Soni, Pranay

Abstract BACKGROUND Gaseous hydrogen sulfide (H2S), a by-product of cysteine metabolism, inhibits cancer cell behavior and growth in glioblastoma (GBM) models. H2S production capacity (HPC) is decreased in human GBM specimens compared to non-tumor controls. Thus, boosting HPC is a novel strategy for GBM treatment. Suppression of thyroid hormone signaling increases production of H2S. Hypothesis: methimazole-induced hypothyroidism will increase tumor HPC to enhance chemotherapy efficacy in GBM. GOAL Proof of concept that methimazole, by reducing thyroid hormone signaling, can increase HPC in patients with recurrent/progressive GBM (rGBM). PRIMARY ENDPOINTS 10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling. METHODS This window of opportunity trial evaluates safety, HPC in plasma and tumor, and efficacy of methimazole + chemotherapy in patients with rGBM. rGBM patients planned for a resection begin methimazole 15 mg/d 5-7 days pre-op with investigator’s choice chemotherapy added 10-28 days post-op. Patients receive combination until progression. Pre- and post-op plasma and resected tumor tissue are assayed for HPC and proteins relevant to H2S production. Key eligibility: rGBM for whom a clinically-indicated resection is planned; normal thyroid function with no history of thyroid dysfunction. Patients may have received unlimited prior regimens including bevacizumab. RESULTS To date 15 patients (8 male), median age 56 years, enrolled. The trial was amended to increase methimazole to 25 mg/d; 3 patients have received this dose. Median TSH rose from 1.3 mU/ml to 20.5 at cycle 6. Free T3 and T4 did not fall significantly. Median plasma HPC rose 3-fold while tumor HPC did not rise significantly. No treatment-related grade 3-5 toxicities. Efficacy: PFS6 – 15% and OS12 – 21%. CONCLUSIONS Induction of subclinical hypothyroidism is feasible and safe in rGBM with significant increases in plasma but not tumor HPC. Further tumor correlative data for the dose-escalated methimazole will be presented.

Abstract Context Pituitary apoplexy (PA) has been traditionally considered a neurosurgical emergency, yet retrospective single-institution studies suggest similar outcomes among patients managed medically. Objective We established a multicenter, international prospective registry to compare presentation and outcomes in PA patients treated with surgery or medical management alone. Methods A centralized database captured demographics, comorbidities, clinical presentation, visual findings, hormonal status, and imaging features at admission. Treatment was determined independently by each site. Key outcomes included visual, oculomotor, and hormonal recovery, complications, and hospital length of stay. Outcomes were also compared based on time from symptom onset to surgery, and from admission or transfer to the treating center. Statistical testing compared treatment groups based on 2-sided hypotheses and P less than .05. Results A total of 100 consecutive PA patients from 12 hospitals were enrolled, and 97 (67 surgical and 30 medical) were evaluable. Demographics, clinical features, presenting symptoms, hormonal deficits, and imaging findings were similar between groups. Severe temporal visual field deficit was more common in surgical patients. At 3 and 6 months, hormonal, visual, and oculomotor outcomes were similar. Stratifying based on severity of visual fields demonstrated no difference in any outcome at 3 months. Timing of surgery did not affect outcomes. Conclusion We found that medical and surgical management of PA yield similar 3-month outcomes. Although patients undergoing surgery had more severe visual field deficits, we could not clearly demonstrate that surgery led to better outcomes. Even without surgery, apoplectic tumor volumes regress substantially within 2 to 3 months, indicating that surgery is not always needed to reduce mass effect.

Abstract Purpose To characterize and classify the location of recurrence in surgically resected World Health Organization (WHO) grade II intracranial meningiomas that did not receive adjuvant radiation, and compare the recurrence pattern of those that underwent gross total (GTR) versus subtotal resection (STR). Methods A retrospective review of patients who underwent surgical resection of WHO grade II meningiomas at our institution between 2006 and 2019 was performed. Patients that were observed postoperatively without adjuvant radiation and subsequently developed a recurrence were included. Recurrence was defined as evidence of radiographic progression on postoperative surveillance MRI. Location of recurrence were categorized as: (1)central - growth observed inside the area of the previously resected tumor more than 1 cm inside the original tumor margin; (2)marginal - growth observed within 1 cm (inside or outside) of the original tumor margin; and (3)distant - growth observed more than 1 cm outside of the original tumor margin. Results A total of 22 patients matched the inclusion criteria. Twelve (55%) underwent GTR while ten (45%) underwent STR. Of the GTR patients, ten (83.3%) had central recurrence, 11 (91.7%) had marginal recurrence, and only 4 (33.3%) had distant recurrence. Of the STR patients, 9 (90.0%) had central recurrence, all 10 (100.0%) had marginal recurrence, and only 4 (40.0%) had distant recurrence. Conclusion The present study evaluating patterns of recurrence for WHO grade II meningiomas after surgical resection showed that recurrence occurred centrally and/or at the original tumor margin, with only a minority recurring > 1cm outside the original tumor margin.

OBJECTIVE Surgery is the primary treatment for craniopharyngioma with the preservation of hypothalamic function of paramount importance. Infundibular preservation is debated, as maximal resection decreases recurrence rates but causes hypopituitarism. A triphasic response of diabetes insipidus (DI), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and recurrent DI has been described after pituitary surgery, but the impact of infundibular preservation on the triphasic response following craniopharyngioma resection has not been well established. The authors’ objective was to assess postoperative fluid and sodium balance and differences in ADH imbalance management following endonasal craniopharyngioma resection based on infundibular transection status. METHODS This is a retrospective cohort study of 19 patients with craniopharyngioma treated with endoscopic endonasal resection between 2014 and 2021. Resection was dichotomized into infundibular transection or preservation. Postoperative triphasic response, time to DI, and time to ADH replacement were compared using Fisher’s exact test and Kaplan-Meier analysis. RESULTS Based on surgeon impression, 10 patients had infundibular transection and 9 had infundibular preservation. Overall, 16 patients experienced DI, 12 experienced persistent DI, and 6 experienced SIADH. A postoperative triphasic response occurred in 40% (n = 4) of transection patients without preoperative DI and 11% (n = 1) of preservation patients without preoperative DI. The median time to postoperative DI (0.5 vs 18.0 hours, p = 0.022) and median time to ADH replacement therapy (4.5 vs 24 hours, p = 0.0004) were significantly shorter in the transection group than in the preservation group. CONCLUSIONS Following endonasal craniopharyngioma resection, the triphasic response occurs in nearly half of infundibular transection cases. DI begins earlier with infundibular transection. On the basis of the study findings in which no patients met the criteria for SIADH or were endocrinologically unstable after postoperative day 6, it is reasonable to suggest that otherwise stable patients can be discharged at or before postoperative day 6 when ADH fluctuations have normalized and endocrinopathy is appropriately managed with oral desmopressin. Infundibular transection status may impact postoperative hormonal replacement strategies, but additional studies should evaluate their efficacies.