Abstract Objective As a result of relevant achievements in the field of translational research, several active drugs and multiple biological targets are available in ovarian cancer (OC). In this ...complex scenario, there is an urgent need to effectively summarize the available data in order to update conclusions, and outline perspectives. Methods The results in terms of target identification and drug development have been summarized using the well-known hallmarks of cancer firstly described, and recently modified by Hanahan and Weinberg 1–2. Published data from clinical trials have been retrieved from PubMed, Embase, CINAHL and Cochrane database. Ongoing clinical trials were searched using clinicaltrials.gov web platform, and identified using NCT number. Results Genomic instability and angiogenesis are the most actively investigated hallmarks in high-grade serous OC, and the inhibition of tumor immune evasion appears as the emerging strategy for molecularly-driven therapy. Targeting sustained proliferative signaling through MEK and mTOR inhibitors seems the most promising approach in clear cell, and low-grade serous OC. Conclusions This substantial amount of data suggests that targeted therapies are already part of the clinical and therapeutic management of OC patients. The expectations of getting from translational research a better knowledge of tumor biology and therefore personalized drugs are high and worthy of maximum effort from referral centers.
Abstract Objective To evaluate the timing and pattern of relapse, and duration of response to second line chemotherapy in advanced ovarian cancer (AOC) patients treated with first line ...carboplatin-paclitaxel chemotherapy with or without bevacizumab. Patients and methods This is a case-control study including 222 AOC patients. Seventy-four women treated with first line carboplatin-paclitaxel-bevacizumab chemotherapy (Cases) were matched based on laparoscopic predictive index value, and residual tumor at first surgery with 148 AOC patients treated with carboplatin-paclitaxel. Distribution of pattern of relapse, and response to second line chemotherapy was compared between the two groups. Time to Progression (TTP) for second line chemotherapy was also analyzed for study purpose. Results Median platinum-free interval (PFI) was 16 months (range 2–65) in Cases, compared with 9 months (1–83) in Controls (p-value = 0.001). Twenty patients (51.3%) among Cases showed recurrence in multiple anatomic sites, compared with 31 (31.9%) in the Control group (p-value = 0.035). Peritoneal recurrence occurred as diffuse in 30 Cases (96.8%), and 60 Controls (82.2%; p-value = 0.046). Secondary cytoreductive surgery (SCS) was successfully completed in 53.5% of Controls compared to 10.0% of Cases (p-value = 0.016). In women with fully platinum-sensitive relapse, response rate to second line chemotherapy was 85.2% in Controls, compared to 38.4% in Cases (p-value = 0.002). Finally, Cases showed a shorter TTP, compared to Controls (5 months vs 8 months; p-value = 0.041). Conclusions Incorporation of bevacizumab into upfront regimens prolongs PFI in AOC patients, but is associated with wider presentation of relapse, lower rate of complete SCS, and shorter TTP to second line chemotherapy in women with platinum-sensitive disease.
Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the ...activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype.
A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms single-nucleotide polymorphisms (SNPs) involved in DNA gene repair was analyzed.
Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1–2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported.
Our data prospectively confirmed that the signature of ‘repeated platinum sensitivity’ identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum.
2011-001298-17.
Speeding up software with VecCore Amadio, G; Canal, P; Piparo, D ...
Journal of physics. Conference series,
09/2018, Letnik:
1085, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Portable and efficient vectorization is a significant challenge in large software projects such as GeantV, ROOT, and experiments' frameworks. Nevertheless, fully exploiting SIMD parallelism will be a ...required step in order to bridge the widening gap between the needs and availability of computing resouces for data analysis and processing in particle physics. Although there are SIMD libraries that wrap compiler intrinsics into a convenient interface, they do not always support all available architectures, or they only perform well in some of them. The VecCore library was created to address some of these performance and portability issues by providing a unified abstraction layer on top of existing libraries, such as Vc or UME::SIMD. In this article, we discuss VecCore's programming model for SIMD code and some use cases in HEP software packages such as VecGeom and GeantV.
Abstract
Making general particle transport simulation for high-energy physics (HEP) single-instruction-multiple-thread (SIMT) friendly, to take advantage of accelerator hardware, is an important ...alternative for boosting the throughput of simulation applications. To date, this challenge is not yet resolved, due to difficulties in mapping the complexity of Geant4 components and workflow to the massive parallelism features exposed by graphics processing units (GPU). The AdePT project is one of the R&D initiatives tackling this limitation and exploring GPUs as potential accelerators for offloading some part of the CPU simulation workload. Our main target is to implement a complete electromagnetic shower demonstrator working on the GPU. The project is the first to create a full prototype of a realistic electron, positron, and gamma electromagnetic shower simulation on GPU, implemented as either a standalone application or as an extension of the standard Geant4 CPU workflow. Our prototype currently provides a platform to explore many optimisations and different approaches. We present the most recent results and initial conclusions of our work, using both a standalone GPU performance analysis and a first implementation of a hybrid workflow based on Geant4 on the CPU and AdePT on the GPU.
