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.     

Breast abnormalities: a retrospective study of 208 patients

Ectopic breast tissue occurs in 0.4-6% of the general population. Usually, these tissues develop along the embryonic milk line but other sites are reported in the literature. Accessory breasts are commonly axillary and may undergo hormonal changes. Some pathologies of normally positioned breasts can occur in ectopic breast tissue, including carcinoma, and therefore require traditional senological flow-charts and imaging strategies. Supernumerary nipples are generally asymptomatic but may sometimes be associated with urological malformations. In our 10-year experience, 208 patients were observed (138 polythelia and 70 polymastia) and 159 surgical procedures were performed, 97 for supernumerary nipple excision and 67 for accessory breast ablation. Five neoplastic lesions and 25 fibrocystic mastopathies were detected in specimens; normal nipple or breast tissue was found in 129. In view of the potentially malignant transformation of accessory breasts, thorough physician evaluation is needed. Surgery is currently suggested in cases of suspected malignancy, in symptomatic cases and for cosmetic problems.     

Magnetic resonance imaging in evaluating functional disorders of female pelvic floor

PURPOSE: To evaluate the diagnostic capabilities of MRI in the study of functional diseases of the female pelvic floor. MATERIALS AND METHODS: Ten healthy volunteers and 30 patients with clinically suspected pelvic floor deficiency, with or without pelvic organ prolapse, were evaluated by a high field strength magnet operating at 1.5 T. In each case SSFSE sequences (TR/TE:25720/67) in axial, coronal and sagittal planes, both at rest and during Valsalva's manoeuvre, were performed. Based on the MRI findings using fixed and mobile anatomical landmarks, the functional disease of the pelvic floor was diagnosed and quantified based on the identification and grading of visceral prolapse. The MRI findings were compared with the clinical findings in all cases and with the surgical data in the 7 patients who had undergone surgery. RESULTS: The MR image quality was adequate in all cases. In the group of symptomatic women MRI diagnosed: urethral hypermobility syndrome: 22 cases; isolated abnormalities of the anterior compartment: 8 cases of cystocele (low grade: 2, middle grade: 2, severe: 4); isolated abnormalities of the middle compartment: 6 cases of hysterocele (low grade: 2, middle grade: 4); isolated abnormalities of the posterior compartment: 5 cases of low-grade rectocele; 2 cases of enterocele (1 low grade, 1 middle grade); multi-compartment abnormalities: 11 cases; joint prolapse of anterior and middle compartment: 5 cases; joint prolapse of posterior and middle compartment: 3 cases; joint prolapse of anterior, middle and posterior compartment: 3 cases. The values of both fixed and mobile landmarks were significantly higher in the symptomatic group compared with the healthy volunteers. MRI confirmed the pelvic examination findings in all cases; in particular MRI findings were in total agreement with the clinical severity of prolapse, as defined by the Baden-Walker classification. In 7 cases MRI detected additional alterations (4 cases of hysterocele and 3 of enterocele) that had been missed at clinical evaluation. DISCUSSION AND CONCLUSIONS: In our experience MRI made an important contribution to the diagnosis and grading of functional disorders of the female pelvic floor and pelvic organ prolapse. The ability to simultaneously demonstrate both muscular and ligamentous structures and pelvic viscera, without using X-rays or contrast agents, is the main reason for the good results achieved by MRI and for its widespread use in this disorder. Furthermore the use of fast, breath-hold sequences can provide high-quality images both at rest and during Valsalva's manoeuvre. In conclusion MRI proved to be an accurate imaging tool that is more sensitive than clinical pelvic evaluation in diagnosing and grading functional disorders of the female pelvic floor and pelvic visceral prolapse.     

A simple technique of oblique anastomosis can prevent stricture formation in primary repair of esophageal atresia

BackgroundAnastomotic stricture is an important problem after esophageal atresia (EA) repair. This study evaluates a technique of oblique esophageal anastomosis without use of a flap in order to prevent stricture formation.MethodsMedical records of 16 patients (14 with EA type III and 2 with EA type IV Ladd-Gross classification) who underwent primary repair of EA at birth without anastomotic tension were reviewed, evaluating long-term follow-up results. All patients were studied with esophageal contrast study, pH-multichannel intraluminal impedance, and endoscopy. The incidence of complications and their management were analysed.ResultsContrast esophagogram and esophagoscopy always showed regular patency of the suture line.ConclusionsOur technique of oblique anastomosis is simple, safe, and effective in preventing stricture formation even in the long-term follow-up.     

Factors in intestinal lymph after shock increase neutrophil adhesion molecule expression and pulmonary leukosequestration

BACKGROUND: Because the ischemic gut may produce factors that initiate systemic inflammation, we tested the hypothesis that factors released from the gut into the mesenteric lymphatics increase neutrophil (PMN) adhesion molecule expression after trauma and shock. METHODS: At 1 and 4 hours after hemorrhagic shock (30 mm Hg x 90 minutes) plus trauma (laparotomy) (T/HS) or sham-shock (T/SS), with or without mesenteric lymph duct ligation, PMN CD11b and CD18 expression was assessed in male rats. In additional rats, mesenteric lymph samples were tested for their ability to increase PMN CD11b expression in vitro. Lastly, at 4 hours after T/SS or T/HS with or without lymph duct ligation, pulmonary PMN sequestration was measured. RESULTS: Compared with T/SS rats, T/HS was associated with up-regulation of PMN CD11b and CD18 expression, which was largely prevented by ligation of the mesenteric lymph duct (p < 0.01). Lymph duct ligation also prevented T/HS-induced pulmonary leukocyte sequestration (p < 0.01). In addition, mesenteric lymph from rats subjected to T/HS but not T/SS increased CD11b expression (p < 0.01). CONCLUSION: Factors produced or released by the postischemic intestine and carried in the mesenteric lymph appear responsible for PMN activation and pulmonary PMN sequestration after an episode of T/HS.     

Epidural analgesia with 0.15% ropivacaine plus sufentanil 0.5 microgram ml-1 versus 0.10% bupivacaine plus sufentanil 0.5 microgram ml-1: a double-blind comparison during labour

Background. Ropivacaine has been claimed to produce less motorblock than bupivacaine during epidural analgesia. However, thisadvantage has not been clearly confirmed in obstetric studiesusing low analgesic concentrations in a ratio close to thatsuggested to be equianalgesic. Methods. This double-blind, randomized, prospective study wasperformed in 140 parturients who requested epidural analgesia.After a lumbar epidural catheter had been placed, patients receivedeither 0.10% bupivacaine plus sufentanil 0.5 µg ml^–1or 0.15% ropivacaine plus sufentanil 0.5 µg ml^–1followed by a continuous infusion. Additional boluses were usedfor inadequate levels of analgesia. Visual analogue pain scores,motor block, level of sensory block, supplementary boluses andmain characteristics of labour were recorded. Results. No differences were observed between the two groupsfor pain scores, total volume of anaesthetic solution used [59(23) and 57 (24) ml in the bupivacaine and ropivacaine groupsrespectively], duration of labour, mode of delivery, side-effectsor satisfaction score. The incidence of motor block was notstatistically different between the groups (54 and 69% in thebupivacaine and ropivacaine groups respectively, P=0.07). However,when motor block occurred, survival analysis showed that itoccurred sooner in the course of labour with ropivacaine comparedwith bupivacaine (log rank test, P=0.012). Conclusion. Combined with sufentanil 0.5 µg ml^–1,0.10% bupivacaine and 0.15% ropivacaine produce effective andequivalent analgesia during labour, with similar incidencesof motor block. Br J Anaesth 2002; 88: 809–13     

Robot assisted laparoscopic partial nephrectomy: initial experience

PURPOSE: Advances in laparoscopy have made laparoscopic partial nephrectomy a technically feasible procedure but it remains challenging to even experienced laparoscopists. We hypothesized that robotic assisted laparoscopic partial nephrectomy may make this procedure more efficacious than the standard laparoscopic approach. MATERIALS AND METHODS: Ten patients with a mean age of 58 years and mean tumor size of 2.0 cm underwent robotic assisted laparoscopic partial nephrectomy and another 10 with a mean age of 61 years and mean tumor size of 2.18 cm underwent laparoscopic partial nephrectomy, as performed by a team of 2 surgeons (MS and ST) between May 2002 and January 2004. Demographic data, intraoperative parameters and postoperative data were compared between the 2 groups. RESULTS: There were no significant differences in patient demographics between the 2 groups. Intraoperative data and postoperative outcomes were statistically similar. In the 10 patients who underwent robotic assisted laparoscopic partial nephrectomy there were 2 intraoperative complications. There was 1 conversion in the laparoscopic partial nephrectomy group. CONCLUSIONS: Robotic assisted laparoscopic partial nephrectomy is a safe and feasible procedure in patients with small exophytic masses. The robotic approach to laparoscopic partial nephrectomy does not offer any clinical advantage over conventional laparoscopic nephrectomy.     

CA19-9 serum levels in obstructive jaundice: clinical value in benign and malignant conditions

Background

Obstructive jaundice is frequently associated with false CA19-9 elevation in benign conditions. The diagnostic accuracy of this tumor marker was evaluated in the present longitudinal study.

Methods

In 128 patients admitted for obstructive jaundice (87 with pancreato-biliary malignancy and 41 benign disease) serum CA19-9 was measured. Statistical analysis of marker levels obtained before and after endoscopic biliary drainage was performed in 60 patients.

Results

Elevated CA19-9 levels (>37 U/mL) were found in 61% of benign cases and 86% of malignancies. After biliary drainage, decrease of serum CA19-9 was observed in 19 of 38 malignant cases and in almost all benign cases (Wilcoxon matched pairs test: P = .207 and P <.001, respectively). Receiver operating characteristic (ROC) analysis identified a cut-off value of 90 U/mL to be associated with improved diagnostic accuracy after biliary drainage (sensitivity 61%, specificity 95%).

Conclusions

In the presence of successfully drained obstructive jaundice, CA19-9 serum levels that remain unchanged or measure more than 90 U/mL are strongly indicative of a malignant cause of obstruction. However, the real clinical utility of this marker remains controversial.