This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible ("unfit") for cisplatin chemotherapy.
The ...primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life.
In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI.
There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.
Energy Autonomous Wearable Sensors (EAWS) have attracted a large interest due to their potential to provide reliable measurements and continuous bioelectric signals, which help to reduce health risk ...factors early on, ongoing assessment for disease prevention, and maintaining optimum, lifelong health quality. This review paper presents recent developments and state-of-the-art research related to three critical elements that enable an EAWS. The first element is wearable sensors, which monitor human body physiological signals and activities. Emphasis is given on explaining different types of transduction mechanisms presented, and emerging materials and fabrication techniques. The second element is the flexible and wearable energy storage device to drive low-power electronics and the software needed for automatic detection of unstable physiological parameters. The third is the flexible and stretchable energy harvesting module to recharge batteries for continuous operation of wearable sensors. We conclude by discussing some of the technical challenges in realizing energy-autonomous wearable sensing technologies and possible solutions for overcoming them.
Summary Background Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that ...binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. Methods VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m2 intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0–1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov , number NCT00519285 Findings Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29–41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3–24·1) in the aflibercept group and 21·2 months (19·6–23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82–1·08; p=0·38). We recorded a higher incidence of grade 3–4 gastrointestinal disorders (182 30% vs 48 8·0%), haemorrhagic events (32 5·2% vs ten 1·7%), hypertension (81 13% vs 20 3·3%), fatigue (97 16% vs 46 7·7%), infections (123 20% vs 60 10%) and treatment-related fatal adverse events (21 3·4% vs nine 1·5%) in the aflibercept group than in the placebo group. Interpretation Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate-resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy. Funding Sanofi and Regeneron Pharmaceuticals Inc.
Objective
To investigate the association between Prostate-Specific Membrane Antigen (PSMA) expression changes on positron emission tomography–computed tomography (PET/CT) and the response to ...treatment following the start of enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) patients.
Methods
All consecutive
68
Ga-PSMA-11 PET/CT scans routinely performed at our institution during more than 4 years were retrospectively screened for inclusion. We included mCRPC patients with a baseline PSMA PET/CT performed less than 2 months before the start of either enzalutamide or abiraterone, and a follow-up PSMA PET/CT performed no more than a year after, while still under those novel antiandrogen drugs (NAD). The associated clinical records were reviewed. Patients were considered treatment responders if they presented decreasing PSA levels > 50% or a radiological response based on RECIST 1.1 criteria. PSMA expression changes on the follow-up PET/CT were assessed using per-patient dominant response criteria to classify patients as PSMA-responders (complete disappearance of pathologic PSMA uptake, or a decreased uptake of the majority of lesions) or PSMA-non-responders (new PSMA-expressing lesions, increased uptake of the majority of lesions, or stable PSMA expression of the disease). Descriptive statistics and measures of associations (two-sided Fisher’s exact test and Phi coefficient) were calculated.
Results
A total of 11 and 15 patients were included in the enzalutamide and abiraterone groups. Median follow-up was 110 (IQR 76–124) and 87 (IQR 71–242) days, respectively. All treatment responders (3 enzalutamide and 4 abiraterone) were considered PSMA-responders, and all treatment non-responders (8 enzalutamide, 11 abiraterone) were considered PSMA-non-responders. PSMA PET response was thus perfectly associated with conventional response criteria (
p
= 0.006, Phi = 1 for enzalutamide;
p
= 0.001, Phi = 1 for abiraterone). In our cohort, no PSMA expression flare phenomenon was detected on follow-up PET/CT scans at a median follow-up of 3 months. However, an early and short-lived flare cannot be excluded.
Conclusions
This retrospective study suggests that, after a median follow-up of 3 months under enzalutamide or abiraterone, PSMA expression changes on PET/CT are strongly associated with response to treatment. Prospective studies are needed to better understand PSMA expression dynamics following the start of enzalutamide and abiraterone, along with the role of PSMA PET/CT in response assessment.
Computing paradigm based on von Neuman architectures cannot keep up with the ever-increasing data growth (also called “data deluge gap”). This has resulted in investigating novel computing paradigms ...and design approaches at all levels from materials to system-level implementations and applications. An alternative computing approach based on artificial neural networks uses oscillators to compute or Oscillatory Neural Networks (ONNs). ONNs can perform computations efficiently and can be used to build a more extensive neuromorphic system. Here, we address a fundamental problem: can we efficiently perform artificial intelligence applications with ONNs? We present a digital ONN implementation to show a proof-of-concept of the ONN approach of “computing-in-phase” for pattern recognition applications. To the best of our knowledge, this is the first attempt to implement an FPGA-based fully-digital ONN. We report ONN accuracy, training, inference, memory capacity, operating frequency, hardware resources based on simulations and implementations of 5 × 3 and 10 × 6 ONNs. We present the digital ONN implementation on FPGA for pattern recognition applications such as performing digits recognition from a camera stream. We discuss practical challenges and future directions in implementing digital ONN.
Cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are ...not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies.
Oncodistinct 004 - AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety.
The study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals.
ClinicalTrials.gov (NCT03674424).
Abstract
Digital electronics based on von Neumann’s architecture is reaching its limits to solve large-scale problems essentially due to the memory fetching. Instead, recent efforts to bring the ...memory near the computation have enabled highly parallel computations at low energy costs. Oscillatory neural network (ONN) is one example of in-memory analog computing paradigm consisting of coupled oscillating neurons. When implemented in hardware, ONNs
naturally
perform gradient descent of an energy landscape which makes them particularly suited for solving optimization problems. Although the ONN computational capability and its link with the Ising model are known for decades, implementing a large-scale ONN remains difficult. Beyond the oscillators’ variations, there are still design challenges such as having compact, programmable synapses and a modular architecture for solving large problem instances. In this paper, we propose a mixed-signal architecture named
Saturated Kuramoto ONN
(SKONN) that leverages both analog and digital domains for efficient ONN hardware implementation. SKONN computes in the analog phase domain while propagating the information digitally to facilitate scaling up the ONN size. SKONN’s separation between computation and propagation enhances the robustness and enables a feed-forward phase propagation that is showcased for the first time. Moreover, the SKONN architecture leads to unique binarizing dynamics that are particularly suitable for solving NP-hard combinatorial optimization problems such as finding the weighted Max-cut of a graph. We find that SKONN’s accuracy is as good as the Goemans–Williamson 0.878-approximation algorithm for Max-cut; whereas SKONN’s computation time only grows logarithmically. We report on Weighted Max-cut experiments using a 9-neuron SKONN proof-of-concept on a printed circuit board (PCB). Finally, we present a low-power 16-neuron SKONN integrated circuit and illustrate SKONN’s feed-forward ability while computing the XOR function.
We report the case of a 76-year-old man presenting with reactive haemophagocytic lymphohistiocytosis (rHLH) in the setting of disseminated prostate cancer. This often fatal syndrome must be diagnosed ...early in order to maximize survival. Treatment should be initiated whenever the clinical diagnosis is suspected, even if the HLH-2004 criteria are not met. The HScore is a useful diagnostic tool for rHLH. In case of neurological symptoms, an extensive assessment must be performed. The goal of this case report is to raise awareness of this rare syndrome among oncologists.
The association of prostate cancer and reactive haemophagocytic lymphohistiocytosis (rHLH) has rarely been described.This often fatal syndrome must be recognized early in order to start specific treatment and maximize survival.Specific treatment for rHLH must be accompanied by treatment of the triggering factors.
Metastasis-directed therapy (MDT) in oligometastatic prostate cancer has the potential of delaying the start of androgen deprivation therapy (ADT) and disease progression. We aimed to analyze the ...efficacy of PSMA-PET/CT in detecting oligometastatic disease (OMD), to look for predictive factors of OMD, and to evaluate the impact of PSMA-PET/CT findings on clinical management. We retrospectively analyzed a homogeneous population of 196 hormone-sensitive prostate cancer patients (HSPC), considered potential candidates for MDT, with a PSMA-PET/CT performed at biochemical recurrence (BCR) after radical prostatectomy (RP). Multivariable logistic regression analysis was performed based on several clinico-pathological factors. Changes in clinical management before and after PSMA-PET/CT were analyzed. The OMD detection rate was 44% for a total positivity rate of 60%. PSMA-PET/CT positivity was independently related to PSA (OR (95% CI), p) (1.7 (1.3–2.3), p < 0.0001) and PSAdt (0.4 (0.2–0.8), p = 0.013), and OMD detection was independently related to PSA (1.6 (1.2–2.2), p = 0.001) and no previous salvage therapy (0.3 (0.1–0.9), p = 0.038). A treatment change was observed in 58% of patients, mostly to perform MDT after OMD detection (60% of changes). This study showed that PSMA-PET/CT is an excellent imaging technique to detect OMD early in HSPC patients with BCR after RP, changing therapeutic management mostly into MDT.
Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade ...toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease.
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