External validation of three prognostic scores for brain metastasis velocity in patients treated with intracranial stereotactic radiotherapy.

BACKGROUND AND INTRODUCTION: Brain metastasis velocity (BMV) has been proposed as a prognostic factor for overall survival (OS) in patients with brain metastases (BMs). In this study, we conducted an external validation and comparative assessment of the performance of all three BMV scores. MATERIALS AND METHODS: Patients treated with intracranial stereotactic radiotherapy (SRT) for BM at a single center between 2014 and 2018 were identified. Where possible, all three BMV scores were calculated. Log-rank tests and linear, logistic and Cox regression analysis were used for validation and predictor identification of OS. RESULTS: For 333 of 384 brain metastasis patients, at least one BMV score could be calculated. In a sub-group of 187 patients, "classic" BMV was validated as categorical (p < 0.0001) and continuous variable (HR 1.02; 95% CI 1.02-1.03; p < 0.0001). In a sub-group of 284 patients, "initial" BMV was validated as categorical variable (high-risk vs. low-risk; p < 0.01), but not as continuous variable (HR 1.02; 95% CI 0.99-1.04; p = 0.224). "Volume-based" BMV could not be validated in a sub-group of 104 patients. On multivariable Cox regression analysis, iBMV (HR 1.85; 95% CI 1.01-3.38; p < 0.05) and cBMV (HR 2.32; 95% CI 1.15 4.68; p < 0.05) were predictors for OS for intermediate-risk patients after first SRT and first DBFs, respectively. cBMV proved to be the dominant predictor for OS for high-risk patients (HR 2.99; 95% CI 1.30-6.91; p < 0.05). CONCLUSION: This study externally validated cBMV and iBMV as prognostic scores for OS in patients treated with SRT for BMs whereas validation of vBMV was not achieved.

Comprehensive summary and retrospective evaluation of prognostic scores for patients with newly diagnosed brain metastases treated with upfront radiosurgery in a modern patient collective.

BACKGROUND: Numerous prognostic scores (PS) for patients with brain metastases (BM) have been developed. Recently, PS based on laboratory parameters were introduced to better predict overall survival (OS). A comprehensive comparison of the wide range of scores in a modern patient collective is still missing. MATERIALS AND METHODS: Twelve PS considering clinical parameters only at the time of BM diagnosis were calculated for 470 patients receiving upfront SRS between January 2014 and March 2020. In a subcohort of 310 patients where a full laboratory dataset was available five additional prognostic scores were compared. Restricted mean survival time (RMST), partial likelihood and c-index were calculated as metrics for performance evaluation. Univariable and multivariable analysis were used to identify prognostic factors for OS. RESULTS: The median OS of the whole cohort was 15.8 months (95% C.I.: 13.4-20.1). All prognostic scores performed well in separating patients into different prognostic groups. RPA achieved the highest c-index, whereas GGS achieved highest partial likelihood with evaluation in the total cohort. With incorporation of the laboratory scores the recently suggested EC-GPA achieved highest c-index and highest partial likelihood. A prognostic score solely based on the assessment of performance status achieved considerable high performance as either 3- or 4-tiered score. Multivariable analysis revealed performance status, systemic disease status and laboratory parameters to be significantly associated with OS among variates included in prognostic scores. CONCLUSION: Although recent PS incorporating laboratory parameters show convincing performance in predicting overall survival, older scores relying on clinical parameters only are still valid and appealing as they are easier to calculate, and as overall performance is almost equal. Moreover, a score just based on performance status is not significantly inferior and should at least be assessed for informed decision making.

Hypofractionated Radiotherapy With Simultaneous-integrated Boost After Breast-conserving Surgery Compared to Standard Boost-applications Using Helical Tomotherapy With TomoEdge.

BACKGROUND/AIM: This comparative plan study examines a range of boost-radiation methods in adjuvant radiotherapy of breast cancer using helical intensity-modulated radiotherapy with TomoEdge-technique. Impact of hypofractionated radiation with simultaneous-integrated boost (SIB) and influence of differing assumed α/ß-values were examined. PATIENTS AND METHODS: For 10 patients with left-sided breast cancer each four helical IMRT-plans with TomoEdge-technique were created: hypofractionated+SIB (H-SIB) (42.4/54.4 Gy, 16 fractions), normofractionated+SIB (N-SIB) (50.4/64.4 Gy, 28 fractions), hypofractionated+sequential-boost (H-SB) (42.4 Gy/16 fractions+16 Gy/8 fractions), normofractionated+ sequential-boost (N-SB) (50.4 Gy/28 fractions+16 Gy/8 fractions). Equivalent doses (EQD2) to organs-at-risk (OAR) and irradiated mammary-gland were analysed for different assumed α/ß-values. RESULTS: The mean EQD2 to OAR was significantly lower using hypofractionated radiation-techniques. H-SIB and H-SB were not significantly different. H-SIB and N-SIB conformed significantly better to the breast planning-target volume (PTV) and boost-volume (BV) than H-SB and N-SB. Regarding BV, mean EQD2 was significantly higher for all α/ß-values investigated when using H-SIB and N-SIB. Regarding PTV, there were no clinically relevant differences. CONCLUSION: Relating to dosimetry, H-SIB is effective compared to standard-boost-techniques.

Breast cancer occurrence after low dose radiotherapy of non-malignant disorders of the shoulder.

Stochastic long-term damages at relatively low doses have the potential for cancer induction. For the first time we investigated the occurrence of breast cancer in female patients after radiotherapy of non-malignant disorders of the shoulder and made a comparison with the estimated spontaneous incidence of mammary carcinoma for this cohort. In a geographically defined district with a population of approximately 100.000 inhabitants, comprehensive data of radiological diagnostics and radiotherapy were registered nearly completely for 41 years; data included mammography and radiotherapy of breast cancer patients as well as of non-malignant disorders. Within this population a collective of 158 women with radiotherapy of the shoulder was investigated. Radiotherapy was performed with cobalt-60 photons (Gammatron) with an average cumulative-dose of 6 Gy. The average follow-up time was 21.3 years. Patients were 55 years old (median) when radiotherapy of the shoulder was performed. Seven patients (4.4%) developed breast cancer after a median of 21 years. According to the incidence statistics, 9.4 +/- 1.8 (95%CI) cases (5.9%) would be expected. In regard to the irradiated shoulder neither the ipsilateral nor the contralateral breasts showed increased rates of breast cancer. An induction of additional breast cancer caused by radiation of non-malignant disorders of the shoulder wasn't detected in the investigated cohort.

Molecular Mechanisms and Kinetic Effects of FXYD1 and Phosphomimetic Mutants on Purified Human Na,K-ATPase.

Phospholemman (FXYD1) is a single-transmembrane protein regulator of Na,K-ATPase, expressed strongly in heart, skeletal muscle, and brain and phosphorylated by protein kinases A and C at Ser-68 and Ser-63, respectively. Binding of FXYD1 reduces Na,K-ATPase activity, and phosphorylation at Ser-68 or Ser-63 relieves the inhibition. Despite the accumulated information on physiological effects, whole cell studies provide only limited information on molecular mechanisms. As a complementary approach, we utilized purified human Na,K-ATPase (α1ß1 and α2ß1) reconstituted with FXYD1 or mutants S63E, S68E, and S63E,S68E that mimic phosphorylation at Ser-63 and Ser-68. Compared with control α1ß1, FXYD1 reduces Vmax and turnover rate and raises K0.5Na. The phosphomimetic mutants reverse these effects and reduce K0.5Na below control K0.5Na. Effects on α2ß1 are similar but smaller. Experiments in proteoliposomes reconstituted with α1ß1 show analogous effects of FXYD1 on K0.5Na, which are abolished by phosphomimetic mutants and also by increasing mole fractions of DOPS in the proteoliposomes. Stopped-flow experiments using the dye RH421 show that FXYD1 slows the conformational transition E2(2K)ATP → E1(3Na)ATP but does not affect 3NaE1P → E2P3Na. This regulatory effect is explained simply by molecular modeling, which indicates that a cytoplasmic helix (residues 60-70) docks between the αN and αP domains in the E2 conformation, but docking is weaker in E1 (also for phosphomimetic mutants). Taken together with previous work showing that FXYD1 also raises binding affinity for the Na(+)-selective site III, these results provide a rather comprehensive picture of the regulatory mechanism of FXYD1 that complements the physiological studies.

Surface charges of the membrane crucially affect regulation of Na,K-ATPase by phospholemman (FXYD1).

The human α1/His10-ß1 isoform of Na,K-ATPase has been reconstituted as a complex with and without FXYD1 into proteoliposomes of various lipid compositions in order to study the effect of the regulatory subunit on the half-saturating Na⁺ concentration (K(½)) of Na⁺ ions for activation of the ion pump. It has been shown that the fraction of negatively charged lipid in the bilayer crucially affects the regulatory properties. At low concentrations of the negatively charged lipid DOPS (<10 %), FXYD1 increases K(½) of Na⁺ ions for activation of the ion pump. Phosphorylation of FXYD1 by protein kinase A at Ser68 abrogates this effect. Conversely, for proteoliposomes made with high concentrations of DOPS (>10 %), little or no effect of FXYD1 on the K(½) of Na⁺ ions is observed. Depending on ionic strength and lipid composition of the proteoliposomes, FXYD1 can alter the K(½) of Na⁺ ions by up to twofold. We propose possible molecular mechanisms to explain the regulatory effects of FXYD1 and the influence of charged lipid and protein phosphorylation. In particular, the positively charged C-terminal helix of FXYD1 appears to be highly mobile and may interact with the cytoplasmic N domain of the α-subunit, the interaction being strongly affected by phosphorylation at Ser68 and the surface charge of the membrane.