Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.

BACKGROUND: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. PATIENTS AND METHODS: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms. RESULTS: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome. CONCLUSIONS: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.

BACKGROUND: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). METHODS: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. RESULTS: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 µg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 µg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range. CONCLUSIONS: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine.

BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889.

TELEMAM: a cluster randomised trial to assess the use of telemedicine in multi-disciplinary breast cancer decision making.

AIM: The TELEMAM trial aimed to assess the clinical effectiveness and costs of telemedicine in conducting breast cancer multi-disciplinary meetings (MDTs). METHODS: Over 12 months 473 MDT patient discussions in two district general hospitals (DGHs) were cluster randomised (2:1) to the intervention of telemedicine linkage to breast specialists in a cancer centre or to the control group of 'in-person' meetings. Primary endpoints were clinical effectiveness and costs. Economic analysis was based on a cost-minimisation approach. RESULTS: Levels of agreement of MDT members on a scale from 1 to 5 were high and similar in both the telemedicine and standard meetings for decision sharing (4.04 versus 4.17), consensus (4.06 versus 4.20) and confidence in the decision (4.16 versus 4.07). The threshold at which the telemedicine meetings became cheaper than standard MDTs was approximately 40 meetings per year. CONCLUSION: Telemedicine delivered breast cancer multi-disciplinary meetings have similar clinical effectiveness to standard 'in-person' meetings.

A comprehensive approach for evaluating telemedicine-delivered multidisciplinary breast cancer meetings in southern Scotland.

Multidisciplinary team (MDT) meetings for decisions on cancer management are a cornerstone of UK cancer policy. We have proposed a comprehensive methodology to assess the clinical and economic effectiveness of telemedicine in this setting, which is being tested in a randomized breast cancer trial. Pre- and post-telemedicine assessment includes attitudes to and expectations of telemedicine, based on semistructured interviews. The communication content of videotapes of the MDT meeting is being scored using Borgatta's revised Interaction Process Analysis System. The technical performance of the telemedicine equipment is reported on a standardized pro forma. A short questionnaire captures key elements of professional satisfaction for each patient discussion (consensus on future management, confidence in and sharing of decision), added value of linkage, group atmosphere, overall conduct of the meeting and compliance with SIGN guidelines. A cost-minimization analysis will be used for economic assessment.

Attitudes of breast cancer professionals to conventional and telemedicine-delivered multidisciplinary breast meetings.

We surveyed the attitudes of breast cancer professionals to standard face-to-face and future telemedicine-delivered breast multidisciplinary team (MDT) meetings. Interviews, which included the Group Behaviour Inventory, were conducted face-to-face (n = 19) or by telephone (n = 26). The mean total score on the Group Behaviour Inventory was 96 (SD 19) for 33 respondents, which indicated satisfaction with standard MDT meetings, irrespective of role and base hospital. Positive attitudes to videoconferencing were more common among participants with previous experience of telemedicine (Spearman's rank correlation 0.26, P = 0.91). Common themes emerging from the interviews about telemedicine-delivered MDTs included group leadership, meeting efficiency, group interaction, group atmosphere and technical quality of communication. Most participants were satisfied with standard breast MDTs. Nurses and allied health professionals were least supportive of telemedicine.

The special operations aviation flight medic.

Medical support in the Army Special Operations Forces is a comprehensive continuum of care that begins at the point of injury and extends through definitive management. Each special operations unit has unique medical needs and, as a result, has developed specially trained medical personnel to fulfill those needs. The 160th Special Operations Aviation Regiment has developed the special operations aviation flight medic to fill this role. The training of these medics involves a systematic, graduated approach with specific milestones to ensure a standardized level of training.

HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway.

