Purpose/Objective(s) The use of pre-radiation therapy (RT) planning MRI for glioblastoma (GBM) is inconsistent. Current NCCN guidelines recommend treatment planning on preoperative or immediate postoperative MRI. We characterized and investigated implications of rapid early progression (REP) on pre-RT planning MRIs standardly performed at our institution. We hypothesized that REP is associated with worse survival, earlier need for intervention, and performs better than extent of resection as a prognostic variable for risk stratification. Materials/Methods We reviewed patients with a new pathologic diagnosis of IDH-wildtype GBM who received ≥40 Gy RT between 2016-2024. Inclusion required a pre-RT planning MRI ≥2 weeks after postoperative MRI. REP was defined as >1cm thickness of new enhancing disease between postoperative and pre-RT MRI. Extent of surgical resection was scored 1-4 as an ordinal variable, 1: gross total resection (GTR, >95%); 2: near total resection (NTR, 90-95%); 3: subtotal resection (STR); 4: biopsy only. Endpoints included overall survival (OS) and bevacizumab/re-resection. Cox proportional hazards model was used to analyzed age, extent of resection, MGMT methylation, short course RT, and presence of REP. Significant covariates were included in the multivariate analysis. Results The final cohort included 84 patients (median age 63). The median number of days from postoperative MRI to pre-RT MRI was 27 days, and 10 patients (12%) received short course RT. Surgical extent was GTR in 45 (54%), NTR in 15 (18%), STR in 17 (20%), and biopsy only in 7 (8%). REP occurred in 46% of patients and was less frequent after GTR (31%) vs. NTR (73%), STR (59%), or biopsy (57%). On univariate analysis, MGMT methylation, REP, and extent of resection were prognostic for OS and freedom from bevacizumab/re-resection (Table). On multivariate analysis, REP remained significant (HR = 2.2, P = 0.005 for OS; HR = 2.7, P = 0.002 for bevacizumab/re-resection) while extent of resection lost significance. Median OS was 1.1 years with REP vs. 1.7 years without. Conclusion REP occurs frequently in GBM patients, adds a measure of "growth rate", and may perform equal or better than surgical resection in predicting survival and need for bevacizumab or re-resection for fast progressing GBM's. These data have implications for clinical trial design and support pre-RT planning MRIs as standard of care for accurate tumor delineation, risk stratification, and identification of high-risk patients who may need earlier intervention.

Purpose/Objective(s) Meningiomas express estrogen and progesterone receptors, but hormonal risk is poorly characterized and not always considered by treating neurosurgeons and radiation oncologists. We hypothesized that hormonal contraceptives lead to tumor-related visual deficits in premenopausal women referred for radiation. Materials/Methods We performed a retrospective case-control study with the primary endpoint of visual deficit prior to receipt of radiation for intracranial meningioma in women age ≤55. Records were reviewed to determine key risk factors including age, grade, skull base location, hormonal supplementation / contraception, and neurofibromatosis / prior radiation (NF/PriorRT). Univariate and multivariate (including factors with P<0.05 on univariate) logistic regression was performed to analyze associations with visual deficit. Results The final cohort comprised of 64 women age ≤55 (median 46), out of a total 253 patients who received radiation for meningioma between 2012 and 2024 at one center. 24 patients (38%) had meningioma grade ≥2; 45 (70%) had skull base tumors; 6 (9%) had NF/PriorRT. 33 women (52%) had used estrogen or progesterone, and 23 (36%) had used unopposed progesterone only, of whom 15 used medroxyprogesterone acetate (Provera). Visual deficit was present in 35 patients (55%) and was strongly and independently associated with both skull base location (P = 0.002, OR 11.5) and unopposed progesterone only use (P = 0.008, OR 12) but not estrogen or progesterone use on multivariate analysis (see table). Proportion with history of progesterone only use was 57% vs. 11% in patients with vs. without visual deficit, respectively (chi-sq P<0.001). ER/PR status was reported in 5 of 51 cases (10%) with available pathology; PR was positive in 3 (all with visual deficits and history of Provera use) and negative in 2 (neither with visual deficits nor hormone use). At time of radiation, 13 women (20%) were actively using progesterone. At time of analysis, 13 women (20%) were still using progesterone, 17 women have been contacted for risk counseling, and 4 have discontinued progesterone as a result. Conclusion Progesterone use is a significant risk factor for meningioma-related visual deficits in premenopausal women referred for radiotherapy, with a disproportionate number on Provera specifically. These data highlight the importance of age-appropriate counseling, consistent pathologic assessment of ER/PR status, and greater awareness of this issue amongst neurosurgeons and radiation oncologists.

High grade neurologic events were common in patients with predominantly active, unresected high grade gliomas receiving ReRT. Though ascertainment and survival bias are significant limitations, pseudoprogression and necrosis appeared to be more prominent in patients receiving protons. These results contribute to ongoing efforts to both optimize ReRT for high grade glioma and investigate biologic effects of proton therapy.

Although heterogeneous, patients treated with SRS/SRT and ongoing CNS-active targeted systemic therapies have on average >6 month intracranial PFS and little evidence of significant toxicity. We observed <6% G2+ radiation necrosis for this cohort, and no particular class of agent was associated with a significantly higher rate of G2+ radiation necrosis.

Purpose/Objective(s) Immune checkpoint inhibitors (ICI) are increasingly used to treat patients with brain metastases, while stereotactic radiosurgery (SRS, 1 fraction) and stereotactic radiotherapy (SRT, 3-5 fractions) are established modalities. Emerging data suggest that ICI and SRS/SRT may work synergistically, with reports of increased efficacy and toxicity. We characterized factors associated with intracranial control and radiation necrosis in patients receiving both ICI and SRS/SRT. Materials/Methods We retrospectively identified patients treated with ICI and SRS/SRT for intact brain metastases at two institutions from 2013-2020. Patients had diagnoses of non-small cell lung cancer, renal cell carcinoma, or melanoma and were followed for a minimum of 2 months after receipt of both SRS/SRT and ICI with brain MRI. The analysis was completed on a per-metastasis basis. Local failure (LF) and radiation necrosis (determined radiographically with clinical impression or pathologically; included grade 2 (symptomatic) or higher) were analyzed by univariate and multivariate logistic regression which included tumor diameter, timing of ICI relative to SRS/SRT, PD-L1 (positive defined as ≥ 1%), and SRT vs. SRS. Progression-free survival (PFS) was defined as time from SRS/SRT to local or distant brain failure, death, or last follow up for those without progression. Results There were 179 patients with 549 metastases, 492 metastases treated with SRS, and 57 metastases treated with SRT. Median follow up from the time of SRS/SRT was 14.7 months. Median tumor size was 7mm (< 5mm: 253, ≥ 5 & < 10mm: 159, ≥ 10 and < 20mm: 91, and ≥ 20mm: 46). Rates of LF and grade 2+ radiation necrosis for the entire cohort were 5.8% (32/549) and 6.9% (38/549), respectively (15.6% (28/179) rate of grade 2+ radiation necrosis per-patient). LF rates for those who received ICI outside +/- 3 months from SRS/SRT vs. within +/- 3 months from SRS/SRT were 9.0% and 4.4%, respectively. Rates of grade 2+ radiation necrosis for those with positive vs. negative PD-L1 were 9.2% vs. 1.6%, respectively. Positive PD-L1 status was associated with improved intracranial PFS (HR 0.53, p = 0.03). Conclusion Combination ICI and SRS/SRT is increasingly used to treat brain metastases. Our study showed improved local control when ICI is given within 3 months from time of SRS/SRT without an associated increase in radiation necrosis. Increasing tumor size was associated with LF and radiation necrosis. Positive PD-L1 was associated with improved intracranial PFS and increased radiation necrosis. We recommend further study, ideally prospectively, to better characterize this treatment combination.

