Background
Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of ...RM‐1929 photoimmunotherapy in patients with heavily pretreated rHNSCC.
Methods
RM‐1929 (anti‐EGFR–IR700 dye conjugate) was infused, followed by tumor illumination. We evaluated safety, tumor response, and pharmacokinetics.
Results
Nine patients were enrolled in Part 1 (dose‐finding) and 30 patients in Part 2 (safety and efficacy). No dose‐limiting toxicities were experienced in Part 1; 640 mg/m2 with fixed light dose (50 J/cm2 or 100 J/cm) was recommended for Part 2. Adverse events (AEs) in Part 2 were mostly mild to moderate but 19 (63.3%) patients had AE ≥Grade 3, including 3 (10.0%) with serious AEs leading to death (not treatment related). Efficacy in Part 2: unconfirmed objective response rate (ORR) 43.3% (95% CI 25.46%–62.57%); confirmed ORR 26.7% (95% CI 12.28%–45.89%); median overall survival 9.30 months (95% CI 5.16–16.92 months).
Conclusions
Treatment was well tolerated. Responses and survival following RM‐1929 photoimmunotherapy in heavily pretreated patients with rHNSCC were clinically meaningful and warrant further investigation.
Clinical Trial Information
NCT02422979.
Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy ...could improve treatment outcomes for this patient population.
In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy 35 fractions during 7 weeks; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued.
Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5–19·6) in the avelumab group and 14·8 months (11·6–18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months–not estimable) in the avelumab group and not reached (23·0 months–not estimable) in the placebo group (stratified hazard ratio 1·21 95% CI 0·93–1·57 favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 16% of 348 patients in the avelumab group vs 52 15% of 344 patients in the placebo group), mucosal inflammation (50 14% vs 45 13%), dysphagia (49 14% vs 47 14%), and anaemia (41 12% vs 44 13%). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure).
The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT.
Pfizer and Merck KGaA, Darmstadt, Germany.
Stormwater runoff is a major concern in urban areas which is mostly the result of vast urbanization. To reduce urban stormwater runoff and improve water quality, low impact development (LID) is used ...in urban areas. Therefore, it is vital to find the optimal combination of LID controls to achieve maximum reduction in both stormwater runoff and pollutants with optimal cost. In this study, a simulation–optimization model was developed by linking the EPA Storm Water Management Model (SWMM) to the Multi-Objective Particle Swarm Optimization (MOPSO) using MATLAB. The coupled model could carry out multi-objective optimization (MOO) and find potential solutions to the optimization objectives using the SWMM simulation model outputs. The SWMM model was developed using data from the BUNUS catchment in Kuala Lumpur, Malaysia. The total suspended solids (TSS) and total nitrogen (TN) were selected as pollutants to be used in the simulation model. Vegetated swale and rain garden were selected as LID controls for the study area. The LID controls were assigned to the model using the catchment characteristics. The target objectives were to minimize peak stormwater runoff, TSS, and TN with the minimum number of LID controls applications. The LID combination scenarios were also tested in SWMM to identify the best LID types and combination to achieve maximum reduction in both peak runoff and pollutants. This study found that the peak runoff, TSS, and TN were reduced by 13%, 38%, and 24%, respectively. The optimal number of LID controls that could be used at the BUNUS catchment area was also found to be 25.
A non-enzymatic dopamine electrochemical sensing probe was developed. A hexagonal shape zinc-doped cobalt oxide (Zn-Co
2
O
4
) nanostructure was prepared by a facile hydrothermal approach. The ...combination of Zn, which has an abundance of electrons, and Co
3
O
4
exhibited a synergistically electron-rich nanocomposite. The crystallinity of the nanostructure was investigated using X-ray diffraction. A scanning electron microscope (SEM) was used to examine the surface morphology, revealing hexagonal nanoparticles with an average particle size of 400 nm. High-resolution transmission electron microscopy (HR-TEM) was used to confirm the nanostructure of the doped material. The nanostructure’s bonding and functional groups were verified using Fourier transform infrared spectroscopy (FTIR). The electrochemical characterization was conducted by using electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and amperometry. The resistivity of the electrode was confirmed through EIS and showed that the bare glassy carbon electrode (GCE) exhibited higher charge transfer resistance as compared to modified Zn-Co
2
O
4
/GCE. The sensing probe was developed by modifying the surface of GCE with Zn-Co
2
O
4
nanostructure and tested as an electrochemical sensor for dopamine oxidation; it operated best at a working potential of 0.17 V (vs Ag/AgCl). The developed sensor exhibited a low limit of detection (0.002 µM), a high sensitivity (126 µA. µM
−1
cm
−2
), and a wide linear range (0.2 to 185 µM). The sensor showed a short response time of < 1 s. The sensor’s selectivity was investigated in the presence of coexisting species (uric acid, ascorbic acid, adrenaline, epinephrine, norepinephrine, histamine, serotonin, tyramine, phenethylamine, and glucose) with no effects on dopamine determination results. The developed sensor was also successfully used for determining dopamine concentrations in a real sample.
Graphical abstract
Hybrid supercapacitors are energy storage technology offering higher power and energy density as compared to capacitors and batteries. Cobalt-doped manganese oxide (Co@MnO
2
) was synthesized using ...an easy and affordable sol–gel process and measured the electrochemical properties. A value of the specific capacity of 1141.42 Cg
−1
was obtained which was larger in comparison to the reference sample (MnO
2
= 673.79 Cg
−1
). The value of the specific capacitance was achieved 1902 Fg
−1
. To design a hybrid supercapacitor device, Co@MnO
2
was used as the positive electrode and the activated carbon was employed as the negative electrode in two-electrode assembly. According to calculations, the measured value of the specific capacitance of Co@MnO
2
was 713.25 Fg
−1
. The charge storage mechanism is supported with the help of Randles–Ševčík and Dunn’s models. The estimated value of energy and power densities were 3200 Wh kg
−1
and 24 Wkg
−1
, respectively. The stability of this device was checked by putting it to 1000 charging and discharging cycles, and it retained 86% of its initial capacity. Our result provides a platform for enhancing the functionality of energy storage systems.
Graphical abstract
Exosomes are small membranous vesicles implicated in intercellular signalling. Through their uncanny ability to carry and deliver donor cellular cargo (biomolecules) to target cells, they exert a ...profound effect on the regular functioning of healthy cells and play a significant role in pathogenesis and progression of several diseases, including cancer. The composition and number of endogenously circulating exosomes frequently vary, which is often reflective of the pathophysiological status of the cell. Applicability of exosomes derived from normal cells as a drug carrier with or without modifying their intraluminal and surface components are generally tested. Conversely, exosomes also are reported to contribute to resistance towards several anti-cancer therapies. Therefore, it is necessary to carefully evaluate the role of exosomes in cancer progression, resistance and the potential use of exosomes as a delivery vehicle of cancer therapeutics. In this review, we summarize the recent advancements in the exploitation of exosomes as a drug delivery vehicle. We also discuss the role of exosomes in conferring resistance to anti-cancer therapeutics. While this review is focused on cancer, the exosome-based drug delivery and resistance is also applicable to other human diseases.
•Exosomes are potential, natural drug delivery vehicles.•Engineering of exosome cargo and surface receptors can make exosomes suitable for targeted drug delivery.•Exosomes mediate resistance to multiple anti-cancer therapies.
Background
To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. ...In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS‐mutant, R/M SGC.
Methods
The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow‐up was 22 months (range, 6‐55 months). Subjects with HRAS‐mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.
Results
A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1‐3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3‐14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression‐free survival was 7 months (95% confidence interval, 5.9‐10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6‐22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co‐occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.
Conclusions
Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS‐mutant, R/M SGC who developed disease progression within the last 6 months.
In this prospective, multicenter cohort study that includes 13 adults, 1 patient (8%) is found to achieve a partial response to therapy, and an additional 58% of patients demonstrate stable disease (the majority with >10% tumor regression), with responses often found to last >6 months. Tipifarnib demonstrates a meaningful and often durable disease control rate among patients with a more aggressive subgroup of HRAS‐mutant salivary gland cancers, with evidence of a potential benefit across several variant HRAS mutational genotypes and allele frequencies.
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