Malignant pheochromocytoma: current status and initiatives for future progress

Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors that are usually benign, but which may also present as or develop into a malignancy. Predicting such behavior is notoriously difficult and there are currently no curative treatments for malignant tumors. This report follows from a workshop at the Banbury Conference Center, Cold Spring Harbor, New York, on the 16th-18th November 2003, held to review the state of science and to facilitate future progress in the diagnosis and treatment of malignant pheochromocytoma. The rarity of the tumor and the resulting fragmented nature of studies, typically involving small numbers of patients, represent limiting factors to the development of effective treatments and diagnostic or prognostic markers for malignant disease. Such development is being facilitated by the availability of new genomics-based tools, but for such approaches to succeed ultimately requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data and tumor samples, and interdisciplinary collaborations among multiple specialist centers. Nevertheless, the well-characterized hereditary basis and the unique functional nature of these neuroendocrine tumors provide a useful framework that offers advantages for establishing the pathways of tumorigenesis and malignancy. Such findings may have relevance for understanding the basis of other more common malignancies where similar frameworks are not available. As the relevant pathways leading to pheochromocytoma are established it should be possible to take advantage of the new generation of drugs being developed to target specific pathways in other malignancies. Again the success of this will require well-designed and coordinated multi-center studies.     

Release of cardiac troponin I after temporally graded acute coronary ischaemia with electrocardiographic ST depression

BACKGROUND: Elevation of cardiac biochemical markers and ST segment depression in the electrocardiogram have important roles in the risk stratification of unstable coronary syndromes. We assessed graded duration of acute coronary ischaemia with ST depression versus release of cardiac troponin I (cTnI) and conventional cardiac markers in 15 ischaemic pigs and 11 controls. METHODS: Coronary ischaemia was induced via percutaneous technique by semiinflating an angioplasty balloon in the left circumflex artery. Blood velocity monitored by Doppler was reduced until ST depression > or =0.1 mV was obtained. Among 26 pigs, six controls had jugular vein sheath introduced only, five controls jugular vein and bilateral femoral sheaths, and 15 pigs were divided into three equal groups (n=5) in which ischaemia was maintained for 10, 20 and 30 min, respectively. RESULTS: Mean blood flow velocity (cm/s) at baseline was 16.3+/-6.5 and was reduced to 4.1+/-3.2 (25% of normal, range 20-29%) during ischaemia. cTnI (microg/l) did not increase in controls but increased from 0.05 to 0.52 (P<0.05) and 0.76 (P<0.05) with 10 and 20 min of ischaemia, and to 30.77 (P<0.05) with 30 min of ischaemia. A rise of myoglobin and conventional cardiac enzymes did not distinguish controls with arterial cut-down from the ischaemia groups. CONCLUSION: Release of cTnI depends on the duration of ST depression ischaemia. The critical time for a major release seems to be between 20 and 30 min. Thus, very early intervention in patients with prolonged ST depression ischemia should be focused on in future clinical trials.     

Investigation of the Mechanical Properties of Mn-Alloyed Tin-Silver-Copper Solder Solidified with Different Cooling Rates

Manganese can be an optimal alloying addition in lead-free SAC (SnAgCu) solder alloys because of its low price and harmless nature. In this research, the mechanical properties of the novel SAC0307 (Sn/Ag0.3/Cu0.7) alloyed with 0.7 wt.% Mn (designated as SAC0307-Mn07) and those of the traditionally used SAC305 (Sn96.5/Ag3/Cu0.5) solder alloys were investigated by analyzing the shear force and Vickers hardness of reflowed solder balls. During the preparation of the reflowed solder balls, different cooling rates were used in the range from 2.7 K/s to 14.7 K/s. After measuring the shear force and the Vickers hardness, the structures of the fracture surfaces and the intermetallic layer were investigated by SEM (Scanning Electron Microscopy). The mechanical property measurements showed lower shear force for the SAC0307-Mn07 alloy (20–25 N) compared with the SAC305 alloy (27–35 N), independent of the cooling rate. However, the SAC0307-Mn07 alloy was softer; its Vickers hardness was between 12 and 13 HV, whereas the Vickers hardness of the SAC305 alloy was between 19 and 20 HV. In addition, structural analyses revealed rougher intermetallic compound layers in the case of the SAC0307-Mn07 alloy, which can inhibit the propagation of cracks at the solder–substrate interface. These two properties of SAC0307-Mn07 alloy, the softer nature and the rougher intermetallic layer, might result in better thermomechanical behavior of the solder joints during the lifetime of electronic devices.     

