Citations

Abstract Background: Objective methods to assess the adequacy of medication therapy for patients with advanced heart failure are lacking. Serial measurements of biomarkers might be beneficial. Therapy guided by N-terminal pro-B-type natriuretic peptide (NT-proBNP) might be helpful because NT-proBNP should be lowered by therapies that decrease endogenous BNP secretion. Methods: NT-proBNP and BNP were measured in a nonconsecutive patient cohort receiving clinically indicated intravenous nesiritide. Blood samples were drawn before, at 6 and 24 h during, and at 6 h after infusion. A reduction in NT-proBNP was defined as a decrease from baseline during infusion (“infusion responders”) of >3 SD of the variability of the assay measurement (∼20%). Patients with decreases >20% in both NT-pro BNP and BNP at 6 h post infusion were designated “biochemical responders”. Results: Forty patients [27 males; mean (SE) age, 68 (2) years; mean (SE) left ventricular ejection fraction, 25 (1.4)%] were studied. All patients improved clinically. Overall, the changes in NT-proBNP were a 18 (4.6)% [mean (SE)] and 19.8% (median) decrease from baseline at 24 h of infusion and a 22 (6.0)% and 17.8% decrease at 6 h post infusion (P <0.001 compared with baseline). In a large number of patients, decreases in NT-proBNP were, however, within the variability of the assay. Subgroup analysis showed that 22 of 40 patients were infusion responders with a >20% decrease from baseline in NT-proBNP during nesiritide infusion, whereas only 12 patients were biochemical responders with >20% decreases from baseline postinfusion for both NT-proBNP and BNP. Conclusions: In this study, many patients had decreased NT-proBNP and BNP values after therapy with nesiritide, but the majority of patients did not demonstrate biochemically significant decreases in analytes despite a clinical response. Until we know more about the responses of natriuretic peptides to therapies such as nesiritide, a strategy of monitoring NT-proBNP and BNP to guide therapy cannot be universally advocated.

Background— Sirolimus-eluting stents (SESs) reduce angiographic restenosis in patients with focal, native coronary artery stenoses. This study evaluated the usefulness of SESs in complex native-vessel lesions at high risk for restenosis. Methods and Results— Angiographic follow-up at 240 days was obtained in 701 patients with long (15- to 25-mm) lesions in small-diameter (2.5- to 3.5-mm) native vessels who were randomly assigned to treatment with SESs or bare-metal stents (BMSs) in the SIRIUS trial. Quantitative angiographic measurements of minimal lumen diameter and percent diameter stenosis were obtained within the treated segment, within the stent, and within its 5-mm proximal and distal edges. Patients treated with SESs had lower rates of binary (>50% diameter stenosis) angiographic restenosis within the segment (8.9% versus 36.3% with the BMS; P <0.001) and within the stent (3.2% versus 35.4% with the BMS; P <0.001). SESs were associated with significantly less late lumen loss within the treated segment, within the stent, and within its 5-mm proximal and distal edges (all P <0.001). The reduction of restenosis with the SES was consistent in patients at risk for restenosis, including those with small vessels, long lesions, and diabetes mellitus. The frequency of late aneurysms was similar in the 2 groups. Conclusions— Compared with BMSs, SESs reduced angiographic late lumen loss within the stent and its adjacent 5-mm margins in patients with complex native-vessel lesions.

Estrogens play a crucial role in the causation and development of sporadic human breast cancer (BC). Chromosomal instability (CIN) is a defining trait of early human ductal carcinoma in situ (DCIS) and is believed to precipitate breast oncogenesis. We reported earlier that 100% of female ACI (August/Copenhagen/Irish) rats treated with essentially physiological serum levels of 17β-estradiol lead to mammary gland tumors with histopathologic, cellular, molecular, and ploidy changes remarkably similar to those seen in human DCIS and invasive sporadic ductal BC. Aurora-A (Aur-A), a centrosome kinase, and centrosome amplification have been implicated in the origin of aneuploidy via CIN. After 4 mo of estradiol treatment, levels of Aur-A and centrosomal proteins, γ-tubulin and centrin, rose significantly in female ACI rat mammary glands and remained elevated in mammary tumors at 5–6 mo of estrogen treatment. Centrosome amplification was initially detected at 3 mo of treatment in focal dysplasias, before DCIS. At 5–6 mo, 90% of the mammary tumor centrosomes were amplified. Comparative genomic hybridization revealed nonrandom amplified chromosome regions in seven chromosomes with a frequency of 55–82% in 11 primary tumors each from individual rats. Thus, we report that estrogen is causally linked via estrogen receptor α to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells.

Abstract 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 multicenter studies.

Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94–10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.

