The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology.

The environment in which the field of cardiology finds itself has been rapidly changing. This supplement, an expansion of a report created for the Board of Trustees, is intended to provide a timely snapshot of the socio-economic, political, and scientific aspects of this environment as it applies to practice both in the United States and internationally. This publication should assist healthcare professionals looking for the most recent statistics on cardiovascular disease and the risk factors that contribute to it, drug and device trends affecting the industry, and how the practice of cardiology is changing in the United States.

Cardiovascular toxicity associated with small molecule tyrosine kinase inhibitors currently in clinical use.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have changed the concepts of systemic therapy for a variety of advanced solid and hematologic malignancies. However, their toxicity can be significant, and includes both cardiac and non-cardiac effects. AREAS COVERED: The authors evaluate comprehensively the adverse cardiovascular portfolio of small molecule TKIs, postulate their underlying mechanisms and offer recommendations regarding prevention and therapy of these toxicities. EXPERT OPINION: For most pan-selective TKIs, there might not be a clear-cut relationship between specific patterns of TK inhibition and cardiovascular toxicity. Cardiovascular side effects are likely due to dysregulation of multiple kinase regulated pathways. The cardiovascular effects of small molecule TKIs include peripheral edema and congestive heart failure, systemic and pulmonary hypertension, acute coronary syndromes and cardiac arrest due to QTc prolongation. Caution should be sought in patients with pre-existing cardiac dysfunction before initiating any of these agents. It is hoped that newer TKI generations will display minimal if any cardiovascular toxicity, while maintaining their anticancer efficacy. As of today, the high likelihood of morbidity without treatment mandates that cardiovascular toxicity of TKIs be carefully assessed and balanced with the known benefits of administering these agents.

Polycystic ovary syndrome: focus on platelets and prothrombotic risk.

OBJECTIVES: Subjects with polycystic ovary syndrome (PCOS) were shown to carry an increased long-term cardiovascular risk. Systemic inflammation and reactive leukocytosis have also been described in PCOS. Recent research suggests the presence of an increased thrombotic risk in these patients. METHODS: We describe a cohort of PCOS patients presenting with persistent thrombocytosis. Our cohort included women aged 20-37 who also had moderate leukocytosis and neutrophilia. They showed normal mean platelet volume and platelet aggregation. We excluded any myeloproliferative conditions in all patients. RESULTS: The mean platelet count and standard deviation (SD) at presentation were 587 ± 61 × 10/L (normal 140-440 × 10/L). Median C-reactive protein (CRP) was 1.66 (range 1.2-2.2, normal <1 mg/dL). The platelet counts did not correlate with the CRP levels in our patients (Pearson correlation coefficient 0.171 and 0.170, respectively, P = 0.08). CONCLUSION: While the inflammatory state of PCOS could play a role in triggering an increased platelet count, the persistent thrombocytosis in our patients did not correlate with the CRP levels. Therefore, from an etiological perspective, thrombocytosis appears to be at least partially independent from the classical pathways of systemic inflammation. The preexisting procoagulant state in PCOS due to coagulation cascade stimulation, platelet activation, and endothelial dysfunction may be further fueled by the presence of persistent thrombocytosis. We propose a unique model for cardiovascular risk assessment in women with PCOS to include not only the classic cardiovascular risk factors, but also the parameters related to the proinflammatory and procoagulant tendencies manifested in PCOS.

Tumor fever, paraneoplastic leukocytosis and necrotic liver metastases: a triad worth remembering.

Arriving at the diagnosis of tumor fever may prove difficult for the clinician and should always be based upon investigations that exclude other potential causes of fever. Timely recognition of this entity is essential for the effective delivery of care to cancer patients. In solid malignancies, tumor fever is commonly associated with rapidly progressive metastatic disease and a limited survival. Liver metastases are present in many of these patients and some of them may display significant systemic inflammation. We report two unique patients with adenocarcinoma of the lung associated with tumor fever, necrotic liver metastases and granulocyte-colony stimulating factor (G-CSF) driven leukocytosis.

Small cell lung cancer with paraneoplastic lipase production.

Kulchitsky cells represent the cells of origin of small cell lung cancer (SCLC). They display an antigenic makeup characteristic of both the neural crest and epithelium and have been shown to secrete both polypeptide hormones and enzymes. The coexistence of two or more (concomitant or sequential) paraneoplastic endocrine syndromes is possible with SCLC, and paraneoplastic amylase production has also been described with this malignancy. We present here the first patient with an extensive stage SCLC, exhibiting a marked paraneoplastic lipase production and a syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In our patient, the paraneoplastic hyperlipasemia paralleled both the initial SCLC response to chemotherapy and its subsequent clinicoradiological relapse.

Reactions of 2-(pyrrol-1-yl)benzyl radicals and related species under flash vacuum pyrolysis conditions.

2-(Pyrrol-1-yl)phenoxyl, aminyl, thiophenoxyl and benzyl radicals 2a-2d, respectively, were generated in the gas-phase under flash vacuum pyrolysis conditions. In all cases except the phenoxyl, cyclisation took place providing acceptable synthetic routes to the fused heterocycles 11, 14 and 15, respectively. Only sigmatropic rearrangement products were isolated, in low yields, from the phenoxyl 2a. The pyrrolo[1,2-a]benzimidazole 11 adopts the 1H-tautomer exclusively in chloroform solution. Electrophilic substitution reactions of pyrrolo[2,1-b]benzothiophene 14 were studied, including protonation, deuterium exchange, Vilsmeier formylation and reaction with dimethyl acetylenedicarboxylate. 2-(2,5-Diarylpyrrol-1-yl)thiophenoxyl, phenoxyl and aminyl radicals 23a-f, were also generated in the gas-phase under similar conditions. The thiophenoxyls 23a/b gave extremely complex pyrolysate mixtures in which primary cyclisation products were formed by attack of the radical at the pyrrrole ring and attack at the ipso-, ortho- and meta- positions of the aryl ring. Secondary pyrolysis products were obtained by specific sigmatropic shifts of the N-aryl group. The 2,5-di(thien-2-yl)thiophenoxyl radical 23c gave the pyrrolobenzothiazole 31c as the only cyclisation product in low yield. FVP of the phenoxyl and aminyl radical generators 26d and 26f, respectively, gave 3-arylpyrrolo[1,2-f]phenanthridines 46d and 46f, respectively, by a hydrogen transfer-cyclisation mechanism.

mTOR-blocking agents in advanced renal cancer: an emerging therapeutic option.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-alpha. OBJECTIVE: The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development. METHODS: The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs. RESULTS/CONCLUSIONS: Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.