Iron status in patients with pyruvate kinase deficiency: neonatal hyperferritinaemia associated with a novel frameshift deletion in the PKLR gene (p.Arg518fs), and low hepcidin to ferritin ratios

Pyruvate kinase (PK) deficiency is an iron‐loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease‐causing PKLR mutations. Two of these mutations ‐ the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) ‐ have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease‐causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK‐deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor‐15, were increased in PK‐deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as‐yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency.     

Tissue- and cell-specific functions of the androgen receptor revealed through conditional knockout models in mice

This review aims to evaluate the contribution of individual cell-selective knockout models to our current understanding of androgen action. Cre/loxP technology has allowed the generation of cell-selective knockout models targeting the androgen receptor (AR) in distinct putative target cells in a wide variety of organs and tissues including: testis, ovary, accessory sex tissues, muscle, bone, fat, liver, skin and myeloid tissue. In some androgen-regulated processes such as spermatogenesis and folliculogenesis this approach has lead to the identification of a key cellular mediator of androgen action (Sertoli and granulosa cells, respectively). In many target tissues, however, the final response to androgens appears to be more complex. Here, cell-selective knockout technology offers a platform upon which we can begin to unravel the more complex interplay and signaling pathways of androgens. A prototypic example is the analysis of mesenchymal-epithelial interactions in many accessory sex glands. Furthermore, for some actions of testosterone, in which part of the effect is mediated by the active metabolite 17β-estradiol, conditional knockout technology offers a novel strategy to study the relative contribution of AR and estrogen receptor-mediated signaling. The latter approach has already resulted in a better understanding of androgen action in brain and bone. Finally, cell-selective knockout technology has generated valuable models to search for AR-controlled molecular mediators of androgen action, a strategy that has successfully been applied to the study of androgen action in the testis and in the epididymis. Although some conditional knockout models have provided clear answers to physiologic questions, it should be noted that others have pointed to unexpected complexities or technical limitations confounding interpretation of the results.     

Acute Effects of Glucocorticoids on Serum Markers of Osteoclasts, Osteoblasts, and Osteocytes

The aim of this study was to investigate the acute effects of oral glucocorticoids in doses used in clinical practice on biochemical indices of the function of osteoclasts, osteoblasts, and osteocytes. In 17 adult patients suffering from various medical pathologies requiring systemic steroid therapy that were never before treated with glucocorticoids, glucocorticoid treatment was initiated (mean prednisolone equivalent dose of 23.1 ± 12.7 mg/day, range 10–50). Fasting morning serum concentrations of osteocalcin (OC), amino-terminal propeptide of type I procollagen (PINP), type 1 collagen cross-linked C-telopeptide (βCTX), soluble receptor activator of nuclear factor kappaB ligand (sRANKL), osteoprotegerin (OPG), sclerostin, Dickkopf-1 (Dkk-1), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline and on three consecutive days. Significant reductions in serum OC, PINP, OPG, sclerostin, and hsCRP were observed during 96 h of glucocorticoid administration, while serum βCTX showed a significant percentual increase. A significant positive correlation was found between serum concentrations of Dkk-1 and βCTX after 96 h of treatment with glucocorticoids. A significant drop in serum sclerostin, OPG, and OC observed in this study may reflect the rapid glucocorticoid-induced apoptosis of osteocytes.     

Metastases of esophageal carcinoma to skeletal muscle: Single center experience

Metastases of esophageal carcinoma to the skeletal muscle are rare, but the incidence may be increasing because of better diagnosis resulting from widespread use of positron emission tomography/computed tomography (PET/CT). A cohort of 205 patients with esophageal carcinoma treated at our center who had PET/CT between 2006 and 2010 was retrospectively evaluated for the presence of skeletal muscle metastases. Four patients had skeletal muscle metastases of esophageal carcinoma, including two patients with squamous cell carcinoma. In another patient with squamous cell carcinoma of the esophagus and synchronous skeletal muscle metastases, muscle metastases were subsequently shown to be related to second primary pancreatic adenocarcinoma. In all cases, skeletal muscle metastases were the first manifestation of systemic disease. In three patients palliation was obtained with the combination of external beam radiation therapy, systemic chemotherapy or surgical resection. Skeletal muscle metastases are a rare complication of esophageal carcinoma.