Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy

Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3–5 sessions, 20–26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.     

The drop technique: a method to control the amount of fluoride dentifrice used by young children

PURPOSE: The purpose of this study was to evaluate the amount of dentifrice applied to the toothbrush by school children using a liquid dentifrice (drop technique), when compared to toothpaste. MATERIALS AND METHODS: A total of 178 school children (4-8 years old) from two cities in Brazil (Bauru and Bariri) participated in the present two-part crossover study. Children from Bauru received training regarding tooth-brushing techniques and use of dentifrice before data collection. In each phase, the amount of toothpaste or liquid dentifrice applied by the children to the toothbrush was measured, using a portable analytical balance (+ 0.01 g). Data were tested by analysis of covariance (Ancova) and linear regression (p < 0.05). RESULTS: The mean (+/- standard deviation) amounts of toothpaste and liquid dentifrice applied to the toothbrushes for children from Bauru were 0.41 +/- 0.20 g and 0.15 +/- 0.06 g, respectively. For children from Bariri, the amounts applied were and 0.48 +/- 0.24 g and 0.14 +/- 0.05 g, respectively. The amount of toothpaste applied was significantly larger than the amount of liquid dentifrice for both cities. Children from Bariri applied a significantly larger amount of toothpaste, when compared to those from Bauru. However, for the liquid dentifrice, there was no statistically significant difference between the cities. A significant correlation between the amount of toothpaste applied and the age of the children was verified, but the same was not found for the liquid dentifrice. CONCLUSION: The use of the drop technique reduced and standardised the amount of dentifrice applied to the toothbrush, which could reduce the risk of dental fluorosis for young children.     

Volume contraction in photocured dental resins: the shrinkage-conversion relationship revisited.

Polymerization shrinkage and degree of conversion (DC) of resin composites are closely related manifestations of the same process. Ideal dental composite would show an optimal degree of conversion and minimal polymerization shrinkage. These seem to be antagonistic goals, as increased monomer conversion invariably leads to high polymerization shrinkage values. OBJECTIVES: This paper aims at accurately determining the polymerization volume contraction of experimental neat resins and to link it to the number of actual vinyl double bonds converted in single ones instead of, as generally done, to the degree of conversion. METHODS: Different mixtures of Bis-GMA/TEGDMA (traditionally used monomers) were analyzed. Contraction of the polymers was determined by pycnometry and the use of a density column. DC was determined by the use of Raman spectrometry. RESULTS: An univocal relationship has been found between the volume contraction and the actual number of vinyl double bonds converted into single ones. A contraction value of 20.39 cm3/mole (of converted C=C) was deduced from 27 measurements. SIGNIFICANCE: This relationship helps in finding solutions to the polymerization shrinkage problem. A reduction of the polymerization shrinkage due to the chemical reaction may obviously be expected from the addition of molecules allowing a decrease in the number of double bonds converted per unit volume of resin matrix, while maintaining the degree of conversion (of Bis-GMA and TEGDMA) and thus the mechanical properties. Further research will be directed at this objective.     

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.