Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several ...subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum‐based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP‐ribose) polymerase (PARP) molecules involved in the DNA damage‐repair process, which have been approved in a recurrent setting and recently in a first‐line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence‐based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.
Epithelial ovarian cancer generally presents at an advanced stage and is the most common cause of gynaecological cancer death. Treatment requires expert multidisciplinary care. Population-based ...screening has been ineffective, but new approaches for early diagnosis and prevention that leverage molecular genomics are in development. Initial therapy includes surgery and adjuvant therapy. Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1). Rapidly evolving techniques to measure genomic changes in tumour and blood allow for assessment of sensitivity and emergence of resistance to therapy, and might be accurate indicators of residual disease. Recurrence is usually incurable, and patient symptom control and quality of life are key considerations at this stage. Treatments for recurrence have to be designed from a patient's perspective and incorporate meaningful measures of benefit. Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.
The authors conduct a meta-analysis on the effect of electronic word of mouth on sales by examining 51 studies (involving 339 volume and 271 valence elasticities) and primary data collected on ...product characteristics (durability, trialability, and usage condition), industry characteristics (industry growth and competition), and platform characteristics (expertise and trustworthiness). Their analysis reveals that electronic word-of-mouth volume (valence) elasticity is .236 (.417). More importantly, the findings show that volume and valence elasticities are higher for privately consumed, low-trialability products that operate in less competitive industries and whose reviews are carried on independent review sites. Furthermore, volume elasticities are higher for durable goods and for reviews on specialized review sites, whereas valence elasticities are greater for community-based sites. Drawing on the results, they discuss several implications for managers and researchers and explain why valence elasticities are often found to be insignificant. Finally, they propose numerous directions for future research in the area on the basis of their findings.
Polymer 3D printing is an emerging technology with recent research translating towards increased use in industry, particularly in medical fields. Polymer printing is advantageous because it enables ...printing low-cost functional parts with diverse properties and capabilities. Here, we provide a review of recent research advances for polymer 3D printing by investigating research related to materials, processes, and design strategies for medical applications. Research in materials has led to the development of polymers with advantageous characteristics for mechanics and biocompatibility, with tuning of mechanical properties achieved by altering printing process parameters. Suitable polymer printing processes include extrusion, resin, and powder 3D printing, which enable directed material deposition for the design of advantageous and customized architectures. Design strategies, such as hierarchical distribution of materials, enable balancing of conflicting properties, such as mechanical and biological needs for tissue scaffolds. Further medical applications reviewed include safety equipment, dental implants, and drug delivery systems, with findings suggesting a need for improved design methods to navigate the complex decision space enabled by 3D printing. Further research across these areas will lead to continued improvement of 3D-printed design performance that is essential for advancing frontiers across engineering and medicine.
Summary Cancer treatment should allow patients to live better or longer lives, and ideally, both. Trial endpoints should show clinically meaningful improvements in patient survival or quality of ...life. Alternative endpoints such as progression-free survival, disease-free survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is controversial. In this Review we discuss the measurement, assessment, and benefits and limitations of trial endpoints in use for cancer treatment. Many stakeholders are affected, including regulatory agencies, industry partners, clinicians, and most importantly, patients. In an accompanying Review, reflections from individual stakeholders are incorporated into a discussion of what the future holds for clinical trial endpoints and design.
Objective To evaluate associations between neonatal intensive care unit (NICU) room type (open ward and private room) and medical outcomes; neurobehavior, electrophysiology, and brain structure at ...hospital discharge; and developmental outcomes at 2 years of age. Study design In this prospective longitudinal cohort study, we enrolled 136 preterm infants born <30 weeks gestation from an urban, 75-bed level III NICU from 2007-2010. Upon admission, each participant was assigned to a bedspace in an open ward or private room within the same hospital, based on space and staffing availability, where they remained for the duration of hospitalization. The primary outcome was developmental performance at 2 years of age (n = 86 infants returned for testing, which was 83% of survivors) measured using the Bayley Scales of Infant and Toddler Development, 3rd Edition. Secondary outcomes were: (1) medical factors throughout the hospitalization; (2) neurobehavior; and (3) cerebral injury and maturation (determined by magnetic resonance imaging and electroencephalography). Results At term equivalent age, infants in private rooms were characterized by a diminution of normal hemispheric asymmetry and a trend toward having lower amplitude integrated electroencephalography cerebral maturation scores ( P = .02; β = −0.52 CI −0.95, −0.10). At age 2 years, infants from private rooms had lower language scores ( P = .006; β = −8.3 CI −14.2, −2.4) and a trend toward lower motor scores ( P = .02; β = −6.3 CI −11.7, −0.99), which persisted after adjustment for potential confounders. Conclusion These findings raise concerns that highlight the need for further research into the potential adverse effects of different amounts of sensory exposure in the NICU environment.
Summary Background Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss ...of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor. Methods ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov , number NCT01891344 . Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing. Findings 256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tumours from 12 patients were established as BRCA wild-type, but could not be classified for LOH, because of insufficient neoplastic nuclei in the sample. The median duration of treatment for the 204 patients was 5·7 months (IQR 2·8–10·1). 24 patients in the BRCA mutant subgroup, 56 patients in the LOH high subgroup, and 59 patients in the LOH low subgroup had disease progression or died. Median progression-free survival after rucaparib treatment was 12·8 months (95% CI 9·0–14·7) in the BRCA mutant subgroup, 5·7 months (5·3–7·6) in the LOH high subgroup, and 5·2 months (3·6–5·5) in the LOH low subgroup. Progression-free survival was significantly longer in the BRCA mutant (hazard ratio 0·27, 95% CI 0·16–0·44, p<0·0001) and LOH high (0·62, 0·42–0·90, p=0·011) subgroups compared with the LOH low subgroup. The most common grade 3 or worse treatment-emergent adverse events were anaemia or decreased haemoglobin (45 22% patients), and elevations in alanine aminotransferase or aspartate aminotransferase (25 12%). Common serious adverse events included small intestinal obstruction (10 5% of 204 patients), malignant neoplasm progression (10 5%), and anaemia (nine 4%). Three patients died during the study (two because of disease progression and one because of sepsis and disease progression). No treatment-related deaths occurred. Interpretation In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours. Funding Clovis Oncology, US Department of Defense Ovarian Cancer Research Program, Stand Up To Cancer—Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research Grant, and V Foundation Translational Award.
Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last ...decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5 years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair (HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.
Electromyography (EMG) signal is gaining popularity to developn intelligent bionics and prosthetic devices using machine learning techniques. Feature extraction is essential step for the EMG pattern ...recognition based application. In this article, a fused wavelet packet transform based feature extraction approach is proposed for EMG pattern classification. Total nine subjects (six intact and three amputees) are recruited for the data acquisition. Data acquisition is performed by an ADS1298-based system with eight bipolar electrodes. Further 11 activities are performed by each subject at the time of EMG signal recording including lateral grasp, cylindrical grasp, spherical grasp, and grasp with force. The visual feedback system is utilized for EMG signal acquisition of amputees. The comparison of commonly used wavelet transform based features and proposed fused wavelet transform based features is also presented with respect to classification accuracy and time complexity. The proposed method exhibits highest classification accuracy up to 98.32% for the amputees using discriminant analysis classification with marginal variation in time complexity. Similar trends in results are observed when standard dataset (NinaPro) has been utilized. The results validate the enhanced performance of the proposed technique over conventional counterparts.
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