Patients ranged in age from four to 18 years. Heart mean dose was 8 cGy and 105 cGy for the VBS and VB plans, respectively (P < 0.01). Heart maximum dose was significantly higher in the VB plans (814 cGy vs. 2988 cGy, P < 0.01). Esophagus maximum dose was 1995 cGy and 3676 cGy for the VBS and VB plans, respectively (P < 0.01). Mean esophagus dose was also significantly higher in the VB plans (358 cGy vs. 1546 cGy, P < 0.01). Liver mean dose (25 cGy vs. 78 cGy, P < 0.01) and maximum dose to the bowel (813 cGy vs. 3443 cGy, P < 0.01) were higher in the VB plans. The absolute excess risk of SMN for liver (0.11 vs. 0.13, P < 0.05), esophagus and bowel were significantly higher if the vertebral body was included in the target volume. The average absolute excess risk of SMN for the GI tract (esophagus and bowel) per 10,000 patients per year was 0.86 and 2.49 for the VBS and VB plans, respectively. The average absolute excess risk of SMN for the entire body was 13.26 in the VBS plans and 15.08 in the VB plans, and this difference was approaching statistical significance (P = 0.08) CONCLUSION: VBS CSI leads to significantly lower radiation dose to the heart, esophagus, kidney, liver and bowel compared to VB proton CSI. Excluding the vertebral body also significantly decreases the absolute excess risk of SMN of the liver, esophagus and bowel. For these reasons, VBS pencil beam scanning proton CSI should be considered.

Craniospinal irradiation (CSI) is a key component of therapy for many pediatric central nervous system (CNS) malignancies. There has been increased availability and utilization of proton therapy for CSI which offers dosimetric advantages due to reduced normal tissue exposure because of the lack of exit dose. For maximal tissue sparing, protons can target the thecal sac alone, but this results in a dose gradient across the vertebral bodies, and raises concerns about partial coverage resulting in uneven growth in growing pediatric patients with possible lordosis. For this reason, some physicians target the entire vertebral body, while others will allow a dose gradient to better spare organs at risk. This study was done in order to assess current practice patterns regarding vertebral body coverage for pediatric patients undergoing CSI. Pediatric radiation oncologists who treat with proton therapy were identified from membership in the Particle Therapy Co-Operative Group pediatric sub-committee or by affiliation with U.S. proton centers. An institutional review board approved, anonymized web-based survey was distributed by email to these physicians on June 21st, 2017 with a follow-up email on October 10th, 2017. The survey included up to 11 questions regarding practice patterns relating to vertebral body coverage/sparing in the treatment of children with CSI, and utilized skip logic to focus relevant follow-up questions based on initial responses. Thirty-three physicians responded to the survey, five of whom were excluded for lack of recent pediatric proton CSI experience. Of the 28 included responses, 23 physicians sometimes treat the entire vertebral body. Five physicians report always treating the entire vertebral body and zero report never treating the entire vertebral body. Most common responses regarding anterior CTV expansion beyond the thecal sac were no expansion (n=9) and 3-4 mm (n=8). The majority of physicians report modification of the anterior margin for some structures, most commonly the esophagus (n=15), thyroid (n=6), heart (n=5), bowel (n=4) and pharynx (n=2). Vertebral body coverage in proton based CSI varies amongst radiation oncologists in respect to target delineation, CTV expansions and modifications for ventral organs at risk with many factors influencing this decision. These data suggest an opportunity for developing a more standardized approach to vertebral body coverage in pediatric proton based CSI.

Stereotactic radiosurgery (SRS), in combination with whole brain radiation therapy or alone, has been shown in multiple studies to improve local control, functional independence, and survival. However, the use of SRS is limited in high risk patients, those with large brain metastases, lesions in previously irradiated brain, or in close proximity to critical dose-limiting structures, owing to the increased risk of radiation necrosis. With advances in non-invasive, frameless, image-guided stereotactic techniques, fractionated stereotactic radiosurgery (FSRS) is increasingly employed to treat such high risk patients, with the intention of preserving the high rates of local control seen with SRS while minimizing late radiation-induced toxicity. The purpose of this retrospective analysis is to review and present our FSRS outcome data for lesions thought to be at high risk for necrosis with traditional high dose single fraction SRS. Patients treated with FSRS between November 2009 and July 2011 were identified for analysis. FSRS was recommended for large brain metastases, previously irradiated, or those located in high risk areas of the brain or brainstem. All lesions received 30Gy in 5 fractions utilizing LINAC-based, image-guided localization and frameless immobilization. Stereotactic treatment plans were developed using a treatment planning system. Primary endpoints evaluated were local control, distant in-brain failure, radionecrosis, and survival and were estimated using Kaplan-Meier methods calculated from the completed treatment date. Forty patients with 58 lesions were eligible for analysis. Mean treatment volume was 9.4cc (range: 0.1-57.4cc). Seventeen lesions were greater than 10cc, 30 were previously treated with whole brain radiation therapy, and six were located in the brainstem. Mean follow-up was 12.4 months. The crude local control rate was 84%. The actuarial local control at 12 and 24mo was 86% and 64%, respectively. The 12 and 24mo actuarial rates of distant in-brain failure were 41% and 56%, respectively. Radiation necrosis was identified in one lesion for an overall necrosis risk of 2%. The median survival for the entire cohort was 21mo. The overall actuarial survival at 6, 12, and 24mo was 62%, 55% and 39%, respectively. Local control rates of brain metastases using high dose single fraction SRS (18-22Gy) have been reported in the range of 80-90% at 12mo. Large lesions (>3-4cm) treated to lower single doses, as recommended by the RTOG to reduce the risk of radiation necrosis, demonstrate worse local control rates and inferior outcomes. This retrospective review of our experience with FSRS for high risk brain metastases demonstrates a low risk of radiation necrosis while maintaining local control rates comparable to high dose single fraction SRS.

The sarcoplasmic reticulum Ca 2+ -cycling proteins are key regulators of cardiac contractility, and alterations in sarcoplasmic reticulum Ca 2+ -cycling properties have been shown to be causal of familial cardiomyopathies. Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure. No homozygous individuals were identified. By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy exhibiting similar histopathologic abnormalities and premature death. Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca 2+ -ATPase superinhibition. The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum Ca 2+ -ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice.

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.

Heart failure is a worldwide public health problem. Despite significant improvements in the management of congestive heart failure, morbidity and mortality rates remain high with a 5-year mortality rate approaching 50% [ [1] Cohn J.N. Heart failure: future treatment approaches. Am J Hypertens. 2000; 13: 74S-78S Crossref PubMed Google Scholar ]. The syndrome of heart failure is a common complication that ensues from a wide variety of cardiovascular pathologies, including coronary artery disease, cardiomyopathy, valvular heart disease, or congenital malformations [ [2] Seidman J.G. Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001; 104: 557-567 Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar ]. Despite the multiplicity of inciting mechanisms, the response of the heart to these diverse events indicates that only a few molecules are critical for monitoring myocyte malfunction [ [2] Seidman J.G. Seidman C. The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell. 2001; 104: 557-567 Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar ]. Among these, calcium is the most crucial ion for regulation of both cardiac excitation-contraction coupling and remodeling [ 3 Hasenfuss G. Reinecke H. Studer R. Meyer M. Pieske B. Holtz J. et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res. 1994; 75: 434-442 Crossref PubMed Scopus (636) Google Scholar , 4 Marx S.O. Reiken S. Hisamatsu Y. Jayaraman T. Burkhoff D. Rosemblit N. et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000; 101: 365-376 Abstract Full Text Full Text PDF PubMed Scopus (1660) Google Scholar ]. In turn, calcium itself is under the regulatory control of the sarcoplasmic reticulum (SR). Evidence from several laboratories indicates that SR-calcium cycling is depressed in heart failure, and this may have a prominent role in the progression of the disease. Specifically, decreases in SR-calcium uptake, elicited by either depressed SR-Ca2+-ATPase (SERCA2a) levels or increased inhibition by phospholamban (PLN), have been suggested to contribute to SR dysfunction in failing hearts [ 5 Meyer M. Schillinger W. Pieske B. Holubarsch C. Heilmann C. Posival H. et al. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation. 1995; 92: 778-784 Crossref PubMed Scopus (437) Google Scholar , 6 Dash R. Frank K.F. Carr A.N. Moravec C.S. Kranias E.G. Gender influences on sarcoplasmic reticulum Ca2+-handling in failing human myocardium. J Mol Cell Cardiol. 2001; 33: 1345-1353 Abstract Full Text PDF PubMed Scopus (139) Google Scholar ]. Moreover, recent studies indicate that inhibition of the SERCA2a-PLN interaction may prevent the progression of dilated cardiomyopathy [ 7 Minamisawa S. Hoshijima M. Chu G. Ward C.A. Frank K. Gu Y. et al. Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell. 1999; 99: 313-322 Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar , 8 Hoshijima M. Ikeda Y. Iwanaga Y. Minamisawa S. Date M.O. Gu Y. et al. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat M. 2002; 8: 864-871 PubMed Google Scholar ].

In human disease and experimental animal models, depressed Ca2+ handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca2+-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy.