Summary Background Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an ...engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. Methods For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov , number NCT02108652. Findings Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% 95% CI 19–37, p<0·0001; IC1/2/3: 18% 13–24, p=0·0004) and in all patients (15% 11–20, p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18–36) in the IC2/3 group, 18% (13–24) in the IC1/2/3 group, and 15% (11–19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4–12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3–4 treatment-related adverse events, of which fatigue was the most common (five patients 2%), occurred in 50 (16%) of 310 treated patients. Grade 3–4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study. Interpretation Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma. Funding F Hoffmann-La Roche Ltd.
Summary Front-line platinum-based combination chemotherapy leads to high response rates but suboptimum overall survival for patients with advanced transitional-cell carcinoma of the urothelium. ...Bevacizumab is being assessed in combination with platinum-based first-line chemotherapy in a large phase 3 trial. Current second-line systemic therapies, including taxanes, yield disappointing outcomes. Vinflunine, a novel vinca alkaloid, showed some activity and was recently approved in Europe based on results of the first completed phase 3 trial in the second-line setting. Better understanding of molecular biology and the emergence of novel biological agents now offer the possibility of improved outcomes. Neoadjuvant therapy before cystectomy and consolidation therapy with biological agents after first-line therapy provide a framework for the development of new drugs. We propose that trials to approve new drugs target two separate populations; multicentre non-randomised phase 2 trials should include patients with chemotherapy-resistant disease progressing within 6 months of first-line therapy, and randomised trials might be appropriate for chemotherapy-sensitive disease progressing more than 6 months after first-line therapy. A multidisciplinary approach is necessary to make therapeutic advances. This review discusses current second-line therapy and emerging drugs for advanced transitional-cell carcinoma.
We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic ...urothelial carcinoma.
We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed.
Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78–1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied.
Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.
Summary Background Germline genetic polymorphisms might affect the risk of recurrence in patients with localised renal-cell carcinoma. We investigated the association between genetic polymorphisms ...and recurrence of renal-cell carcinoma. Methods We analysed germline DNA samples extracted from patients with localised renal-cell carcinoma treated at the Dana-Farber/Harvard Cancer Center (Boston, MA, USA). We selected a discovery cohort from a prospective database at the Dana-Farber/Harvard Cancer Center and selected a validation cohort from department records at the Brigham and Women's Hospital (Boston, MA, USA). We validated the findings from the discovery cohort in the validation cohort. We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms. We assessed the association between genotype and recurrence-free survival, adjusted for baseline characteristics, with the Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. We used a false discovery rate q value to adjust for multiple comparisons. Findings We included 554 patients (403 in the discovery cohort and 151 in the validation cohort). We successfully genotyped 290 single nucleotide polymorphisms in the discovery cohort, but excluded five because they did not have a variant group for comparison. The polymorphism rs11762213, which causes a synonymous aminoacid change in MET (144G→A, located in exon 2), was associated with recurrence-free survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio HR 1·86, 95% CI 1·17–2·95; p=0·0084) in multivariate analysis. Median recurrence-free survival for carriers of the risk allele was 19 months (95% CI 9–not reached) versus 50 months (95% CI 37–75) for patients without the risk allele. In the validation cohort the HR was 2·45 (95% CI 1·01–5·95; p=0·048). Interpretation Patients with localised renal-cell carcinoma and the MET polymorphism rs11762213 might have an increased risk of recurrence after nephrectomy. If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma. Funding Conquer Cancer Foundation and American Society of Clinical Oncology (Career Development Award); The Trust Family Research Fund for Kidney Cancer; US National Institutes of Health, National Cancer Institute Kidney Cancer Specialized Program of Research Excellence.
About 1 of 10 night-shift workers suffers from severe excessive sleepiness on the job. This realization has led to the development of specific diagnostic criteria for people affected with shift-work ...sleep disorder. In this multicenter study, patients meeting this case definition were treated with placebo or modafinil. Although there was a significant improvement in laboratory measures of sleep, treated patients were still quite sleepy.
Modafinil improves performance among patients with shift-work sleep disorder but does not come close to returning them to a normal level of sleepiness.
Nearly 6 million Americans work at night on a permanent or rotating basis.
1
Night-shift work disrupts both sleep and waking because of the misalignment of circadian regulation and sleep–wake behavior.
2
,
3
In about 5 to 10 percent of night-shift workers, the sleep–wake disturbance is severe enough to warrant diagnosis as shift-work sleep disorder,
4
–
6
which is characterized by a level of excessive sleepiness during night work and insomnia when attempting to sleep in the daytime that is judged to be clinically significant.
4
,
5
Persons with shift-work sleep disorder miss family and social activities more frequently and have higher rates of . . .
Objectives
To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV.
Methods
Records of people ...aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow‐up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan–Meier and Cox regression.
Results
At the final paediatric visit, the 474 participants 51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5–13) years had a median age of 18 (17–19) years and CD4 count of 471 (280–663) cell/μL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow‐up in adult care of 3 (2–6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person‐years). In multivariable analyses, lower CD4 count at the last paediatric visit adjusted hazard ratio = 0.8 (95% confidence interval: 0.7–1.0)/100 cells/μL increment and AIDS diagnosis in paediatric care 2.7 (1.4–5.5) were associated with a new AIDS event/mortality in adult care.
Conclusions
Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.
A 100-element HBT grid amplifier Moonil Kim; Sovero, E.A.; Hacker, J.B. ...
IEEE transactions on microwave theory and techniques,
10/1993, Letnik:
41, Številka:
10
Journal Article
Recenzirano
Odprti dostop
A 100-element 10-GHz grid amplifier has been developed. The active devices in the grid are chips with heterojunction-bipolar-transistor (HBT) differential pairs. The metal grid pattern was ...empirically designed to provide effective coupling between the HBTs and free space. Two independent measurements, one with focusing lenses and the other without, were used to characterize the grid. In each case, the peak gain was 10 dB at 10 GHz with a 3-dB bandwidth of 1 GHz. The input and output return losses were better than 15 dB at 10 GHz. The maximum output power was 450 mW, and the minimum noise figure was 7 dB. By varying the bias, a signal could be amplitude modulated with a modulation index as large as 0.65. Tests show that the grid was quite tolerant of failures-the output power dropped by only 1 dB when 10% of the inputs were detuned. The grid amplifier is a multimode device that amplifies beams of different shapes and angles. Beams with incidence angles up to 30 degrees were amplified with less than a 3-dB drop in gain.< >
A 100-element HBT grid amplifier Kim, M.; Sovero, E.A.; Hacker, J.B. ...
1993 IEEE MTT-S International Microwave Symposium Digest,
1993
Conference Proceeding
Odprti dostop
A 100-element 10-GHz grid amplifier has been developed. The active devices in the grid are chips with heterojunction bipolar transistor (HBT) differential pairs that include a resistive network to ...provide self-bias to the base. The planar metal grid structure was empirically designed to provide effective coupling between the HBTs and free space. Two independent measurements, one with focusing lenses, the other without, were used to measure the gain of the grid. In each case the peak gain of the grid was 10 dB at 10 GHz with a 3-dB bandwidth of 1 GHz. The input and output matches are better than 15 dB at 10 GHz. The maximum output power is 450 mW, and the minimum noise figure is 7 dB. Tests show that the grid is quite tolerant of failures-the output power dropped by only 1 dB when 10% of the inputs were detuned. The device amplifies beams with incidence angles up to 30 degrees with less than a 3-dB drop in power.< >
PDF