▪ Abstract The assembly of the cystic fibrosis transmembrane regulator (CFTR) chloride channel is of interest from the broad perspective of understanding how ion channels and ABC transporters are formed as well as dealing with the mis-assembly of CFTR in cystic fibrosis. CFTR is functionally distinct from other ABC transporters because it permits bidirectional permeation of anions rather than vectorial transport of solutes. This adaptation of the ABC transporter structure can be rationalized by considering CFTR as a hydrolyzable-ligand-gated channel with cytoplasmic ATP as ligand. Channel gating is initiated by ligand binding when the protein is also phosphorylated by protein kinase A and made reversible by ligand hydrolysis. The two nucleotide-binding sites play different roles in channel activation. CFTR self-associates, possibly as a function of its activation, but most evidence, including the low-resolution three-dimensional structure, indicates that the channel is monomeric. Domain assembly and interaction within the monomer is critical in maturation, stability, and function of the protein. Disease-associated mutations, including the most common, ΔF508, interfere with domain folding and association, which occur both co- and post-translationally. Intermolecular interactions of mature CFTR have been detected primarily with the N- and C-terminal tails, and these interactions have some impact not only on channel function but also on localization and processing within the cell. The biosynthetic processing of the nascent polypeptide leading to channel assembly involves transient interactions with numerous chaperones and enzymes on both sides of the endoplasmic reticulum membrane.

AbstractThe etiology, prognosis, and optimal management of primary gastric carcinoids remain controversial. Records of 36 consecutive patients with gastric carcinoid (15 men) were reviewed retrospectively between 1975 and 1990. Follow‐up was complete in 97% of cases. Mean age at diagnosis was 58.4 years (range 24–82 years). The clinical presentations included anemia (72%), pain (69%), and carcinoid syndrome (11%). Associated autoimmune and endocrine abnormalities were common and included atrophic gastritis (67%), pernicious anemia (58%), hypothyroidism (39%), diabetes (19%), Addison's disease (6%), and hyperparathyroidism (6%). Lesions were nonantral in 78%, involving only the corpus in 42%, the fundus in 28%, and only the antrum in 8%; 42% were multiple. Urinary 5‐hydroxyindoleacetic acid (5‐HIAA) and serum gastrin levels were elevated in 17% and 50% of those tested, respectively. Histologic examination revealed that 28% of lesions were ≥2 cm, and 33% had liver metastases on presentation or developed them during follow‐up. Eight patients (22%) died of tumor with a median survival of 39 months. The presence of metastases, atypical histology, serosal involvement, and size > 2 cm were adverse prognostic factors. In patients without hypergastrinemia (n=6), 66% developed metastases, 60% had elevated 5‐HIAA, and 50% died of carcinoid tumor. In sharp contrast, those patients with hypergastrinemia and “typical” gastric carcinoids (n=15), metastases and death did not occur (p<0.003 and p < 0.005, respectively, compared with eugastrinemic patients). In the latter group (hypergastrinemia and typical histology), pernicious anemia was common (73%); solitary lesions and serosal penetration were seen comparatively less often (33% versus 100%, p<0.005 and 0% versus 33%, p<0.05, respectively); and no lesion measured > 2.0 cm compared to 66% in the group without elevated gastrin (p<0.002). No patient with hypergastrinaemia had elevated levels of 5‐HIAA. Overall survival at 5 and 10 years was 58% and 28%, respectively. Survival was 80% at 5 and 10 years in the hypergastrinemic group. Gastric carcinoid tumors that are histologically atypical, large (>2 cm), or present without elevated gastrin are potentially lethal and require aggressive therapy. In contrast, gastric carcinoids with typical histology and hypergastrinemia are rarely lethal, and conservative management with local excision and close observation is appropriate.

AbstractInsulinoma in patients with multiple endocrine neoplasia (MEN) is a rare condition that because of its usual multicentricity presents difficulties not encountered in sporadic patients. In contrast to gastrinoma, which is the most common pancreatic neoplasm associated with MEN I, malignancy and duodenal tumors are much less common for patients with insulinomas, and excellent palliative medication is not available. Accordingly, there is a much greater reliance on surgical therapy for this group of patients. Between 1970 and 1991 a total of 19 patients had surgical treatment of MEN I‐related insulinoma. Each patient had hyperinsulinemic hypoglycemia. One patient, with extensive metastases, had unresectable disease. Of the remaining 18, there were 16 (89%) multiple pancreatic tumors. Tumors were located in the neck, body, or tail in 17 cases, 10 of whom also had tumors in the head. Pancreatic resections performed were 1 total, 12 subtotal (7 also had enucleation of tumors from the pancreatic head), and 5 limited distal resections and/or enucleation (conservative resection). There was no operative mortality. One patient developed pancreatitis, fistula, and diabetes following subtotal resection and enucleation. Postoperative cure was achieved in 17 of 18 cases. Recurrent disease occurred in 2 of 5 conservative resections compared to 0 of 12 subtotal resections, with median follow‐up times of 10.4 and 10.3 years, respectively. During the follow‐up period, four patients died, possibly all due to MEN I‐related conditions. Hyperinsulinism in MEN I is associated with the occurrence of multiple, usually benign, pancreatic islet cell tumors, and surgery is an effective treatment modality. Surgical management should be guided by two principles: total removal of gross disease and safe prophylactic pancreatic resection. Acceptable morbidity, low recurrence rates, and a low risk of inducing diabetes lead us to recommend routine subtotal distal pancreatectomy. Meticulous evaluation of the pancreatic head using intraoperative ultrasonography to locate tumors and to locate the pancreatic duct, followed by precise enucleation of residual tumors, is essential to ensure cure.