Dial a ride problem (DARP) is a complex version of the pick-up and delivery problem with many practical applications in the field of transportation. This study proposes an enhanced deterministic ...annealing algorithm for the solution of large-scale multi-vehicle DARPs. The proposed method always explores the feasible search space; therefore, a feasible solution is guaranteed at any point of termination. This method utilises advanced local search operators to accelerate the search for optimal solutions and it relies on a linearly decreasing deterministic annealing schedule to limit poor jumps during the course of search. This study puts forward a systematic series of experiments to compare the performance of solution methods from various angles. The proposed method is compared with the most efficient methods reported in the literature i.e., the Adaptive Large Neighbourhood Search (ALNS), Evolutionary Local Search (ELS), and Deterministic Annealing (DA) using standard benchmarks. The results suggest that the proposed algorithm is on average faster than the state-of-the-art algorithms in reaching competitive objective values across the range of benchmarks.
Immunotherapy has emerged as an important approach for cancer treatment, but its clinical efficacy has been limited in prostate cancer compared to other malignancies. This review summarizes key ...immunotherapy strategies under evaluation for prostate cancer, including immune checkpoint inhibitors, bispecific T cell-engaging antibodies, chimeric antigen receptor (CAR) T cells, therapeutic vaccines, and cytokines. For each modality, the rationale stemming from preclinical studies is discussed along with outcomes from completed clinical trials and strategies to improve clinical efficacy that are being tested in ongoing clinical trials. Imperative endeavors include biomarker discovery for patient selection, deciphering resistance mechanisms, refining cellular therapies such as CAR T cells, and early-stage intervention were reviewed. These ongoing efforts instill optimism that immunotherapy may eventually deliver significant clinical benefits and expand treatment options for patients with advanced prostate cancer.
Liquefied natural gas (LNG) plants are energy intensive. One way to reduce their energy consumption is to apply optimization methods when designing such plants. In this paper, genetic algorithm (GA) ...from Matlab optimization toolbox was used to optimize a propane pre-cooled mixed refrigerant (C3-MR) LNG plant that was originally designed by Mortazavi et al.
1. GA was chosen because it can reach a global optimum with any problem. A computer model was developed for the LNG plant using HYSYS and verified with the model developed by Mortazavi et al., with good agreement.
The optimization problem has 22 variables and 24 constraints. In order to reduce the complexity of the problem, optimization was carried out in two stages. First, MCR cycle optimization and then Propane cycle optimization were conducted with respective constraints. New refrigerant mixtures were found, with savings in power consumption as high as 13.28%. Propane cycle optimization resulted in a savings of 17.16% in power consumption. The optimized C3-MR LNG plant model consumes 100.78 MW, whereas the baseline consumes 110.84 MW. The optimum composition of refrigerant mixture obtained was compared with two optimized compositions of refrigerant mixtures from the open literature. The resulting power consumption utilizing the literature-referenced mixtures is 6.98% and 13.6% more than this work’s optimum composition of refrigerant mixture.
C3-MR LNG plant optimization was conducted with four pinch temperatures (0.01, 1, 3 and 5 K) that represent different common heat exchangers in LNG applications (e.g., spiral-wound heat exchanger and plate fin heat exchanger). Power savings is increased significantly with a pinch temperature of 1 K as compared to 3 or 5 K, but with little improvement as compared to 0.01 K. This figure can have a significant impact on LNG plants selection.
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►Verified computer model for a propane pre-cooled mixed refrigerant (C3-MR) LNG plant was developed using HYSYS software. The LNG plant model was optimized for minimum power consumption with the help of GA from Matlab software. ►Different optimum composition of refrigerant mixtures were found as a function of the cryogenic heat exchanger’s pinch temperature which represent different heat exchanger type. ►This work optimum composition of refrigerant mixtures was compared with two optimized compositions of refrigerant mixtures from the open literature.
Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal ...cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.
We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.
Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 52%), and diarrhoea (38 34%). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five 4%) and hypertension (four 4%). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 22%) and MET (11 20%) with responses seen irrespective of mutational status.
While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.
None.
In the most data hiding methods, the cover media is entirely distorted and it cannot be recovered when the secretive data is extracted. However, in some applications, such as medical imaging, ...military imaging and law enforcement, even a slight modification in the cover image is impermissible. Therefore, reversible data hiding schemes have proposed as a solution of this issue, recently. Histogram based embedding schemes are among wide investigated reversible data hiding schemes owing to the high quality of the marked images. In histogram based embedding techniques, construction of histogram greatly affects the embedding capacity and the distortion performance of schemes. In this study, the authors propose a novel reversible data hiding scheme for grey scale images. In this method, a new histogram is generated according to the differences between pixels and their neighbouring pixels values. The proposed scheme can achieve higher embedding capacity than other existing reversible data hiding algorithms in the literature by considering the same value of peak signal-to-noise ratio. Experimental and analytical results show that this scheme is successfully employed for data hiding in a wide range of images.
Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with ...docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy.
The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m(2) intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives.
In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months.
In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.
Purpose
Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and ...tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity.
Methods
This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD.
Results
Seventeen patients were enrolled with NF2 (
n
= 5), urothelial carcinoma (
n
= 3), breast cancer (
n
= 2), non-NF2-related meningioma (
n
= 2), carcinoma of unknown primary (
n
= 2), small cell lung cancer (
n
= 1), Sertoli cell carcinoma (
n
= 1), and uveal melanoma (
n
= 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6–78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2–9.1). Among evaluable patients with NF2 or meningioma (
n
= 5), median PFS was 9.1 months (95% CI 1.9–not reached).
Conclusion
Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors.
Trial registration
NCT01129193, registered 5/24/2010.
Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors.
We report a ...case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia.
This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.
Urothelial cancer is an immune-responsive cancer, but only a subset of patients benefits from immune checkpoint inhibition. Currently, single-agent immune checkpoint inhibitors (ICIs) and the ...combination of pembrolizumab with the antibody-drug conjugate enfortumab vedotin are approved to treat patients with metastatic UC (mUC). Approval of first-line nivolumab in combination with gemcitabine and cisplatin is expected imminently. Many treatment approaches are being investigated to better harness the immune system to fight mUC. In this review, we summarize the landmark clinical trials of ICIs that led to their incorporation into the current standard of care for mUC. We further discuss recent and ongoing clinical trials in mUC, which are investigating ICIs in combination with other agents, including chemotherapy, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Lastly, we review novel approaches utilizing bispecific antibodies, cellular therapies, and vaccines. The landscape of immunotherapy for mUC is rapidly evolving and will hopefully lead to better outcomes for patients.
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