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Rhabdomyolysis is a skeletal muscle injury that can cause myoglobinuria and acute kidney injury (AKI). Risk factors for AKI in children are not clearly understood with no standardized treatment guidelines for rhabdomyolysis. Our study explores factors associated with AKI and management of pediatric patients with rhabdomyolysis. Medical records from a children's hospital network over a 5-year period were retrospectively reviewed. The results are described with respect to the presence or absence of AKI. Of the 112 patients who met the inclusion criteria, AKI incidence was 7.1% (n = 8), with all affected patients having exertional etiology. The overall mean age was 13.5 years; patients without AKI were younger than patients with AKI (13.3 versus 17; p < 0.001). Using regression models for hypothesis generation, we found that patients with AKI were more likely to be older (OR = 1.44, 95%CI [1.11-2.19]; p = 0.03), have myoglobinuria (OR = 22.98, 95%CI [2.05-432.48]; p = 0.02), and have received intravenous bicarbonate (OR = 16.02, 95%CI [1.44-228.69]; p = 0.03). In our study, AKI was uncommon and associated with older age, myoglobinuria and bicarbonate treatment. Larger, prospective studies are needed to further understand AKI risk factors and optimal management of pediatric rhabdomyolysis.

Background: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition., Methods: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n = 34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n = 50). Gene expression of peripheral blood macrophages was assessed., Results: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10 , rs28360457 in P2RX7 , rs1126930 in PRKAG1 and rs80308281 in SLC12A9 . Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10 , P2RX7 , PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls., Conclusion: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx., (©2023 American Association for Cancer Research.)

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity., Competing Interests: Jonathon VallejoEmployment: AstraZeneca (I)No other potential conflicts of interest were reported.

Background: Pathology testing and diagnostic imaging together contribute 9% of healthcare's carbon footprint. Whilst the carbon footprint of pathology testing has been undertaken, to date, the carbon footprint of the four most common imaging modalities is unclear., Methods: We performed a prospective life cycle assessment at two Australian university-affiliated health services of five imaging modalities: chest X-ray (CXR), mobile chest X-ray (MCXR), computerised tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US). We included scanner electricity use and all consumables and associated waste, including bedding, imaging contrast, and gloves. Analysis was performed using both attributional and consequential life cycle assessment methods. The primary outcome was the greenhouse gas footprint, measured in carbon dioxide equivalent (CO 2 e) emissions., Findings: Mean CO 2 e emissions were 17·5 kg/scan for MRI; 9·2 kg/scan for CT; 0·8 kg/scan for CXR; 0·5 kg/scan for MCXR; and 0·5 kg/scan for US. Emissions from scanners from standby energy were substantial. When expressed as emissions per additional scan (results of consequential analysis) impacts were lower: 1·1 kg/scan for MRI; 1·1 kg/scan for CT; 0·6 kg/scan for CXR; 0·1 kg/scan for MCXR; and 0·1 kg/scan for US, due to emissions from standby power being excluded., Interpretation: Clinicians and administrators can reduce carbon emissions from diagnostic imaging, firstly by reducing the ordering of unnecessary imaging, or by ordering low-impact imaging (X-ray and US) in place of high-impact MRI and CT when clinically appropriate to do so. Secondly, whenever possible, scanners should be turned off to reduce emissions from standby power. Thirdly, ensuring high utilisation rates for scanners both reduces the time they spend in standby, and apportions the impacts of the reduced standby power of a greater number of scans. This therefore reduces the impact on any individual scan, maximising resource efficiency., Funding: Healthy Urban Environments (HUE) Collaboratory of the Maridulu Budyari Gumal Sydney Partnership for Health, Education, Research and Enterprise MBG SPHERE. The National Health and Medical Research Council (NHMRC) PhD scholarship., Competing Interests: Scott McAlister was funded by a National Health and Medical Research Council of Australia (NHMRC) PhD scholarship, and from the Healthy Urban Environments (HUE) Collaboratory of the Maridulu Budyari Gumal Sydney Partnership for Health, Education, Research and Enterprise MBG SPHERE. Alexandra Barrett is funded by a National Health and Medical Research Council of Australia (NHMRC) Centre of Research Excellence Grant, No 1004136. Kate Charlesworth was funded from the Healthy Urban Environments (HUE) Collaboratory of the Maridulu Budyari Gumal Sydney Partnership for Health, Education, Research and Enterprise MBG SPHERE., (© 2022 The Author(s).)

Over the last decade, there has been tremendous progress in the treatment of patients with gynecologic cancers with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for gynecologic cancers from 2010 to 2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression-free survival (n = 10), objective response rate (n = 6), and overall survival (n = 1) and showed a favorable benefit-risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently under way will be discussed., (©2021 American Association for Cancer Research.)

Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described., (©2021 American Association for Cancer Research.)

Background: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant., Methods: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating., Findings: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs., Interpretation: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Cancer clinical trials often accrue slowly or miss enrollment targets. Strict eligibility criteria are a major reason. Restrictive criteria also limit opportunities for patient participation while compromising external validity of trial results. We examined the impact of broadening select eligibility criteria on characteristics and number of patients eligible for trials, using recommendations of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research., Experimental Design: A retrospective, observational analysis used electronic health record data from ASCO's CancerLinQ Discovery database. Study cohort included patients with advanced non-small cell lung cancer treated from 2011 to 2018. Patients were grouped by traditional criteria [no brain metastases, no other malignancies, and creatinine clearance (CrCl) ≥ 60 mL/minute] and broadened criteria (including brain metastases, other malignancies, and CrCl ≥ 30 mL/minute)., Results: The analysis cohort included 10,500 patients. Median age was 68 years, and 73% of patients were White. Most patients had stage IV disease (65%). A total of 5,005 patients (48%) would be excluded from trial participation using the traditional criteria. The broadened criteria, however, would allow 98% of patients (10,346) to be potential participants. Examination of patients included by traditional criteria (5,495) versus those added (4,851) by broadened criteria showed that the number of women, patients aged 75+ years, and those with stage IV cancer was significantly greater using broadened criteria., Conclusions: This analysis of real-world data demonstrated that broadening three common eligibility criteria has the potential to double the eligible patient population and include trial participants who are more representative of those encountered in practice. See related commentary by Giantonio, p. 2369 ., (©2021 American Association for Cancer Research.)

By studying healthy women who do not request analgesia during their first delivery, we investigate genetic effects on labor pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff pressure pain. We find an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant K V 6.4-Met419 has a dominant-negative effect and cannot modulate the voltage dependence of K V 2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (K V 6.4) expression occurs in 40% of retrograde-labeled mouse uterine sensory neurons, all of which express K V 2.1, and over 90% express the nociceptor genes Trpv1 and Scn10a. In neurons overexpressing K V 6.4-Met419, the voltage dependence of inactivation for K V 2.1 is more depolarized compared with neurons overexpressing K V 6.4. Finally, K V 6.4-Met419-overexpressing neurons have a higher action potential threshold. We conclude that K V 6.4 can influence human labor pain by modulating the excitability of uterine nociceptors., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (g BRCA m vs. non-g BRCA m). Progression-free survival (PFS) in each cohort was the primary endpoint. In the g BRCA m cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17-0.41; P < 0.0001]. In the non-g BRCA m cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of g BRCA m status. Clin Cancer Res; 24(17); 4066-71. ©2018 AACR See related commentary by Konstantinopoulos and Matulonis, p. 4062 ., (©2018 American Association for Cancer Research.)

Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention's benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.

Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute-sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute-sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.

Objectives The aim of this study was to quantify the radiation dose reduction during coronary angiography and percutaneous coronary intervention (PCI) through removal of the anti-scatter grid (ASG), and to assess its impact on image quality in adult patients with a low body mass index (BMI). Methods A phantom with different thicknesses of acrylic was used with a Westmead Test Object to simulate patient sizes and assess image quality. 129 low BMI patients underwent coronary angiography or PCI with or without the ASG in situ. Radiation dose was compared between both patient groups. Results With the same imaging system and a comparable patient population, ASG removal was associated with a 47% reduction in total dose-area product (DAP) (p < 0.001). Peak skin dose was reduced by 54% (p < 0.001). Operator scatter was reduced to a similar degree and was significantly reduced through removal of the ASG. Using an image quality phantom it was demonstrated that image quality remained satisfactory. Conclusions Removal of the ASG is a simple and effective method to significantly reduce radiation dose in coronary angiography and PCI. This was achieved while maintaining adequate diagnostic image quality. Selective removal of the ASG is likely to improve the radiation safety of cardiac angiography and interventions.

Aims: The aim of this study was to evaluate whether a real-time (RT) colour pictorial radiation dose monitoring system reduces patient skin and total radiation dose during coronary angiography and intervention., Methods and Results: Patient demographics, procedural variables and radiation parameters were recorded before and after institution of the RT skin dose recording system. Peak skin dose as well as traditionally available measures of procedural radiation dose were compared. A total of 1,077 consecutive patients underwent coronary angiography, of whom 460 also had PCI. Institution of the RT skin dose recording system resulted in a 22% reduction in peak skin dose after accounting for confounding variables. Radiation dose reduction was most pronounced in those having PCI but was also seen over a range of subgroups including those with prior coronary artery bypass surgery, high BMI, and with radial arterial access. This was associated with a significant reduction in the number of patients placed at risk of skin damage. Similar reductions in parameters reflective of total radiation dose were also demonstrated after institution of RT radiation monitoring., Conclusions: Institution of an RT skin dose recording reduced patient peak skin and total radiation dose during coronary angiography and intervention. Consideration should be given to widespread adoption of this technology.

