Cardiac Tumors: Clinical Presentation, Diagnosis, and Management.

OPINION STATEMENT: Cardiac masses and tumors are a heterogenous group of disorders and include primary tumors (both benign and malignant), metastatic disease, and numerous masquerades such as thrombus. Clinical presentation ranges from incidental discovery on imaging tests ordered for other reasons to life-threatening presentations such as cardiac tamponade, arrhythmia, obstruction, and systemic embolization. Of the available imaging modalities, cardiac MRI is generally the most useful for assessment and helps to delineate the relevant anatomy. Due to the technical difficulties and risk of biopsy of cardiac masses, a presumptive diagnosis is typically made using imaging techniques with surgery serving both a diagnostic and curative role. Because these conditions can vary widely in their management, we recommend early involvement of a multidisciplinary group which should include a cardiologist, cardiac surgeon, and oncologist.

Usefulness of magnetic resonance imaging to guide referral for pulmonary valve replacement in repaired tetralogy of Fallot.

The aim of this study was to determine if adult patients with repaired tetralogy of Fallot are being referred for pulmonary valve replacement (PVR) earlier on the basis of cardiac magnetic resonance imaging (CMR) parameters despite the absence of CMR-based recommendations in the American College of Cardiology and American Heart Association joint guidelines. Variables defined by the guidelines were analyzed in conjunction with CMR-based parameters across 3 groups defined by the release of the guidelines: (1) patients referred before the guidelines, (2) patients referred 0 to 3 years after the guidelines, and (3) patients referred ≥3 years after the guidelines. Seventy-nine patients were identified. No significant trend was observed in guideline-defined variables. Significant trends in indexed right ventricular end-diastolic volume (p = 0.034), indexed right ventricular end-systolic volume (p = 0.001), and the right ventricular ejection fraction (p = 0.005) were observed across groups. By multivariate regression, patients who underwent PVR ≥3 years after the release of the guidelines had a 29 ml/m(2) smaller indexed right ventricular end-diastolic volume (p = 0.01) and a 33 ml/m(2) smaller indexed right ventricular end-systolic volume (p <0.001) compared with patients who underwent PVR before the release of the guidelines. PVR 0 to 3 years after the guidelines was not a significant predictor of either indexed right ventricular end-diastolic volume (p = 0.93) or indexed right ventricular end-systolic volume (p = 0.18). Patients referred for PVR ≥3 years after the guidelines had significantly smaller CMR-based right ventricular volumes without significant trends in guideline-defined variables. Given the increased use of CMR to guide PVR referral, revisiting the guidelines to address appropriate use of CMR derived thresholds is indicated.

Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis.

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4-5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr(34) by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr(34)-->Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr(34) enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr(34) phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34(cdc2) kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells.

A p34(cdc2) survival checkpoint in cancer.

A checkpoint surveying the entry into mitosis responds to defects in spindle microtubule assembly/stability. This has been used to trigger apoptosis in cancer cells, but how the spindle checkpoint couples to the cell survival machinery has remained elusive. Here, we report that microtubule stabilization engenders a survival pathway that depends on elevated activity of p34(cdc2) kinase and increased expression of the apoptosis inhibitor and mitotic regulator, survivin. Pharmacologic, genetic, or molecular ablation of p34(cdc2) kinase after microtubule stabilization resulted in massive apoptosis independent of p53, suppression of tumor growth, and indefinite survival without toxicity in mice. By ablating this survival checkpoint, inhibitors of p34(cdc2) kinase could safely improve the efficacy of microtubule-stabilizing agents used to treat common cancers.

Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function.

Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosis. However, the subcellular distribution of survivin has been controversial and variously described as a microtubule-associated protein or chromosomal passenger protein. Here, we show that antibodies directed to the survivin sequence Ala(3)-Ile(19) exclusively recognized a nuclear pool of survivin that segregated with nucleoplasmic proteins, but not with outer nuclear matrix or nuclear matrix proteins. By immunofluorescence, nuclear survivin localized to kinetochores of metaphase chromosomes, and to the central spindle midzone at anaphase. However, antibodies to Cys(57)-Trp(67) identified a cytosolic pool of survivin, which associated with interphase microtubules, centrosomes, spindle poles and mitotic spindle microtubules at metaphase and anaphase. Polyclonal antibodies recognizing survivin epitopes Ala(3)-Ile(19), Met(38)-Thr(48), Pro(47)-Phe(58) and Cys(57)-Trp(67) identified both survivin pools within the same mitotic cell. A ratio of approximately 1:6 for nuclear versus cytosolic survivin was obtained by quantitative subcellular fractionation. In synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on Thr(34), in vivo. By contrast, nuclear survivin began to accumulate in S phase, was not complexed with p34(cdc2) and was not phosphorylated on Thr(34). Intracellular loading of a polyclonal antibody to survivin caused microtubule defects and resulted in formation of multipolar mitotic spindles, but did not interfere with cytokinesis. These data demonstrate that although both reported localizations of survivin exist in mitotic cells, the preponderant survivin pool is associated with microtubules and participates in the assembly of a bipolar mitotic spindle.