Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study.

PURPOSE: To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. METHODS: Eligible patients had advanced HCC, Child-Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a ≥3-point decrease from baseline and PS deterioration was defined as a change of ≥2. Both intention-to-treat and pre-specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) ≥400 ng/mL were assessed. RESULTS: There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP ≥400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. CONCLUSIONS: We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP ≥400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits. CLINICAL TRIAL REGISTRATION: NCT01140347.

Soluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.

An international feasibility study of parental decision making in pediatric oncology.

PURPOSE/OBJECTIVES: To describe parental decision making about treatment options for children with cancer and determine the feasibility of a similar but larger international study. DESIGN: Exploratory. SETTINGS: A pediatric catastrophic illness research hospital in the United States and children's hospitals in Australia and Hong Kong. SAMPLE: A convenience sample of 43 parents (5 fathers and 38 mothers ages 23-59 years). METHODS: Six open-ended interview questions posed to parents during private individual interviews. Content analysis techniques were used. MAIN RESEARCH VARIABLES: Parental perceptions of (a) factors considered in the decision-making process, (b) behaviors of healthcare professionals that affected the process, and (c) satisfaction with the process. Feasibility of a larger study was estimated by considering ease of access to parents, number of refusals to participate, understanding of the interview questions, and level of interest at each setting. FINDINGS: Access to parents was possible at all sites. Refusal to participate was reported only at the U.S. site. Certain factors (e.g., getting information from the healthcare team, trusting staff) were important to all parents considering end-of-life decisions. Site-specific factors included considering alternative therapies (at the Australian site) and strengthening faith (at the U.S. site). CONCLUSIONS: A larger international study of parental decision making is feasible. Sufficient similarities in parental decision making exist across these sites to justify future efforts to identify universal decision-making factors that, in conjunction with site-specific differences, could be helpful in developing guidelines for healthcare professionals who assist parents in making treatment-related decisions for a sick child.

Dynamic association of L-selectin with the lymphocyte cytoskeletal matrix.

L-selectin mediates lymphocyte extravasation into lymphoid tissues through binding to sialomucin-like receptors on the surface of high endothelial venules (HEV). This study examines the biochemical basis and regulation of interactions between L-selectin, an integral transmembrane protein, and the lymphocyte cytoskeleton. Using a detergent-based extraction procedure, constitutive associations between L-selectin and the insoluble cytoskeletal matrix could not be detected. However, engagement of the L-selectin lectin domain by Abs or by glycosylation-dependent cell adhesion molecule-1, an HEV-derived ligand for L-selectin, rapidly triggered redistribution of L-selectin to the detergent-insoluble cytoskeleton. L-selectin attachment to the cytoskeleton was not prevented by inhibitors of actin/microtubule polymerization (cytochalasin B, colchicine, or nocodozole) or serine/threonine and tyrosine kinase activity (staurosporine, calphostin C, or genistein), although L-selectin-mediated adhesion of human PBL was markedly suppressed by these agents. Exposure of human PBL or murine pre-B transfectants expressing full-length human L-selectin to fever-range hyperthermia also markedly increased L-selectin association with the cytoskeleton, directly correlating with enhanced L-selectin-mediated adhesion. In contrast, a deletion mutant of L-selectin lacking the COOH-terminal 11 amino acids failed to associate with the cytoskeletal matrix in response to Ab cross-linking or hyperthermia stimulation and did not support adhesion to HEV. These studies, when taken together with the previously demonstrated interaction between the L-selectin cytoplasmic domain and the cytoskeletal linker protein alpha-actinin, strongly implicate the actin-based cytoskeleton in dynamically controlling L-selectin adhesion.

Reductions in self-injury produced by transcutaneous electrical nerve stimulation.

Transcutaneous electrical nerve stimulation is used to reduce pain but also may be useful for self-injurious behavior (SIB). In the current investigation, a microcurrent electromedical device, classified as a transcutaneous electrical nerve stimulator (TENS), was applied with a man with Down syndrome who displayed SIB that persisted in the absence of social contingencies. Although clinically significant results were not maintained, a clear difference in the rates of SIB during active and inactive TENS was observed.

New Stark regulations: Key issues for health care decision-makers.

On Jan. 9, 1998, The Health Care Financing Administration (HCFA) issued long-awaited Proposed Regulations for what has become known as Stark II. The regulations are subject to a comment period and later refinement. However, they lay out HCFA's basic understanding of what kinds of practices constitute an illegal kickback. In general terms, the law prohibits physicians from referring Medicare or Medicaid patients to entities with which they (or an immediate family member) have a "financial relationship" for the delivery of a specific list of designated health services. There are, however, exceptions also included in the new proposal. Group practices will want to pay special attention to HCFA's new definition of group practice.

Childhood chondrosarcoma: MR imaging with gadolinium-DTPA.

The radiologic, CT, MR, and histological features of a case of chondrosarcoma of the femur presenting in childhood are reported. This case emphasizes the use of correlative imaging in establishing the diagnosis as well as the value of MR supplemented by Gadolinium-DTPA enhancement in disclosing abundant necrosis within the tumor.

Evaluation of the protective efficacy of Haemophilus influenzae type b vaccines in an animal model.

The infant rat model for Haemophilus influenzae type b (Hib) disease was modified to test the protective efficacy of candidate vaccines. The administration of 0.4 micrograms of polyribosylribitol phosphate (PRP) combined with pertussis vaccine or with diphtheria toxoid-tetanus toxoid-pertussis vaccine (DTP) to infant rats at 5, 10, and 15 days of age resulted in significant (P less than 0.001) protection against Hib bacteremia after challenge at 20 days of age. A dose-response effect was demonstrated, and suppression of the protective effect was noted with high doses of PRP. The administration of pertussis vaccine alone or DTP alone did not protect against Hib bacteremia. The degree of protection against Hib bacteremia correlated (P less than 0.005) with the serum anti-PRP antibody response measured before bacterial challenge. High-molecular-weight PRP preparations administered alone or in combination with pertussis vaccine were less effective than standard PRP combined with pertussis vaccine. These data compare favorably with the antibody response in human infants receiving the same vaccines. The observations in this animal model should facilitate the development and testing of other vaccine preparations for human infants.

Cognitive flexibility in hypnosis: response to change communication from the hypnotist.

It was predicted that modification of response as it indexes cognitive flexibility in the hypnotic subject is related to susceptibility to hypnosis and the difficulty of the hypnotic task attempted. Experiment 1 isolated two distinct hypnotic tasks (easy and difficult); alternative forms of each item conveyed either clear or unclear structure concerning the response that was perceived as most appropriate. In Experiment 2, 101 subjects were administered hypnotic induction procedures and tested for modification of response on both items; for each subject, the hypnotist posed a conflict in communication by plausibly requesting an alteration in response from the behavior that the subject had chosen to indicate previously. Change data demonstrated that hypnotic subjects modified their behavior in hypnosis, but their cognitive flexibility was much more relevant to easy than to difficult tasks. Results highlight a further dimension of role enactment as well as the special role cognitive skills in play in our understanding of performance on hypnotic test items.