Carabenciov, Ivan D.

Abstract Panobinostat (PBST) is a histone deacetylase inhibitor with biologic rationale in the treatment of gliomas harboring H3 K27M mutation. METHODS We performed a retrospective medical record review of adult patients with H3 K27M mutant diffuse midline glioma treated with PBST at Mayo Clinic (Rochester, MN). RESULTS Four patients were identified with a mean age 40 years (range 22–62 years). Tumor location was: spinal cord (thoracic n=1, cervical n=1), brainstem (n=1), and thalamus (n=1).Two patients underwent biopsy alone while two underwent a partial resection. Three patients were treated with radiation (36–54 Gy) immediately prior to PBST monotherapy, and one patient was treated with PBST monotherapy without preceding radiation. All patients were otherwise chemotherapy naïve and did not receive any concurrent chemotherapy with PBST. PBST was dosed at either 10 mg (n=1) or 20mg (n=3) administered on days 1, 3, 5, 8, 10 and 12 of 21 day cycles. The mean duration of PBST therapy was 5 months (range 2–11 months). PBST was well tolerated overall. One patient experienced an objective response per RANO criteria. Two patients continue on therapy (5 cycles, 12 cycles) with stable disease. One patient rapidly progressed after 2 cycles of PBST therapy. In contrast with the patients who derived benefit from PBST, this patient was younger (22) and had multifocal disease with leptomeningeal involvement at treatment onset. The average progression free survival post PBST initiation was 8 months. CONCLUSION This single institution case series shows promise that PBST may have therapeutic benefit in adult patients with H3 K27M mutant diffuse midline glioma.

Abstract BACKGROUND The Tumor Treating Fields (TTF) mechanism of action is hypothesized act upon mitosis by disrupting the cell spindle apparatus. However, biomarkers and human tissue correlation of the effect of the TTF device are lacking. CASE: A 41 year-old previously healthy woman was found to have a right frontoparietal glioblastoma after she developed subacute onset of left hemiparesis and headache. The tumor was IDH wild type MGMT promoter unmethylated and TERT mutated. Chromosomal Microarray (CMA) was performed and demonstrated genome wide aneuploidy primarily characterized by hyperdiploidy. She underwent a gross total resection of the enhancing portion of the tumor and subsequent standard chemoradiotherapy (60 Gy IMRT with concomitant temozolomide) followed by initiation of the TTF device and adjuvant temozolomide. Six months after diagnosis, after 72 days of using the TTF device with 75% compliance and completion of the third cycle of temozolomide the patient had radiographic recurrence. She underwent a repeat resection. Pathology demonstrated recurrent tumor. Genetic analysis no longer demonstrated chromosomal losses or gains: the tumor was diploid. DISCUSSION This case may be a demonstration of effect of the TTF device applying a selective pressure to cells with multiple chromosomal gains and losses as the efficiency of mitosis in these cells may already be severely compromised. We are currently performing CMA on all patients with available tissue treated with the TTF device at our institution, with a planned retrospective analysis to explore this hypothesis further. CONCLUSION Repeat resection with detailed genetic analysis of GBM recurrence after therapies may help generate hypotheses regarding mechanisms of resistance, and in this case, mechanisms of action of the TTF.

Pilocytic astrocytomas (PA) are highly vascular tumors with vascular endothelial growth factor (VEGF)–vascular endothelial growth factor receptor-2 (VEGFR-2) signaling present in the tumor vasculature. PA may, therefore, be responsive to VEGF blockade with bevacizumab (BEV). Data regarding the use of BEV in refractory PA in adults are limited primarily to case reports and case series of patients with recurrent PA. We conducted a single-center, retrospective cohort study from 2009 to 2018. We screened 426 patients with pathologically confirmed PA. We identified 5 adult patients with PA who received BEV at our institution with sufficient clinical follow-up to derive evidence of the efficacy and toxicity. All 5 patients experienced tumor progression after initial therapies which included surgery, radiation, and chemotherapy. Four patients received BEV as monotherapy, whereas 1 received BEV with the continuation of previously initiated alkylating chemotherapy (temozolomide). The average duration of BEV therapy was 10.2 months (range, 1 to 20 mo) with an average follow-up of 47 months (range, 6 to 112 mo). One patient had a severe necrotizing rash in areas of skin contact and discontinued after 1 cycle of BEV. All patients had stabilization per RANO criteria, with 1 patient experiencing progression after 10 months on treatment. One patient had disease progression 5 years after completion of BEV, but the tumor responded to repeat treatment with BEV. Our institution’s experience with the use of BEV in recurrent PA is in line with previous reports of therapeutic benefit in recurrent adult PA.

Objective: To assess the long-term outcomes of patients hospitalized with severe West Nile neuroinvasive disease. Design: Retrospective cohort. Setting: Patients admitted to a referral center (Saint Mary’s Hospital, Mayo Clinic). Participants: Twenty-six patients with West Nile neuroinvasive disease were identified by retrospective search of electronic database of Saint Mary’s Hospital from January 1999 to November 2016. Interventions: Retrospective electronic medical records review and prospective telephone follow-up. Measurements and Main Results: Functional disability and cognitive outcomes were evaluated with the modified Rankin Scale and the Telephone Interview for Cognitive Status scores. Data on the time that the patient returned home after the hospitalization for West Nile neuroinvasive disease and the time of return to work were also collected. We identified 26 patients (81% males), 59 ± 17 years old. After a median hospital stay of 14.5 days (3–126), four patients died and 90% of survivors had a modified Rankin Scale of 3–5. Two additional patients died, and 80% of survivors had a modified Rankin Scale of 0–2 after a median follow-up of 73 months (1–144). Seven patients had cognitive impairment, which was severe in two of them. The combination of encephalitis and acute flaccid paralysis at presentation was associated with lower likelihood of returning home within 1 month after discharge (p < 0.01). Patients who required mechanical ventilation were more likely to have a modified Rankin Scale of 3–5 at last follow-up (p = 0.03), less likely to return home within 1 month of discharge (p < 0.01), less likely to return to their jobs (p < 0.01), and showed a trend toward having cognitive impairment (p = 0.05). Conclusions: Despite having poor outcomes at discharge, most West Nile neuroinvasive disease survivors with severe early disability can recover functional independence in the long term, justifying aggressive support during the acute phase and extensive rehabilitation efforts.

Pulmonary hypertension (PH) has been found to have significant morbidity and mortality. The treatment of PH has advanced considerably with increasingly more effective and safer options. With an increasing effort to diagnose patients early, non-invasive techniques are often used to screen those patients likely to have PH. Computerized tomography (CT) chest scans are increasingly utilized in the evaluation of patients with exertional dyspnea, including those with suspected PH. The main role of the CT scan is to evaluate for any associated underlying diseases. There have been attempts to address the utility of CT to predict the presence of PH. This article reviews previously published investigations to summarize the relationship between pulmonary artery dimensions and PH to determine both the strength of the correlation and its discriminatory ability for use in clinical practice.