Bone metastases are a common cause of skeletal morbidity in patients with advanced cancer. The pattern of skeletal morbidity is complex, and the number of skeletal complications is influenced by the ...duration of survival. Because many patients with cancer die before trial completion, there is a need for survival-adjusted methods to accurately assess the effects of treatment on skeletal morbidity.
Recently, a survival-adjusted cumulative mean function model has been generated that can provide an intuitive graphic representation of skeletal morbidity throughout a study. This model was applied to the placebo-control arm of a pamidronate study in patients with malignant bone disease from breast cancer.
Analysis by bone lesion location showed that spinal metastases were associated with the highest cumulative mean incidence of skeletal-related events (SREs), followed by chest and pelvic metastases. Metastases located in the extremities were associated with an intermediate incidence of SREs, and those in the skull were associated with the lowest incidence of SREs.
Application of this model to data from the placebo arm of this trial revealed important insight into the natural history of skeletal morbidity in patients with bone metastases. Based on these observations, treatment for the prevention of SREs is warranted regardless of lesion location except for metastases on the skull.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Worldwide efforts are being made to develop vaccines to mitigate this ...pandemic. We engineered two recombinant Newcastle disease virus (NDV) vectors expressing either the full-length SARS-CoV-2 spike protein (NDV-FLS) or a version with a 19 amino acid deletion at the carboxy terminus (NDV-Δ19S). Hamsters receiving two doses (prime-boost) of NDV-FLS developed a robust SARS-CoV-2-neutralizing antibody response, with elimination of infectious virus in the lungs and minimal lung pathology at five days post-challenge. Single-dose vaccination with NDV-FLS significantly reduced SARS-CoV-2 replication in the lungs but only mildly decreased lung inflammation. NDV-Δ19S-treated hamsters had a moderate decrease in SARS-CoV-2 titers in lungs and presented with severe microscopic lesions, suggesting that truncation of the spike protein was a less effective strategy. In summary, NDV-vectored vaccines represent a viable option for protection against COVID-19.
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•Recombinant NDV passively incorporates SARS-CoV-2 spike into the virion•Vaccination with NDV expressing SARS-CoV-2 spike protects hamsters from disease•No infectious SARS-CoV-2 was detectable in the lungs of vaccinated hamsters•NDV-vectored vaccines represent a viable option for protection against COVID-19
Immune respons; Virology
Epithelial ovarian cancer is the deadliest gynecological malignancy. The lack of effective treatments highlights the need for novel therapeutic interventions. The aim of this study was to investigate ...whether sustained adeno-associated virus (AAV) vector-mediated expression of vascular normalizing agents 3TSR and Fc3TSR and the antiangiogenic monoclonal antibody, Bevacizumab, with or without oncolytic virus treatment would improve survival in an orthotopic syngeneic mouse model of epithelial ovarian carcinoma. AAV vectors were administered 40 days post-tumor implantation and combined with oncolytic avian orthoavulavirus-1 (AOaV-1) 20 days later, at the peak of AAV-transgene expression, to ascertain whether survival could be extended. Flow cytometry conducted on blood samples, taken at an acute time point post-AOaV-1 administration (36 h), revealed a significant increase in activated NK cells in the blood of all mice that received AOaV-1. T cell analysis revealed a significant increase in CD8
tumor specific T cells in the blood of AAV-Bevacizumab+AOaV-1 treated mice compared to control mice 10 days post AOaV-1 administration. Immunohistochemical staining of primary tumors harvested from a subset of mice euthanized 90 days post tumor implantation, when mice typically have large primary tumors, secondary peritoneal lesions, and extensive ascites fluid production, revealed that AAV-3TSR, AAV-Fc3TSR+AOaV-1, or AAV-Bevacizumab+AOaV-1 treated mice had significantly more tumor-infiltrating CD8
T cells than PBS controls. Despite AAV-mediated transgene expression waning faster in tumor-bearing mice than in non-tumor bearing mice, all three of the AAV therapies significantly extended survival compared to control mice; with AAV-Bevacizumab performing the best in this model. However, combining AAV therapies with a single dose of AOaV-1 did not lead to significant extensions in survival compared to AAV therapies on their own, suggesting that additional doses of AOaV-1 may be required to improve efficacy in this model. These results suggest that vectorizing anti-angiogenic and vascular normalizing agents is a viable therapeutic option that warrants further investigation, including optimizing combination therapies.
Purpose: Previous phase 1 trials of i.v.-administered PV701 have shown this virus to be well-tolerated with toxicity primarily associated
with the first dose. Our hypothesis, based on preclinical ...evidence, was that patient tolerability could be improved by slowing
the i.v. infusion rate, and that this approach would allow for the safe administration of higher doses. Additionally, this
phase 1 trial was the first to measure PV701 clearance.
Experimental Design: For the first dose, a 3-h infusion was used compared with the 10- and 30-min infusions administered in the two previous trials.
Subsequent doses were infused over 1 h. Six doses were given per 3-week cycle. Escalation of the first dose was done separately
from the escalation of doses 2 to 6. Viral clearance was determined using whole blood reverse transcription-PCR.
Results: Eighteen patients with advanced chemorefractory cancer were enrolled. The first dose was safely escalated to 24 × 10 9 plaque-forming units/m 2 and doses 2 to 6 were safely escalated to 120 × 10 9 plaque-forming units/m 2 . Tolerability was improved compared with the rapid bolus dosing used previously with the elimination of severe flu-like symptoms.
Furthermore, infusion reactions were markedly decreased in this trial compared with previous PV701 trials. The presence of
neutralizing antibodies did not significantly affect PV701 clearance. Four major and two minor tumor responses were observed.
Conclusions: Using slow infusion, patient tolerability was improved, while the first dose was safely escalated relative to two previous
PV701 trials. Based on improved tolerability and encouraging signs of activity, this slow infusion regimen was selected for
further PV701 clinical development.
Bisphosphonates are the current standard of palliative care for patients with bone lesions from breast cancer and multiple myeloma. This article discusses the selection of endpoints and statistical ...methods used to assess clinical efficacy of bisphosphonate therapies in patients with bone metastases. Recent studies of pamidronate and zoledronic acid have set the standards for the design and conduct of multicenter, randomized, placebo-controlled trials to assess the clinical benefit of bisphosphonates in patients with bone metastases. Studies of zoledronic acid have demonstrated objective, significant, and enduring benefits in patients with a broad range of primary cancers, including prostate cancer, using robust clinical endpoints. Other bisphosphonates, including clodronate, have been investigated for the treatment of bone metastases, but these studies have been relatively small. This review first considers issues of trial design and analysis, with particular emphasis on the statistical requirements for the rigorous analysis of multiple events occurring in the same patient, and then reviews the results of bisphosphonate trials in patients with breast or prostate cancers metastatic to bone in the light of these statistical considerations.
Abstract Background Zoledronic acid (ZOL) is an important component of therapy for patients with metastatic bone disease (MBD) to reduce the risk of skeletal-related events (SREs). We evaluated ...overall survival (OS) in patients with MBD secondary to solid tumours included in placebocontrolled ZOL trials. Patients and methods Exploratory analyses were performed using databases from three randomised trials of ZOL versus placebo. 1126 patients (ZOL, n =731; placebo, n =395) with complete baseline data for 18 predefined parameters were evaluated for OS. Relative risks (RRs) with 95% confidence intervals were assessed using stratified and adjusted Cox regression models. Baseline covariates defining patient populations with significantly different effects of ZOL treatment on OS (identified by stepwise backward elimination) were included in multivariate models. Results Although OS was similar between the overall treatment groups, ZOL significantly improved OS in the subset of patients ( n =423; 38%) with elevated baseline NTX (≥100 nmol/mmol creatinine; RR, 0.692; P =.0028). Notably, this effect was independent of SRE prevention. Additional covariates associated with OS benefits with ZOL (e.g., low albumin, SRE history, elevated lactate dehydrogenase, shorter cancer duration) were characteristic of advanced disease. Conclusion These exploratory analyses suggest a beneficial effect of ZOL on OS in patients with highly aggressive or advanced MBD.
Increases in life expectancy in the developed world will inevitably lead to larger numbers of elderly patients with cancer-associated (malignant) bone disease. Most elderly patients with metastatic ...cancer also suffer from numerous comorbidities. The management of bone health in this setting requires special consideration. This article centers on malignant bone disease in the elderly and the role of bisphosphonates in geriatric oncology. The challenges involved in the treatment of older patients with bone metastases are described, and the potential utility of bisphosphonates, such as zoledronic acid, is discussed. Moreover, recent data from several large clinical trials suggest that zoledronic acid provides additional benefits, including antitumor effects that may extend beyond the preservation of bone health and prevention of skeletal-related events.
The epidermal growth factor receptor (EGFR) appears relevant in the pathogenesis and progression of colorectal cancer. After completing a phase I pharmacodynamic trial of ZD1839, we undertook a dose ...expansion trial to examine the antitumour efficacy and adverse effect profile of this agent in a homogeneous group of patients with metastatic colorectal cancer (CRC).
Eligible patients with metastatic or recurrent CRC received ZD1839 750 mg daily by mouth. This dose was selected based on a phase I trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Treatment was continued until unacceptable toxicity or disease progression.
Twenty-eight patients were enrolled at three NCIC CTG centers. Twenty-three patients had received prior chemotherapy; 12 patients had received three or more regimens. No objective responses were observed in 24 evaluable patients, although 8 patients had stable disease (median duration of 2.2 months). The most frequent drug related adverse events were diarrhea, rash and nausea. Eleven patients required dosing modification (hold or reduction), while 3 patients discontinued therapy because of toxicity. There were no treatment related deaths.
ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.
Nitrogen (N) is an essential macronutrient for plants. N levels in soil vary widely, and plants have developed strategies to cope with N deficiency. However, the regulation of these adaptive ...responses and the coordinating signals that underlie them are still poorly understood. The aim of this study was to characterize N starvation in adult Arabidopsis (Arabidopsis thaliana) plants in a spatiotemporal manner by an integrative, multilevel global approach analyzing growth, metabolites, enzyme activities, and transcript levels. We determined that the remobilization of N and carbon compounds to the growing roots occurred long before the internal N stores became depleted. A global metabolite analysis by gas chromatography-mass spectrometry revealed organ-specific differences in the metabolic adaptation to complete N starvation, for example, for several tricarboxylic acid cycle intermediates, but also for carbohydrates, secondary products, and phosphate. The activities of central N metabolism enzymes and the capacity for nitrate uptake adapted to N starvation by favoring N remobilization and by increasing the high-affinity nitrate uptake capacity after long-term starvation. Changes in the transcriptome confirmed earlier studies and added a new dimension by revealing specific spatiotemporal patterns and several unknown N starvation-regulated genes, including new predicted small RNA genes. No global correlation between metabolites, enzyme activities, and transcripts was evident. However, this multilevel spatiotemporal global study revealed numerous new patterns of adaptation mechanisms to N starvation. In the context of a sustainable agriculture, this work will give new insight for the production of crops with increased N use efficiency.
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