Gastrointestinal toxicity of vorinostat: reanalysis of phase 1 study results with emphasis on dose-volume effects of pelvic radiotherapy

<p>Abstract</p> <p>Background</p> <p>In early-phase studies with targeted therapeutics and radiotherapy, it may be difficult to decide whether an adverse event should be considered a dose-limiting toxicity (DLT) of the investigational systemic agent, as acute normal tissue toxicity is frequently encountered with radiation alone. We have reanalyzed the toxicity data from a recently conducted phase 1 study on vorinostat, a histone deacetylase inhibitor, in combination with pelvic palliative radiotherapy, with emphasis on the dose distribution within the irradiated bowel volume to the development of DLT.</p> <p>Findings</p> <p>Of 14 eligible patients, three individuals experienced Common Terminology Criteria of Adverse Events grade 3 gastrointestinal and related toxicities, representing a toxicity profile vorinostat has in common with radiotherapy to pelvic target volumes. For each study patient, the relative volumes of small bowel receiving radiation doses between 6 Gy and 30 Gy at 6-Gy intervals (V6-V30) were determined from the treatment-planning computed tomography scans. The single patient that experienced a DLT at the second highest dose level of vorinostat, which was determined as the maximum-tolerated dose, had V6-V30 dose-volume estimates that were considerably higher than any other study patient. This patient may have experienced an adverse radiation dose-volume effect rather than a toxic effect of the investigational drug.</p> <p>Conclusions</p> <p>When reporting early-phase trial results on the tolerability of a systemic targeted therapeutic used as potential radiosensitizing agent, radiation dose-volume effects should be quantified to enable full interpretation of the study toxicity profile.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00455351">NCT00455351</a></p

Back-illuminated electron multiplying technology: The world&apos;s most sensitive CCD for ultra low-light microscopy

ABSTRACT The back-illuminated Electron Multiplying Charge Coupled Device (EMCCD) camera stands to be one the most revolutionary contributions ever to the burgeoning fields of low-light dynamic cellular microscopy and single molecule detection, combining extremely high photon conversion efficiency with the ability to eliminate the readout noise detection limit. Here, we present some preliminary measurements recorded by a very rapid frame rate version of this camera technology, incorporated into a spinning disk confocal microscopy set-up that is used for fast intracellular calcium flux measurements. The results presented demonstrate the united effects of: (a) EMCCD technology in amplifying the very weak signal from these fluorescently labelled cells above the readout noise detection limit, that they would otherwise be completely lost in; (b) back-thinned CCD technology in maximizing the signal/shot noise ratio from such weak photon fluxes. It has also been shown how this innovative development can offer significant signal improvements over that afforded by ICCD technology. Practically, this marked advancement in detector sensitivity affords benefits such as shorter exposure times (therefore faster frame rates), lower dye concentrations and reduced excitation powers and will remove some of the barriers that have been restricting the development of new innovative low-light microscopy techniques

Endothelin inhibitors for advanced prostate cancer

This is the protocol for a review and there is no abstract. The objectives are as follows: Our review aims to determine the effectiveness and adverse effects of endothelin inhibitors for advanced prostate cancer. The primary objectives are to assess the effect of endothelin inhibitors on overall survival, prostate cancer-speci?c survival, and progression-free survival. The secondary objectives are to determine: 1. the frequency of adverse events; 2. the effect of treatment on target lesions identi?ed by radiological imaging; 3. the effect of treatment on molecular biomarkers, including PSA and bone alkaline phosphatase; 4. the impact on quality of life

Design and conduct of early-phase radiotherapy trials with targeted therapeutics: Lessons from the PRAVO experience

AbstractNew strategies to facilitate the improvement of physical and integrated biological optimization of high-precision treatment protocols are an important priority for modern radiation oncology. From a clinical perspective, as knowledge accumulates from molecular radiobiology, there is a complex and exciting opportunity to investigate novel approaches to rational patient treatment stratification based on actionable tumor targets, together with the appropriate design of next-generation early-phase radiotherapy trials utilizing targeted therapeutics, to formally evaluate relevant clinical and biomarker endpoints. A unique aspect in the development pathway of systemic agents with presumed radiosensitizing activity will also be the need for special attention on patient eligibility and the rigorous definition of radiation dose–volume relationships and potential dose-limiting toxicities. Based on recent experience from systematically investigating histone deacetylase inhibitors as radiosensitizing agents, from initial studies in preclinical tumor models through the conduct of a phase I clinical study to evaluate tumor activity of the targeted agent as well as patient safety and tumor response to the combined treatment modality, this communication will summarize principles relating to early clinical evaluation of combining radiotherapy and targeted therapeutics

Close practice encounters of the teenage kind.

Research by GPs in Ballymun provides an informative snapshot of the health needs of teenage patients and some important pointers from dealing with this often vulnerable group. Substance misuse and recording of this issue was reviewed. In general, it was noted that whether or not the person attending used alcohol, smoked cigarettes or used other substances was not recorded. No reference was made to alcohol in any of the 380 teenagers' records, but that this was not recorded does not in our view indicate that none of these 380 teenagers drinks alcohol. Seven teenagers were noted to be smokers of cigarettes, seven were noted to be smokers of hash, and there was not mention in the clinical records of other drugs being used....