Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG): clinical trial design for rare ovarian tumours.

This manuscript reports the consensus statements on designing clinical trials in rare ovarian tumours reached at the fifth Ovarian Cancer Consensus Conference (OCCC) held in Tokyo, November 2015. Three important questions were identified concerning rare ovarian tumours (rare epithelial ovarian cancers (eOC), sex-cord stromal tumours (SCST) and germ cell tumours (GCT)): (i) What are the research and trial issues that are unique to rare ovarian tumours? There is a lack of randomised phase III data defining standards of care which makes it difficult to define control arms, but identifies unmet needs that merit investigation. Internationally agreed upon diagnostic criteria, expert pathological review and translational research are crucial. (ii) What should be investigated in rare eOC, GCT and SCST? Trials dedicated to each rare ovarian tumour should be encouraged. Nonetheless, where the question is relevant, rare eOC can be included in eOC trials but with rigorous stratification. Although there is emerging evidence suggesting that rare eOC have different molecular profiles, trials are needed to define new type-specific standards for each rare eOC (clear cell, low grade serous and mucinous). For GCTs, a priority is reducing toxicities from treatment while maintaining cure rates. Both a robust prognostic scoring system and more effective treatments for de novo poor prognosis and relapsed GCTs are needed. For SCSTs, validated prognostic markers as well as alternatives to the current standard of bleomycin/etoposide/cisplatin (BEP) should be identified. (iii) Are randomised trials feasible? Randomised controlled trials (RCT) should be feasible in any of the rare tumours through international collaboration. Ongoing trials have already demonstrated the feasibility of RCT in rare eOC and SCST. Mucinous OC may be considered for inclusion, stratified, into RCTs of non-gynaecological mucinous tumours, while RCTs in high risk or relapsed GCT may be carried out as a subset of male and/or paediatric germ cell studies.

Two birds with one stone: experiences of combining clinical and research training in addiction medicine.

BACKGROUND: Despite a large evidence-base upon which to base clinical practice, most health systems have not combined the training of healthcare providers in addiction medicine and research. As such, addiction care is often lacking, or not based on evidence or best practices. We undertook a qualitative study to assess the experiences of physicians who completed a clinician-scientist training programme in addiction medicine within a hospital setting. METHODS: We interviewed physicians from the St. Paul's Hospital Goldcorp Addiction Medicine Fellowship and learners from the hospital's academic Addiction Medicine Consult Team in Vancouver, Canada (N = 26). They included psychiatrists, internal medicine and family medicine physicians, faculty, mentors, medical students and residents. All received both addiction medicine and research training. Drawing on Kirkpatrick's model of evaluating training programmes, we analysed the interviews thematically using qualitative data analysis software (Nvivo 10). RESULTS: We identified five themes relating to learning experience that were influential: (i) attitude, (ii) knowledge, (iii) skill, (iv) behaviour and (v) patient outcome. The presence of a supportive learning environment, flexibility in time lines, highly structured rotations, and clear guidance regarding development of research products facilitated clinician-scientist training. Competing priorities, including clinical and family responsibilities, hindered training. CONCLUSIONS: Combined training in addiction medicine and research is feasible and acceptable for current doctors and physicians in training. However, there are important barriers to overcome and improved understanding of the experience of addiction physicians in the clinician-scientist track is required to improve curricula and research productivity.

Constitutive Model of Radiation Aging Effects in Filled Silicone Elastomers under Strain.

Filled silicone elastomers, an essential component in many technological applications, are often subjected to controlled or unintended radiation for a variety of reasons. Radiation exposure can lead to permanent mechanical and structural changes in the material, which is manifested as altered mechanical response, and in some cases, a permanent set. For unfilled elastomers, network theories developed and refined over decades can explain these effects in terms of chain-scission and cross-link formation and a hypothesis involving independent networks formed at different strain levels of the material. Here, we expose a filled silicone rubber to gamma radiation while being under finite elongational strain and show that the observed mechanical and structural changes can be quantitatively modeled within the same theoretical framework developed for unfilled elastomers as long as nuances associated with the Mullins effect are accounted for in a consistent manner. In this work, we employ Ogden's incompressible hyperelastic model within the framework of Tobolsky's two-network scheme to describe the observed permanent set and mechanical modulus changes as a function of radiation dosage. In the process, we conclude that gamma radiation induces both direct cross-linking at chain crossings (H-links) and main-chain-scission followed by cross-linking (Y-links). We provide an estimate of the ratio of chain-scission to cross-linking rates, which is in reasonable agreement with previous experimental estimate from Charlesby-Pinner analysis. We use density functional theory (DFT)-based quantum mechanical calculations to explore the stability of -Si and -SiO radicals that form upon a radiation-induced chain-scission event, which sheds light on the relative rates of Y-linking and H-linking processes.

An international survey of imaging practices in radiotherapy.

Improvements in delivery of radiation dose to target tissues in radiotherapy have increased the need for better image quality and led to a higher frequency of imaging patients. Imaging for treatment planning extends to function and motion assessment and devices are incorporated into medical linear accelerators (linacs) so that regions of tissue can be imaged at time of treatment delivery to ensure dose distributions are delivered as accurately as possible. A survey of imaging in 97 radiotherapy centres in nine countries on six continents has been undertaken with an on-line questionnaire administered through the International Commission on Radiological Protection mentorship programme to provide a snapshot of imaging practices. Responses show that all centres use CT for planning treatments and many utilise additional information from magnetic resonance imaging and positron emission tomography scans. Most centres have kV cone beam CT attached to at least some linacs and use this for the majority of treatment fractions. The imaging options available declined with the human development index (HDI) of the country, and the frequency of imaging during treatment depended more on country than treatment site with countries having lower HDIs imaging less frequently. The country with the lowest HDI had few kV imaging facilities and relied on MV planar imaging intermittently during treatment. Imaging protocols supplied by vendors are used in most centres and under half adapt exposure conditions to individual patients. Recording of patient doses, a knowledge of which is important in optimisation of imaging protocols, was limited primarily to European countries.

The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection.

Bevacizumab (Avastin™; rhuMab VEGF), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has seen increased use in the perioperative treatment of colorectal and pancreatic cancer. Little is known, however, regarding its impact on surgical outcomes in patients undergoing resection. The objective of this review was to examine if the addition of bevacizumab to existing neoadjuvant regimens increases morbidity after cancer resection.

Age-aware constitutive materials model for a 3D printed polymeric foam.

Traditional open or closed-cell stochastic elastomeric foams have wide-ranging applications in numerous industries: from thermal insulation, shock absorbing/gap-filling support cushions, packaging, to light-weight structural and positional components. Recent developments in 3D printing technologies by direct ink-write have opened the possibility of replacing stochastic foam parts by more controlled printed micro-structures with superior stress-distribution and longer functional life. For successful deployment as mechanical support or structural components, it is crucial to characterize the response of such printed materials to long-term external loads in terms of stress-strain behavior evolution and in terms of irreversible structural and load-bearing capacity changes over time. To this end, here we report a thermal-age-aware constitutive model for a 3D printed close-packed foam structure under compression. The model is based on the Ogden hyperfoam strain-energy functional within the framework of Tobolsky two-network scheme. It accurately describes experimentally measured stress-strain response, compression set, and load retention for various aging times and temperatures. Through the technique of time-temperature-superposition the model enables the prediction of long-term changes along with the quantification of uncertainty stemming from sample-to-sample variation and measurement noise. All aging parameters appear to possess the same Arrhenius activation barrier, which suggests a single dominant aging mechanism at the molecular/network level.

Studies on manganese. 3. The biological half-life of radiomanganese in man and factors which affect this half-life.

The biological half-life of manganese and some factors influencing it have been studied in man. The disappearance of manganese from the body in normal subjects is described by a curve having two exponential components. An average of 70% of the injected material was eliminated by the "slow" pathway. The half-time characterizing this component showed a small variation in normal subjects and had an average value of 39 days. The half-time for the "fast" component also showed a small variation and had an average value of 4 days. In a normal subject presumed to have a low manganese intake due to a voluntary low caloric intake, the percentage eliminated by the slow pathway increased to 84% and the half-time characterizing the pathway increased to 90 days. The half-time of the "fast" component was the same as for the normal group. 2 months after initiation of the study in this subject, a large "flushing" dose of manganese markedly increased the elimination rate which was described by a single exponential curve.A mildly iron-deficient subject showed a marked decrease in the percentage of manganese eliminated by the "slow" pathway accompanied by a less dramatic decrease in the half-time characterizing this pathway. Oral iron therapy, which corrected the mild anemia, caused a decrease in the elimination rate and the altered curve was described by a single exponential component. Preloading two subjects with manganese resulted in a great decrease in the fraction eliminated by the "slow" pathway with less effect on the half-time. The subject with the largest preloading dose showed no "slow" component at all. Observations on the red cells of some of these subjects showed that a small but definite fraction was incorporated into the erythrocytes. In the mildly iron-deficient subject, our observations suggest an interrelationship between manganese and iron metabolism.

Embolectomy in a rabbit acute arterial occlusion model using a novel electromechanical extraction device.

A prototype endovascular electromechanical clot-extraction device was fabricated using a combination of shape memory polymer and shape memory nickel-titanium alloy (nitinol). Five embolic vascular occlusions were created in 4 rabbits by injecting thermally coagulated blood through a 4F catheter in the common carotid artery. Angiography immediately after clot injection showed complete or partial occlusion of the common carotid artery. Posttreatment angiography showed complete (2/5), partial (2/5), or no (1/5) restoration of blood flow.

Intramitochondrial functions regulate nonmitochondrial citrate synthase (CIT2) expression in Saccharomyces cerevisiae.

We have examined the effects of perturbation of mitochondrial function on expression of two nuclear genes encoding the mitochondrial and peroxisomal forms of citrate synthase in Saccharomyces cerevisiae, CIT1 and CIT2. CIT2 expression was as much as 30-fold higher in [rho0] petites, than in isochromosomal [rho+] cells, whereas CIT1 expression was slightly down regulated in [rho0] cells. CIT2 expression was also increased in [rho+] cells by inhibition of respiration with antimycin A or in [rho+] cells containing a disruption of the CIT1 gene. These effects were additive, and together they approached the level of CIT2 expression seen in [rho0] cells. Experiments using heterologous gene fusions showed that all of the effects leading to increased expression of CIT2 were transcriptionally controlled through 5'-flanking CIT2 DNA sequences. Analysis of [rho+] and [rho0] cells containing disruptions of CIT1 and CIT2, singly and in combination, showed that the peroxisomal citrate synthase could partially spare the mitochondrial isoform for growth yield in [rho+] but not in [rho0] cells. These studies suggest a physiological role for increased expression of CIT2 in cells with altered mitochondrial function. They also provide additional evidence for a retrograde path of communication from mitochondria to the nucleus in yeast cells.

Barriers and facilitators to implementing addiction medicine fellowships: a qualitative study with fellows, medical students, residents and preceptors.

BACKGROUND: Although progress in science has driven advances in addiction medicine, this subject has not been adequately taught to medical trainees and physicians. As a result, there has been poor integration of evidence-based practices in addiction medicine into physician training which has impeded addiction treatment and care. Recently, a number of training initiatives have emerged internationally, including the addiction medicine fellowships in Vancouver, Canada. This study was undertaken to examine barriers and facilitators of implementing addiction medicine fellowships. METHODS: We interviewed trainees and faculty from clinical and research training programmes in addiction medicine at St Paul's Hospital in Vancouver, Canada (N = 26) about barriers and facilitators to implementation of physician training in addiction medicine. We included medical students, residents, fellows and supervising physicians from a variety of specialities. We analysed interview transcripts thematically by using NVivo software. RESULTS: We identified six domains relating to training implementation: (1) organisational, (2) structural, (3) teacher, (4) learner, (5) patient and (6) community related variables either hindered or fostered addiction medicine education, depending on context. Human resources, variety of rotations, peer support and mentoring fostered implementation of addiction training. Money, time and space limitations hindered implementation. Participant accounts underscored how faculty and staff facilitated the implementation of both the clinical and the research training. CONCLUSIONS: Implementation of addiction medicine fellowships appears feasible, although a number of barriers exist. Research into factors within the local/practice environment that shape delivery of education to ensure consistent and quality education scale-up is a priority.

A multi-institutional analysis of intraoperative radiotherapy for early breast cancer: Does age matter?

BACKGROUND: Single-session intraoperative radiation therapy (IORT) minimizes treatment demands associated with traditional whole breast radiation therapy (WBRT) but outcomes on local disease control and morbidity among the elderly is limited. METHODS: A multi-institutional retrospective registry was established from 19 centers utilizing IORT from 2007 to 2013. Patient, tumor, and treatment variables were analyzed for ages <70 and ≥70. RESULTS: We evaluated 686 patients (<70 = 424; ≥70 = 262) who were margin and lymph node negative. Patients <70 were more likely to have longer operative time, oncoplastic closure, higher rates of IORT used as planned boost, and receive chemotherapy and post-operative WBRT. Wound complication rates were low and not significantly different between age groups. Median follow-up was 1.06 (range 0.51-1.9) years for < 70 and 1.01 (range 0.5-1.68) years for ≥ 70. There were 5 (0.73%) breast recurrences (4 in <70 and 1 ≥ 70, p = 0.65) and no axillary recurrences during follow-up. CONCLUSIONS: IORT was associated with a low rate of wound complication and local recurrence on short-term follow-up in this cohort.

