Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Histiocytoses are diverse hematopoietic diseases with disabling neurologic involvement. Recently, targeted mitogen-activated protein kinase pathway inhibitors have been used with clinical and radiologic response; however, some patients are unable to tolerate these treatments or have isolated and/or refractory neurologic, ocular, or head and neck (NOHN) disease. Intra-arterial administration of chemotherapy has conferred favorable responses in various neoplasms; however, treatment and outcomes across histiocytosis subtypes have not been examined. METHODS:Patients with biopsy-proven histiocytosis involving NOHN structures underwent an outpatient interventional procedure with angiography, selective catheterization, and intra-arterial infusion of melphalan, with target arteries depending on the site of disease. Patients were followed with radiologic (i.e., PET/CT, CT, MRI, or ophthalmic ultrasound and optical coherence tomography) and quantified functional assessments (i.e., vision, speech, or balance) as appropriate. Complete or partial radiologic and functional response rates were captured as well as frequency of subsequent progression. RESULTS:Eighteen patients underwent 74 total treatment instances. For 14 patients with radiologically evaluable tumorous disease, 10 (71%) had partial or complete response and the remaining 4 had stable disease; 3 of 14 (21%) had subsequent radiologic progression. Of 13 functionally evaluable patients, including 6 with neurodegenerative histiocytosis, 12 (92%) experienced functional improvement; 7 of 13 (54%) had subsequent functional worsening consistent with disease progression. There were no intraprocedural complications; 3 patients required hospitalization following treatment, including 1 patient with allergic reaction to melphalan. DISCUSSION/CONCLUSIONS:For patients with tumorous and neurodegenerative histiocytosis, intra-arterial melphalan represents a safe and highly effective treatment with potential to improve neurologic function. Additional study may clarify patients most suitable for this intervention. This novel treatment modality may represent a practice-changing innovation for refractory histiocytosis involving neurologic and ocular structures, as well as neurodegenerative forms. The treatment delivery form is novel, and future work should be directed at studying the efficacy of this modality to other forms of neurologic, ocular, head, and neck cancers. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class IV evidence that in patients with tumorous or neurodegenerative histiocytosis, selective angiographic catheterization and intra-arterial infusion of melphalan result in radiologic and functional improvement.

BACKGROUND/UNASSIGNED:I-PU-H71 is an imaging biomarker of epichaperome formation. The tracer has been established to localize in tissues under chronic stress, specifically in cancer cells and neurodegenerative brain cells. A first-in-human imaging trial using positron emission tomography (PET) in cancer patients revealed unexpected tracer accumulation in the myocardium. PURPOSE/UNASSIGNED:I-PU-H71 myocardial biodistribution and pharmacokinetics in a series of cancer patients with no history of cardiovascular disease. METHODS/UNASSIGNED:I-PU-H71 while at rest, followed by dynamic and gated/non-gated PET image data acquisitions. Region-of-interest (ROI) analysis of left ventricular myocardium (LVmyo) and background left atrium quantified tracer concentrations as standardized uptake value (SUV) and uptake ratios. Kinetic rate constants were evaluated by a two-tissue compartment model. RESULTS/UNASSIGNED:(IQR, 0.0015-0.0057). Regional assessment demonstrated essentially uniform tracer uptake in LV and myocardial segments; with normal LVEF in all patients (mean 57.7 ± 3.5%); and no patients suffered cardiac events over subsequent 12-month period. CONCLUSION/UNASSIGNED:I-PU-H71 PET. Our data indicates PU-H71 PET merits further study as a myocardial epichaperome biomarker, with potential application in drug development, possibly as a biomarker in subclinical cardiac dysfunction.

Somatostatin receptor imaging using 68Ga-DOTATATE PET is widely popular for evaluation of neuroendocrine tumors. 68Ga-DOTATATE PET/CT shows highest physiologic uptake in spleen followed by other organs such as kidneys, adrenal glands, and liver. Hemangiomas, although rare, are the most common primary benign neoplasm of the spleen, composed of endothelial-lined vascular channels. We present a case of 77-year-old man who underwent 68Ga-DOTATATE PET/CT scan for evaluation of pancreatic neuroendocrine tumor and incidentally demonstrated intense radiotracer uptake in splenic hemangiomata.

To investigate diagnostic and prognostic value of ¹⁸F-FDG PET/CT for surveillance imaging in patients treated for Stage III Merkel cell carcinoma (MCC). Methods: This retrospective study included 61 consecutive stage III MCC patients, who were clinically asymptomatic and underwent surveillance FDG-PET/CT. Findings were correlated with either pathology and/or clinical/imaging follow-up. Median follow-up period was 4.8 years. Statistical analyses were performed. Results: FDG-PET/CT detected unsuspected recurrences in 33% patients (20/61) with lesion-based sensitivity, specificity, and accuracy of 92%, 93%, and 93%, respectively. Mean±SD SUV for malignant and benign lesions was 7.5±3.9 and 3.8±2.0, respectively. Unknown distant metastases, as first recurrence site, were noted in 12 of 61 patients. Those with positive disease on FDG-PET/CT within one year of definitive treatment had relatively worse overall survival (p<0.0001). After adjustment on stage, risk of death increased with higher SUV_max (HR for one unit=1.17;P = 0.006) and with a higher number of positive lesions on FDG-PET/CT (HR for one additional lesion = 1.60;p<0.001). Conclusion: Post-definitive treatment surveillance FDG-PET/CT scan detects unsuspected recurrences and has prognostic value. Inclusion of FDG-PET/CT within the first 6 months after definitive treatment would be appropriate for surveillance and early detection of recurrence. Our data merits further studies to evaluate the prognostic implications.

Prostate specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. Radioligand therapy using beta-emitting Lutetium-177 (¹⁷⁷Lu)-labeled-PSMA-617, a radiolabeled small molecule, has gained attention as a novel targeted therapy for metastatic prostate cancer, given its high affinity and long tumor retention, and rapid blood pool clearance. In March 2022, the United States Food and Drug administration has granted approval to the targeted ¹⁷⁷Lu-PSMA-617 therapy for treatment of patients with PSMA-positive metastatic castration resistant prostate cancer, who have been previously treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy. Studies have demonstrated the adverse effects of this treatment, mainly encountered due to radiation exposure to non-target tissues. Salivary glands show high PSMA-ligand uptake and receive increased radiation dose secondary to accumulation of ¹⁷⁷Lu-PSMA-617. This predisposes the glands to radiation-mediated toxicity. The exact mechanism, scope and severity of radiation-mediated salivary gland toxicity are not well understood, however, the strategies for its prevention and treatment are under evaluation. This review will focus on the current knowledge about salivary gland impairment post ¹⁷⁷Lu labeled PSMA-based radioligand therapies, diagnostic methodologies, and imaging with emphasis on salivary gland scintigraphy. The preventive strategies and known treatment options would also be briefly highlighted.