Citations

AbstractBackgroundMotion of lung tumors during radiotherapy leads to decreased accuracy of the delivered dose distribution. This is especially true for proton radiotherapy due to the finite range of the proton beam. Methods for mitigating motion rely on knowing the position of the tumor during treatment.PurposeProton radiography uses the treatment beam, at an energy high enough to traverse the patient, to produce a radiograph. This work shows the first results of using an integrated‐mode proton radiography system to track the position of moving objects in an experimental phantom study; demonstrating the potential of using this method for measuring tumor motion.MethodsProton radiographs of an anthropomorphic lung phantom, with a motor‐driven tumor insert, were acquired approximately every 1 s, using tumor inserts of 10, 20, and 30 mm undergoing a known periodic motion. The proton radiography system used a monolithic scintillator block and digital cameras to capture the residual range of each pencil beam passing through the phantom. These ranges were then used to produce a water equivalent thickness map of the phantom. The centroid of the tumor insert in the radiographs was used to determine its position. This measured position was then compared to the known motion of the phantom to determine the accuracy.ResultsSubmillimeter accuracy on the measurement of the tumor insert was achieved when using a 30 mm tumor insert with a period of 24 s and was found to be improved for decreasing motion amplitudes with a mean absolute error (MAE) of 1.0, 0.9, and 0.7 mm for 20, 15, and 10 mm respectively. Using smaller tumor inserts reduced the accuracy with a MAE of 1.8 and 1.9 mm for a 20 and 10 mm insert respectively undergoing a periodic motion with an amplitude of 20 mm and a period of 24 s. Using a shorter period resulted in significant motion artifacts reducing the accuracy to a MAE of 2.2 mm for a 12 s period and 3.1 mm for a 6 s period for the 30 mm insert with an amplitude of 20 mm.ConclusionsThis work demonstrates that the position of a lung tumor insert in a realistic anthropomorphic phantom can be measured with high accuracy using proton radiographs. Results show that the accuracy of the position measurement is the highest for slower tumor motions due to a reduction in motion artifacts. This indicates that the primary obstacle to accurate measurement is the speed of the radiograph acquisition. Although the slower tumor motions used in this study are not clinically realistic, this work demonstrates the potential for using proton radiography for measuring tumor motion with an increased scanning speed that results in a decreased acquisition time.

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.

Abstract Introduction Cardiopulmonary exercise testing (CPET) parameters such as peak VO2 ≤ 14ml/kg/min, percentage predicted peak VO2 (ppVO2) ≤ 50% and ventilation equivalent of carbon dioxide (Ve/VCO2) >35 l/min/l/min are recommended thresholds to list for isolated heart transplant. There is minimal data on clinical events after listing to guide clinical management or priority in organ allocation. Purpose To assess the effect of peak VO2, ppVO2, Ve/VCO2 on clinical events after listing for isolated heart transplant. Methods In a single centre retrospective study, we identified patients who were status 6 or status 2 prior to 2018 at time of listing for isolated heart transplant between 2007 and 2021. Clinical data were collected by chart review. Primary outcome of progressive heart failure was defined as death or upgrade in transplant priority status (new inotropes or mechanical circulatory support). Comparison was made between peak VO2 strata (> 14 vs ≤ 14 ml/kg/min), ppVO2 strata (> 50% vs 40-50% vs <40%) and Ve/VCO2 strata (<35 vs >35 l/min/l/min). Secondary outcome was time dependent survival after listing for heart transplant. Results We identified 141 patients of which 133 underwent CPET and follow up was available for 130 who were included in the analysis. Median age was 53 years (interquartile range 41-59 years), 29.1% of patients were female. Median peak VO2 was 14.0 ml/kg/min (11.2-15.7), ppVO2 was 44% (36-52), Ve/VCO2 slope was 34.0 (31.0-37.0) and RER was 1.1 (1.1-1.2). 87 patients had progressive heart failure consisting of 34 deaths and 83 patients having upgrade in priority status. There was a significant difference in risk of progressive heart failure comparing peak VO2 strata (Figure 1) (freedom from event at one year 71.4% with peak VO2 > 14 vs 46.5% with peak VO2 ≤ 14, p=0.00061) and ppVO2 strata (Figure 2) (freedom from event at one year 75.0% with ppVO2 >50% vs 61.2% with ppVO2 40-50% vs 42.6% with ppVO2 <40%, p=0.0015). There was no significant difference with Ve/VCO2 strata (freedom from event at one year 59.8% with Ve/VCO2 <34 vs 54.9% with Ve/VCO2 >34, p=0.52). There were 34 deaths before transplant and 23 deaths after transplant. 87 patients underwent transplant. In a time dependent survival analysis, age, gender and ppVO2<50% (HR 1.65 (0.87-3.12)) were not significant predictors of mortality. Both early transplant (defined as < 1 year after listing, HR 0.14 (0.06-0.34) and late transplant (defined as > 1 year after listing, HR 0.16 (0.08-0.32)) were significant predictors of lower mortality whilst Ve/VCO2>35 (HR 2.09 (1.19-3.68)) was a significant predictor of higher mortality. Conclusions Peak VO2 and ppVO2 stratify risk of progressive heart failure in ambulatory patients awaiting isolated heart transplant. However, Ve/VCO2 is a predictor of significantly higher mortality. These findings should affect clinical management and transplant priority status; and influence revision of future guidelines.Freedom from event by peak VO2 strataFreedom from event by ppVO2 strata

