Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.     

Primary Nasal Tip Surgery: A Conservative Approach

Background

Rhinoplasty and rhinoseptoplasty are very important and complex surgical procedures because the nose plays a pivotal aesthetic role in the face and an important functional role in breathing. Mild bulbous, plunging, undefined tips are very common, and tip refining and repositioning often are required surgical procedures.

Methods

For 97 selected patients, the authors performed their personal technique consisting of a transcartilaginous approach, incomplete vertical interruption, and retrograde undermining of the lower lateral cartilages to improve tip projection and definition. The five aspects analyzed were nasal tip symmetry, nostril symmetry, tip projection, tip definition, and appearance of the nasal tip only. Each parameter was assessed using pre- and postoperative quantification according to a visual analog scale. Postoperative evaluation was performed during a mean follow-up period of 1?year.

Results

The results at 1?year showed high rates of improvement in tip definition (mean, 7.9?±?2.4) and nasal tip only evaluation (mean, 6.5?±?3.1). The patients reported an improvement in nasal tip symmetry (mean, 4.2?±?3.2), nostril symmetry (mean, 4.5?±?4.1), and tip projection (mean, 5.8?±?2.9).

Conclusions

This simple, safe, and effective technique is proposed for mild bulbous, plunging, undefined, and hypoprojected tips.     

Renal arteriovenous fistulas after renal biopsy. Percutaneous embolization

PURPOSE: We report our experience relative to transcatheter percutaneous embolization of post-biopsy renal intraparenchymal arteriovenous fistulas in patients with chronic renal insufficiency. MATERIAL AND METHODS: We observed 5 patients affected with post-bioptic fistulas for possible embolization. In three cases the symptoms were represented by intermittent macro-microhematuria; one patient had hypertension of nephrovascular origin and one patient was asymptomatic. In all cases we performed angiography and it was possible to catheterize the peripheral afferent branch of the fistula with a superselective technique using a hydrophilic guide of 0.035 F and a hydrophilic Cobra catheter of 4-5 F. The occlusion was obtained by the positioning of Granturco metal coils: in 1 case we adapted a coil of 3 mm diameter and 1 cm length; in 3 cases 2 coils of 3 mm and in 1 case 2 coils of 3 mm and 1 coil of 5 mm diameter and 1 cm length were necessary. The success of the procedure was always checked with an immediate angiogram and color Doppler US after 48 hrs. RESULTS: The diagnosis of arteriovenous fistulas was always confirmed by a preliminary angiography that demonstrated the normal anatomic disposition of the renal arteries except in one case in which the fistula was fed by a peripheral branch originating from an inferior polar artery. All the lesions were localized in the inferior pole, the site of biopsy, and ranged from 3 mm to 2.5 cm in diameter. We never had any difficulties in the positioning and placement of the coils. The arterial occlusion and exclusion of the fistula was accomplished in all cases. The induced parenchymal loss ranged from 10 to 30% of the renal volume. There was a complete disappearance of symptoms in 3 of the patients, with hematuria without any modification of the blood pressure values in the patient with hypertension. Considering the patient status renal function did not worsen after the embolization. Each patient was followed-up with color Doppler US every two months. CONCLUSIONS: The intrarenal arteriovenous fistula represents a relative frequent complication of renal needle biopsy in patients with arterial hypertension and nephroangiosclerosis as risk factors. Embolization is a valid alternative therapeutic option to surgical treatments. The use of small size catheters permits the successful embolization also of peripheral lesions, reducing the induced parenchymal ischemia. We believe that among the embolization material available metal coils represent a valid solution as they are easily positioned and permit definitive occlusion without any risks of systemic venous microembolization.     

