Accuracy of mandibular proximal segment position using virtual surgical planning and custom osteosynthesis plates.

The purpose of this study was to determine whether the use of custom osteosynthesis plates increased the accuracy of proximal segment position following bilateral sagittal split osteotomy in a cohort of 30 patients when compared to a control group of 25 patients who had surgery with conventional plates. Surgery was performed by a single surgeon between October 2015 and December 2017. Post-surgical cone beam computed tomography scans were segmented using Mimics Innovation Suite (Materialise NV), and surface-based superimposition was achieved using ProPlan CMF (Materialise NV). However, there was a tendency for the rotational error to be smaller in the custom group than in the control group. The root mean square error in both groups and for all variables fell within clinical parameters of 2 mm and 4°. In conclusion, the results of this study indicate that customized mandibular fixation plates do not necessarily improve the accuracy of the proximal segments post-surgically; however they may be of benefit in individual patients.

Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome.

BACKGROUND: Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. PATIENTS AND METHODS: Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. RESULTS: In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. CONCLUSION: Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.

The evolution and understanding of skeletal complication endpoints in clinical trials of tumors with metastasis to the bone.

Bone metastases are a frequent complication of solid tumors, leading to significant skeletal sequelae that negatively impact quality of life and survival. Prevention and management of skeletal-related complications are critical treatment goals in oncology. Endpoints used in clinical trials to evaluate skeletal-related complications have evolved. In contrast to single measures of bone health, contemporary clinical trial endpoints reflect composite measures of skeletal-related complications, and increasingly also survival. In addition, key symptomatic components, which are more reflective of quality of life and the patient experience, are being incorporated. Given the evolution and resulting diversity of the endpoints being used in pivotal trials, it is becoming increasingly relevant to clarify the utility and the potential clinical impact of these measures not only within the context of trials but also in the real-world setting. Here, we describe the development and evolution of skeletal endpoints used in trials, and discuss their clinical relevance.

Prediction and monitoring of relapse in stage III melanoma using circulating tumor DNA.

BACKGROUND: The advent of effective adjuvant therapies for patients with resected melanoma has highlighted the need to stratify patients based on risk of relapse given the cost and toxicities associated with treatment. Here we assessed circulating tumor DNA (ctDNA) to predict and monitor relapse in resected stage III melanoma. PATIENTS AND METHODS: Somatic mutations were identified in 99/133 (74%) patients through tumor tissue sequencing. Personalized droplet digital PCR (ddPCR) assays were used to detect known mutations in 315 prospectively collected plasma samples from mutation-positive patients. External validation was performed in a prospective independent cohort (n = 29). RESULTS: ctDNA was detected in 37 of 99 (37%) individuals. In 81 patients who did not receive adjuvant therapy, 90% of patients with ctDNA detected at baseline and 100% of patients with ctDNA detected at the postoperative timepoint relapsed at a median follow up of 20 months. ctDNA detection predicted patients at high risk of relapse at baseline [relapse-free survival (RFS) hazard ratio (HR) 2.9; 95% confidence interval (CI) 1.5-5.6; P = 0.002] and postoperatively (HR 10; 95% CI 4.3-24; P < 0.001). ctDNA detection at baseline [HR 2.9; 95% CI 1.3-5.7; P = 0.003 and postoperatively (HR 11; 95% CI 4.3-27; P < 0.001] was also associated with inferior distant metastasis-free survival (DMFS). These findings were validated in the independent cohort. ctDNA detection remained an independent predictor of RFS and DMFS in multivariate analyses after adjustment for disease stage and BRAF mutation status. CONCLUSION: Baseline and postoperative ctDNA detection in two independent prospective cohorts identified stage III melanoma patients at highest risk of relapse and has potential to inform adjuvant therapy decisions.

Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients.

INTRODUCTION: Tumour burden is a prognostic biomarker in metastatic melanoma. However, tumour burden is difficult to measure and there are currently no reliable surrogate biomarkers to easily and reliably determine it. The aim of this study was to assess the potential of plasma total cell free DNA as biomarker of tumour burden and prognosis in metastatic melanoma patients. MATERIALS AND METHODS: A prospective biomarker cohort study for total plasma circulating cell-free DNA (cfDNA) concentration was performed in 43 metastatic melanoma patients. For 38 patients, paired blood collections and scan assessments were available before treatment and at first response evaluation. Tumour burden was calculated as the sum of volumes from three-dimensional radiological measurements of all metastatic lesions in individual patients. RESULTS: Baseline cfDNA concentration correlated with pre-treatment tumour burden (ρ = 0.52, P < 0.001). Baseline cfDNA levels correlated significantly with hazard of death and overall survival, and a cut off value of 89 pg/µl identified two distinct prognostic groups (HR = 2.22 for high cfDNA, P = 0.004). Patients with cfDNA ≥89 pg/µl had shorter OS (10.0 versus 22.7 months, P = 0.009; HR = 2.22 for high cfDNA, P = 0.004) and the significance was maintained when compared with lactic dehydrogenase (LDH) in a multivariate analysis. We also found a correlation between the changes of cfDNA and treatment-related changes in tumour burden (ρ = 0.49, P = 0.002). In addition, the ratio between baseline cfDNA and tumour burden was prognostic (HR = 2.7 for cfDNA/tumour volume ≥8 pg/(µl*cm3), P = 0.024). CONCLUSIONS: We have demonstrated that cfDNA is a surrogate marker of tumour burden in metastatic melanoma patients, and that it is prognostic for overall survival.

Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma.

Background: Patients with high-risk stage II/III resected melanoma commonly develop distant metastases. At present, we cannot differentiate between patients who will recur or those who are cured by surgery. We investigated if circulating tumor DNA (ctDNA) can predict relapse and survival in patients with resected melanoma. Patients and methods: We carried out droplet digital polymerase chain reaction to detect BRAF and NRAS mutations in plasma taken after surgery from 161 stage II/III high-risk melanoma patients enrolled in the AVAST-M adjuvant trial. Results: Mutant BRAF or NRAS ctDNA was detected (≥1 copy of mutant ctDNA) in 15/132 (11%) BRAF mutant patient samples and 4/29 (14%) NRAS mutant patient samples. Patients with detectable ctDNA had a decreased disease-free interval [DFI; hazard ratio (HR) 3.12; 95% confidence interval (CI) 1.79-5.47; P < 0.0001] and distant metastasis-free interval (DMFI; HR 3.22; 95% CI 1.80-5.79; P < 0.0001) versus those with undetectable ctDNA. Detectable ctDNA remained a significant predictor after adjustment for performance status and disease stage (DFI: HR 3.26, 95% CI 1.83-5.83, P < 0.0001; DMFI: HR 3.45, 95% CI 1.88-6.34, P < 0.0001). Five-year overall survival rate for patients with detectable ctDNA was 33% (95% CI 14%-55%) versus 65% (95% CI 56%-72%) for those with undetectable ctDNA. Overall survival was significantly worse for patients with detectable ctDNA (HR 2.63; 95% CI 1.40-4.96); P = 0.003) and remained significant after adjustment for performance status (HR 2.50, 95% CI 1.32-4.74, P = 0.005). Conclusion: ctDNA predicts for relapse and survival in high-risk resected melanoma and could aid selection of patients for adjuvant therapy. Clinical trial number: ISRCTN 81261306.

Endovascular Therapy Research in Lower Limb Peripheral Arterial Disease Published Over a 5-Year Period: Who is Publishing and Where?

INTRODUCTION: Peripheral arterial disease (PAD) is being increasingly managed by endovascular therapies. In this study, we identified the clinical services publishing research as well as the journals of publication over a 5-year period. METHODS: Twenty keywords and phrases related to endovascular intervention were identified, and a literature search was performed through the PubMed database from January 2009 to January 2014. Inclusion criteria were English language, study population more than five patients, and matching the keyword search. Eligible studies were collated into a database and classified by journal of publication, PubMed number, article title, publishing clinical service, type of publication, country of origin, and authors. RESULTS: 825 studies from 114 different journals were identified. 297 papers were excluded. Of the 528 included papers, 204 (39%) were published by Vascular Surgery (VS), 157 (30%) by Interventional Radiology (IR), 101 (19%) by Cardiology, 43 (8%) by Angiology, 6 (1%) by Vascular Medicine, and 17 (3%) from miscellaneous services. 283 (54%) studies originated from Europe, 157 (30%) from North America, 76 (14%) from Asia, 6 from Australia, 3 each from South America and Africa. IR published the most papers on PAD endovascular intervention in Europe with VS second while this trend was reversed in the USA. The 528 papers were published in 98 different journals with retrospective case series (72%), the majority. CONCLUSION: IR continues to play a significant research role in endovascular intervention in PAD, particularly in Europe, and specifically in below the knee intervention, pedal intervention, and drug-eluting technologies.

Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA.

BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole-exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available.

Patient characteristics associated with risk of first hospital admission and readmission for acute exacerbation of chronic obstructive pulmonary disease (COPD) following primary care COPD diagnosis: a cohort study using linked electronic patient records.

OBJECTIVES: To investigate patient characteristics of an unselected primary care population associated with risk of first hospital admission and readmission for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). DESIGN: Retrospective open cohort using pseudonymised electronic primary care data linked to secondary care data. SETTING: Primary care; Lothian (population approximately 800,000), Scotland. PARTICIPANTS: Data from 7002 patients from 72 general practices with a COPD diagnosis date between 2000 and 2008 recorded in their primary care record. Patients were followed up until 2010, death or they left a participating practice. MAIN OUTCOME MEASURES: First and subsequent admissions for AECOPD (International Classification of Diseases (ICD) 10 codes J44.0, J44.1 in any diagnostic position) after COPD diagnosis in primary care. RESULTS: 1756 (25%) patients had at least 1 AECOPD admission; 794 (11%) had at least 1 readmission and the risk of readmission increased with each admission. Older age at diagnosis, more severe COPD, low body mass index (BMI), current smoking, increasing deprivation, COPD admissions and interventions for COPD prior to diagnosis in primary care, and comorbidities were associated with higher risk of first AECOPD admission in an adjusted Cox proportional hazards regression model. More severe COPD and COPD admission prior to primary care diagnosis were associated with increased risk of AECOPD readmission in an adjusted Prentice-Williams-Peterson model. High BMI was associated with a lower risk of first AECOPD admission and readmission. CONCLUSIONS: Several patient characteristics were associated with first AECOPD admission in a primary care cohort of people with COPD but fewer were associated with readmission. Prompt diagnosis in primary care may reduce the risk of AECOPD admission and readmission. The study highlights the important role of primary care in preventing or delaying a first AECOPD admission.

Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia.

Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (⩾60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.

Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia.

High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in the upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs the survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. As high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.

Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia.

Selective cytotoxicity to cancer cells without compromising their normal counterparts pose a huge challenge for traditional drug design. Here we developed a tumor antigen-targeted delivery of immunonanoparticle carrying a novel non-immunosuppressive FTY720 derivative OSU-2S with potent cytotoxicity against leukemic B cells. OSU-2S induces activation of protein phosphatase 2A (PP2A), phosphorylation and nuclear translocation of SHP1(S591) and deregulation of multiple cellular processes in chronic lymphocytic leukemia (CLL) resulting in potent cytotoxicity. To preclude OSU-2S-mediated effects on these ubiquitous phosphatases in unintended cells and avoid potential adverse effects, we developed an OSU-2S-targeted delivery of immunonanoparticles (2A2-OSU-2S-ILP), that mediated selective cytotoxicity of CLL but not normal B cells through targeting receptor tyrosine kinase ROR1 expressed in leukemic but not normal B cells. Developing a novel spontaneous CLL mouse model expressing human ROR1 (hROR1) in all leukemic B cells, we demonstrate the therapeutic benefit of enhanced survival with 2A2-OSU-2S-ILP in vivo. The newly developed non-immunosuppressive OSU-2S, its delivery using human CLL directed immunonanoparticles and the novel transgenic (Tg) mouse model of CLL that expresses hROR1 exclusively in leukemic B cell surface are highly innovative and can be applied to CLL and other ROR1+ malignancies including mantle cell lymphoma and acute lymphoblastic leukemia.

Oxidised cellulose powder for haemostasis following sinus surgery: a pilot randomised trial.

BACKGROUND: Haemorrhage is the most common major complication of endoscopic sinus surgery. Post-operative absorbable or non-absorbable nasal packing can cause pain and blockage. Haemostatic powders or gels may prevent this problem. However, when based on factors in the clotting cascade, they induce an inflammatory reaction and can cause post-operative synechiae. Oxidised cellulose powder produces haemostasis without inducing synechiae formation, but has not been trialled for sinus surgery. METHOD: A randomised clinical trial was performed to compare cellulose powder to non-absorbable packing following sinus surgery. Participants were 50 consecutive patients undergoing sinus surgery, 47 of whom completed the study. The main outcome measures were post-operative bleeding, pain scores and synechiae formation. RESULTS: Cellulose powder was effective at stopping bleeding, and was associated with less pain than nasal packing, with no evidence of increased synechiae formation. CONCLUSION: Cellulose powder appears to be a good haemostatic agent following sinus surgery. A larger trial would allow more accurate quantification of its effectiveness.

