Deep learning as a parton shower Monk, J. W.
The journal of high energy physics,
12/2018, Volume:
2018, Issue:
12
Journal Article
Peer reviewed
Open access
A
bstract
We make the connection between certain deep learning architectures and the renormalisation group explicit in the context of QCD by using a deep learning network to construct a toy parton ...shower model. The model aims to describe proton-proton collisions at the Large Hadron Collider. A convolutional autoencoder learns a set of kernels that efficiently encode the behaviour of fully showered QCD collision events. The network is structured recursively so as to ensure self-similarity, and the number of trained network parameters is low. Randomness is introduced via a novel custom masking layer, which also preserves existing parton splittings by using layer-skipping connections. By applying a shower merging procedure, the network can be evaluated on unshowered events produced by a matrix element calculation. The trained network behaves as a parton shower that qualitatively reproduces jet-based observables.
Among patients with platinum-sensitive, recurrent ovarian cancer, the use of niraparib, a PARP inhibitor, was associated with a significantly longer duration of progression-free survival than ...placebo, with moderate bone marrow toxicity.
Ovarian cancer is a leading cause of death from gynecologic cancers worldwide.
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Despite a high initial response rate to platinum and taxane treatment in patients with advanced cancer, the effectiveness of the treatments diminishes over time, and most patients have a relapse.
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Platinum retreatment is used in patients in whom there is an assumed platinum sensitivity, with diminishing effectiveness and a cumulative increase in toxicity.
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Niraparib is a highly selective inhibitor of poly(adenosine diphosphate ADP–ribose) polymerase (PARP) 1/2,
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nuclear proteins that detect DNA damage and promote its repair. Clinical studies have evaluated PARP inhibitors in patients with recurrent ovarian . . .
A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the ...addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m(2) intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity.
In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005).
Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.
The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics, despite prolific drug development. ...Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free survival and overall survival, although the cure rates have been affected only modestly. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, growth in our armamentarium offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial 'ovarian' cancer and describes the direction and early results of clinical investigation.
We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary ...peritoneal carcinoma.
A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration
time curve 6) and paclitaxel (175 mg/m
) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for
and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.
Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8
32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for
mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-
HRR, the HR was 0.65 (95% CI, 0.51 to 0.85).
, HRR, and CD31 were not predictive of bevacizumab activity.
No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for
mutations and homologous recombination deficiency is essential.
Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after ...third-line therapy of 5–9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.
QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.
Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3–5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7–22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6–42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 24% of 463 patients) and thrombocytopenia (95 21% of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 7% of 463 patients), thrombocytopenia (34 7% of 463 patients), and vomiting (27 6% of 463 patients). One death due to gastric haemorrhage was considered treatment related.
We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.
Tesaro.
Full text
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A randomized, double-blind trial compared pembrolizumab with placebo in patients with advanced cervical cancer who were also receiving platinum-based chemotherapy with or without bevacizumab. The ...median progression-free survival was 10.4 months with pembrolizumab and 8.2 months with placebo. Overall survival at 2 years was 50.4% and 40.4%, respectively.
A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% ...with placebo.
The key to perfect radiation endurance is perfect recovery. Since surfaces are perfect sinks for defects, a porous material with a high surface to volume ratio has the potential to be extremely ...radiation tolerant, provided it is morphologically stable in a radiation environment. Experiments and computer simulations on nanoscale gold foams reported here show the existence of a window in the parameter space where foams are radiation tolerant. We analyze these results in terms of a model for the irradiation response that quantitatively locates such window that appears to be the consequence of the combined effect of two length scales dependent on the irradiation conditions: (i) foams with ligament diameters below a minimum value display ligament melting and breaking, together with compaction increasing with dose (this value is typically ∼5 nm for primary knock on atoms (PKA) of ∼15 keV in Au), while (ii) foams with ligament diameters above a maximum value show bulk behavior, that is, damage accumulation (few hundred nanometers for the PKA's energy and dose rate used in this study). In between these dimensions, (i.e., ∼100 nm in Au), defect migration to the ligament surface happens faster than the time between cascades, ensuring radiation resistance for a given dose-rate. We conclude that foams can be tailored to become radiation tolerant.
Full text
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IJS, KILJ, NUK, PNG, UL, UM
Incorporating bevacizumab in a chemotherapy regimen (7.5 mg/kg every 3 weeks for five or six cycles) and then continuing bevacizumab alone for a total of 12 months of treatment extended ...progression-free survival in advanced and high-risk early-stage ovarian cancer.
Epithelial ovarian cancer and related cancers lead to 15,000 deaths in the United States annually, representing the fifth leading cause of death from cancer among women.
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The poor prognosis is usually attributed to advanced stage at diagnosis and inadequate chemotherapy.
Vascular endothelial growth factor (VEGF) and angiogenesis are important promoters of ovarian-cancer progression.
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Both correlate directly with the extent of disease and inversely with progression-free survival
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and overall survival,
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often independently of known prognostic factors.
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Bevacizumab, a humanized VEGF-neutralizing monoclonal antibody, inhibits tumor angiogenesis
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and has shown single-agent activity in phase 2 epithelial . . .
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