Effects of alkyl-lysophospholipids on human leukemic cell lines measured by nuclear magnetic resonance.

Part of the cytotoxic action of alkyl-lysophospholipids (ALP) on leukemic cells is known to result from the lack of an O-alkyl cleavage enzyme and its antimetabolic effect which results in a toxic lysophospholipid buildup. Further, ALP (5 micrograms/ml) suppresses clonogenicity and tritiated thymidine uptake in HL60 cultures after 24 hr of exposure. The effect of ALP on two leukemic cell lines, HL60 and K562, measured by two nuclear magnetic resonance (NMR) techniques and examined by electron microscopy is reported. 31P-NMR spectroscopy indicates that the adenosine 5'-triphosphate:adenosine 5'-diphosphate ratios are unaffected after 24 hr, as is mitochondrial morphology, judging by electron micrographs. However, cell membrane integrity in HL60 is altered at that time. The earliest ALP effects occur in NMR internal water relaxation at 1 hr after ALP exposure, followed by a small reduction in tritiated thymidine uptake at 4 hr. No effect is observed in K562 cell cultures in morphology or NMR measurements. No new 31P-labeled metabolites were detected in either cell line as a result of drug treatment.

3D printed cellular solid outperforms traditional stochastic foam in long-term mechanical response.

3D printing of polymeric foams by direct-ink-write is a recent technological breakthrough that enables the creation of versatile compressible solids with programmable microstructure, customizable shapes, and tunable mechanical response including negative elastic modulus. However, in many applications the success of these 3D printed materials as a viable replacement for traditional stochastic foams critically depends on their mechanical performance and micro-architectural stability while deployed under long-term mechanical strain. To predict the long-term performance of the two types of foams we employed multi-year-long accelerated aging studies under compressive strain followed by a time-temperature-superposition analysis using a minimum-arc-length-based algorithm. The resulting master curves predict superior long-term performance of the 3D printed foam in terms of two different metrics, i.e., compression set and load retention. To gain deeper understanding, we imaged the microstructure of both foams using X-ray computed tomography, and performed finite-element analysis of the mechanical response within these microstructures. This indicates a wider stress variation in the stochastic foam with points of more extreme local stress as compared to the 3D printed material, which might explain the latter's improved long-term stability and mechanical performance.

The effect of changing extracellular osmolality on water transport in the human red blood cell as measured by the cell water residence time and the activation energy of water transport.

A pulse NMR technique employing low extracellular Mn2+ concentrations has been used in following the effect of variations in extracellular osmolality on water transport through the human red blood cell membrane. We report results including the effect of osmolality on the cell water lifetime (tau a) and, for the first time, the effect on the proton spin-spin relaxation of the intracellular water (T2a) and the activation energy for the water transport process. Current results are encouraging in correlating the effects seen in this study with suspected membrane functional changes occurring in both in vivo and in vitro aging and during in vitro preservation attempts.

The effect of the cryoprotectants, dimethylsulfoxide and glycerol on water transport in the human red blood cell.

The response of human red blood cells to the cryoprotective agents, DMSO and glycerol, has been investigated using a pulsed NMR method. The experimentally determined parameters are: (1) the intracellular transverse relaxation time, T2a; (2) the mean residence time of intracellular water, tau a, which is effectively a reciprocal measure of the rate of water transport across the red blood cell membrane; and (3) the activation energy for this process. The quantitative data indicate that the observed effects are colligative rather than species-specific in origin.

Photodynamic therapy with PhotoPoint photosensitiser MV6401, indium chloride methyl pyropheophorbide, achieves selective closure of rat corneal neovascularisation and rabbit choriocapillaris.

AIM: The new photosensitiser PhotoPoint MV6401, indium chloride methyl pyropheophorbide, was assessed as a possible ocular photodynamic therapy agent in a rat model of experimentally induced corneal neovascularisation and in choriocapillaris closure in the rabbit. Optimal drug and light activation parameters were determined. METHODS: MV6401 (Miravant Pharmaceuticals, Inc, Santa Barbara, CA, USA) was activated at 664 nm using a DD3-0665 (Miravant Systems Inc) 0.5 W diode laser. Corneal neovascularisation in rats was induced using an N-heptanol technique. The evaluated drug dosages, light dosages, and post-injection activation times ranged from 0.01-0.1 micromol/kg, 5-25 J/cm(2), and 10-60 minutes, respectively. The efficacy of MV6401 on normal choriocapillaris and choroidal vessels was evaluated in rabbits with indirect ophthalmoscopy, fundus photography, fluorescein angiography, and histology. In rabbits, the evaluated drug dosages, light dosages, and post-injection activation times ranged from 0.025-0.25 micromol/kg, 3.3-20 J/cm(2), and 10 minutes, respectively. RESULTS: In the rat corneal neovascularisation model, an optimal intravenous drug dosage of 0.075 micromol/kg was activated by a 20 J/cm(2) light dose at 10 minutes after drug administration, the results of which demonstrated early evidence of efficacy in ocular neovascularisation. In rabbits, closure of the normal choriocapillaris was selectively achieved at a drug dosage of 0.15 micromol/kg using light doses from 3.3 to 20 J/cm(2). CONCLUSION: PhotoPoint MV6401 is a potent photosensitiser that demonstrates both efficacy and selectivity in experimental ocular models.

Local graft irradiation after failure of modern immunosuppression in acute cellular and vascular graft rejection.

PURPOSE: With improved chemical immunosuppressive agents, approximately 90% of rejection episodes can be reversed. However, in situations of failed immunosuppression, graft loss becomes inevitable. Our objective is to assess the efficacy of local graft irradiation (LGI) as an effort of last resort in a contemporary group of patients in whom graft failure to irreversible cellular and vascular rejection is imminent. METHODS AND MATERIALS: A total of 308 renal transplantations were performed at our institution from 1992 to 1995, and an overall 1-year graft survival rate of 90% has been seen as a result of improvement in chemical immunosuppression. However, 6 patients were referred for LGI when all other measures failed to reverse the rejection crisis. Parameters that were studied in these patients included graft function and postirradiation graft histology. RESULTS: Irradiation was associated with reversal of the rejection crisis and resulted in documented histological long-term graft survival in 1 of the 6 patients (17%). Two of the six patients (33%) had reversal of the rejection episode based on postirradiation biopsy of the renal allograft. Three of the six patients showed some level of clinical improvement of graft function for varying periods of time. One patient maintained stable allograft function without deterioration and with continued independence from hemodialysis. One recipient died from sepsis despite histologic improvement after irradiation. CONCLUSIONS: Our impression is that LGI is indicated when all other measures have failed to reverse an acute rejection episode in the transplanted renal allograft. The role of radiation in this setting should be studied further.

Primary gastrointestinal sarcomas: analysis of prognostic factors and results of surgical management.

BACKGROUND: This study was done to review the clinical presentation, surgical management, and prognostic factors for primary gastrointestinal sarcomas. METHODS: We reviewed medical records of 55 patients who were treated for primary gastrointestinal sarcomas from 1981 through 1996. Mean follow-up time was 32 months. RESULTS: Clinical findings included gastrointestinal bleeding (51%), palpable mass (36%), and abdominal pain (33%). The stomach was the most common site of disease (53%), followed by the small intestine (33%). Tumors were high grade in 76% of patients and low-grade in 24% of patients. Complete resection of all gross disease was accomplished in 35 patients (64%), incomplete resection in 17 patients (31%), and biopsy only in 3 patients (5%). Adjacent organ resection was required in 19 patients (35%). Overall actuarial survival was 22% (median survival, 32 months). Unfavorable prognostic factors were incomplete resection, high-grade histologic features, and tumor size of 5 cm or more (P<.05). En bloc resection of contiguous organs did not adversely effect survival. In patients with complete resections, tumor grade was the most important prognostic factor (median survival, 55 months vs 19 months for low-grade vs high-grade tumors; P<.05). CONCLUSIONS: Aggressive surgical resection, including en bloc resection of locally advanced tumors, appears warranted. Despite complete resections, patients with high-grade tumors remain at risk for recurrence.

Management of Ocular Metastasis.

BACKGROUND: Intraocular metastasis is a significant clinical problem in patients with metastatic cancer. The frequency of intraocular metastasis in all patients dying of cancer is approximately 12%, but in breast cancer patients, the frequency can be as high as 37%. METHODS: A review of pertinent literature and the author's experience are used to describe the epidemiology, diagnosis, and management of metastatic tumors of the eye. RESULTS: Intraocular metastases occur frequently and are diagnosed by ophthalmologic examination. Radiotherapy remains the cornerstone of therapy and allows the majority of patients to maintain useful vision for the remainder of their lives. CONCLUSIONS: The recognition and treatment of intraocular metastasis are important clinical oncologic issues. With proper management, patients with ocular metastasis can maintain vision and thus maximize quality of life.