Evaluation of take-home exposure and risk associated with the handling of clothing contaminated with chrysotile asbestos.

The potential for para-occupational (or take-home) exposures from contaminated clothing has been recognized for the past 60 years. To better characterize the take-home asbestos exposure pathway, a study was performed to measure the relationship between airborne chrysotile concentrations in the workplace, the contamination of work clothing, and take-home exposures and risks. The study included air sampling during two activities: (1) contamination of work clothing by airborne chrysotile (i.e., loading the clothing), and (2) handling and shaking out of the clothes. The clothes were contaminated at three different target airborne chrysotile concentrations (0-0.1 fibers per cubic centimeter [f/cc], 1-2 f/cc, and 2-4 f/cc; two events each for 31-43 minutes; six events total). Arithmetic mean concentrations for the three target loading levels were 0.01 f/cc, 1.65 f/cc, and 2.84 f/cc (National Institute of Occupational Health and Safety [NIOSH] 7402). Following the loading events, six matched 30-minute clothes-handling and shake-out events were conducted, each including 15 minutes of active handling (15-minute means; 0.014-0.097 f/cc) and 15 additional minutes of no handling (30-minute means; 0.006-0.063 f/cc). Percentages of personal clothes-handling TWAs relative to clothes-loading TWAs were calculated for event pairs to characterize exposure potential during daily versus weekly clothes-handling activity. Airborne concentrations for the clothes handler were 0.2-1.4% (eight-hour TWA or daily ratio) and 0.03-0.27% (40-hour TWA or weekly ratio) of loading TWAs. Cumulative chrysotile doses for clothes handling at airborne concentrations tested were estimated to be consistent with lifetime cumulative chrysotile doses associated with ambient air exposure (range for take-home or ambient doses: 0.00044-0.105 f/cc year).

Penile cancer: current therapy and future directions.

Background Penile cancer (PC) is a rare cancer in western countries, but is more common in parts of the developing world. Due to its rarity and the consequent lack of randomized trials, current therapy is based on retrospective studies and small prospective trials. Design Studies of PC therapy were searched in PubMed and abstracts at major conferences. Results PC is generally an aggressive malignancy characterized by early locoregional lymph node (LN) spread and later metastases in distant sites. Given the strong predictive value of LN involvement for overall survival, evaluating regional LNs is critical. Advanced LN involvement is increasingly being treated with multimodality therapy incorporating chemotherapy and/or radiation. A single superior cisplatin-based regimen has not been defined. Further advances may occur with a better collaboration on an international scale and comprehensive understanding of tumor biology. To this end, the preventive role of circumcision and understanding of the oncogenic roles of Human Papilloma Virus-16, and smoking may yield advances. Preliminary data suggest a role for agents targeting epidermal growth factor receptor and angiogenesis. Conclusion Advances in therapy for PC will require efficient trial designs, synergistic collaboration, incentives to industry and the efforts of patient advocacy groups and venture philanthropists.

Physiological sex steroid replacement in premature ovarian failure: randomized crossover trial of effect on uterine volume, endometrial thickness and blood flow, compared with a standard regimen.

BACKGROUND: Premature ovarian failure (POF) is currently managed by non-physiological sex steroid regimens which are inadequate at optimizing uterine characteristics. Previous short-term studies have demonstrated some benefits of a sex steroid replacement (SSR) regimen devised to replicate the physiological cycle. This study aimed to directly compare the effects of longer-term administration of physiological SSR (pSSR) and standard SSR (sSSR) regimens on the uterine volume, blood flow and endometrial thickness (ET) in women with POF. METHODS: In a controlled crossover trial, 34 women with POF were randomized to receive 12 months of 4-week cycles of transdermal estradiol and vaginal progesterone (pSSR) followed by 12 months of 4-week cycles of oral ethinylestradiol and norethisterone (sSSR), or vice versa. Each treatment period was preceded by a 2-month washout period. At 0, 3, 6 and 12 months of each treatment period, transvaginal ultrasound examined the uterine volume and ET, as primary end-points, and uterine artery resistance (UARI) and pulsatility indices (UAPI), as secondary end-points. Serum estradiol, progesterone and gonadotrophins were also measured. RESULTS: Of the 29 women eligible for the uterine analysis, 17 completed the entire study protocol, but 25 women contributed data to statistical analysis of treatment effect. There was a greater estimated mean ET with the use of pSSR (4.8 mm) compared to that with standard therapy (3.0 mm), with an estimated difference of 1.8 mm [95% confidence interval (CI), 0.7 to 2.8, P=0.002]. The estimated mean uterine volume was also greater during physiological treatment (24.8 cm(3)) than during standard treatment (20.6 cm(3)), but the estimated difference of 4.2 cm(3) (95% CI -0.4 to 8.7) was not statitsically significant, P=0.070. The small differences between the two treatments in the mean UARI and mean UAPI were not statistically significant. The estimated treatment differences were fairly constant across the treatment periods, suggesting that prolonged treatment does not increase response. CONCLUSIONS: pSSR has a greater beneficial effect upon ET in women with POF in comparison with standard therapy. A similar trend was seen for uterine volume. Further studies are required to optimize treatment and to assess pregnancy rate and outcome. Trial Registration www.ClinicalTrials.gov, NCR00732693.

Multicenter phase II study of trabectedin in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP). RESULTS: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase. CONCLUSIONS: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Naturally occurring asbestos: a recurring public policy challenge.

The potential environmental hazards and associated public health issues related to exposure to respirable dusts from the vicinity of natural in-place asbestos deposits (commonly referred to as naturally occurring asbestos, NOA) have gained the regulatory and media spotlight in many areas around the United States, such as Libby, MT, Fairfax County, VA, and El Dorado Hills, CA, among others. NOA deposits may be present in a variety of geologic formations. It has been suggested that airborne asbestos may be released from NOA deposits, and absent appropriate engineering controls, may pose a potential health hazard if these rocks are crushed or exposed to natural weathering and erosion or to human activities that create dust. The issue that needs to be addressed at a policy level is the method of assessing exposures to elongated rock fragments ubiquitous in dust clouds in these same environments and the associated risk. Elongated rock fragments and single crystal minerals present in NOA have been construed by some as having attributes, including the health effects, of asbestos fibers. However, the Occupational Safety and Health Administration (OSHA), Mine Safety and Health Administration (MSHA), and the Consumer Products Safety Commission (CPSC) found that the scientific evidence did not support this assumption. As in many environmental fields of study, the evidence is often disputed. Regulatory policy is not uniform on the subject of rock fragments, even within single agencies. The core of the issue is whether the risk parameters associated with exposures to commercial asbestos can or should be applied to rock fragments meeting an arbitrary set of particle dimensions used for counting asbestos fibers. Inappropriate inclusion of particles or fragments results in dilution of risk and needless expenditure of resources. On the other hand, inappropriate exclusion of particles or fragments may result in increased and unnecessary risk. Some of the fastest growing counties in the United States are in areas where NOA is known to exist and therefore this issue takes on national significance. This ongoing national dilemma has raised public and business concerns. There has been continuing political and scientific debate and widespread miscommunication over perceived versus actual health risks, the validity of various analytical sampling and testing methods, the questionable necessity and escalating costs of remediation procedures, and the combined negative impact on numerous commercial and public interests. Thus, conflicting research and regulatory positions on the distinctions between and hazards of true asbestos and ordinary rock fragments is all that is presently available to the public until the differing scientific communities and government agencies arrive at a consensus on these issues. The risk assessment methodology and the analytical technology needed to support inferences drawn from existing research are available, but have not been organized and implemented in the manner needed to resolve the NOA controversy. There should exist nationally adopted and peer-reviewed NOA standards (developed jointly by the scientific community, health risk professionals, and government regulators) that establish: (1) a scientific basis for risk evaluation and assessment of NOA and rock fragments; (2) accepted analytical protocols for determining if NOA actually exists in a given area and for separating NOA from related non-asbestos rock fragments and single crystal minerals; and (3) effective public policies for managing NOA, minimizing potential hazards, and protecting public health. This article will review some of the key issues involved with the current NOA debate, propose improved analytical methodologies, describe potential solutions for dealing with NOA, and outline the benefits to be gained by creating a practical national NOA public policy.