Abstract Background Cardiopulmonary exercise testing (CPET) has emerged as an important tool for risk stratification and prognosis assessment in patients with cardiac diseases. The Weber and Ventilatory Functional Classification have been correlated with outcomes in patients with Heart Failure (HF). Weber classification is based on VO2: Weber class A, peak VO2 >20 mL/kg per minute; class B, peak VO2 16–20 mL/kg per minute; class C, peak VO2 10–16 mL/kg per minute; and class D, peak VO2 ≤10 mL/kg per minute and Ventilatory classification on VE/VCO2 slope I-IV (Figure A). Although VO2 and VE/VCO2 variables have found altered in the amyloidosis population, the applicability of this classification in a cohort of amyloidosis patients and its correlation with all-cause mortality have not been explored. Purpose To evaluate if the Weber and Ventilatory Classification of HF predicts mortality amyloidosis patients. Methods 194 with diagnosis of amyloidosis who underwent CPET from February 2010 to February 2024 were included in this retrospective cohort study. Patients with at least one CPET complete data were included in the analysis. Data on the type of amyloidosis, comorbidities, and echocardiogram were retrieved from medical records. Cohort was divided into two groups according to the Weber Classification: Weber Class A/B and Weber Class C/D. Individuals with CPET studies after heart transplant were excluded from the analysis. Statistical analyses including Fisher’s exact test, chi-square, Tukey-Kramer (TK), Cox regression model analysis, proportional hazards model for time to event, and Kaplan–Meier curves were performed. A p-value <0.05 was considered significant. Results Out of the 194 patients, 94 were classified as Weber A-B and 100 as Weber B-C. The age at stress test was similar between the groups: Weber A/B 62.9 ± 11.7 years and Weber C/D 62.3 ± 10.7 years (p=0.087). Ejection Fraction was similar between groups, 32% and 28.9% in A-B and C-D respectively (p =0.207). Higher levels of NT-proBNP were found in the Weber C/D group. The prevalence of comorbidities was balanced among the groups except chronic kidney disease, which was higher in Weber Class C/D (40%) vs (20.2%) in Weber Class A/B (Table 1). Cox analysis revealed a strong association between higher Weber class and the outcome HR 2.36 (1.18 – 4.71) p=0.014. For Higher Ventilatory Class (Group III-IV) similar results were found HR 2.95 (1.60 – 5.45) p=0.005(Table 2). Mortality was significantly higher during the follow-up in the Weber C/D group (25%) vs (10%) in the Weber A-B group p=0.007(Figure D). Conclusion Weber and ventilatory Classification based on CPET, besides predicting outcomes in patients with cardiac disease, are strong predictors of mortality in patients with amyloidosis. These findings suggest that this patient group benefits from earlier stratification to assess prognosis and the potential requirement for transplant independently from other factors.

