Biochemical and Clinical Features of Insulinoma in a Patient with Turner Syndrome

Turner syndrome (TS), i.e., mosaic or nonmosaic states with only one normal X chromosome in females, is characterized by a wide spectrum of somatic, hormonal, and metabolic features. Here we report an unusual case of recurrent hypoglycemia in a 53-year-old woman with TS. Biochemical work-up following a 72h fast revealed detectable, inappropriate for low glucose insulin levels and elevated proinsulin and beta-hydroxybutyrate (BOHB) levels. MR and multiphase CT showed a solid 2.5 cm pancreatic tail mass with absent uptake in the 111In-pentetreotide (Octreoscan) scan. Subsequent hepatic vein blood sampling after intra-arterial calcium stimulation showed sharp increase in insulin and modest increase in proinsulin levels. The patient underwent excision of the mass with resolution of symptoms. Histopathologic examination confirmed the neuroendocrine etiology of the tumor. This is, to our knowledge, the third report of TS and concomitant insulinoma. Impaired counterregulatory response to hypoglycemia in patients with TS may result in symptomatic hypoglycemia with only mild insulin elevation and elevated proinsulin in setting of hypoglycemia may be the only indication of insulinoma in these patients. BOHB levels should not be used for ruling out EHH in patients with TS

Radioimmunotherapy with 90Y-DOTA-BC8 (anti-CD45 Antibody): Effect of Spleen Size and Uptake on Bone Marrow Absorbed Dose

1018 Objectives 90Y-DOTA-BC8 (anti-CD45 antibody) is being investigated as a treatment for hematologic malignancies in several ongoing clinical trials at the Fred Hutchinson Cancer Research Center. We analyzed the effect of spleen size and relative splenic uptake (%ID/g) of radiolabeled antibody on the absorbed dose to bone marrow. Methods: We reviewed biokinetic data on 39 patients who received radiotracer infusions of (129.5 to 406 MBq) 111In-DOTA-BC8 (0.5 or 0.75 mg/kg) followed by serial gamma camera imaging. Iliac crest bone marrow biopsies were obtained approximately 24 hours after antibody infusion to calculate the percent of administered activity (% ID/g) in marrow and to normalize the marrow time-activity curves from direct counting for dosimetry. Patient-specific organ absorbed doses were calculated with correction for organ volumes obtained from CT scans. We compared the calculated red marrow dose with spleen size and splenic uptake to ascertain whether the spleen acts as a sink for radiolabeled antibody and reduces the dose to the marrow. Results: Spleen size ranged from 62 to 758 cm3 (321.692 ± 144.33); initial antibody uptake in the spleen ranged from 0.054 to 0.317 % ID/g (0.184 ± 0.069). Calculated marrow doses ranged from 1.98 to 26.8 cGy/mCi (12.39 ± 7.70). Increasing spleen size reduced the marrow dose, but measurement uncertainties associated with biopsy specimen marrow content may have reduced the correlation coefficient (r = 0.25). The spleen acts as a natural sink for radiolabeled antibody which reduces uptake and retention of radiolabeled antibody in red marrow. Conclusions: Radioimmunotherapy with 90Y-DOTA-BC8-antibody has the ability to deliver substantial radiation doses to hematopoietic tissues in patients treated for hematologic malignancies. Spleen size weakly correlated with both red marrow clearance half-time (r = 0.19) and marrow dose (r = 0.25). (Research was supported by NCI P01CA044991, K08CA151682, and the David and Patricia Giuliani Family Foundation.

Megadose 90Y-ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCLs), although outcomes are worse in aggressive disease, and most patients will still experience relapse. Radioimmunotherapy using 90Y-ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that megadoses of 90Y-ibritumomab tiuxetan with reduced- intensity conditioning could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo- HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-ibritumomab tiuxetan (1.5 mCi/kg; maximum, 120 mCi), fludarabine, and then 2 Gy total body irradiation before HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy, including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y-ibritumomab tiuxetan activity of 113.6 mCi (range, 71.2-129.2 mCi) was administered, delivering a median of 552 cGy to the liver (range, 499-2411 cGy). The estimated 1- and 5-year progression-free survival was 55% (95% confidence interval [CI], 31-73) and 50% (95% CI, 27-69) with a median progression-free survival of 1.57 years. The estimated 1- and 5-year overall survival was 80% (95% CI, 54-92) and 63% (95% CI, 38-81) with a median overall survival of 6.45 years. Sixteen patients (80%) experienced grade 3 or higher toxicities, although nonrelapse mortality was 10% at 1 year. No patients developed secondary acute myeloid leukemia/myelodysplastic syndrome. Megadose 90Y-ibritumomab tiuxetan, fludarabine, and low-dose total body irradiation followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified end point while producing nonhematologic toxicities comparable to those of standard reduced-intensity conditioning regimens

90 Y-labeled anti-CD45 antibody allogeneic hematopoietic cell transplantation for high-risk multiple myeloma

To improve disease control without increasing the toxicity of a reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM), a phase I trial was performed using an antibody-radionuclide conjugate targeting CD45 (90Y-DOTA-BC8) as conditioning. 90Y-DOTA-BC8 was combined with fludarabine and low-dose TBI followed by allogeneic HCT in patients with MM and ≥1 adverse risk characteristic at diagnosis, relapse after autologous transplant, or plasma cell leukemia (PCL). The primary objective was to estimate the maximum tolerated radiation absorbed dose. Fourteen patients were treated (one with PCL, nine failed prior autologous HCT, and nine with ≥1 adverse cytogenetics). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicities were manageable and included primarily gastrointestinal (43%) and metabolic/electrolyte disturbances (36%). Treatment-related mortality at 100 days was 0%. At a median follow-up of 5 years, the overall survival was 71% (median not reached) and the progression-free survival was 41% (median 40.9 months). The incorporation of CD45-targeted radioimmunotherapy (RIT) into a reduced-intensity allogeneic HCT is well-tolerated and may induce long-term remissions among patients with poor-risk MM, supporting further development of RIT-augmented conditioning regimens for HCT