HIV causes a chronic infection by evading immune eradication. A key element of HIV immune escape is the HIV-1 Nef protein. Nef causes a reduction in the level of cell surface major histocompatibility complex class I (MHC-I) protein expression, thus protecting HIV-infected cells from anti-HIV cytotoxic T lymphocyte (CTL) recognition and killing. Nef also reduces cell surface levels of the HIV receptor, CD4, by accelerating endocytosis. We show here that endocytosis is not required for Nef-mediated downmodulation of MHC-I molecules. The main effect of Nef is to block transport of MHC-I molecules to the cell surface, leading to accumulation in intracellular organelles. Furthermore, the effect of Nef on MHC-I molecules (but not on CD4) requires phosphoinositide 3-kinase (PI 3-kinase) activity. We propose that Nef diverts MHC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface.

Functional characterization of monoclonal antibodies to interferon-tau.

Interferon tau (IFNtau) produces an array of biological effects, including antiluteolytic, antiviral, antiproliferative and immunomodulatory activities, without the consequent cytotoxicity associated with other type I IFNs. Four anti-IFNtau monoclonal antibodies (MAbs) have been characterized by determining regional epitopes and observation of their effects on IFNtau binding, antiviral and antiproliferative activity. Using an enzyme-linked immunoadsorbent assay (ELISA) developed against six overlapping synthetic peptides representing the entire linear sequence of IFNtau, three antibodies, HL-98, HL-100 and HL-127, were found to react with the carboxy terminal peptide, while HL-129 bound the penultimate amino terminal peptide. Binding studies indicated that MAbs directed against either region could effectively inhibit the binding of alkaline phosphatase labeled IFNtau to cells expressing type I IFN receptors. While only two of the MAbs significantly reversed IFNtau-induced growth inhibition, the antiviral activity of IFNtau was significantly inhibited by MAbs that bound the amino and carboxy termini, confirming the functional importance of these domains in the binding and subsequent activity of IFNtau.

Role of cysteine residues in pseudouridine synthases of different families.

The pseudouridine synthases catalyze the isomerization of uridine to pseudouridine in RNA molecules. An attractive mechanism was proposed based on that of thymidylate synthase, in which the thiol(ate) group of a cysteine side chain serves as the nucleophile in a Michael addition to C6 of the isomerized uridine. Such a role for cysteine in the pseudouridine synthase TruA (also named Psi synthase I) has been discredited by site-directed mutagenesis, but sequence alignments have led to the conclusion that there are four distinct "families" of pseudouridine synthases that share no statistically significant global sequence similarity. It was, therefore, necessary to probe the role of cysteine residues in pseudouridine synthases of the families that do not include TruA. We examined the enzymes RluA and TruB, which are members of different families than TruA and each other. Substitution of cysteine for amino acids with nonnucleophilic side chains did not significantly alter the catalytic activity of either pseudouridine synthase. We conclude, therefore, that neither TruB nor RluA require thiol(ate) groups to effect catalysis, excluding their participation in a Michael addition to C6 of uridine, although not eliminating that mechanism (with an alternate nucleophile) from future consideration.

Critical aspartic acid residues in pseudouridine synthases.

The pseudouridine synthases catalyze the isomerization of uridine to pseudouridine at particular positions in certain RNA molecules. Genomic data base searches and sequence alignments using the first four identified pseudouridine synthases led Koonin (Koonin, E. V. (1996) Nucleic Acids Res. 24, 2411-2415) and, independently, Santi and co-workers (Gustafsson, C., Reid, R., Greene, P. J., and Santi, D. V. (1996) Nucleic Acids Res. 24, 3756-3762) to group this class of enzyme into four families, which display no statistically significant global sequence similarity to each other. Upon further scrutiny (Huang, H. L., Pookanjanatavip, M., Gu, X. G., and Santi, D. V. (1998) Biochemistry 37, 344-351), the Santi group discovered that a single aspartic acid residue is the only amino acid present in all of the aligned sequences; they then demonstrated that this aspartic acid residue is catalytically essential in one pseudouridine synthase. To test the functional significance of the sequence alignments in light of the global dissimilarity between the pseudouridine synthase families, we changed the aspartic acid residue in representatives of two additional families to both alanine and cysteine: the mutant enzymes are catalytically inactive but retain the ability to bind tRNA substrate. We have also verified that the mutant enzymes do not release uracil from the substrate at a rate significant relative to turnover by the wild-type pseudouridine synthases. Our results clearly show that the aligned aspartic acid residue is critical for the catalytic activity of pseudouridine synthases from two additional families of these enzymes, supporting the predictive power of the sequence alignments and suggesting that the sequence motif containing the aligned aspartic acid residue might be a prerequisite for pseudouridine synthase function.

