Stafford, Scott L.

Abstract OBJECTIVE This study aimed to analyze the hemorrhagic risk of melanoma brain metastases following SRS. METHODS A retrospective analysis was conducted using a prospective institutional database between 1990 and 2021. Lesional hemorrhage was categorized as definite or possible, and hemorrhage severity was graded using CTCAE. RESULTS The study identified 291 patients with 1083 lesions. The mean age of patients was 60 ± 15 years, with 61% being male. Median follow-up was 11 months, corresponding to 581 patient-years. Among the patients, 82 (28%) experienced 135 lesional hemorrhages (13%). Of these, 88 lesions in 61 patients were grade 1-2 hemorrhages, 42 lesions in 25 patients were grade 3, and five lesions in five patients progressed from grade 1 to 3. Surgical intervention was required for 17 lesions (2%) in 16 patients (5%). Lesional hemorrhage was associated with radiosurgery performed between 2015 and 2021 (OR, 0.373; 95% CI, 0.231-0.60; p < 0.001), increasing marginal dose (OR, 0.89; 95% CI, 0.82-0.98; p = 0.017), antiplatelet use (OR, 0.192; 95% CI, 0.082-0.45; p < 0.001), and WBRT (OR, 0.51; 95% CI, 0.330-0.77; p = 0.0017). The cumulative lesional hemorrhage risk reached 17–20% at 36 months following radiosurgery, with 95-96% of hemorrhages occurring within the initial year. Median OS was 11 months (95% CI, 9-13 months). Patients who received radiosurgery between 2015 and 2021 exhibited a median OS of 17 months (95% CI, 10-24 months; p < 0.001), while those without hemorrhage had a median OS of 12 months (95% CI, 10-14 months; p = 0.054). CONCLUSIONS Definitive hemorrhage risk was 17% for melanoma brain metastases after SRS within the first three years, with 95% of lesional hemorrhages occurring within the initial year. Surgical intervention was necessary in 5% of patients. Hemorrhage risk and overall survival improved after 2015.

OBJECTIVE The objective of this study was to analyze the hemorrhagic risk of melanoma brain metastases after Gamma Knife radiosurgery (GKRS). METHODS A prospective institutional database was retrospectively queried to identify patients who underwent GKRS for melanoma brain metastases between 1990 and 2021. Lesional hemorrhage was defined as definite or possible based on radiologists’ readings, and severity was graded according to Common Terminology Criteria for Adverse Events. RESULTS Two hundred ninety-one patients with 1083 lesions treated in 419 sessions were identified. The mean (± SD) patient age was 60 ± 15 years, and 61% were male. The median follow-up period for overall survival (OS) was 11 (range 0–214) months with 581 patient-years. Definite/possible lesional hemorrhages occurred in 13% of lesions, with grade 3 hemorrhages observed in 4% of lesions. Surgical intervention was required in 2% of cases (5% of patients), and all resected lesions were pathologically consistent with melanoma. A decreased risk of definite/possible lesional hemorrhage was associated with a later time period between 2015 and 2021 (OR 0.45, 95% CI 0.266–0.75, p = 0.0021), increased marginal dose (OR 0.91, 95% CI 0.83–0.99, p = 0.037), antiplatelet use post-GKRS (OR 0.195, 95% CI 0.083–0.46, p < 0.001), and whole-brain radiotherapy (WBRT; OR 0.53, 95% CI 0.344–0.82, p = 0.0042). After 2015, more patients received anticoagulation, B-Raf proto-oncogene inhibitors, and immune checkpoint inhibitors, and fewer received bevacizumab (p < 0.001). The cumulative risk of lesional hemorrhage was 17%–20% at 36 months from GKRS, with 95%–96% of cases occurring within 12 months. The median patient OS was 11 (95% CI 9–13) months, and multivariate Cox regression analysis revealed that antiplatelet agents (hazard ratio [HR] 0.66, 95% CI 0.45–0.96, p = 0.031) and immune checkpoint inhibitors (HR 0.35, 95% CI 0.26–0.48, p < 0.001) were associated with longer OS, while WBRT (HR 1.36, 95% CI 1.02–1.81, p = 0.037) and definite/possible hemorrhage (HR 1.39, 95% CI 1.04–1.85, p = 0.024) were associated with shorter OS. CONCLUSIONS The definite hemorrhage risk of melanoma brain metastases after GKRS was 17% in the first 3 years and 95% of the lesional hemorrhage occurred within the 1st year. Surgical intervention was needed in 5% of patients. Antiplatelet agents and immune checkpoint inhibitors were associated with improved OS, while definite/possible hemorrhage was associated with worse OS.

