Trastuzumab for treatment of refractory/relapsed HER2-positive adult B-ALL: results of a phase 2 GRAALL study

The aim of this phase 2 study was to evaluate the efficacy and safety of trastuzumab, a humanized monoclonal antibody targeted against the human epidermal growth factor receptor 2 (HER2), for adult patients with relapsed/refractory HER2-positive B-ALL. Fifteen patients, with a median age of 62 years, received trastuzumab according to the schedule approved for breast cancer patients (ie, 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly). The overall response rate was 13% with 2 patients achieving partial response and partial remission cytolytic response, respectively. Two other patients were documented with blast clearance. Only 1 reversible grade 3 cardiac toxic event occurred. This phase 2 study showed that trastuzumab monotherapy can allow for some responses in a very high-risk refractory/relapsed HER2-positive adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future.     

Daily and Circadian Variations in 2-[125I]-Iodomelatonin Binding Sites in the Pike Brain (Esox Iucius)

The fish pineal organ, through its 24  h rhythmic release of melatonin, acts as a transducer of the photoperiod, influencing different physiological functions (e.g. reproduction, growth). We have investigated the binding of 2-[¹²⁵I]iodomelatonin to whole brain membrane preparations from pikes ( Esox lucius L., teleost) maintained for 24–48  h under different photoperiodic conditions. Specific binding was stable, reversible, saturable and sensitive to the presence of a GTP analogue. Scatchard analysis revealed one class of binding sites. Displacement experiments suggested the presence of two components with affinities in the femtomolar and nanomolar range of concentrations, respectively. The B_max exhibited monophasic nycthemeral variations, with higher values at the light-to-dark transition (34.0±4.5  fmol/mg protein) and low values during the second half of night (10.0±1.0  fmol/mg protein). Under the same conditions, the K_D exhibited biphasic variations: values were low during daytime and at the middle of the dark phase (approximately 100  pM); they were high at the beginning (approximately 225  pM) and at the end (approximately 330  pM) of the night. These variations were maintained under constant light (LL) and constant darkness (DD). Thus, the variations in the number and affinity of the melatonin binding sites were controlled by circadian oscillators, synchronized by the photoperiod. The nature of these oscillators is not known. Therefore, in fish, we suggest that the photodependent effects of melatonin result from the circadian variations of both its production by the pineal and its binding sites in the brain.     

Serum neurofilament light chain cut-off definition for clinical diagnosis and prognosis of amyotrophic lateral sclerosis

Background

The neurofilament light chain (NfL) assay is gradually becoming an essential diagnostic tool for the diagnosis of many neurological diseases including amyotrophic lateral sclerosis (ALS). Different methods for the determination of this biomarker in serum have been developed in recent years.

Methods

We measured blood NfL in 429 patients referred to the tertiary ALS center of Montpellier, France using two different ultrasensitive methods (Ella™ and Simoa™) and we compared the clinical performances of these two approaches. We also converted NfL values into age and body mass index-adjusted Z-scores to assess cut-off values of this biomarker in this clinical context.

Results

We show comparable diagnostic and prognostic performance of Ella™ and Simoa™ technologies in ALS, with specificities and sensitivities exceeding 80% for both. We propose cut-off values for serum NfL in this clinical context, thus enabling the routine clinical use of this biomarker.

Conclusion

The use of NfL in routine clinical practice will help predict survival and improve diagnostic accuracy by distinguishing ALS from other neurological diseases and motor neuron disease mimics.     

Sorafenib in Thyroid Cancer Patients: Learning From Toxicity

A recent review showed frequent reductions of sorafenib dose in the treatment of metastatic thyroid cancer because of toxicity consistent with the findings of the phase III DECISION trial and contrasting with the safety of sorafenib in other cancer populations. The unexpected excess of toxicity observed in thyroid cancer patients may be linked to a high prevalence of sarcopenia in this population, resulting in frequent overexposure to sorafenib.Thomas et al. [1] have recently published a review article addressing the use of sorafenib in metastatic thyroid cancer. Results concerning efficacy are of importance, but in our opinion the safety results deserve some comments. As highlighted by the authors, this review showed frequent dose reductions because of toxicity consistent with the findings of the phase III DECISION trial [2] and contrasting with the safety of sorafenib in other cancer populations. In the phase III TARGET trial of sorafenib in renal-cell carcinoma (RCC) patients, doses were reduced and interrupted only in 13% and 21%, respectively, of patients receiving sorafenib [3]. This excess of toxicity is intriguing because patients with metastatic thyroid cancer, a frequently slow growing disease, are expected to have better performance status and better renal and liver functions. The authors reported that 72% of patients could not tolerate the initial planned dosage of 400 mg twice daily and that 56% had dose reductions, suggesting that toxicity may be linked to sorafenib overexposure. Consistently more than 70% of patients suffered from hand-foot syndrome, an adverse reaction that has been associated with high sorafenib plasma concentrations [4].A key for understanding these results may lie in lean body mass. Patients with thyroid cancer receive long-term thyroxine suppressive therapy, which leads to hyperthyroidism, a major cause of muscle (lean body mass) loss [5]. This muscle loss, named sarcopenia, has been associated with a higher incidence of severe and early dose-limiting toxicities in RCC and hepatocellular carcinoma (HCC) patients treated with sorafenib or sunitinib [6, 7]. In HCC patients, sarcopenia has been associated with higher sorafenib exposure [6]. The unexpected excess of toxicity observed in thyroid cancer patients [1, 2] may therefore be linked to a high prevalence of sarcopenia in this population, resulting in frequent overexposure to sorafenib. Finally, if dose reduction is needed, sorafenib pharmacokinetics prefers a 200 mg twice daily regimen rather than 400 mg once daily [8, 9].     

