Contemporary analysis of pelvic and para-aortic metastasis in endometrial cancer using the SEER registry.

OBJECTIVE: To determine the incidence of regional lymph node involvement for early-stage endometrial cancer by using the Surveillance, Epidemiology, and End Results (SEER) registry. METHODS: In a retrospective study, data were analyzed from patients who were diagnosed with stage IA-IIB endometrioid adenocarcinoma and were treated between 1998 and 2003. The incidence of pelvic and para-aortic lymph node involvement was determined. RESULTS: Data were analyzed from 4052 patients. Incidences of pelvic and para-aortic lymph node metastases were: 1% and 0% in stage IA, grade 1 disease; 2% and 0% in IA, grade 2; 2% and 1% in IA, grade 3; 2% and 0% in IB, grade 1; 3% and 1% in IB, grade 2; 3% and 2% in IB, grade 3; 7% and 3% in IC, grade 1; 8% and 5% in IC, grade 2; 12% and 8% in IC, grade 3; 7% and 3% in IIA, grade 1; 10% and 4% in IIA, grade 2; 10% and 5% in IIA, grade 3; 8% and 4% in IIB, grade 1; 13% and 8% in IIB, grade 2; and 19% and 12% in IIB, grade 3. CONCLUSION: Incidences of pelvic and para-aortic metastases were lower than previously reported. Patients at higher stages and grades had a 10% or higher risk of lymph node involvement and might benefit from aggressive therapy.

Outcomes and tolerance of human immunodeficiency virus--positive U.S. veterans undergoing dose-escalated external beam radiotherapy for localized prostate cancer.

INTRODUCTION: There are little data on the outcomes and tolerance, as well as the impact on the CD4 counts, of human immunodeficiency virus (HIV)-positive patients with prostate cancer who undergo high-dose external beam radiotherapy. MATERIALS AND METHODS: We identified 15 HIV-positive patients with prostate cancer who were treated with external beam radiation to a dose ≥ 75.6 Gy at the New York Harbor Department of Veterans Affairs between 2003 and 2010. Kaplan-Meier analyses were used to measure biochemical control outcomes. Toxicity and CD4 counts before, after, and during treatments were analyzed. RESULTS: A total of 15 patients were identified, with a median follow-up period of 49 months. There were 2 biochemical failures, which occurred at 28 months and 63 months, respectively. In neither of these 2 patients was there evidence of metastatic disease. The overall 5-year biochemical control was 92.3%. There appeared to be a consistent decline in the CD4 counts both during and immediately after the radiation treatments. Most of these patients had a subsequent improvement in their CD4 counts. Toxicity was mild overall, though there was 1 patient who developed rectal bleeding 11 months post treatment, which required argon plasma coagulation. CONCLUSION: Dose-escalated external beam radiation is well tolerated in HIV-positive patients with durable biochemical control and mild toxicity. A substantial decline in CD4 counts is associated with the radiation; therefore, these counts need to be monitored closely, in conjunction with the infectious-disease specialist.

Computerized tomography-based radiotherapy improves heterotopic ossification outcomes.

PURPOSE: To report the impact of computerized tomography (CT) based radiotherapy (RT) on heterotopic ossification (HO) outcomes. METHODS: This is a single institution, retrospective study of 532 patients who were treated for traumatic acetabular fractures (TAF). All patients underwent open-reduction internal-fixation (ORIF) of the TAF followed by RT for HO prophylaxis. Postoperative RT was delivered within 72h, in a single fraction of 7Gy. The patients were divided into 2 groups based on RT planning: CT (A) vs. clinical setup (B). RESULTS: At a median follow up of 8years the incidence of HO was 21.6%. Multivariate regression analysis revealed that group (A) vs. (B) had HO incidence of 6.6% vs. 24.6% (p<0.001), respectively. Furthermore, HO Brooker grade ≥3 was observed in 2.2% vs. 10.8% (p=0.007) in group (A) vs. (B), respectively. Thus, the odds of developing HO and Brooker grades ≥3 were 4.7 and 4.5 times higher, respectively, in patients who underwent clinical setup. CONCLUSION: Our data suggest that using CT based RT allowed more accurate delineation of the tissues and better clinical outcomes. Although CT-based RT is associated with additional cost the efficacy of CT-based RT reduces the risk of HO, thereby decreasing the need for additional surgical interventions.

Survival following sublobar resection for early-stage non-small cell lung cancer with or without adjuvant external beam radiation therapy: a population-based study.

BACKGROUND: Patients undergoing sublobar resection for early-stage non-small cell lung cancer may receive adjuvant radiation therapy in an effort to improve outcomes despite limited data regarding its efficacy. METHODS: Using the Surveillance, Epidemiology, and End-Results (SEER) registry we identified patients diagnosed with stage I non-small cell lung cancer between 1988 and 2003 who were definitively treated with sublobar surgical resection with or without adjuvant external beam radiation therapy. Kaplan-Meier, Cox regression, and propensity-score-matched survival analyses were performed to evaluate the effect of adjuvant external beam radiation therapy on survival. RESULTS: A total of 5,908 eligible cases were identified: 493 received external beam radiation therapy and 5,415 received no additional local-regional treatment. The use of external beam radiation therapy was associated with significantly worse median overall and disease-specific survival compared with no additional local-regional therapy: 31 and 45 months vs 51 and 98 months, respectively (P < .001). On multivariate analysis, the most significant predictor of death was the use of adjuvant radiation therapy (hazard ratio 1.505; 95% CI, 1.318-1.717; P < .001). The survival detriment associated with external beam radiation therapy remained after propensity-score-matched analysis. CONCLUSIONS: The use of adjuvant external beam radiation therapy is associated with a significant decrease in overall and disease-specific survival for patients with T1-2N0M0 non-small cell lung cancer treated with sublobar resection. Although this finding may be related to covariables not reported in SEER, such as margin status, chemotherapy use, radiation dose, and portal, alternative radiation treatment strategies should be explored.

The calcium channel alpha2/delta1 subunit is involved in extracellular signalling.

The alpha2/delta1 subunit forms part of the dihydropyridine receptor, an essential protein complex for excitation-contraction (EC) coupling in skeletal muscle. Because of the lack of a viable knock-out animal, little is known regarding the role of the alpha2/delta1 subunit in EC coupling or in other cell functions. Interestingly, the alpha2/delta1 appears before the alpha1 subunit in development and contains extracellular conserved domains known to be important in cell signalling and inter-protein interactions. These facts raise the possibility that the alpha2/delta1 subunit performs vital functions not associated with EC coupling. Here, we tested the hypothesis that the alpha2/delta1 subunit is important for interactions of muscle cells with their environment. Using confocal microscopy, we followed the immunolocalization of alpha2/delta1 and alpha1 subunits with age. We found that in 2-day-old myotubes, the alpha2/delta1 subunit concentrated towards the ends of the cells, while the alpha1 subunit clustered near the centre. As myotubes aged (6-12 days), the alpha2/delta1 became evenly distributed along the myotubes and co-localized with alpha1. When the expression of alpha2/delta1 was blocked with siRNA, migration, attachment and spreading of myoblasts were impaired while the L-type calcium current remained unaffected. The results suggest a previously unidentified role of the alpha2/delta1 subunit in skeletal muscle and support the involvement of this protein in extracellular signalling. This new role of the alpha2/delta1 subunit may be crucial for muscle development, muscle repair and at times in which myoblast attachment and migration are fundamental.

Skeletal muscle cells express different isoforms of the calcium channel alpha2/delta subunit.

We examined developmental changes in calcium channel alpha2/delta subunit mRNA in skeletal muscle and their possible influence on L-type calcium currents (ICa-L). Several isoforms of alpha2/delta-1 mRNA were found in myotubes and muscle fibers, and their relative levels changed with time in culture or age of the animal. Levels of alpha2/delta-1a were largest in older myotubes and was the only alpha2/delta-1 isoform present in adult muscle. Both myotubes and muscle fibers also expressed low levels of alpha2/delta-2 and alpha2/delta-3 mRNA at all ages. alpha2/delta-4 mRNA could not be detected in either myotubes or muscle fibers. Changes in amplitude and voltage-dependent inactivation of the ICa-L concurred with the shift in alpha2/delta-1 isoform message, suggesting that alternative splicing of this subunit might be important for modulation of ICa-L.

Imperatoxin a enhances Ca(2+) release in developing skeletal muscle containing ryanodine receptor type 3.

Most adult mammalian skeletal muscles contain only one isoform of ryanodine receptor (RyR1), whereas neonatal muscles contain two isoforms (RyR1 and RyR3). Membrane depolarization fails to evoke calcium release in muscle cells lacking RyR1, demonstrating an essential role for this isoform in excitation-contraction coupling. In contrast, the role of RyR3 is unknown. We studied the participation of RyR3 in calcium release in wild type (containing both RyR1 and RyR3 isoforms) and RyR3-/- (containing only RyR1) myotubes in the presence or absence of imperatoxin A (IpTxa), a high-affinity agonist of ryanodine receptors. IpTxa significantly increased the amplitude and the rate of release only in wild-type myotubes. Calcium currents, recorded simultaneously with the transients, were not altered with IpTxa treatment. [(3)H]ryanodine binding to RyR1 or RyR3 was significantly increased in the presence of IpTxa. Additionally, IpTxa modified the gating and conductance level of single RyR1 or RyR3 channels when studied in lipid bilayers. Our data show that IpTxa can interact with both RyRs and that RyR3 is functional in myotubes and it can amplify the calcium release signal initiated by RyR1, perhaps through a calcium-induced mechanism. In addition, our data indicate that when RyR3-/- myotubes are voltage-clamped, the effect of IpTxa is not detected because RyR1s are under the control of the dihydropyridine receptor.