Melanoma Cell Death Mechanisms.

Over recent years, several new molecular and immunogenic therapeutic approaches to melanoma treatment have been approved and implemented in clinical practice. Mechanisms of resistance to these new therapies have become a major problem. Mutation-specific pharmacotherapy can result in simultaneous emergence of resistant clones at many separate body sites despite an initially positive therapeutic response. Additionally, treatments aimed at inducing apoptosis are subject to resistance due to escape through other known mechanisms of regulated cell death (RCD). In this review, we discuss the complexity in pharmacological manipulation of melanoma with c-Kit, BRAF, MEK, and/or mTOR mutant cell lines. This study also addresses melanoma evasion of cell death through modalities of RCD such as apoptosis, autophagy, and necroptosis. This study also examines new combination therapies which have been approved to target both cell cycle dysregulation and cell death pathways. Lastly, we recognize the importance of immunomodulation though manipulation of the body's natural killing mechanisms with CTLA4, PD1, and CSF1 inhibition. As we begin to recognize tumor cell activation of alternate pathways, evasion of programmed cell death, and manipulation of the tumor microenvironment, it is increasingly important to grasp the complexity of personalized therapy in melanoma treatment.

Computed tomographic analysis of the esophagus, left atrium, and pulmonary veins: implications for catheter ablation of atrial fibrillation.

PURPOSE: The aim of this study was to investigate the anatomic relationship around the left atrium (LA) and to provide clinical information to help avoid the risk of an atrio-esophageal fistula during atrial fibrillation (AF) ablation. METHODS: The multidetector spiral computed tomography images of 77 male patients (mean age, 54 ± 9 years) with drug-refractory AF and 37 male control subjects (mean age, 50 ± 11 years) were analyzed. We measured the following variables: (1) distance between the ostia of the pulmonary veins (PVs) and the ipsilateral esophageal border, (2) presence of a pericardial fat pad around each PV, and (3) contact width/length and presence of a fat pad between the LA and the esophagus. RESULTS: The distance between the esophagus and the ostia of right superior PV, right inferior PV (RIPV), left superior PV, and left inferior PV (LIPV) was 27.2 ± 9.4 mm, 22.9 ± 10.3 mm, 2.7 ± 9.4 mm, and 7.1 ± 8.8 mm, respectively. A fat pad between the esophagus and the superior PV was present in more than 90% of the subjects in both groups. However, the fat pad around inferior PV was present less frequently in the patients than in the control group (p = 0.011, RIPV; p < 0.001, LIPV). The average length of the LA-esophagus contact in the patients and the control group subjects was 26.2 ± 10.4 and 18.5 ± 5.1 mm, respectively (p < 0.001). CONCLUSION: Caution should be exercised when ablating the LIPV because the esophagus is located in close proximity to the left-sided PV and most of the inferior PVs in patients with AF are not covered with fat pads.

Helical heart on ECG gated 99mTc-tetrofosmin SPECT: counterclockwise rotation of lesion axis on wall thickening polar map as compared with that on perfusion polar map in patients with coronary artery disease.

OBJECTIVE: The location of a myocardial lesion on a wall thickening polar map often does not coincide with the location of the lesion on a perfusion polar map, especially when the myocardial lesion is located at the mid cardiac region. The purpose of this study was to determine the frequency and extent of discrepancy in the location of the lesion between perfusion and wall thickening polar maps on gated single photon emission computed tomography (SPECT) using lesion axis angle (LAA). METHODS: One hundred and forty-seven consecutive patients (male : female = 80 : 67, age range: 41-96 years) who underwent myocardial gated (99m)Tc-tetrofosmin SPECT on the suspicion of myocardial ischemia or infarct between September 2003 and September 2008 and showed both reduced myocardial perfusion and wall thickening on gated SPECT at mid cardiac region were reviewed. LAA, which is the angle between the lesion axis on perfusion and wall thickening polar maps, was measured for the patients who showed a discrepancy in lesion axis between the two polar maps. LAA was said to have a positive value when the lesion axis of the wall thickening polar map showed a counterclockwise angular rotation as compared with that of a perfusion polar map. The patients with LAA of less than 10 degrees were considered as having no lesion axis discrepancy between perfusion and wall thickening polar maps. LAA was correlated with left ventricular ejection fraction (LVEF) on gated SPECT using Pearson's correlation. Furthermore, two groups, one with LAA of >or=10 degrees and the other with LAA less than 10 degrees were correlated with dichotomous groups with >or=50% and less than 50% LVEF, using the chi(2) test. Then, 35 patients with acute coronary syndrome (ACS group) were analyzed separately for correlation between LAA and LVEF. RESULTS: The mean +/- SD of LAA was 44.31+/-30.77 degrees (range: 0-145 degrees ). LAA was 0-10 degrees in 25 patients, 11-30 degrees in 24 patients, 31-60 degrees in 58 patients, 61-90 degrees in 30 patients, and >90 degrees in 10 patients. In addition, the lesion axis of the wall thickening polar map as compared with that of the perfusion polar map was rotated in the counterclockwise direction in 122 patients and not rotated in 25 patients. LVEF on gated SPECT showed positive correlation with LAA (P = 0.000147). In addition, there was statistically significant correlation (P = 0.001) when the two groups with LAA of >or=10 degrees and less than 10 degrees , respectively, were correlated with the groups of >or=50% and less than 50% LVEF. For the ACS group, the mean +/- SD of LAA was 45.88+/-30.30 degrees (range: 0-135 degrees ) and LVEF showed positive correlation with LAA (P = 0.0001). There was no significant statistical difference concerning LAA and LVEF between ACS group and non-ACS group (P = 0.725 and P = 0.473, respectively). CONCLUSION: In most of our patients with coronary artery disease, the lesion axis of reduced wall thickening was rotated in the counterclockwise direction as compared with that of reduced perfusion on SPECT polar maps, especially when the myocardial lesion was at mid cardiac region. The LAA decreased as the LVEF decreased. This might be related to spatiotemporal distortion of myocardial contraction mentioned in the helical heart concept.

18F-fluorodeoxyglucose positron emission tomography in patients with recurrent ovarian cancer: in comparison with vascularity, Ki-67, p53, and histologic grade.

The aim of this study was to assess the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG PET) positivity of tumor recurrence and vascularity, Ki-67, p53, and histologic grade in patients with ovarian cancer. Nineteen patients with recurrent ovarian cancer underwent FDG PET before second-look surgery. Archival paraffin-embedded tissue materials were used to assess histologic grade including architectural pattern, mitotic activity, and nuclear pleomorphism; intratumor microvessel density (MVD); Ki-67; and p53. Univariate analysis was used to evaluate the correlation between FDG PET positivity and each biomarker. Stepwise logistic regression analysis was used to determine the best parameter to explain FDG PET positivity. MVD revealed significant positive correlation with FDG PET positivity (p=0.0341). There was no significant correlation between FDG PET positivity and Ki-67 or p53 (p=0.4040, p=0.6027). Mitotic activity yielded statistically significant positive correlations with FDG PET positivity (p=0.0448) although histologic grade revealed no positive correlation (p=1). Stepwise logistic regression analysis revealed MVD to be the strongest parameter for FDG PET positivity (OR=0.696, 95% CI 0.487-0.993, p=0.0458). In conclusion, FDG PET positivity revealed positive correlation with MVD and mitotic activity. MVD was the strongest parameter in predicting positive tumor recurrence on FDG PET.