Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review

New targeted cancer therapies such as bisphosphonates, denosumab, and bevacizumab are routinely used in adult for the past decades. Their introduction into pediatric medicine is more recent that means there is a paucity of data on long‐term effects on dental development and on the risk of osteonecrosis of jaw. This study aimed to outline adverse effects of new targeted cancer therapies on oral cavity including dental abnormalities observed in pediatric population treated with these molecules and the risk of osteonecrosis of the jaw (ONJ). The impact of bisphosphonates and denosumab on bone remodeling (inhibition of osteoclasts) could interfere with teeth exfoliation and eruption processes, causing a tooth eruption delay. This hypothesis was confirmed, bisphosphonate‐treated rats presented tooth eruption delay, and bisphosphonate therapy was associated with a mean delay of 1.67 years in tooth eruption in children with osteogenesis imperfecta. Another study showed that the inhibition of RANK/RANKL by denosumab was associated with a lack of tooth eruption in animals. Several animal studies reported that bisphosphonate could also induce dental abnormalities including defective amelogenesis and dentinogenesis in rats, but there is no evidence of such effects in children; only one case of enamel hypoplasia in a child treated for idiopathic arterial calcification with bisphosphate was reported. To date, there has been no reported case of ONJ in children treated with bisphosphonates, denosumab, or bevacizumab.     

From a non-targeted metabolomics approach to a targeted biomarkers strategy to highlight testosterone abuse in equine. Illustration of a methodological transfer between platforms and laboratories

In order to overcome the challenge associated with the screening of Anabolic-Androgenic Steroids abuses in animal competitions, a non-targeted liquid chromatography coupled to high resolution mass spectrometry based metabolomics approach was implemented on equine urine samples to highlight potential biomarkers associated with the administration of such compounds, using testosterone esters as model steroids. A statistical model relying on four potential biomarkers intensity could be defined to predict the status of the samples. With a routine application perspective, the monitoring of the highlighted potential biomarkers was first transferred into high-throughput liquid chromatography-selected reaction monitoring (LC-SRM). The model's performances and robustness of the approach were preserved and providing a first demonstration of metabolomics-based biomarkers integration within a targeted workflow using common benchtop MS instrumentation. In addition, with a view to the widespread implementation of such biomarker-based tools, we have transferred the method to a second laboratory with similar instrumentation. This proof of concept allows the development and application of biomarker-based strategies to meet current doping control needs.     

Ischemic Gastric Conditioning by Preoperative Arterial Embolization Before Oncologic Esophagectomy: A Single-Center Experience

Purpose

Surgical esophagectomy is the gold standard treatment of early-stage esophageal cancer. The procedure is complicated with significant morbidity; the most severe complication being the anastomotic leakage. Anastomotic fistulas are reported in 5–25% of cases and are mainly due to gastric transplant ischemia. Here, we report our experience of ischemic pre-conditioning using preoperative arterial embolization (PreopAE) before esophagectomy.

Materials and Methods

The medical records of all patients who underwent oncologic esophagectomy from 2008 to 2015 were retrospectively reviewed. Patients were divided into two groups: patients who received PreopAE, and a control group of patients who did not benefit from ischemic pre-conditioning. The target arteries selected for PreopAE were the splenic artery, left gastric artery, and right gastric artery. Evaluation of the results was based on anastomotic leakage, postoperative mortality, technical success of PreopAE, and complications related to the embolization procedure.

Results

Forty-six patients underwent oncologic esophagectomy with PreopAE and 13 patients did not receive ischemic conditioning before surgery. Thirty-eight PreopAE were successfully performed (83%), but right gastric artery embolization failed for 8 patients. Anastomotic leakage occurred in 6 PreopAE patients (13%) and in 6 patients (46%) in the control group (p = 0.02). The mortality rate was 2% in the PreopAE group and 23% in the control group (p = 0.03). Eighteen patients suffered from partial splenic infarction after PreopAE, all treated conservatively.