Obtaining an accurate higher order statistical description of heterogeneous materials and using this information to predict effective material behaviour with high fidelity has remained an outstanding ...problem for many years. In a recent letter, Gillman & Matouš (2014 Phys. Lett. A 378, 3070-3073. ()) accurately evaluated the three-point microstructural parameter that arises in third-order theories and predicted with high accuracy the effective thermal conductivity of highly packed material systems. Expanding this work here, we predict for the first time effective thermo-mechanical properties of granular Platonic solid packs using third-order statistical micromechanics. Systems of impenetrable and penetrable spheres are considered to verify adaptive methods for computing n-point probability functions directly from three-dimensional microstructures, and excellent agreement is shown with simulation. Moreover, a significant shape effect is discovered for the effective thermal conductivity of highly packed composites, whereas a moderate shape effect is exhibited for the elastic constants.
When processing large amounts of data, the rate at which reading and writing can take place is a critical factor. High energy physics data processing relying on ROOT is no exception. The recent ...parallelisation of LHC experiments' software frameworks and the analysis of the ever increasing amount of collision data collected by experiments further emphasised this issue underlying the need of increasing the implicit parallelism expressed within the ROOT I/O. In this contribution we highlight the improvements of the ROOT I/O subsystem which targeted a satisfactory scaling behaviour in a multithreaded context. The effect of parallelism on the individual steps which are chained by ROOT to read and write data, namely (de)compression, (de)serialisation, access to storage backend, are discussed. Performance measurements are discussed through real life examples coming from CMS production workflows on traditional server platforms and highly parallel architectures such as Intel Xeon Phi.
The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging ...tumour blood vessels.
Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m(-2) and doxorubicin 60 mg m(-2) every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients.
A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI<6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001).
Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.
•Telehealth has the potential to transform home health care (HHC) and improve care delivery.•We examined reasons HHC patients use acute care and assessed the acceptability of on-demand telehealth ...services.•Reasons for seeking acute care included a sense of urgency, behavioral and psychosocial factors, and access to care.•Patients and HHC personnel identified roles that telehealth services could play in improving communication and access.
Background/Objectives: Home health care (HHC) agencies provide an important role in helping to transition patients from acute care to independent residential living. Telehealth has the potential to transform care delivery in HHC, however the majority of studies in HHC have focused on the use of telemonitoring for patients with specific chronic conditions. The objective of this study was to examine reasons HHC patients use acute care services and assess the acceptability of on-demand telehealth services among HHC patients, caregivers and personnel to help alleviate the need for seeking in-person acute care.
Design/Setting/Participants/Measures: This study was a secondary analysis of qualitative data from in-depth interviews of 30 HHC personnel, patients and caregivers from a Medicare-certified HHC agency affiliated with a large healthcare system from January through May 2020. A conventional content analysis approach was used to identify themes.
Results: Themes associated with reasons for seeking acute care included: sense of urgency, behavioral and psychosocial factors, and access to care. Participants described their perceptions of the benefits, usability and acceptability and barriers to using telehealth. Patients and HHC personnel agreed that on-demand telehealth should not replace in-person visits but all identified roles that on-demand telehealth services could play in improving communication and access to care. The biggest barriers to use of telehealth identified by HHC personnel were cost, access and ability to use technology by HHC patients.
Conclusion: This study identified reasons HHC patients seek unscheduled acute care and the usability and acceptability of on-demand telehealth services to increase access to care among HHC patients. These findings underscore the need to improve communication and coordination between patients, HHC personnel, and primary care providers and the role that on-demand telehealth services can have in transforming HHC.
Inactivating mutations in several genes that encode components of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA ...repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes in genomic DNA from 38 breast tumors, 48 pancreatic tumors, and 10 non-BRCA1/BRCA2 hereditary breast cancer patients. A total of 494 coding exons were screened by denatured high-performance liquid chromatography and direct DNA sequencing. Two inactivating mutations were identified in breast tumor samples, a germline single-nucleotide deletion in POLQ (c.3605delT) and a somatic nonsense change in PRKDC (c.2408C>A, p.Ser803X). Two germline-inactivating mutations in RAD50 (c.1875C>G, p.Tyr625X and IVS14+1G>A) were also detected in separate pancreatic tumor samples. In addition, 35 novel nonsynonymous amino acid substitutions, resulting from two in-frame deletions and 33 single nucleotide alterations, were identified. Seven of these were predicted to influence protein function. A separate analysis of the CLSPN c.3839C>T (rs35490896) variant that was observed more frequently in breast tumors than in pancreatic tumors or normal controls failed to detect a significant association with breast cancer risk in a Mayo Clinic breast cancer case-control study. In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer.
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