OBJECTIVE The supplemented Spetzler-Martin (Supp-SM) grading system was developed to improve the predictive accuracy of surgical risk for patients with brain arteriovenous malformations (AVMs). The aim of this study was to apply the Supp-SM grading system to patients having stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) intermediate- (grade III) or high-grade (grade IV–V) AVMs to enable comparison with published microsurgical series. METHODS In 219 patients who underwent SRS during the period from 1990 to 2016, the Supp-SM grade was calculated for SM grade III (n = 154) or SM grade IV–V (n = 65) AVMs. The Supp-SM grades in these patients were 4 (n = 14, 6%), 5 (n = 36, 16%), 6 (n = 67, 31%), 7 (n = 76, 35%), and 8–9 (n = 26, 12%). Sixty patients (27%) had deep AVMs (basal ganglia, thalamus, or brainstem). Thirty-nine patients (18%) had volume-staged SRS; 41 patients (19%) underwent repeat SRS. The median follow-up period was 69 months for SM grade III AVMs and 113 months for SM grade IV–V AVMs. RESULTS AVM obliteration was confirmed in 163 patients (74%) at a median of 38 months after initial SRS. The obliteration rates at 4 and 8 years were 59% and 76%, respectively. Thirty-one patients (14%) had post-SRS deficits from hemorrhage (n = 7, 3%) or radiation injury (n = 24, 11%). Six patients (3%) died after SRS (hemorrhage, n = 5; radiation injury, n = 1). The rates of neurological decline or death at 4 and 8 years were 11% and 18%, respectively. Factors predictive of nonobliteration were deep location (HR 0.57, 95% CI 0.39–0.82, p = 0.003) and increasing AVM volume (HR 0.96, 95% CI 0.93–0.99, p = 0.002). Increasing AVM volume was the only factor associated with neurological decline (HR 1.05, 95% CI 1.02–1.08, p = 0.002). The Supp-SM grading score did not correlate with either obliteration (HR 0.94, 95% CI 0.82–1.09, p = 0.43) or neurological decline (HR 1.15, 95% CI 0.84–1.56, p = 0.38). CONCLUSIONS The Supp-SM grading system was not predictive of outcomes after SRS of intermediate- or high-grade AVM. In a cohort that included a high percentage (47%) of "inoperable" AVMs according to Supp-SM grade (≥ 7), most patients had obliteration after SRS, although there was a high risk of neurological decline.

Abstract PurposeTo clarify the role of stereotactic radiosurgery (SRS) for atypical meningiomas (AM).MethodsA retrospective analysis of 68 patients with AM having SRS from 1995 until 2019. Nineteen patients (28%) had undergone prior external beam radiation therapy (EBRT) (median dose, 54 Gy). The median follow-up period was 52 months.ResultsEighteen (26%), 17 (25%), and 33 (49%) patients received SRS as an upfront adjuvant (≤ 6 months), early salvage (7-18 months), or late salvage treatment (> 18 months), respectively. The 3-, 5-, and 10-year progression-free survivals (PFSs) were 52%, 35%, and 25%, respectively. The 3-, 5-, and 10-year disease-specific survivals (DSSs) were 85%, 78%, and 61%, respectively. Adverse radiation events (AREs) were observed in 12 patients (18%), with increased or new seizures being the most frequent complication (n=7). Prior EBRT was associated with reduced PFS (HR = 5.92, P <0.01), reduced DSS (HR = 5.84, P <0.01), and an increased risk of ARE (HR = 3.31, P = 0.04). Timing of SRS was correlated with reduced PFS for patients having early salvage treatment compared to upfront adjuvant (HR = 3.17, P = 0.01) or late salvage treatment (HR = 4.39, P <0.01). ConclusionPFS for patients with residual/recurrent AM remains poor despite SRS. Prior EBRT was associated with worse tumor control, higher tumor-related mortality, and an increased risk of ARE. Further study on the timing of SRS is needed to determine if upfront adjunctive SRS improves tumor control compared to salvage SRS.

Abstract Absolute lymphocyte count (ALC) post-autologous stem cell transplantation is an independent predictor for survival in Hodgkin’s Disease (HD). Lymphopenia at diagnosis is associated with worse prognosis in patients with newly diagnosed HD. The role of ALC recovery during standard chemotherapy for HD is unknown. We analyzed all patients managed for HD at the Mayo Clinic from 1986 to 2003. Of the 141 consecutive patients, two patients were excluded due to missing ALC data. Of the 139 patients, 63 patients were females and 76 males. The median age of patients at diagnosis was 31 years (range 6–75 years). 118 (85%) patients presented with nodular sclerosis HD, 10 (7%) with mixed cellularity, 2 (1%) with lymphocyte predominance, 1(1%) with lymphocyte depletion, 4 (3%) with lymphocyte predominant (nodular variant), and 4 (3%) unclassified. Frontline chemotherapy included ABVD (N = 79), MOPP-ABV (N = 47), COPP-ABV (N = 8), BEACOPP (N = 3), and Stanford V (N =2). The median number of cycles was 6 (range: 2–10). The median follow-up for the cohort was 62 months (range: 4–221 months). The ALC recovery was analyzed during the first 4 cycles as 90% of the patients received at least 4 cycles of therapy. Patients with an ALC ≥ 1.3 x 109/l at any time point within the first four cycles of chemotherapy (N = 93) demonstrated improved overall survival (OS) and progression-free survival (PFS) compared to patients with an ALC &lt; 1.3 x 109/L at all time points within the first four cycles of chemotherapy (N =46) (10 years OS and PFS: 91% vs 51%, p &lt; 0.0001; 85% vs 52%, p &lt; 0.0001, respectively). Both groups were balanced for the Hasenclever Index: albumin &lt; 4g/dl (p = 0.1), hemoglobin &lt; 10.5 g/dl (p = 0.46), male gender (p =0.21), age ≥ 45 years (p = 0.06), stage IV disease (p = 0.68), leukocytosis ≥ 15 x 109/L (p = 0.58), and lymphopenia &lt; 600 cell/ml (p = 0.211). Multivariate analysis demonstrated ALC recovery to be independent predictor of OS and PFS when compared to the Hasenclever index. These data suggest a critical role of lymphocyte (immune) recovery during standard chemotherapy in HD.

Abstract BACKGROUND Treatment of temporal lobe glioma (TLG) frequently includes partial or complete temporal lobectomy (TL) followed by radiotherapy (RT). However, there are two approaches for temporal resection cavity RT, 1) standard target volumes (STV) targeting the entire TL resection cavity, dura, and peri-tumoral brain parenchyma or 2) modified target volumes (MTV) targeting only the adjacent peri-tumoral brain parenchyma. We report patterns of failure and a dosimetric comparison of these approaches. MATERIALS AND METHODS This was a retrospective review of 49 patients with WHO grade II-IV TLG who underwent partial or complete TL and post-operative RT between 1998 and 2018. Progression-free survival (PFS) was estimated using the Kaplan-Meier method. RESULTS The median patient age was 56 years (range,21–76). Patients were diagnosed with glioblastoma (n=32,65%), anaplastic glioma (n=10,20%) and low-grade glioma (n=7,14%). Treatment included partial TL with STV (n=33,67%), partial TL with MTV (n=5,10%), complete TL with STV (n=8,16%) and complete TL with MTV (n=3,6%). Mean RT dose was 60 Gy (range,40–76) in 30 fractions (range,15–39). At median follow-up time of 18 months (range, 3–161), 44 patients (90%) experienced recurrence: 34 (77%) in-field, 5 (11%) out-of-field, and 5 (11%) both in- and out-of-field. Among the 39 in-field failures, the location of recurrence included brain parenchyma (n=38,97%), ventricle (n=6,15%), and dura (n=5,13%). No patient experienced isolated dural recurrence regardless of tumor grade, extent of TL, or radiation volume. Median PFS was 20 months (95% confidence interval [CI]: 15–24). RT volume (STV vs. MTV) was not associated with worsened PFS (hazard ratio: 1.1, 95% CI: 0.5–2.6). MTV was associated with significant reductions in mean or max doses to brain stem, optic chiasm, optic nerves, hippocampus, and pituitary compared to STV. CONCLUSION Omitting RT to the entire TL cavity may reduce dose to multiple normal tissues with no detriments in dural recurrence or PFS.

OBJECTIVEStereotactic radiosurgery (SRS) is an accepted treatment option for patients with benign parasellar tumors. Here, the authors’ objective was to determine the risk of developing new or progressive internal carotid artery (ICA) stenosis or occlusion after single-fraction SRS for cavernous sinus meningioma (CSM) or growth hormone–secreting pituitary adenoma (GHPA).METHODSThe authors queried their prospectively maintained registry for patients treated with single-fraction SRS for CSM or GHPA in the period from 1990 to 2015. Study criteria included no prior irradiation and ≥ 12 months of post-SRS radiological follow-up. Pre-SRS grading of ICA involvement was applied according to the 1993 classification schemes of Hirsch for CSM or Knosp for GHPA.RESULTSThe authors conducted a retrospective review of 283 patients, 155 with CSMs and 128 with GHPAs. Ninety-three (60%) CSMs were Hirsch category 2 and 3 tumors; 97 (76%) GHPAs were Knosp grade 2–4 tumors. Median follow-up after SRS was 6.6 years (IQR 1–24.9 years). No GHPA or category 1 CSM developed ICA stenosis or occlusion. Three (5.2%) patients with category 2 CSMs had asymptomatic ICA stenosis (n = 2) or occlusion (n = 1); 1 (1.1%) category 2 CSM patient had transient ischemic symptoms. Five (14.3%) category 3 CSMs progressed to ICA occlusion (4 asymptomatic, 1 symptomatic). The median time to stenosis/occlusion was 4.8 years (IQR 1.8–7.6). Five- and 10-year risks of ICA stenosis/occlusion in category 2 and 3 CSM patients were 7.5% and 12.4%, respectively. Five- and 10-year risks of ischemic stroke from ICA stenosis/occlusion in category 2 and 3 CSM patients were both 1.2%. Multivariate analysis showed patient age (HR 0.92, 95% CI 0.86–0.98, p = 0.01), meningioma pathology (HR and 95% CI not defined, p = 0.03), and pre-SRS carotid category (HR 4.51, 95% CI 1.77–14.61, p = 0.004) to be associated with ICA stenosis/occlusion. Internal carotid artery stenosis/occlusion was not related to post-SRS tumor growth (HR and 95% CI not defined, p = 0.41).CONCLUSIONSNew or progressive ICA stenosis/occlusion was common after SRS for CSM but was not observed after SRS for GHPA, suggesting a tumor-specific mechanism unrelated to radiation dose. Pre-SRS ICA encasement or constriction increases the risk of ICA stenosis/occlusion; however, the risk of ischemic complications is very low.

Abstract Introduction: Outcomes of multidisciplinary and molecular tumor boards have been reported. Lymphoma specific tumor board outcomes have not been reported in the molecular era. In addition, the utility of multi-site, interactive tumor boards using videoconference technology are not widely reported. We prospectively followed the outcomes of a multidisciplinary multi-site lymphoma tumor board in the molecular era and during a change in the revision of the World Health Organization Classification in first published in 2016. Methods: The Mayo Clinic Lymphoma Tumor Board is a component of the international Mayo Clinic Care Network (MCCN). The format includes the clinical case presentation, presentation of radiology and hematopathology findings by the appropriate specialist, proposed treatment options, review of the literature pertinent to the case, and discussion followed by recommendations. Requirement for presentation includes having a diagnosis of lymphoma with pathology reviewed at Mayo Clinic, Rochester, MN (MCR). Pathology and radiology material, when relevant to the case, are required to be reviewed at MCR and presented by MCR pathologists/radiologists. Patients must be presented prospectively, and have active clinical issues or questions to be addressed. Four cases are presented per 60-minute meeting. 309 consecutive highly selected cases with a diagnosis of lymphoma were presented at the Mayo Clinic Lymphoma Tumor Board from 2014 to 2018. The pathology material was independently reviewed by the presenting hematopathologists and radiology material by the presenting radiologist. Participants are office based and included multiple members of the health care team which also incudes pharmacists, clinical research associates affiliated with lymphoma research, and physicians in training. Recommendations were prospectively tracked for changes in radiology interpretation, pathologic diagnosis, and treatment approaches. Actual follow-up of all patients after the meeting was not allowed in the MCCN. Participation in the meeting can be either via in-room attendance at MCR, video conference at a participating MCCN site, or via non-participatory live-stream online. Results: 309 cases were presented were presented from 2014-2018. 258 cases were from MCR, and 51 were not physically seen at MCR. 16 cases were presented at a subsequent meeting for further recommendations in the course of their disease after the initial presentation. 54% of patients presented had changes in some aspect of their care as a result of the meeting. Changes in radiologic interpretation occurred in 5 (1.6%) patients. The pathologic diagnosis changed in 27 (8.7%). Additional testing was recommended in 44 (14%). Clinical management changes were recommended in 90 (29%) cases. These included alterations in treatment approach in 43 (14%), change from undecided to pursuit of treatment 10 (3%), change from undecided regarding treatment approach to further diagnostic testing 4 (1.3%), change from observation to treatment 9 (3%), change from treatment to observation 4 (1.3%), and treatment to further tests in 2 (0.6%) Site in room average attendance (internal/external) was 16.8/8.6. Non-participatory live-stream attendance was not possible to track. In an annual electronic evaluation of this activity, 93% of the responders reported an improvement in knowledge and competence, and 100% recommended no changes to the format of the conference. Enhancements over time have included Continuous Medical Education credit, an in room microscope, and real-time radiology images. Selected cases will now be on line on an international web site. Conclusion: In this highly selected group of lymphoma cases from multiple sites over a 4-year period, 54% of the (167/309) case presentations resulted in changes to some aspect of care as a direct result of this tumor board. A multidisciplinary lymphoma tumor board approach was of value, efficacious, and meaningfully impacted lymphoma patients while substantially enhancing interdisciplinary interactions. Disclosures Ansell: Celldex: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding.