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This phase II, multicenter, open-label, sequential-cohort, dose-escalation study was designed to evaluate the safety and efficacy of romiplostim, a novel peptibody that increases platelet production, in Japanese patients with chronic immune thrombocytopenic purpura (ITP). Sequential cohorts of four patients each received romiplostim (1, 3, or 6 μg/kg) subcutaneously on days 1 and 8 of the dose-escalation phase. Patients who achieved platelet responses (doubling of baseline platelet counts to ≥50 × 10 9 /L) continued romiplostim weekly during the treatment-continuation phase. Romiplostim produced dose-dependent increases in mean and peak platelet counts. Five patients received romiplostim during the treatment-continuation phase, with platelet counts ≥50 × 10 9 /L maintained in approximately half of the weekly assessments. Romiplostim was well tolerated. No severe, serious, or life-threatening adverse events were reported. No binding antibodies to romiplostim or thrombopoietin were detected. Romiplostim is safe and well tolerated in Japanese patients with chronic ITP and is effective in producing platelet count increases, consistent with the results from studies in non-Japanese patients. On the basis of these findings, a starting dose of 3 μg/kg was recommended for phase III evaluation of romiplostim in Japanese patients with chronic ITP.

Pheochromocytomas are a feature of two disorders with an autosomal dominant pattern of inheritance -- multiple endocrine neoplasia type 2 (MEN-2) and von Hippel-Lindau disease. Persons carrying the MEN-2 mutation are predisposed to have C-cell hyperplasia or medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism (in the MEN-2A subtype) or mucosal neuromas and marfanoid habitus (in the MEN-2B subtype) 1 , 2 . The major components of von Hippel-Lindau disease are retinal angioma, hemangioblastoma of the central nervous system, renal cysts and carcinoma, pheochromocytoma, pancreatic cysts, and epididymal cystadenoma 3 – 8 . Affected members of families with these disorders (carriers) may have one or several . . .

Mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment. It can have a negative impact on both quality of life and health economics. Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parentral nutrition, suboptimal delivery of anti‐neoplastic treatment, and morbidity and mortality. Palifermin, a recombinant derivative of human keratinocyte growth factor, is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing haematopoietic stem cell transplantation (HSCT). Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high‐risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer. The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient‐reported outcome in multiple studies. The clinical response to palifermin appears to be related in part to epithelial proliferation and mucosal thickening. Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft‐versus‐host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT. Palifermin is generally well tolerated with mild‐to‐moderate skin and oral adverse events. Future studies may expand the use of palifermin into other areas that would benefit from its cytoprotective and regenerative effects.

BACKGROUND Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect. METHODS This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carryingVHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed. RESULTS Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHLgermline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany. CONCLUSIONS Our results are an important example that a specific genotype, at least in the case ofVHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.

IntroductionFollowing the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years.Methods and analysisWomen with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18–32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children’s Abilities-Revised questionnaire.Ethics and disseminationThe Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy.Trial registration numberMain sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200.

Objectives People living with HIV (PLWH) are a risk group for severe symptoms and higher mortality during COVID-19. We analyzed the dynamic rise of SARS-CoV-2 seroprevalence induced by coinfections and vaccinations in PLWH in the first three years of the pandemic in Germany and compared it with corresponding data available for the general population. Methods Each month on average 93 blood samples from the German HIV-1 Seroconverter Cohort, a prospective longitudinal multicenter study that includes PLWH whose date of seroconversion is well defined, were received. The samples from 1569 PLWH were tested for the presence of anti-S1 and if positive, also for anti-N antibodies. Results In 2020 the number of anti-S1 positive cases/month was between 0.0 and 6.9% (average 1.6%). Since then the anti-S1 prevalence increased reaching already 35% (33/94) in May 2021. At that time 3.2% of the cases were also anti-N positive. In 2022 the average anti-S1 seroprevalence reached 97.5%. In the vaccination era a positive anti-N response was associated with a younger age and females were overrepresented among anti-S1/anti-N negative samples (assuming no vaccination or infection). Conclusions The average 1.6% anti-S1 seroprevalence in the cohort in 2020 was comparable to that in the general population (1.3%). The increase in anti-S1 seroprevalence in the first half of 2021 occurred slightly earlier. This increase was likely caused by the prioritization of PLWH at the early stage of the vaccination campaign and by infections during the third wave of the pandemic.

Background Noninvasive applanation tonometry (APT) is useful to assess aortic stiffness and pulse wave reflection. Moreover, APT can predict outcome in many conditions such as arterial hypertension. In this study, we test whether APT measurements relate to progression of aortic disease in Marfan syndrome (MFS). Methods We performed APT in 50 consecutive, medically treated adults with MFS (19 men and 31 women aged 32 ± 13 years), who had not undergone previous cardiovascular surgery. During 22 ± 16 months of follow-up, 26 of these patients developed progression of aortic disease, which we defined as progression of aortic root diameters ≥5 mm/annum (18 individuals), aortic surgery ≥3 months after APT (seven individuals), or onset of acute aortic dissection any time after APT (one individual). Results Univariate Cox regression analysis suggested an association of aortic disease progression with age (P = 0.001), total cholesterol levels (P = 0.04), aortic root diameter (P = 0.007), descending aorta diameter (P = 0.01), aortic root ratio (P = 0.02), and augmentation index (AIx@HR75; P < 0.006). Multivariate Cox regression analysis confirmed an independent impact on aortic disease progression exclusively for baseline aortic root diameters (hazard ratio = 1.347; 95% confidence interval (CI) 1.104–1.643; P = 0.003) and AIx@HR75 (hazard ratio = 1.246; 95% CI 1.029–1.508; P = 0.02). In addition, Kaplan–Meier survival curve analysis illustrated significantly lower rates of aortic root disease progression both with lower AIx@HR75 (P = 0.025) and with lower pulse wave velocity (PWV) values (P = 0.027). Conclusions We provide evidence that APT parameters relate to aortic disease progression in medically treated patients with MFS. We believe that APT has a potential to improve risk stratification in the clinical management of MFS patients.

The neuropeptide galanin (GAL) has been shown to be present in certain brain tumors. In order to learn more about GAL and its receptors in human tumors of the peripheral nervous system, we investigated the expression of the GAL peptide and the GAL receptors in tumor tissue from childhood neuroblastic tumors. GAL peptide concentrations up to 674 ± 166 fmol/mg of tissue were detected by radioimmunoassay, but no significant correlation with standard tumor markers or the prognosis of the 14 patients investigated was observed. Ligand binding experiments showed different levels of GAL binding in all 28 primary neuroblastomas and 7 ganglioneuromas investigated. All three human GAL receptor subtypes cloned to date could be detected, with the GALR1 receptor subtype being expressed most prominently. GAL binding did not significantly correlate with genetic markers such as unfavorable DNA ploidy, amplification of the oncogene MYCN and allelic loss of chromosome 1p. However, low galanin binding was significantly correlated with survival (p = 0.021) in this limited analysis of neuroblastic tumor samples. These results raise the possibility that the expression of GAL binding sites may play a role in neuroblastic tumor biology and behavior.