Beer Affects Oxidative Stress due to Ethanol in Rats

The relationship between chronic moderate beerconsumption and oxidative stress was studied in rats.Animals were fed three different isocaloric diets forsix weeks: a beercontaining diet (30% w/w), an ethanol-supplemented diet (1.1 g/100 g, thesame as in the beer diet) and an alcohol-free basaldiet. At the end of the feeding period, rats wereanalyzed for plasma and liver oxidative status. Somelivers were isolated and exposed toischemiareperfusion to assess the additional oxidativestress determined by reperfusion. No significantdifferences in plasma antioxidant status were foundamong the three dietary groups. Lipoproteins from the beer group,however, showed a greater propensity to resist lipidperoxidation. Ischemia caused a decrease in liver energyand antioxidant status in all groups. Nevertheless, ATP was lower in the livers of rats exposed tothe ethanol diet. During reperfusion, lipoperoxidationincreased significantly in all groups. However, liversobtained from ethanoltreated rats showed the higher formation of lipoperoxides. Inconclusion, a moderate consumption of beer in awell-balanced diet did not appear to cause oxidativestress in rats; moreover, probably through its minorcomponents, beer could attenuate the oxidative action ofethanol by itself.     

Long pentraxin‐3 as an epithelial–stromal fibroblast growth factor‐targeting inhibitor in prostate cancer

Fibroblast growth factors (FGFs) exert autocrine/paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth. Here dihydrotestosterone (DHT) up‐regulates FGF2 and FGF8b production in murine TRAMP‐C2 prostate cancer cells, activating a FGF‐dependent autocrine loop of stimulation. The soluble pattern recognition receptor long pentraxin‐3 (PTX3) acts as a natural FGF antagonist that binds FGF2 and FGF8b via its N‐terminal domain. We demonstrate that recombinant PTX3 protein and the PTX3‐derived pentapeptide Ac‐ARPCA‐NH₂ abolish the mitogenic response of murine TRAMP‐C2 cells and human LNCaP prostate cancer cells to DHT and FGFs. Also, PTX3 hampers the angiogenic activity of DHT‐activated TRAMP‐C2 cells on the chick embryo chorioallantoic membrane (CAM). Accordingly, human PTX3 overexpression inhibits the mitogenic activity exerted by DHT or FGFs on hPTX3_TRAMP‐C2 cell transfectants and their angiogenic activity. Also, hPTX3_TRAMP‐C2 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice. A similar inhibitory effect is observed when TRAMP‐C2 cells overexpress only the FGF‐binding N‐terminal PTX3 domain. In keeping with the anti‐tumour activity of PTX3 in experimental prostate cancer, immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression, abundant in basal cells of normal glands, is lost in high‐grade prostatic intraepithelial neoplasia and in invasive tumour areas. These results identify PTX3 as a potent FGF antagonist endowed with anti‐angiogenic and anti‐neoplastic activity in prostate cancer. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

Homozygous or compound heterozygous mutations in the GJC2 gene, encoding the gap junction protein connexin47 (Cx47), cause the autosomal recessive hypomyelinating Pelizaeus–Merzbacher-like disease (PMLD1, MIM# 608804). Although clinical and neuroradiological findings resemble those of the classic Pelizaeus–Merzbacher disease, PMLD patients usually show a greater level of cognitive and motor functions. Unpredictably a homozygous missense GJC2 mutation (p.Glu260Lys) was found in a patient presenting with a very severe clinical picture characterised by congenital nystagmus and severe neurological impairment. Also magnetic resonance imaging was unusually severe, showing an abnormal supra- and infratentorial white matter involvement extending to the spinal cord. The novel p.Glu260Lys (c.778G>A) mutation, occurring in a highly conserved motif (SRPTEK) of the Cx47 extracellular loop-2 domain, was predicted, by modelling analysis, to break a ‘salt bridge network'', crucial for a proper connexin–connexin interaction to form a connexon, thus hampering the correct formation of the connexon pore. The same structural analysis, extended to the previously reported missense mutations, predicted that most changes were expected to have less severe impact on protein functions, correlating with the mild PMLD1 form of the patients. Our study expands the spectrum of PMLD1 and provides evidence that the extremely severe clinical and neuroradiological PMLD1 form of our patient likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein.     

Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe

Background

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe.