A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors.

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).

Unnoticed swallowing of a unilateral removable partial denture.

OBJECTIVE: This paper presents a case report about an unnoticed swallowing of a partial denture impacted in the esophagus in a 74-year old man without serious complications. BACKGROUND DATA: Dental prostheses (removable/fixed dental prostheses or fragments of dentures) appear to constitute a significant proportion of swallowed of impacted foreign bodies in the orolaryngopharynx. CONCLUSION: This case emphazises that is advisable to contraindicate this type of unilateral removable partial denture to replace teeth as temporary or definitive dental prosthesis.

Distribution of breath sound images in patients with pneumothoraces compared to healthy subjects. Diagnostic yield of vibration response imaging technology.

BACKGROUND: Vibration response imaging (VRI) is a new technology that provides a radiation-free dynamic lung image from the vibrations produced by airflow. The vibration energy from the respiratory cycle can be quantified for any lung region. This is obtained by integrating the energy profiles from 42 acoustic sensors placed on the patient's back. OBJECTIVE: The aim of this study was to evaluate whether a physician trained in interpreting acoustic images can accurately distinguish between normal and abnormal breath sound distribution in patients with pneumothoraces compared to healthy controls. METHODS: In total, 14 patients with spontaneous or iatrogenic pneumothoraces and 15 healthy volunteers were enrolled in the study. VRI recordings and physical examination were obtained in all cases. Chest radiographs (CXRs) were reviewed in patients with pneumothoraces. Dynamic images recorded during one complete respiratory cycle were analyzed for each subject. RESULTS: The VRI images of patients with pneumothoraces demonstrated a reduction in the vibration response on the affected side which correlated with the CXR. Sensitivity was 100%, specificity was 87% and positive predictive value and negative predictive value were 86 and 100%, respectively. CONCLUSIONS: This study demonstrates that VRI can be safely used to assess patients with pneumothoraces. Moreover, the analysis of breath sound distribution images obtained noninvasively can distinguish between patients with a normal chest examination from those with pneumothoraces.

Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes.

OBJECTIVE: Ghrelin, the endogenous ligand of growth hormone secretagogue receptor (GHS-R), acts on the pituitary and the hypothalamus to stimulate the release of growth hormone (GH) and promotes appetite and adiposity. It has also been reported to increase myocardial contractility, induce vasodilation, and protect against myocardial-infarction-induced heart failure. Though principally gastric in origin, it is also produced by other tissues. This work investigated whether cardiomyocytes synthesize and secrete ghrelin, and how its production in these cells responds to stress and exogenous apoptotic agents. METHODS: Ghrelin and its receptor expression was studied by RT-PCR, immunohistochemistry, and competitive binding studies in mouse adult cardiomyocyte cell line HL-1, and primary cultured human cardiomyocytes. Ghrelin accumulation in cardiomyocyte culture medium was measured by radioimmunoassay. Viability and apoptosis assays were carried on by MTT and Hoechst dye vital staining, respectively. RESULTS: RT-PCR showed that HL-1 cells produce mRNAs for both ghrelin and GHS-R, and that GHS-R1a is expressed in human cardiomyocytes; and competitive binding studies using (125)I-labelled ghrelin showed efficient constitutive expression of GHS-R at the surface of HL-1 cells. Immunohistochemistry confirmed the presence of ghrelin in the cytoplasm of HL-1 cells and of isolated human cardiomyocytes in primary culture. Radioimmunoassay showed that ghrelin was secreted by HL-1 cells and human cardiomyocytes into the culture medium. Ghrelin did not modify the viability of HL-1 cells subjected to 12-h starvation, but did protect against the apoptosis inducer cytosine arabinoside (AraC). Finally, production of ghrelin mRNA in HL-1 cardiomyocytes was reduced by AraC but increased if exposure to AraC was preceded by GH treatment. CONCLUSIONS: Ghrelin is synthesized and secreted by isolated murine and human cardiomyocytes, probably with paracrine/autocrine effects, and may be involved in protecting these cells from apoptosis.

Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas.

Orexin-A and -B are hypothalamic peptides derived from a precursor called prepro-orexin and related with the regulation of the energy balance and arousal. They act on G protein receptors named orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). In the present study, we used immunohistochemical techniques to detect the distribution of OXR in normal human adrenal gland and adrenal tumours (adrenocortical adenomas and pheochromocytomas). OX1R was expressed in the cortex of the normal human adrenal gland (glomerulosa, fasciculata and reticular zones) and OX2R was located in the medulla (epinephrine and norepinephrine cells). By the double immunofluorescence techniques, we demonstrated that virtually all medullar cells (epinephrine and norepinephrine cells) expressed OX2R. As was expected, according to the results obtained in normal tissues, cortical tumours (adrenocortical adenomas) were positive for OX1R but not for OX2R and conversely, medullar tumours (pheochromocytomas) expressed only OX2R.

Bronchovascular reconstruction with a bovine pericardial conduit and surgical reintervention due to thrombosis with revascularisation.

We present the case of a 57-year-old male with left hilar squamous cell carcinoma infiltrating the pulmonary artery and in whom a sleeve bronchoplasty and angioplasty were performed using a bovine pericardial conduit. Three days post-operatively, graft thrombosis was detected; thrombectomy and graft reconstruction were performed with revascularisation of the graft.

Two-incision approach for video-assisted thoracoscopic sleeve lobectomy.

The video-assisted thoracoscopic approach for bronchoplasty procedures is not standardized. Although 3 to 4 incisions are usually made, with adequate surgical technique, the operation can be successfully carried out using only 2 incisions. We describe the technique of video-assisted thoracoscopic surgery for a right upper lobe sleeve lobectomy for a carcinoid tumor in the right upper bronchus, using only 2 ports.

A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer.

PURPOSE: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies. EXPERIMENTAL DESIGN: We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2-3-4 vs. 0-1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome. RESULTS: In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2-15.75, P = 0.02), in which it remained the only statistically significant prognostic factor. CONCLUSIONS: A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies.

Cellular localization of orexins in human anterior pituitary.

Orexins A and B are hypothalamic peptides derived from a precursor called prepro-orexin and are associated with the stimulation of food intake and arousal. There is evidence that orexins act on some pituitary functions. Since no studies have been done concerning the presence of orexins in human pituitary, it is unclear whether the local effect of these peptides is due to orexins synthesized in the pituitary or to circulating-derived orexins. To define a possible paracrine regulatory role of orexins on pituitary cell function, we have sought to characterize the expression of orexins in the human adenohypophysis as well as to identify the cell types that express these proteins. In the present study, we used immunohistochemistry and double labeling to detect the presence of orexin A and orexin B in human pituitary. Orexin A was localized in 33% of pituitary cells. With double immunofluorescence techniques we demonstrated that orexin A is present in PRL (82 +/- 5.3%), TSH (18 +/- 2.3%), GH (10 +/- 2.3%), FSH (8 +/- 2.6%), and LH (7 +/- 3.2%) cells, but not in corticotroph cells. Orexin B was found in virtually all corticotrophs cells of the anterior pituitary. These results demonstrate that lactotroph cells are the main source of orexin A and corticotroph cells of orexin B. In summary the present findings provide the first evidence that orexins A and B are expressed in specific human pituitary cell types. Our data provide the cellular basis for a paracrine role of orexins in human pituitary cell function and further our understanding regarding the mechanisms by which orexins influence neuroendocrine function.

Merkel cells, a new localization of prepro-orexin and orexin receptors.

Orexins (OXA and OXB) are peptides derived from a common precursor called prepro-orexin. They act through G-protein receptors named orexin 1 receptor (OX(1)R) and orexin 2 receptor (OX(2)R). Orexins were first demonstrated in neurons of the lateral hypothalamus and found to be related to the control of food intake. However, it has been shown that they are widely distributed in both the nervous system and peripheral tissues, including endocrine organs such as the pituitary and adrenal glands. Merkel cells are neuroendocrine cells situated in the epidermis, tactile hairs and oral mucosa, and act as mechanoreceptors. Up to the present, various neuropeptides have been detected in these cells. The aim of the present study was to detect the presence of prepro-orexin and orexin receptors (OX(1)R and OX(2)R) in porcine Merkel cells using immunohistochemistry. Prepro-orexin was expressed in the cytoplasm of Merkel cells in the skin of the pig snout. Immunoreactivity for prepro-orexin was more intense in the mature side of the cell, where the dense-cored granules are accumulated. Epidermal nerve terminals associated with Merkel cells and dermal nerve fibres showed no immunostaining. Both orexin receptors (OX(1)R and OX(2)R) were also demonstrated in the cytoplasm of Merkel cells of pig snout skin. The finding of orexins and their receptors in Merkel cells suggests that they have an autocrine function. Further studies are needed to ascertain the significance of this function.

Ontogenesis of the vitamin D receptor in rat heart.

1,25-Dihydroxyvitamin D(3) through its receptor (vitamin D receptor; VDR) has important physiological effects such as calcium transport and cell growth and differentiation. Although the VDR is present in a variety of cell lines as well as in numerous tissues, including rat and human heart, no data are available about the presence of VDR in heart at different steps of rat life. In this study we evaluated the VDR expression using RT-PCR and immunohistochemical techniques in fetal (17, 18 and 20 gestational days), neonatal (4 and 8 days) and adult rat heart. Immunohistochemical techniques showed the VDR protein localisation in the nuclei of cardiac muscle fibres. Also, we demonstrated that VDR mRNA expression is changing over these different periods of development, showing significant differences in 20 days versus 18 days of fetal age. These changes in VDR expression may be related to other parameters associated with the development of the cardiac muscle and/or intracellular cardiac cell calcium homeostasis.