Endothelial Dysfunction and Circulating Microparticles from Patients with Obstructive Sleep Apnea

Endothelial dysfunction is involved in vascular complications of obstructive sleep apnea (OSA). In this study, circulating microparticles (MPs) from patients with OSA-induced nocturnal desaturations were characterized and their effects on endothelial function were evaluated. Two age-matched groups of patients undergoing polysomnography for OSA were compared: 35 desaturators with a 3% oxyhemoglobin desaturation index (ODI) ≥ 10 events per hour of sleep and 27 nondesaturators with ODI <10 events per hour. MPs were characterized by flow cytometry and then either used to treat in vitro human endothelial cells or to study endothelial function in mice. Circulating MPs did not differ between groups, but MPs from granulocytes and activated leukocytes (CD62L⁺) were found at higher levels in desaturators. In vitro, MPs from desaturators reduced endothelial nitric oxide (NO) production by enhancing phosphorylation of endothelial NO synthase at the site of inhibition and expression of caveolin-1. CD62L⁺ MPs positively correlated with ODI. Endothelial NO production negatively correlated with both CD62L⁺ MPs and ODI. MPs from desaturators increased expression of endothelial adhesion molecules including E-selectin, ICAM-1 and ITGA5, and cyclooxygenase 2. Moreover, injection of MPs from desaturators into mice impaired endothelium-dependent relaxation in aorta and flow-induced dilation in small mesenteric arteries. This study demonstrates an association between endothelial dysfunction and increased circulating levels of CD62L⁺ MPs. This may initiate atherogenic processes in patients with OSA and severe nighttime hypoxia.Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by recurrent episodes of partial or complete obstruction of the upper airways during sleep, leading to repeated falls in oxygen saturation. There is growing evidence in support of an independent association between OSA and cardiovascular diseases,¹ particularly for sleep disordered breathing accompanied by marked nocturnal oxygen desaturations.^2,3 Various pathophysiological mechanisms have been proposed to contribute to the pathogenesis of vascular morbidity, including autonomic dysfunction, hypercoagulability, inflammation, oxidative stress, and endothelial dysfunction.⁴ An impairment of endothelial function has been recently demonstrated in patients with OSA and nocturnal desaturations compared with matched OSA patients without desaturations.⁵ Very recently, it was shown that OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress, and decreasing nitric oxide (NO) availability and repair capacity, as shown by reduced circulating levels of endothelial progenitor cells.⁶Microparticles (MPs) are small membrane vesicles that are shed from cells in response to activation and apoptosis. The number, cellular source, and composition of MPs are altered in various disease states including diabetes, metabolic syndrome, sepsis, and pre-eclampsia.^7,8,9,10 Recent data suggested that MPs might play a major role in interactions with circulating cells or the components of the vessel wall. MPs have been implicated in coagulation, inflammation, and vascular function.¹¹ With regard to OSA, Geiser et al¹² did not report an increase of platelet-derived MPs despite enhanced in vivo platelet activation. Recently, Ayers et al¹³ found that procoagulant, platelet-, and leukocyte-derived MPs were significantly increased in patients with OSA with marked nocturnal desaturations (>7.5 oxygen desaturations per hour).To our knowledge, the role of circulating MPs in the regulation of endothelial dysfunction in OSA is unknown. Thus, the aims of this study were to characterize circulating MPs from patients with OSA according to their cellular origins and determine in vitro effects of MPs from OSA patients on endothelial cells with respect to NO and superoxide anion (O₂⁻) productions and the expression of adhesion and proinflammatory molecules involved in inflammation. Finally, MPs were injected into mice intravenously to test their pathophysiological relevance.