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.     

Dynamic contrast-enhanced ultrasound with carbon dioxide microbubbles as adjunct to arteriography of liver tumors

Purpose The goal of the study is to evaluate utility of contrast enhanced ultrasound (US) with carbon dioxide microbubbles in evaluation of hepatic lesions.Methods Twenty eight patients with single or multiple t hepatic lesions (11 hepatocellular carcinoma, 8 hemangiomas, 5 metastases, 1 adenoma, 1 focal nodular hyperplasia, 2 regenerative nodules) were examined. US exam was performed during intraarterial injection of 10 ml of CO₂ through the same catheter employed for liver arteriography. The US exam was videotaped in its salient phases. Characteristics of enhancement were evaluated and correlated with histological findings or patient follow up.Results Sonographic angiography clearly demonstrated vascularization of the lesions. Hepatocellular carcinoma, hemangioma, metastases, focal nodular hyperplasia, and regenerative nodules had very characteristic patterns. The injection of CO₂ allowed detection of small additional nodules.Conclusion Sonographic angiography can improve characterization and staging of hepatic tumors. Low cost and the simplicity of the technique should encourage further experimentation.     

Bedside diagnostic laparoscopy for critically ill patients: a retrospective study of 62 patients

Background

Bedside diagnostic laparoscopy has an important role of diagnosing acute abdomen in critically ill patients hospitalized in the intensive care unit (ICU). Delayed diagnosis of intraabdominal pathology increases the morbidity and mortality rates for these patients, whose clinical signs often are absent due to analgesic medication and sedation.

Methods

In this retrospective study performed from January 2007 to December 2009, 62 consecutive ICU patients whose blood test results showed them to be hemodynamically unstable underwent bedside diagnostic laparoscopy. The inclusion criteria specified clinically suspected acute cholecystitis, unknown sepsis, acidosis with a high level of lactate, elevated lab tests (white blood cell count, bilirubin, lactic dehydrogenase, creatine phosphokinase, gamma glutamyl transferase [??GT]), and acute anemia with suspected intraabdominal bleeding. The major contraindications to bedside diagnostic laparoscopy were coagulopathy, endocranic hypertension, and heart failure. Patients with a clear indication for an open surgical procedure were excluded from the study.

Results

Of the 62 patients who underwent bedside diagnostic laparoscopy, 43 (69.3?%) had positive findings and 29 (46.7?%) had acute acalculous cholecystitis. The mean operation time was 38 min, and no procedure-related deaths occurred. The procedure was performed for postsurgery patients, especially after cardiac operations, and for trauma or septic patients. Respiratory and hemodynamic parameters were monitored before, during, and after the procedure.

Conclusions

As a minimally invasive procedure, bedside diagnostic laparoscopy can be performed in the ICU for hemodynamically unstable patients. It is safe procedure with high diagnostic accuracy for acute intraabdominal conditions that avoids negative laparotomies for unstable patients. The bedside diagnostic laparoscopy procedure is not performed widely, and prospective studies are needed to better evaluate outcome and advantages for critically ill patients.     

Quantitative evaluation of background parenchymal enhancement (BPE) on breast MRI. A feasibility study with a semi-automatic and automatic software compared to observer-based scores

Objective:

To evaluate quantitative measurements of background parenchymal enhancement (BPE) on breast MRI and compare them with observer-based scores.

Methods:

BPE of 48 patients (mean age: 48 years; age range: 36–66 years) referred to 3.0-T breast MRI between 2012 and 2014 was evaluated independently and blindly to each other by two radiologists. BPE was estimated qualitatively with the standard Breast Imaging Reporting and Data System (BI-RADS) scale and quantitatively with a semi-automatic and an automatic software interface. To assess intrareader agreement, MRIs were re-read after a 4-month interval by the same two readers. The Pearson correlation coefficient (r) and the Bland–Altman method were used to compare the methods used to estimate BPE. p-value <0.05 was considered significant.

Results:

The mean value of BPE with the semi-automatic software evaluated by each reader was 14% (range: 2–79%) for Reader 1 and 16% (range: 1–61%) for Reader 2 (p > 0.05). Mean values of BPE percentages for the automatic software were 17.5 ± 13.1 (p > 0.05 vs semi-automatic). The automatic software was unable to produce BPE values for 2 of 48 (4%) patients. With BI-RADS, interreader and intrareader values were κ = 0.70 [95% confidence interval (CI) 0.49–0.91] and κ = 0.69 (95% CI 0.46–0.93), respectively. With semi-automated software, interreader and intrareader values were κ = 0.81 (95% CI 0.59–0.99) and κ = 0.85 (95% CI 0.43–0.99), respectively. BI-RADS scores correlated with the automatic (r = 0.55, p < 0.001) and semi-automatic scores (r = 0.60, p < 0.001). Automatic scores correlated with the semi-automatic scores (r = 0.77, p < 0.001). The mean percentage difference between automatic and semi-automatic scores was 3.5% (95% CI 1.5–5.2).

Conclusion:

BPE quantitative evaluation is feasible with both semi-automatic and automatic software and correlates with radiologists'' estimation.

Advances in knowledge:

Computerized BPE quantitative evaluation is feasible with both semi-automatic and automatic software. Computerized BPE quantitative scores correlate with radiologists'' estimation.     