On December 11, 2015, the FDA approved uridine triacetate (VISTOGARD; Wellstat Therapeutics Corporation) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs, and the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of administration of these drugs has not been established. The approval is based on data from two single-arm, open-label, expanded-access trials in 135 patients receiving uridine triacetate (10 g or 6.2 g/m(2) orally every 6 hours for 20 doses) for fluorouracil or capecitabine overdose, or who exhibited severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Ninety-six percent of patients met the major efficacy outcome measure, which was survival at 30 days or survival until the resumption of chemotherapy, if prior to 30 days. The most common adverse reactions were vomiting, nausea, and diarrhea. This article summarizes the FDA review of this New Drug Application, the data supporting approval of uridine triacetate, and the unique regulatory situations encountered by this approval. Clin Cancer Res; 22(18); 4545-49. ©2016 AACR., (©2016 American Association for Cancer Research.)

Historically, oncology clinical trials have focused on comparing a new drug's efficacy to the standard of care. However, as our understanding of molecular pathways in oncology has evolved, so has our ability to predict how patients will respond to a particular drug, and thus comparison with a standard therapy has become less important. Biomarkers and corresponding diagnostic testing are becoming more and more important to drug development but also limit the type of patient who may benefit from the therapy. Newer clinical trial designs have been developed to assess clinically meaningful endpoints in biomarker-enriched populations, and the number of modern, molecularly driven clinical trials are steadily increasing. At the same time, barriers to clinical trial enrollment have also grown. Many barriers contribute to nonenrollment in clinical trials, including patient, physician, institution, protocol, and regulatory barriers. At the protocol level, eligibility criteria have become a large roadblock to clinical trial accrual. Over time, eligibility criteria have become more and more restrictive. To accrue an adequate number of patients to molecularly driven trials, we should consider eligibility criteria carefully and attempt to reduce restrictive criteria. Reducing restrictive eligibility criteria will allow more patients to be eligible for clinical trial participation, will likely increase the speed of drug approvals, and will result in clinical trial results that more accurately reflect treatment of the population in the clinical setting.

On December 19, 2014, the FDA approved olaparib capsules (Lynparza; AstraZeneca) for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. The BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.) was approved concurrently. An international multicenter, single-arm trial enrolled 137 patients with measurable gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy. Patients received olaparib at a dose of 400 mg by mouth twice daily until disease progression or unacceptable toxicity. The objective response rate (ORR) was 34% with median response duration of 7.9 months in this cohort. The most common adverse reactions (≥20%) in patients treated with olaparib were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/upper respiratory infection, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, and abdominal pain/discomfort. Myelodysplatic syndrome and/or acute myeloid leukemia occurred in 2% of the patients enrolled on this trial., (©2015 American Association for Cancer Research.)

Background: Coronary angiography and angioplasty have to date been performed using digital angiography and fluoroscopic systems which incorporate an image intensifier (II). More recently flat-panel (FP) detectors have been introduced which are thought to improve spatial resolution. However, there is limited data on the effect of flat-panel detection on radiation exposure. We sought to determine the impact of flat-panel on cumulative radiation exposure in patients undergoing elective coronary angioplasty at our institution., Methods: Patients who underwent elective coronary angioplasty in the six months prior to and following upgrade of our Toshiba catheterisation laboratory from image intensifier to flat-panel were included. Demographic and radiation data were collected prospectively and the same five operators performed interventions during the 12-month period. Radiation data was obtained from the dose-area product meter intrinsic to the fluoroscopy system., Results: One hundred and thirty seven patients underwent elective angioplasty over the 12-month period (68 II, 69 FP). Cumulative radiation exposure was increased in flat-panel cases (99, 129 Gy cm(2) versus 71, 77 Gy cm(2), p=0.001). This increase was independent of patient weight (78+/-15 kg versus 78+/-17 kg, p=NS), screening time (19+/-12 min versus 18+/-13 min, p=NS) and total number of digital acquisitions (1475, 820 versus 1668, 1365, p=NS). The total amount of contrast dye did not differ between flat-panel and image intensifier cases (195+/-76 ml versus 194+/-79 ml, p=NS)., Conclusions: Adoption of flat-panel detector technology increases radiation exposure. This may have important safety implications for catheterisation laboratory staff and patients undergoing multiple interventional procedures.