Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours

PurposeTo evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies.Patients and methodsMulticentre, phase I study with a standard ‘3 + 3’ design in five dose increments. Eligible patients: aged 6 months to 21 years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100 mg/m²/d, and TPT intravenously over 30 min, starting at 0.75 mg/m²/d over 5 consecutive days every 28 d. A pharmacokinetics analysis was performed on Day 1 and Day 5 of cycle 1.ResultsBetween February and October 2007, 16 patients were treated. The median age was 8.5 years (range, 3–19 years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7 d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150 mg/m²/d and TPT 1.0 mg/m²/d) and was always manageable. Confirmed complete and partial responses were observed in 4 patients (25%), three with metastatic neuroblastoma and one with high-grade glioma. Seven patients had a stable disease. Pharmacokinetic data show a wide inter-individual variability. No significant differences were observed between plasma TMZ and TPT concentrations on Day 1 and Day 5 indicating the absence of pharmacokinetic interaction between the drugs.ConclusionsThe RD for the combination is TMZ 150 mg/m²/d and TPT 0.75 mg/m²/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies.     

Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity

Introduction

Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53 mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC).

Methods

Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53 gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs.

Results

All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p = 0.0004). TP53 mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC.

Conclusion

Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.     

Evaluation of arterial blood gas parameters as prognostic markers in amyotrophic lateral sclerosis

Background

Forced vital capacity (FVC) remains difficult to determine for some patients suffering from amyotrophic lateral sclerosis (ALS) due to the rapid progression of the disease. Arterial blood gas (ABG) parameters could represent a valuable alternative. The aim of this study was therefore to evaluate the correlation between ABG parameters and FVC, along with the prognostic ability of ABG parameters, in a large cohort of ALS patients.

Methods

ALS patients (n=302) with FVC and ABG parameters available at diagnosis were included. Correlations between ABG parameters and FVC were evaluated. Cox regression was then carried out to determine the association of each parameter (ABG and clinical data) with survival. Finally, receiver operating characteristic (ROC) curves were built to predict the survival of ALS.

Results

Bicarbonates (HCO₃⁻), oxygen partial pressure (pO₂), carbon dioxide partial pressure (pCO₂), base excess (BE), oxygen saturation and oxyhemoglobin were significantly correlated with FVC both in patients with spinal or bulbar onset. Univariate Cox regression showed that HCO₃⁻ and BE were associated with survival but only in spinal forms. ABG parameters predicted the survival of ALS with a similar performance to FVC, HCO₃⁻ being the parameter with the highest area under the curve.

Conclusions

Our results suggest that there is an interest in conducting a longitudinal evaluation throughout disease progression to confirm the equal performances of FVC and ABG. This study highlights the benefits of performing ABG analysis that could be used as an interesting alternative to FVC when spirometry cannot be performed.     

Pediatric anesthetic for tracheobronchial foreign body extraction: A survey of practice in France

Background

Tracheobronchial foreign body aspiration is a classic pediatric emergency, and its associated morbidity particularly depends on the anesthetic management, which differs according to the center and the practitioner.

Aims

The aim of this study was to evaluate the different anesthetic practices for tracheobronchial foreign body extraction.

Methods

A survey was sent via email to the member physicians of the Association des Anesthésistes Réanimateurs Pédiatriques d'Expression Française (ADARPEF). The survey included 28 questions about the organizational and anesthetic management of an evolving clinical case.

Results

A total of 151 physicians responded to the survey. Only 13.2% of the respondents reported that their institution had a management protocol, and 21.7% required a computerized tomography scan before the procedure was performed for children who were asymptomatic or mildly symptomatic during the night. There were 56.3% of the respondents who reported that extraction with a rigid bronchoscope is the only procedure usually performed in their institution. Regarding rigid bronchoscopy, 47.0% used combined intravenous-inhalation anesthesia. The objective was to maintain the child on spontaneous ventilation for 63.6% of the respondents, but anesthesia management differed according to the physician's experience.

Conclusions

Our study confirms the diversity of practices concerning anesthetic for tracheobronchial foreign body extraction and found reveal differences in practice according to physician experience.     

Epidemiology of rheumatic diseases: a cohort of 23,550 patients in rheumatology clinics in Burkina Faso

Clinical Rheumatology - The aim of this work is to study the epidemiological characteristics of rheumatic conditions in a cohort of 23,550 patients followed up in Ouagadougou, Burkina Faso. This...     

Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B)

Background

Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B-MIM:620174). Whether they represent a common cause of sporadic late-onset cerebellar ataxia (SLOCA) remains to be established.

Objectives

To estimate the prevalence, characterize the phenotypic spectrum, identify discriminative features, and model longitudinal progression of SCA27B in a prospective cohort of SLOCA patients.

Methods

FGF14 expansions screening combined with longitudinal deep-phenotyping in a prospective cohort of 118 SLOCA patients (onset >40 years of age, no family history of cerebellar ataxia) without a definite diagnosis.

Results

Prevalence of SCA27B was 12.7% (15/118). Higher age of onset, higher Spinocerebellar Degeneration Functional Score, presence of vertigo, diplopia, nystagmus, orthostatic hypotension absence, and sensorimotor neuropathy were significantly associated with SCA27B. Ataxia progression was ≈0.4 points per year on the Scale for Assessment and Rating of Ataxia.

Conclusions

FGF14 expansion is a major cause of SLOCA. Our natural history data will inform future FGF14 clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.