Conclusion

Preoperative ischemic conditioning by arterial embolization before oncologic esophagectomy seems to be effective in preventing anastomotic leakage.

     

Impact of treatment‐related liver toxicity on the outcome of HCV‐positive non‐Hodgkin's lymphomas

We studied 160 Hepatitis C virus (HCV)‐positive patients with NHL (59 indolent NHL, 101 aggressive). Median age was 67 years. HCV‐RNA was present in 146. HBsAg was positive in seven patients. At diagnosis, ALT value was above UNL in 67 patients. One hundred and twenty patients received an anthracycline‐based therapy, alkylators, 28 received chemotherapy plus rituximab. Cytotoxic drugs dose was reduced in 63 patients. Among 93 patients with normal ALT at presentation, 16 patients developed WHO grade II–III liver toxicity. Among 67 patients with abnormal ALT, eight patients had a 3.5 times elevation during treatment. Among 28 patients treated with rituximab and chemotherapy, five patients (18%) developed liver toxicity. Thirty four patients (21%) did not complete treatment (eight for liver toxicity). Median progression‐free survival (PFS) for patients who experienced liver toxicity is significantly shorter than median PFS of patients without toxicity (respectively, 2 years and 3.7 years, P = 0.03). After a median F‐UP of 2 years, 32 patients died (three for hepatic failure). A significant proportion of patients with HCV+ NHL develop liver toxicity often leading to interruption of treatment. This could be a limit to the application of immunochemotherapy programs. HCV+ lymphomas represent a distinct clinical subset of NHL that deserves specific clinical approach to limit liver toxicity and ameliorate survival. Am. J. Hematol., 2010. © 2009 Wiley‐Liss, Inc.     

Grading system to assess clinical performance of closed-loop glucose control

Closed-loop control of the glucose concentration in type 1 diabetes has been the subject of extensive research over the last 3 decades. Building on the recent progress in continuous glucose sensing techniques, several prototypes of a closed-loop system have been developed. To complement existing measures of glucose control, we designed a grading system specifically designed to provide clinical assessment of closed-loop systems including that of glucose controllers. The system introduces six grades, A-F, describing the level of control and the therapeutic intervention during outside-meal and postprandial conditions. Grades A and B represent excellent and good glucose control, respectively, without the need for a corrective therapeutic action. Grade C represents suboptimal control with a recommendation for a corrective action. Grade D represents poor control requiring a corrective action. Grades E and F represent very poor and life-threatening control, respectively, with a need for an immediate corrective action or requiring external assistance. The outcome of grading is the quantification of time spent in each grade. The grading system is exemplified using data obtained with a model predictive controller within an in silico simulation environment. We conclude that the grading system provides suitable means to assess efficacy and safety of glucose controllers complementing existing measures of glucose control.     

Differential expression of galectin-3 in medullary thyroid carcinoma and C-cell hyperplasia

OBJECTIVE AND DESIGN: Galectin-3 is a beta-galactoside-binding protein that plays a role in cell adhesion and tumour progression. It was shown recently to diagnose malignant follicular thyroid lesions accurately. The reliability of this marker in the differential diagnosis between medullary thyroid carcinoma and C-cell hyperplasia was studied by immunohistochemistry. PATIENTS: Tissue specimens were obtained from 34 patients belonging to families with medullary thyroid carcinoma who underwent prophylactic thyroidectomy for RET gene mutation and/or abnormally increased plasma calcitonin levels. RESULTS: Galectin-3 was expressed in 23 of 25 cases of medullary thyroid carcinoma and in none of the nine cases of C-cell hyperplasia only, giving a sensitivity of 92% and a specificity of 100% for the diagnosis of carcinoma. A significant association was found between higher galectin-3 expression and occurrence of lymph node metastases (P < 0.05). CONCLUSIONS: Galectin-3 is a reliable diagnostic marker of medullary thyroid carcinoma, and its use may provide relevant information for prognosis and therapy.