Nature-Inspired Effects of Naturally Occurring Trace Element-Doped Hydroxyapatite Combined with Surface Interactions of Mineral-Apatite Single Crystals on Human Fibroblast Behavior.

Innovative engineering design for biologically active hydroxyapatites requires enhancing both mechanical and physical properties, along with biocompatibility, by doping with appropriate chemical elements. Herein, the purpose of this investigation was to evaluate and elucidate the model of naturally occurring hydroxyapatite and the effects of doped trace elements on the function of normal human fibroblasts, representing the main cells of connective tissues. The substrates applied (geological apatites with hexagonal prismatic crystal habit originated from Slyudyanka, Lake Baikal, Russia (GAp) and from Imilchil, The Atlas Mountains, Morocco (YAp)) were prepared from mineral natural apatite with a chemical composition consistent with the building blocks of enamel and enriched with a significant F- content. Materials in the form of powders, extracts and single-crystal plates have been investigated. Moreover, the effects on the function of fibroblasts cultured on the analyzed surfaces in the form of changes in metabolic activity, proliferation and cell morphology were evaluated. Apatite plates were also evaluated for cytotoxicity and immune cell activation capacity. The results suggest that a moderate amount of F- has a positive effect on cell proliferation, whereas an inhibitory effect was attributed to the Cl- concentration. It was found that for (100) GAp plate, fibroblast proliferation was significantly increased, whereas for (001) YAp plate, it was significantly reduced, with no cytotoxic effect and no immune response from macrophages exposed to these materials. The study of the interaction of fibroblasts with apatite crystal surfaces provides a characterization relevant to medical applications and may contribute to the design of biomaterials suitable for medical applications and the evaluation of their bioavailability.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.

The median informs the message: accuracy of individualized scenarios for survival time based on oncologists' estimates.

PURPOSE: To determine the accuracy and usefulness of oncologists' estimates of survival time in individual patients with advanced cancer. PATIENTS AND METHODS: Twenty-one oncologists estimated the "median survival of a group of identical patients" for each of 114 patients with advanced cancer. Accuracy was defined by the proportions of patients with an observed survival time bounded by prespecified multiples of their estimated survival time. We expected 50% to live longer (or shorter) than their oncologist's estimate (calibration), 50% to live from half to double their estimate (typical scenario), 5% to 10% to live ≤ one quarter of their estimate (worst-case scenario), and 5% to 10% to live three or more times their estimate (best-case scenario). Estimates within 0.67 to 1.33 times observed survival were deemed precise. Discriminative value was assessed with Harrell's C-statistic and prognostic significance with proportional hazards regression. RESULTS: Median survival time was 11 months. Oncologists' estimates were relatively well-calibrated (61% shorter than observed), imprecise (29% from 0.67 to 1.33 times observed), and moderately discriminative (Harrell C-statistic 0.63; P = .001). The proportion of patients with an observed survival half to double their oncologist's estimate was 63%, ≤ one quarter of their oncologist's estimate was 6%, and three or more times their oncologist's estimate was 14%. Independent predictors of observed survival were oncologist's estimate (hazard ratio [HR] = 0.92; P = .004), dry mouth (HR = 5.1; P < .0001), alkaline phosphatase more than 101 U/L (HR = 2.8; P = .0002), Karnofsky performance status ≤ 70 (HR = 2.3; P = .007), prostate primary (HR = 0.23; P = .002), and steroid use (HR = 2.4; P = .02). CONCLUSION: Oncologists' estimates of survival time were relatively well-calibrated, moderately discriminative, independently associated with observed survival, and a reasonable basis for estimating worst-case, typical, and best-case scenarios for survival.

Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy.

Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1-5, 200mg/m(2) orally) and PLD (day 1, 40 mg/m(2) intravenous) was given every 4 weeks for six cycles following chemo-radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41-72%). The median time to progression was 6.2 months (95% CI, 5.6-8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7-15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non-hematologic toxicity included nausea and vomiting (8%) and palmar-plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS.