity and character of symptoms, the diagnosis of basilar artery occlusion is often a barrier to care.

Integration of neuropsychology services in a sickle cell clinic and subsequent healthcare use for pain crises.

Objective: Growing literature has documented the clinical utility of neuropsychological evaluations for predicting functional outcomes, including reduced healthcare service utilization, in a variety of clinical samples. The present study investigates the relationship between the integration of clinical neuropsychology services into an existing outpatient sickle cell clinic and frequency of emergency department (ED) visits and hospitalizations for pain crises. Method: Participants included 144 adults diagnosed with sickle cell disease (SCD) who either underwent neuropsychological evaluation (NP+), including interview, neuropsychological testing, and feedback, or treatment as usual (NP-). Medical records were reviewed for a two-year period, one year prior to study enrollment (pre-assessment) and one year post-study enrollment (post-assessment), to track the number of ED visits and hospitalizations related to sickle cell pain crises. Results: When examining pain crises ED visits prior to and following neuropsychological evaluation, there was a significant decrease in ED visits for the NP + group, but no change for the NP - group. No significant changes in pain crises hospitalizations were observed for the NP + and NP - groups. For the NP + group, the decreased incidence of pain crises ED visits and hospitalizations was associated with an estimated total cost savings of $994,821. Discussion: Results highlight that integration of neuropsychology services into an existing outpatient sickle cell clinic may reduce healthcare costs, particularly use of pain crises ED services, for adults with SCD.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease.

BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Expression of three GnRH receptors in specific tissues in male and female sea lampreys Petromyzon marinus at three distinct life stages.

Two recently cloned gonadotropin-releasing hormone (GnRH) receptors (lamprey GnRH-R-2 and lamprey GnRH-R-3) along with lamprey (l) GnRH-R-1 were shown to share similar structural features and amino acid motifs common to other vertebrate receptors. Here we report on our findings of RNA expression of these three GnRH receptors in the three major life stages (larval, parasitic, and adult phases) of the sea lamprey, Petromyzon marinus, a basal vertebrate. For each stage, we examined the expression of messenger RNA encoding the receptors in the brain, pituitary, gonad, heart, muscle, liver, eye, intestine, kidney, skin, thyroid, gill, and endostyle by RT-PCR. In adult lampreys, the spatial expression of the three receptors in the brain and pituitary was investigated by in situ hybridization. In general, the receptors were more widely expressed in adult tissues as compared to parasitic-phase tissues and least widely expressed in the larval tissues. There were noted differences in male and female lampreys in the adult and parasitic phases for all three receptors. The data showed the presence of all three receptor transcripts in brain tissues for adult and parasitic phases and all three receptor transcripts were expressed in the adult pituitaries, but not in the parasitic pituitaries. However, in the larval phase, only lGnRH-R-1 was expressed in the larval brain and pituitary. In situ hybridization revealed that lGnRH-R-2 and -3 were expressed in the pineal tissue of adult female lampreys while lGnRH-R-1 was expressed in the pineal in adult male lampreys, all restricted to the pineal pellucida. In summary, these data provide an initial comparative analysis of expression of three lamprey GnRH receptors suggesting differential regulation within males and females at three different life/reproductive stages.

Hepatitis C management: the challenge of dropout associated with male sex and injection drug use.

BACKGROUND: Anecdotal reports of poor patient compliance with hepatitis C disease management exist yet little data are available on the true rates of dropout. AIMS: To examine all referrals made to an urban tertiary care liver centre for hepatitis C virus (HCV) management, track subsequent progress and identify dropout trends. METHODS: A cross-sectional retrospective review was conducted to examine the HCV referrals received on 2000 through 2007. The demographic, clinical and treatment data were derived from medical charts and the hospital information system. RESULTS: A total of 588 individuals were referred for HCV disease management. The repeated referrals yielded 742 cases for analysis. Of the 742 referrals received, 141 (19%) failed to attend their initial appointment, 180 dropped out from early outpatient management, 29 failed to attend liver biopsy and 81 defected from subsequent outpatient follow-up. In total, 451 (61%) dropouts occurred. In those treated, a sustained viral response rate of 74% was observed (18/30 genotype 1; 4/5 genotype 2; 40/49 genotype 3). Statistically significant associations between history of injection drug use and dropout immediately after the referral (P<0.001), dropout from early outpatient management (P<0.001) and dropout over entire span of disease management (P<0.001) were observed. Male sex was also associated with dropout from disease management (P<0.05). CONCLUSIONS: An exceptionally high rate of dropout exists within the HCV disease management framework, particularly in the early stages of service delivery. Dropout was associated with sex and positive history of injection drug use. The study findings have led to the development of innovative approaches helping to optimize the disease management in this population. These developments are discussed.