Percutaneous implantation of a catheter with subcutaneous reservoir for intraarterial regional chemotherapy: Technique and preliminary results

Purpose: We present the technique and the preliminary results of percutaneous implantation of intraarterial catheters connected to a subcutaneous infusion reservoir for prolonged regional chemotherapy of hepatic and extrahepatic tumors. Methods: Two hundred patients with primary or secondary hepatic neoplasms, pelvic, pancreatic, renal, lingual, and breast cancer underwent the procedure. The access was the left axillary artery (188 patients) and the femoral artery (12 patients). The catheter tip was placed in the hepatic (170 patients), hypogastric (18), splenic (4), internal thoracic (2), gastroduodenal (3), renal (2) or the external carotid artery (1). The catheter was connected to a subcutaneous reservoir and filled with heparin; chemotherapeutic infusion was subsequently started. Results: One hundred percent immediate technical success was obtained. Forty-three of 200 (21.5%) patients had a complication: 29 patients had a catheter dislodgment, nine had arterial thrombosis, three had a pseudoaneurysm of the left axillary artery and two had a port pocket hematoma. Most complications (37/43, 86%) were treated percutaneously without interruption of chemotherapy. In only six cases (3% of the total population) was chemotherapy discontinued due to the complication itself. The mean duration of catheter patency was 7.2 months. Conclusion: Percutaneous placement of an intraarterial catheter is feasible and causes less discomfort to the patient than the surgical approach. The technique has an acceptable complication rate (21.5%), similar to that for surgical implantation (17.8%), with the advantage that in most cases the complications can be resolved percutaneously. This technique represents an alternative to surgical implantation in the treatment of liver metastases from colorectal cancer and opens new therapeutic possibilities for the local prolonged treatment of other kinds of tumor, though its clinical efficacy must be assessed in selected trials.     

Perioperative enteral nutrition

Enteral nutrition, as demonstrated by the many published papers, is not only safer and cheaper than parenteral supply of nutrients, but modulates an exaggerated cytokine response related to surgical trauma that leads to an increase in intestinal permeability, bacterial translocation and infection. The aim of enteral nutrition is to reduce the impact of cytokines on surgical patients and the related infectious complications. Via the enteral route the nutrients can reach the bowel lumen where enterocytes draw upon their fuel, preserving the barrier effect and modulating the cytokine response. Parenteral supply does not achieve this target since the blood supply of nutrients is not as important as the luminal supply. It is only via the enteral supply route that we can preserve the barrier effect. Since the cytokine response sets in immediately after a trauma such as surgery, we implement uninterrupted enteral nutrition, which means before, during and after surgery, plus parenteral support till the full calorie intake is achieved. In a hepatic resection study, we have demonstrated that enteral nutrition modulates the interleukin-6 immunological response and shortens both the period to bowel movement resumption and the duration of hospital stay. Aggressive enteral nutrition has also been implemented in severe pancreatitis, allowing control of the disease without the onset of septic complications. The most important target is not to achieve full calorie intake rapidly, but to supply the enteric mucosa continuously with useful immuno-nutrients, such as glutamine and fibres, to preserve the barrier effect, the mucus layer, and immunological status of the mucosa. In this way we have obtained significant results in the surgical treatment of these patients, reducing the infection rate and hospital stay. New prospects may be,possible in the fight against surgical infections by adding probiotics to enteral nutrition in order to improve the microenvironment of the colon.     

Control results on a sample of patients subjected to total thyroidectomy for papillary carcinoma: proposal for a personal diagnostic-therapeutic follow-up

Well-differentiated thyroid neoplasms may be included among the most frequently occurring thyroid carcinomas. Papillary ca. is without doubt the best behaved type. The aim of the present work is to perform a retrospective case history study to assess patients with con papillary ca. who have been treated surgically over the last 17 years and have been subjected to periodic checks. A sample of patients was therefore extrapolated who had all undergone total thyroidectomy for papillary ca. of the thyroid. The incidence of local recurrence of the disease was verified, together with the results at distance. Furthermore, the assessments performed were evaluated and compared. From the sample of patients observed we inferred that papillary carcinoma of the thyroid can have a good prognosis over time provided periodic random checks are carried out.     

Predictors of renal and patient outcomes in atheroembolic renal disease: a prospective study

Atheroembolic renal disease (AERD) is part of a multisystemic disease accompanied by high cardiovascular comorbidity and mortality. Interrelationships between traditional risk factors for atherosclerosis, vascular comorbidities, precipitating factors, and markers of clinical severity of the disease in determining outcome remain poorly understood. Patients with AERD presenting to a single center between 1996 and 2002 were followed-up with prospective collection of clinical and biochemical data. The major outcomes included end-stage renal disease (ESRD) and death. Ninety-five patients were identified (81 male). AERD was iatrogenic in 87%. Mean age was 71.4 yr. Twenty-three patients (24%) developed ESRD; 36 patients (37.9%) died. Cox regression analysis showed that significant independent predictors of ESRD were long-standing hypertension (hazard ratio [HR] = 1.1; P < 0.001) and preexisting chronic renal impairment (HR = 2.12; P = 0.02); use of statins was independently associated with decreased risk of ESRD (HR = 0.02; P = 0.003). Age (HR = 1.09; P = 0.009), diabetes (HR = 2.55; P = 0.034), and ESRD (HR = 2.21; P = 0.029) were independent risk factors for patient mortality; male gender was independently associated with decreased risk of death (HR = 0.27; P = 0.007). Cardiovascular comorbidities, precipitating factors, and clinical severity of AERD had no prognostic impact on renal and patient survival. It is concluded that AERD has a strong clinical impact on patient and renal survival. The study clearly shows the importance of preexisting chronic renal impairment in determining both renal and patient outcome, this latter being mediated by the development of ESRD. The protective effect of statins on the development of ESRD should be evaluated in a prospective study.