Background/Objectives: Our objective was to describe the use of intraoperative radiation therapy (IORT) for the treatment of recurrent/persistent cervical or endometrial cancer and assess predictors of postoperative complications and 3-year mortality. Methods: In this multi-site retrospective study, data were abstracted for recurrent/persistent endometrial or cervical cancer patients who underwent IORT from June 2004 to May 2021. Complications were graded on the six-point Accordion scale. Variables associated with complications were analyzed with univariate logistic regression, while variables associated with death within 3 years were analyzed with Cox proportional hazards modeling. Survival was analyzed with the Kaplan–Meier method. Results: Eighty patients had planned IORT for recurrent/persistent endometrial (n = 35) or cervical cancer (n = 45). The mean age of the cohort was 56.8 years (SD = 13.7), and the median disease-free interval from primary disease to recurrence was 20.0 months (IQR 10.0–63.1). The overall survival at 3 years was 48.6% (95% CI: 38.3–61.6%) with a median survival of 2.8 years. Within 30 days postoperative, 16 patients (20.1%) had grade 3–5 complications and one death (1.3%) occurred. Factors associated with grade 3+ complication included ECOG PS 2–3 (OR 18.00, p = 0.04), neoadjuvant chemotherapy and/or immunotherapy (OR 6.98, p < 0.01), and pelvic sidewall involvement (OR 8.80, p = 0.04). Factors associated with death within 3 years of surgery included ECOG PS 2–3 (HR 8.97, p < 0.01), neoadjuvant chemotherapy and/or immunotherapy (HR 2.34, p = 0.03), whether exenteration was performed (HR 2.64, p = 0.01), and positive resection margin (HR 3.37, p < 0.01). Conclusions: In well-selected patients, IORT is a feasible and safe option for the treatment of recurrent/persistent gynecologic malignancy with an appreciable survival benefit.

Abstract Background Cardiopulmonary exercise testing (CPET) is a widely used tool for risk stratification and prognosis in patients with chronic heart failure. In amyloid patients, cardiac amyloid deposits are associated with poor prognosis, increased risk for arrhythmias, sudden death, and subsequent exercise limitation due to restrictive cardiomyopathy. The type of amyloidosis and its affectation of the heart are different, and little is known about the CPET parameters according to the type of cardiac amyloidosis. Purpose In this study, we aim to compare CPET data in different types of amyloidosis to determine if CPET variables evaluated could have a significant difference that could impact the follow-up or prognosis of the patients based on the type of amyloidosis. Methods We conducted a retrospective cohort study of 194 patients with a diagnosis of cardiac amyloidosis referred for CPET from February 2010 to February 2024. Patients with at least one CPET data were included in our analysis. The type of amyloidosis, comorbidities, and echocardiogram data were retrieved from medical records. Patients were divided into 3 different groups according to the type of amyloidosis: AL Amyloidosis(AL), Variant TTR Amyloidosis (vTRR), and Wild Type TTR Amyloidosis (wtTTR). Individuals with CPET studies after heart transplant were excluded from the analysis. Fisher’s exact test or chi-square was used to compare categorical variables. ANOVA and Tukey-Kramer (TK) were used to compare continuous variables. Adjustment using General Linear Models (GLM) procedure was used to identify any confounder that could affect the results. A p-value &lt;0.05 was considered significant. Results Out of the 194 patients, 66 had AL Amyloidosis, 40 had vTTR Amyloidosis, and 88 had wtTTR Amyloidosis. Most of the patients were male, and the male predominance was higher in the wtTRR group. There were 41 (62.1%) males in the AL group, 35 (87.5%) in the vTRR group, and 83 (94.3%) in the wtTTR group (p&lt;0.0001). Comorbidities were balanced among the groups. Additional demographic and comorbidities data are shown in Table 1. From the evaluated CPET variables, VE/VCO2 nadir and slope were significantly higher in the wtTTR group when compared to the other groups, as well as Peak VE and Peak TV(Figure A). However, after adjusting for sex, BMI, and age, VE/VCO2 nadir was still significantly higher in the wtTRR group (p=0.003) compared to the other groups, as well as Peak VE, which was higher again in vTTR patients (p=0.001), and Peak TV (Table 2). Conclusion Ventilation variables evaluated in CPET showed alterations in the wtTTR group. These findings suggest that wtTRR amyloid patients could have a severe problem in ventilation that could be of significant relevance in future prognosis.