Features of the structural development of the inferior colliculus in relation to the onset of hearing in a marsupial: the northern quoll, Dasyurus hallucatus.

The time course of synaptogenesis and the arrival and myelination of afferent connections were studied in the developing inferior colliculus (IC) of a marsupial, the Northern Quoll, and related to the onset of hearing and patency of peripheral auditory structures in that species. The quoll is born after 3 weeks of intrauterine growth and completes its development in a pouch for a further 80 days before weaning. Synaptic terminals in the IC at 9 days after arrival in the pouch were extremely rare and were associated with very low vesicle numbers. The number of synapses increased smoothly during pouch life, whereas the number of neurons with nucleoli fell over the same time period. The ratio of synapses to cells steadily increased from day 9 to day 63, then rapidly accelerated to day 73; a similar high ratio was observed in adults. Retrograde labeling from the IC of fibers projected from the medullary auditory nuclei, first observed on day 36, became progressively denser during pouch life. Myelination of lateral lemniscal fibers was absent on day 45, extremely sparse on day 54, and clear on day 63. Myelin sheaths were not observed within the IC electron microscopically until day 73. Examination of the peripheral auditory system revealed that until about day 40 the middle ear was fluid-filled, and middle ear structures were spongy. Between days 51 and 63 the middle ear cleared, the eardrum became shiny, and the ear canal became patent. The structural development of the IC is therefore very mature at the time hearing begins (67 days), and the last major anatomical change preceding hearing appears to be the opening of the external ear canal.

The morphological development of the inferior colliculus in a marsupial, the Northern quoll (Dasyurus hallucatus).

As a part of a project concerning the development of hearing, some features of the morphological development of the inferior colliculus were studied in a marsupial, the Northern quoll or native cat (Dasyurus hallucatus). Marsupials are of particular interest in developmental studies because much embryonic development occurs outside the uterus, in the pouch. Nissl-stained material was prepared from pouch-young at various ages between 11 and 81 days, and for a number of adults. Four pouch-young were injected with tritiated thymidine and killed later during pouch life. The inferior colliculus is first recognizable in pouch-young aged 23 days, when it is bordered by a cell-sparse ring of tissue. By this time, the labelling patterns following injections of tritiated thymidine made on days 7-9 suggest that migration of cells to the inferior colliculus from the ventricular germinal zone has been largely completed. At 81 days, close to the time when the young move out of the pouch, the adult cytoarchitecture--a central nucleus flanked by dorsal and lateral cortical regions--is clear. Cell areas expand monotonically as a function of age. The period of days 45-50 is associated with a large expansion of cell volume and a concomitant decrease in packing density. It is likely that functional connections are forming during this period, which may herald the onset of hearing in the quoll. Total cell numbers increase to a peak at day 36, fall to a minimum at day 50, and rise again to the adult value. The second increase is likely to be a phase of glial proliferation, in part associated with the onset of myelination. This increase correlates with departure of the young from the pouch.

Testing the FOCOMETER--A new refractometer.

The FOCOMETER, an optometer which measures spherical refractive errors, is intended to provide rural or economically disadvantaged populations spherical prescriptions without the need for complicated protocols, expensive equipment, or electricity. FOCOMETER readings were compared with the spherical equivalent determined from autorefraction and subjective trial lens refractions in children, and with retinoscopy in adults. Over the range of refractive errors tested (-4 to +5 D) reasonably close readings, within one-half a diopter, were found for comparisons with autorefraction and retinoscopy and about one-tenth of a diopter difference was found between subjective refractions and the FOCOMETER.

Application of magnetron sputtering for producing ceramic coatings on implant materials.

Radiofrequent magnetron sputtering was used to produce calcium phosphate coatings on metal and plastic substrates. Scanning electron microscopy showed that the deposited films had a uniform thickness and a dense columnar structure. Energy-dispersive X-ray analysis, X-ray crystal diffraction and atomic absorption spectrometry demonstrated that the sputtered layer was well-crystallized calcium phosphate ceramic with a Ca/P ratio varying between 1.9 and 2.5. The biocompatibility of the coatings was determined by in vitro and in vivo experiments. It was found that the coatings were biocompatible without any sign of adverse tissue reaction. It was concluded that magnetron sputtering is a promising method for forming a biocompatible ceramic coating onto an implant material. Nevertheless, several problems have to be solved before magnetron sputtering can be used on a routine basis for the production of Ca/P coatings.

New technology in U.S. Army health care: the role of laparoscopic cholecystectomy.

In the near future, laparoscopic cholecystectomy could become one of the most frequently performed surgical procedures in U.S. military hospitals. To determine the best way to implement this new technology in the U.S. Army Health Services Command (HSC), we have assessed the safety, efficacy, and health consequences of laparoscopic cholecystectomy. Approximately 2,800 open cholecystectomies are performed annually in HSC hospitals, 11% of them on active duty personnel. If cholecystectomies were performed using laparoscopic surgical techniques on active duty patients who meet currently accepted indications, 3,360 personnel duty days lost to convalescence and 7,048 days of limited duty (time on physical profiles) would be recouped. Applying the procedure to other beneficiaries (dependents and retired service members) would result in a potential annual savings of 11,000 hospital bed days. If implemented using stringent criteria for training and certification, these savings could be achieved with no increase in patient morbidity or mortality and with significant improvement in patient outcome.

Neurogenesis in the brain auditory pathway of a marsupial, the northern native cat (Dasyurus hallucatus).

Neurogenesis in the auditory pathway of the marsupial Dasyurus hallucatus was studied. Intraperitoneal injections of tritiated thymidine (20-40 microCi) were made into pouch-young varying from 1 to 56 days pouch-life. Animals were killed as adults and brain sections were prepared for autoradiography and counterstained with a Nissl stain. Neurons in the ventral cochlear nucleus were generated prior to 3 days pouch-life, in the superior olive at 5-7 days, and in the dorsal cochlear nucleus over a prolonged period. Inferior collicular neurogenesis lagged behind that in the medial geniculate, the latter taking place between days 3 and 9 and the former between days 7 and 22. Neurogenesis began in the auditory cortex on day 9 and was completed by about day 42. Thus neurogenesis was complete in the medullary auditory nuclei before that in the midbrain commenced, and in the medial geniculate before that in the auditory cortex commenced. The time course of neurogenesis in the auditory pathway of the native cat was very similar to that in another marsupial, the brushtail possum. For both, neurogenesis occurred earlier than in eutherian mammals of a similar size but was more protracted.

Evaluation of head and neck cancer patients. A national survey.

A review of the recent literature of otolaryngology-head and neck surgery reveals minimal guidance as to the use of laboratory and radiographic studies in the initial evaluation and subsequent follow-up of patients with head and neck cancer. A national survey was prepared and was sent to 105 otolaryngology-head and neck surgery teaching departments with 53 institutions responding. This survey shows that a baseline of laboratory and radiographic studies are routinely ordered. Follow-up is monthly the first year and every other month the second year. Specialized laboratory tests and radiographic studies are ordered on a case-by-case basis and based on cost effectiveness, research orientation, available resources, and, most importantly, the patient's needs.