Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer

PURPOSE: To assess long-term survival and prognostic indicators of survival in patients with advanced urothelial cancer treated with gemcitabine and cisplatin. MATERIALS AND METHODS: Survival data from three previously published phase II trials of gemcitabine/cisplatin were updated. Baseline hemoglobin, performance status, and presence of visceral metastases, which are known prognostic factors with other regimens, were examined. Survival curves were constructed by the Kaplan-Meier method and significance assessed using the log-rank statistic. Cox's Proportional Hazards Model was used to construct univariate and multivariate survival models. RESULTS AND CONCLUSIONS: Overall median survival of 121 included patients was 13.2 (11.0 to 14.9) months and estimated 4 year survival was 13 +/- 6%. In a univariate analysis, the presence of visceral metastases and a hemoglobin < 12.5 mg/dl had significant adverse prognostic implications (P < 0.001 and P = 0.02, respectively). Performance status was not a significant predictor of survival, perhaps due to the fact that only 14% of patients had a performance status of 2. In a multivariate analysis, only the absence of visceral metastases retained its prognostic importance with an estimated 24% 4-year survival in such patients. These results lend further evidence for the clinical benefit of this regimen in advanced transitional cell cancer.     

Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung

Asthma pathogenesis is focused around conducting airways. The reasons for this focus have been unclear because it has not been possible to track the sites and timing of antigen uptake or subsequent antigen presentation to effector T cells. In this study, we use two-photon microscopy of the lung parenchyma and note accumulation of CD11b(+) dendritic cells (DCs) around the airway after allergen challenge but very limited access of these airway-adjacent DCs to the contents of the airspace. In contrast, we observed prevalent transepithelial uptake of particulate antigens by alveolar DCs. These distinct sites are temporally linked, as early antigen uptake in alveoli gives rise to DC and antigen retention in the airway-adjacent region. Antigen-specific T cells also accumulate in the airway-adjacent region after allergen challenge and are activated by the accumulated DCs. Thus, we propose that later airway hyperreactivity results from selective retention of allergen-presenting DCs and antigen-specific T cells in airway-adjacent interaction zones, not from variation in the abilities of individual DCs to survey the lung.     

Wound pH-responsive sustained release of therapeutics from a poly(NIPAAm-co-AAc) hydrogel

Wound pH strongly influences residence time and activity of various growth factors during wound healing. Hence, a pH-responsive sustained release growth factor delivery system could be beneficial for effective treatment of wound. In this context, an effort was made to evaluate the potential of a poly(N-isopropylacrylamide-co-acrylic acid) hydrogel as pH-sensitive sustained release system for wound-pH-dependent therapeutics delivery. The polymer was synthesized via radical copolymerization and influence of pH on lower critical solution temperature (LCST), microarchitechture and swelling of the hydrogel was evaluated. Results showed a pH-dependent variation in the physical properties of the hydrogel within the wound pH range. Fluorescence recovery after photobleaching (FRAP) analysis endorsed a pH dependent restricted diffusion of the BSA in the hydrogel. Later, release of bovine serum albumin (BSA), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) (each 5%, w/v) from the hydrogel within the range of wound pH (pH 6.7-7.9) were examined. Analysis showed non-Fickian release of therapeutics from the hydrogel with a significant variation in release rate and cumulative release with the increase in pH. Retention of the bioactivity of the released EGF was confirmed by studying murine dermal fibroblast cell proliferation in vitro. Finally, a growth factor (EGF or VEGF)-loaded hydrogel was applied on a murine excisional wound model and showed augmentation of wound healing in comparison to conventional sustained release growth factor therapy.     

Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis: a case series of four children

A rare, severe form of immune-mediated encephalitis recently has been described, associated with antibodies against N-methyl-D-aspartate receptors. It is reported mostly in women with ovarian tumors. Nonparaneoplastic presentations are less common. We describe four children with a neuropsychiatric and extrapyramidal syndrome associated with the presence of anti-N-methyl-D-aspartate receptor antibodies in cerebrospinal fluid and serum, without evidence of neoplasia. Three children recovered completely after immunomodulatory therapy, i.e., intravenous immunoglobulin and/or steroids, methylprednisolone, and/or adrenocorticotrophic hormone.     

39-week toxicity and toxicokinetic study of ponezumab (PF-04360365) in cynomolgus monkeys with 12-week recovery period

Ponezumab (PF-04360365) is a novel humanized IgG2Δa monoclonal antibody that binds to amyloid-β (Aβ). It is designed to have reduced immune effector function compared to other passive immunotherapies for Alzheimer's disease (AD). Toxicity was evaluated in cynomolgus monkeys treated intravenously with vehicle or 10, 30, or 100 mg/kg of ponezumab every 10th day for up to 39 weeks, and after a 12-week recovery phase. The Aβ peptide sequence of monkeys is identical to that of humans. No substantial difference in test article exposure between sexes was observed, and mean plasma Cmax and AUC0-n were approximately dose-proportional. Ponezumab was detectable approximately 9 weeks after cessation of dosing. All animals, except two males given 10 mg/kg, maintained exposure to test article. One of these males tested positive for anti-ponezumab antibodies. Ponezumab was detected in the cerebrospinal fluid (CSF) of animals given active treatment. The estimated CSF/plasma ponezumab concentration ratio was <0.008 after multiple doses. At the end of the dosing and recovery phases, plasma Aβ1-40 and Aβ1-x were increased in treated animals versus controls. No test article-related effects were seen after ophthalmogical, cardiovascular, physical examinations, and clinical and anatomic pathology evaluations. Plasma concentrations of ponezumab on day 261 at the no observed adverse effect level of 100 mg/kg were 22.4 and 5.3 times greater on a Cmax and AUC basis, respectively, than human exposures at the highest dose (10 mg/kg) in a single-dose Phase I trial. These data suggest an acceptable safety profile for ponezumab as an immunotherapy for AD.     

Response of narrow QRS tachycardia in a patient with surgical closure of atrial septal defect to atrial overdrive pacing: What is the mechanism?

A 57‐year old woman who had pericardial patch closure of ostium secundum atrial septal defect (ASD) at the age of 23 years presented with shortness of breath. Her echocardiogram showed no residual ASD, good biventricular function and normal pulmonary artery pressures.     

Anaerobes in cardiac infections: A decade experience from the tertiary care center

PurposeAnaerobic infections are common yet life-threatening. They are being recovered from all sites of the body, including the cardiovascular system. This study was aimed to determine the retrospective analysis on the isolation of anaerobes in cardiovascular samples received for a decade-long duration. It helps in knowing the frequency of isolation of anaerobic causes of cardiovascular infection.MethodsAll cardiovascular samples from the department of Cardio-thoracic vascular surgery from January 2010 to December 2020 were studied.ResultsOf 601 samples received, predominant samples were vegetations and valvular tissues of 258, followed by 98 samples of pericardial tissues, 92 samples of embolus, 90 samples of blood and post-operative collections, and 63 excised aneurysms and vascular grafts. Of the total, 15 samples grew anaerobes where Clostridium species were the predominant isolates. Clostridioides difficile was isolated in 2 samples.ConclusionsAnaerobes in cardiovascular samples are uncommon yet form a significant cause of morbidity and mortality. Most infections are from the contiguous spread, penetrating trauma, and hematogenous causing endocarditis or valvular infections. These conditions and samples form the seat of infectious focus and clinical suspicion towards the anaerobic cause of these conditions, especially in conventional routine culture-negative samples. Timely diagnosis of anaerobic infections plays a vital role in the good prognostic outcome of patients undergoing cardiothoracic and vascular surgery.