AbstractIntroductionLong QT syndrome (LQTS) is a cardiac channelopathy characterized by QT prolongation and a potential for arrhythmic syncope, sudden cardiac arrest or deaths (SCA/SCD). It has been speculated that patients with LQTS might have a primary sinoatrial node (SAN) phenotype of chronotropic insufficiency (CI). This has not been demonstrated convincingly before because of the potentially confounding effects of beta blocker (BB) therapy. Herein, we set out to determine whether untreated patients with LQTS demonstrate intrinsic CI.Methods and ResultsA retrospective review of all treadmill exercise stress tests (TEST) was performed on patients with one of the three most common LQTS genotypes: LQT1, LQT2, and LQT3. For each patient, the first TEST completed while off BB was analyzed. Patients with prior left cardiac sympathetic denervation (LCSD) therapy were excluded. CI was defined as having an age‐ and gender‐predicted peak heart rate (HR) < 85% and/or a predicted HR reserve (HRR) < 80%. Overall, 463 LQTS patients (245 LQT1, 125 LQT2, and 93 LQT3) were included (267 female [58%]; mean age at time of TEST [29 ± 17 years]). Mean % predicted peak HR for all LQTS patients was 87.6% (range 42.9% ‐ 119.1%) and mean % predicted HRR was 80% (range 19.1% ‐ 153%). Overall, half of all LQTS patients (n = 234; 51%) displayed CI; 64% of patients with LQT1 (n = 157), 37% with LQT2 (n = 46), and 33% with LQT3 (n = 31). Patients with LQT1 were most likely to exhibit CI compared to patients with LQT2 (p < .0001) and LQT3 (p < .0001). CI was significantly more common in LQT1 compared to controls (p < .0001), while there was no difference between LQT2 (p = .5) or LQT3 and controls (p > .9). Presence of CI was not a predictor of LQTS‐associated symptoms, BB side effects or likelihood of future breakthrough cardiac events (BCE).ConclusionsPatients with LQTS, particularly LQT1, demonstrate a SAN phenotype of CI. If assessing BB therapy effect by impact on peak HR, the patient's pretreatment peak HR, rather than an age‐ and gender‐predicted maximum HR, should be used.

Abstract BACKGROUND Myxopapillary ependymomas (MPE) are slow-growing tumors of the spine typically involving the medullary conus and cauda equina. MPE is regularly managed with surgical resection with radiation therapy reserved for cases where gross total resection cannot be achieved. Management of inoperable cases represents a clinical challenge. No systemic therapy is approved for treatment of MPE. Addition of chemotherapy may improve outcomes for cases not amenable to resection. MATERIAL AND METHODS We report feasibility and preliminary efficacy of combination treatment with proton beam radiation therapy and temozolomide chemotherapy for a patient with large, unresectable MPE. RESULTS A 19-year-old female presented with one year of gradually worsening hip and back pain despite treatment with physical therapy. MRI Lumbar spine identified a destructive and expansile T2-heterogenous and hyperintense intraosseous mass (14 x 12 x 13 cm) with extraosseous expansion involving the sacrum, coccyx, and left SI joint with abnormal soft tissue enhancement extending along the posterior spine. No additional lesions were identified on neuro-axis imaging. Biopsy of the mass was consistent with a WHO grade 2 myxopapillary ependymoma. Standard treatment of care would include complete surgical resection. Unfortunately, this would require a morbid procedure in an en block fashion with immediate and permanent loss of bowel, bladder, sexual, and ambulatory function in a young patient whose primary symptom was pain and mild weakness. It was therefore elected to treat the patient in an unconventional approach and begin with proton beam radiation therapy (59.4 Gy in 33 fractions) with concurrent temozolomide followed by 6 cycles of adjuvant temozolomide. Mild clinical improvement and significant radiographic response were achieved (size reduced to 8 x 7 x 11 cm). CONCLUSION This case suggests a potential role for use of proton radiation therapy with concurrent and adjuvant temozolomide for management of myxopapillary ependymoma not amenable to surgical resection.

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease associated with tumors in multiple organs. VHL is characterized by mutation of the VHL gene which leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. Conventional management of VHL-associated tumors involves surgical resection and radiation therapy. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). Belzutifan was approved by the United States Food and Drug Administration (FDA) in August 2021 as a targeted therapy option for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Our objective here is to report on our clinical experience with use of belzutifan for VHL-associated CNS hemangioblastomas. MATERIAL AND METHODS We retrospectively chart reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2024. RESULTS Nine adults (5 female, 4 male) were included in the study. Of those able to continue the therapy without interruption (6 patients), the median duration of therapy at last follow-up was 11.5 months (range 3-22 months). Seven had radiographic response to therapy after a median of 3 months (1-5 months), with a maximal response to therapy after a median of 13 months (3-29 months). One patient had a mixed radiographic response, and 1 patient had tumor progression while on belzutifan noted at 5 months. The most common adverse effect was fatigue. Seven patients reported fatigue, 4 patients experienced anemia, and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects, specifically fatigue and hypoxia. One patient had to take multiple medication pauses, once due to seizure and once due to kidney injury, but resumed treatment with dose reduction. CONCLUSION Among patients with VHL-associated CNS hemangioblastomas, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to FDA approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, duration of treatment, and effects of cessation after long-term use.