Ixabepilone plus capecitabine in metastatic breast cancer patients with reduced performance status previously treated with anthracyclines and taxanes: a pooled analysis by performance status of efficacy and safety data from 2 phase III studies.

Patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes often have decreased performance status secondary to extensive tumor involvement. Here, we report the pooled analysis of efficacy and safety data from two similarly designed phase III studies to provide a more precise estimate of benefit of ixabepilone plus capecitabine in MBC patients with Karnofsky's performance status (KPS) 70-80. Across the studies, anthracycline/taxane-pretreated MBC patients were randomized to receive ixabepilone plus capecitabine or capecitabine alone. Individual patient data for KPS 70-80 subset (n = 606) or KPS 90-100 subset (n = 1349) from the two studies were pooled by treatment. Analysis included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety. In patients with reduced performance status (KPS 70-80), ixabepilone plus capecitabine was associated with improvements in OS (median: 12.3 vs. 9.5 months; HR, 0.75; P = 0.0015), PFS (median: 4.6 vs. 3.1 months; HR, 0.76; P = 0.0021) and ORR (35 vs. 19%) over capecitabine alone. Corresponding results in patients with high performance status (KPS 90-100) were median OS of 16.7 versus 16.2 months (HR, 0.98; P = 0.8111), median PFS of 6.0 versus 4.4 months (HR, 0.58; P = 0.0009), and ORR of 45 versus 28%. The safety profile of combination therapy was similar between the subgroups. Ixabepilone plus capecitabine appeared to show superior efficacy compared to capecitabine alone in MBC patients previously treated with anthracyclines and taxanes, regardless of performance status, with a possible OS benefit favoring KPS 70-80 patients (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433).

The effects of the Roche AMPLICOR HIV-1 MONITOR UltraSensitive Test versions 1.0 and 1.5 viral load assays and plasma collection tube type on determination of response to antiretroviral therapy and the inappropriateness of cross-study comparisons.

BACKGROUND: Because there are limited head-to-head data comparing antiretroviral combinations, physicians are tempted to rely on cross-trial comparisons to evaluate the relative efficacy of HIV drugs. However, a variety of factors can confound these comparisons, resulting in misleading or invalid conclusions. OBJECTIVES: To compare and evaluate the use of: (i) versions 1.0 and 1.5 of the Roche AMPLICOR HIV-1 MONITOR UltraSensitive assay, and (ii) ethylenediaminetetraacetic acid (EDTA) and plasma preparation (PPT) tubes on the proportion of HIV-infected patients who would be classified as virological responders in a multinational clinical trial. STUDY DESIGN: The study utilized was a randomized, double-blind trial comparing the efficacy and safety of atazanavir with efavirenz, each in combination with fixed-dose zidovudine/lamivudine, in antiretroviral-naïve patients. To evaluate the effect of monitor kit version, paired plasma samples from 634 patients at week 48 were analyzed using both versions 1.0 and 1.5 of the monitor kit. To evaluate the effect of collection tube type, paired plasma samples collected from 584 patients at week 52 using both EDTA and PPT tubes were assayed. Patients were classified as responders if HIV-1 RNA levels were below a pre-determined level of quantification (LOQ), both 400 and 50 copies/ml. RESULTS AND CONCLUSIONS: Substantially higher HIV-1 RNA levels were observed with monitor kit version 1.5, resulting in lower response rates. The version 1.0 monitor kit resulted in a 7% increase in patients classified as responders at the LOQ of 400 copies/ml and a 13% increase at the LOQ of 50 copies/ml. Consistently higher response rates (11% higher at the LOQ of 400 copies/ml and 34% higher at the LOQ of 50 copies/ml) were also observed when samples were collected in EDTA tubes compared with PPT tubes. Differences in monitor kit sensitivity and plasma collection procedures are key factors in study results and suggest caution when performing cross-study comparisons.

Advanced hepatocellular carcinoma associated with cystic fibrosis.

Advances in the treatment of the respiratory complications of cystic fibrosis, including the availability of lung transplantation have led to a greater awareness of the manifestations of liver disease in up to 40% of patients with Cystic Fibrosis (CF). We report the case of an 18 year old female with CF who presented with advanced hepatocellular carcinoma and no prior clinical evidence of chronic liver disease. Hepatocellular carcinoma is usually the most severe manifestation of advanced cirrhosis although its development in non-cirrhotic cases of chronic liver disease has been reported. With the increasing life expectancy of CF patients it is likely that more unusual hepatic complications of this disease may be identified. Greater awareness may perhaps lead to earlier diagnosis in those at risk.

Prediction of hepatic fibrosis in HIV/HCV co-infected patients using serum fibrosis markers: the SHASTA index.

BACKGROUND/AIMS: To examine if serum fibrosis biomarkers could accurately identify the stage of liver disease amongst hepatitis C (HCV) and HIV co-infected patients. METHODS: One hundred and thirty seven HIV/HCV co-infected persons were randomly selected from the Johns Hopkins HIV Clinic cohort. Ninety five had complete testing for fibrosis markers in sera collected at the time of liver biopsy. Biopsies were scored according to Ishak modified histological activity index (F0 no fibrosis to F6 cirrhosis). Fibrosis was evaluated against alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST to platelet ratio (APRI), albumin, total bilirubin, hyaluronic acid (HA) and YKL-40. RESULTS: Sixty nine (73%) had no or minimal portal fibrosis (F0-2) and were compared with remaining subjects (F3-6). Fibrosis scores > or =F3 were found 27 times more often in persons with HA levels >86 ng/ml and 5.5 times more often in persons with HA levels 41-86 ng/ml. Less substantial associations were detected with levels of albumin <3.5 g/dl (OR 4.85) and AST >60 iu (OR 5.91). All 35 subjects who had favorable results of HA, albumin, and AST had minimal fibrosis (F0-2). CONCLUSIONS: Amongst HIV/HCV co-infected patients, serum testing for HA, albumin, and AST (SHASTA Index) was able to accurately stage mild and advanced fibrosis.

Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials.

Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.

DMT1 genetic variability is not responsible for phenotype variability in hereditary hemochromatosis.

BACKGROUND/AIMS: Homozygosity for a cysteine to tyrosine translocation at position 282 within the HFE gene (C282Y) is responsible for over 90% of hereditary hemochromatosis (HH) in Celtic populations. Determining those C282Y homozygotes at greatest risk for iron overload is a major clinical concern as only a small percentage will develop clinically significant iron overload. Divalent metal transport protein (DMT1) on the apical surface of duodenal enterocytes is recognised as the major iron import protein. We investigated whether genetic variability within the DMT1 gene may partly explain the phenotypic variability seen amongst a group of C282Y homozygotes with iron overload. METHODS: One hundred and one unrelated C282Y homozygotes and 103 C282Y negative controls were analysed for the presence of four specific mutations/polymorphisms within the DMT1 gene (1245T/C, 1303C/A, IVS4 + 44C/A, IVS15Ex16-16C/G) using standard PCR techniques. Hepatic iron deposition was determined in 32 HH patients following Perls Prussian blue staining (0-4+). Estimations of the haplotype frequencies were performed utilising the program Arlequin version 2. RESULTS: There were no significant differences in the allele frequencies of the IVS4 + 44C/A, 1303C/A, 1254T/C and IVS15Ex16-16C/G polymorphisms in the patient cohort compared to those observed in the control cohort. The commonest haplotypes identified were CCTC: IVS4C + 44C, 1303C, 1254T, IVS15ex16-16C; ACCC: IVS4C + 44A, 1303C, 1254C, IVS15ex16-16C and ACTG: IVS4C + 44A, 1303C, 1254T, IVS15ex16-16G. Similarly, there were no significant differences in the frequencies of these three haplotypes in the patient cohorts (regardless of the degree of hepatic iron deposition) compared to the control cohort. CONCLUSIONS: Polymorphisms within DMT1 gene do not influence penetrance of the HH phenotype.

Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir.

The purpose of the study was to determine long-term efficacy, safety, and tolerability of atazanavir plus stavudine/lamivudine in 346 HIV-infected patients previously treated with atazanavir or nelfinavir. BMS AI424-044 is an ongoing, multicenter, international, open-label, rollover/switch study initiated in June 2001. Patients completing >or=48 weeks in trial BMS AI424-008 with a plasma HIV RNA viral load <10,000 copies/mL were eligible to continue on atazanavir (400 or 600 mg) or to switch from nelfinavir to atazanavir (400 mg) once daily. Antiviral efficacy, change in CD4 cell counts, and effect on lipid parameters were measured. After 24 weeks of atazanavir use in BMS AI424-044, 83%, 85%, and 87% of the atazanavir 400-mg, atazanavir 600-mg, and nelfinavir-to-atazanavir-switched patients, respectively, had HIV RNA levels <400 copies/mL compared with 76%, 76%, and 63%, respectively, at week 48 of BMS AI424-008. Atazanavir-treated patients showed minimal changes in lipid levels compared with baseline. Patients switched from nelfinavir to atazanavir showed significant mean percent decreases in total cholesterol (-16%), fasting low-density lipoprotein cholesterol (-21%), and fasting triglycerides (-28%) (P<0.0001) by week 12 of atazanavir treatment. No new safety issues were identified, and the overall incidence of treatment-emergent adverse events during BMS AI424-044 was comparable across treatment groups. Atazanavir was safe, tolerable, and effective during extended use and in patients switched from nelfinavir. Extended atazanavir use resulted in continued viral suppression and lipid changes that were not clinically relevant. In virologically suppressed nelfinavir-treated patients switched to atazanavir, virologic improvement continued, whereas nelfinavir-induced lipid elevations were reversed within 12 weeks, approaching pretreatment values.

Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results.

OBJECTIVE: To compare the efficiency and safety of atazanavir and nelfinavir in antiretroviral-naive patients. DESIGN: Randomization to atazanavir 400 mg or 600 mg once daily; nelfinavir 1250 mg twice a day, plus lamivudine and stavudine. METHODS: A blinded (to the atazanavir dose), 48-week trial in patients with HIV-1 RNA > or = 2000 copies/ml, CD4 cell count > or = 100 x 10(6) cells/l. Primary end-point: change in HIV-1 RNA from baseline at 48 weeks. Secondary end-point: subjects with HIV-1 RNA < 400, and < 50 copies/ml, CD4 cell count changes, adverse events. RESULTS: The 467 randomized subjects had comparable baseline characteristics across treatments. With atazanavir 400 mg, 600 mg and nelfinavir, respectively, mean changes in HIV-1 RNA (log10 copies/ml) from baseline to 48 weeks were -2.51, -2.58, -2.31; HIV-1 RNA < 400 copies/ml [intent-to-treat population (ITT), non-completion = failure (NC = F)], 64%, 67%, 53%; HIV-1 RNA < 50 copies/ml (ITT NC = F), 35%, 36%, 34%; mean CD4 cell count increased comparably at 48 weeks (234 x 10(6), 243 x 10(6), 211 x 10(6) cells/l). Adverse events were similar across treatments with the exception of diarrhea (more frequent with nelfinavir) and jaundice (more frequent with atazanavir). Mean changes from baseline to 48 weeks were: fasting low density lipoprotein cholesterol, +5.2%, +7.1% and +23.2% (at 56 weeks) and fasting triglycerides (48 weeks), +7.2%, +7.6% and +49.5%, in the atazanavir 400 mg, 600 mg, and nelfinavir groups, respectively (P < 0.01, atazanavir versus nelfinavir). CONCLUSIONS: Atazanavir is a potent, safe, well tolerated, and effective once-daily protease inhibitor with low pill burden (two capsules/day). Lipid changes with atazanavir were significantly less than with nelfinavir, however, clinical significance of these finding in terms of decreased cardiovascular risk is unknown.