The use of single-timepoint images to link administered radioiodine activity (MBq) to a prescribed lesion radiation-absorbed dose (cGy): a regression-based prediction interval tool for the management of well-differentiated thyroid cancer patients.

PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.

Treatment Response and Clinical Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors to Lutetium-177-DOTATATE.

INTRODUCTION: Lutetium-177 (177Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well-differentiated (WD) high-grade (HG) NETs treated with 177Lu-DOTATATE. MATERIALS AND METHODS: Patients with WD HG NETs treated with 177Lu-DOTATATE at MSK from 2018 to 2020 were identified. Demographics, response (RECIST 1.1), and progression-free survival (PFS) were determined. Next-generation sequencing (NGS) was performed in the archival tumor. RESULTS: Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22-56). Thirteen patients (68%) completed all four 177Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7-20.9). Most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; G3/4, 1 patient, 5%), anemia (7 patients, 37%; G3/4, 2 patients, 11%), leukopenia (6 patients, 32%; G3/4, 0 patients), and liver function test elevation (4 patients, 21%; G3/4, 0 patients). NGS results were available from 13/19 tumors (68%). The most observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations identified. CONCLUSION: We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations.

Predicting malignancy in patients with adrenal tumors using 18 F-FDG-PET/CT SUVmax.

BACKGROUND AND OBJECTIVES: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) parameters may help distinguish malignant from benign adrenal tumors, but few have been externally validated or determined based on definitive pathological confirmation. We determined and validated a threshold for 18 F-FDG-PET/CT maximum standard uptake value (SUVmax) in patients who underwent adrenalectomy for a nonfunctional tumor. METHODS: Database review identified patients with 18 F-FDG-PET/CT images available (training cohort), or only SUVmax values (validation cohort). Discriminative accuracy was assessed by area under the curve (AUC), and the optimal cutoff value estimated by maximally selected Wilcoxon rank statistics. RESULTS: Of identified patients (n = 171), 86 had adrenal metastases, 20 adrenal cortical carcinoma, and 27 adrenal cortical adenoma. In the training cohort (n = 96), SUVmax was significantly higher in malignant versus benign tumors (median 8.3 vs. 3.0, p < .001), with an AUC of 0.857. Tumor size did not differ. The optimal cutoff SUVmax was 4.6 (p < .01). In the validation cohort (n = 75), this cutoff had a sensitivity of 75% and specificity 55%. CONCLUSIONS: 18 F-FDG-PET/CT SUVmax was associated with malignancy. Validation indicated that SUVmax ≥ 4.6 was suggestive of malignancy, while lower values did not reliably predict benign tumor.

Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma.

Identification of prognostic factors for patients with relapsed/refractory Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase 2 study of positron emission tomography (PET)-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, and etoposide (augICE), we assessed clinical factors, quantitative PET assessments, and cytokine and chemokine values. Transplant-eligible patients with relapsed/refractory HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative patients (Deauville score ≤2) proceeded to autologous stem cell transplantation (ASCT) whereas PET-positive patients received augICE before ASCT. Serum cytokine and chemokine levels were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis were measured at baseline, after BV, and after augICE. Sixty-five patients enrolled (45, cohort 1; 20, cohort 2); 49 (75%) achieved complete response and 64 proceeded to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predictive for EFS by multivariable analysis were baseline MTV (bMTV) (P < .001) and refractory disease (P = .003). Low bMTV (<109.5 cm3) and relapsed disease identified a favorable group (3-year EFS, 100%). For patients who received a transplant, bMTV and pre-ASCT PET were independently prognostic; 3-year EFS for pre-ASCT PET-positive patients with low bMTV was 86%. In this phase 2 study of PET-adapted therapy with BV and augICE for relapsed/refractory HL, bMTV and refractory disease were independent prognostic factors for EFS. Furthermore, bMTV improved the predictive power of pre-ASCT PET. Future studies should optimize efficacy and tolerability of salvage therapy by stratifying patients according to risk factors such as bMTV.

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.

BACKGROUND: Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS: We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS: Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS: Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study.

BACKGROUND: Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. FINDINGS: Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). INTERPRETATION: PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. FUNDING: Seattle Genetics.

Prospective evaluation of 18F-fluorodeoxyglucose positron emission tomography in patients receiving hepatic arterial and systemic chemotherapy for unresectable colorectal liver metastases.

BACKGROUND: The prognostic and predictive abilities of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) coupled with conventional computed tomography (CT) have not been studied in patients with unresectable colorectal liver metastases (uCRLM) treated with combined hepatic arterial infusion (HAI) and systemic chemotherapy. OBJECTIVES: The ability of PET-CT metabolic response parameters to predict conversion to resectability and oncologic outcome in this setting was evaluated. METHODS: Thirty-eight patients undergoing serial PET-CT as part of a Phase II trial of HAI and systemic chemotherapy for uCRLM were included. Metabolic response was determined as the percentage change in standard uptake value (SUV) and total lesion glycolysis (TLG). Conversion to resection, overall survival (OS), progression-free survival (PFS) and recurrence-free survival were evaluated using standard statistics. RESULTS: Volumetric response sufficient to facilitate resection was seen in 53% of patients after a median of 5 months of therapy. Median follow-up was 38 months (range: 32-52 months). Median OS was not reached [95% confidence interval (CI) 32 months-unknown] and 3-year OS was 54% (range: 33-71%). Median PFS was 13 months (95% CI 6-21 months) and 3 year PFS was 10% (range: 3-20%). Neither baseline values nor the percentage change in any of the metabolic parameters evaluated correlated with conversion to resection, survival variables or hepatic recurrence on Cox regression analysis. CONCLUSIONS: Pre- and post-treatment PET-related metabolic parameters do not predict conversion to resection or oncologic outcome in patients with uCRLM treated with HAI and systemic chemotherapy. Metabolic parameters should not be used to monitor response or to determine prognosis in these patients.

Complete blood counts are frequently abnormal 1 year after dosimetry-guided radioactive iodine therapy for metastatic thyroid cancer.

OBJECTIVE: Radioactive iodine (RAI) has been associated with hematologic abnormalities. Previous research has shown that even a single dose of RAI can cause changes in the peripheral complete blood count (CBC). It is unclear if the use of dosimetry guidance would prevent the effects of high doses of RAI on bone marrow suppression. METHODS: CBC at baseline was compared to a CBC obtained 1 year after the last RAI treatment in 50 thyroid cancer patients that received ≥250 mCi RAI during the course of their disease. Cumulative dose, number of treatments, patients' age, and the use of external beam radiation therapy (EBRT) were considered in the analysis. RESULTS: We observed a small but statistically significant decrease in hemoglobin (Hb), hematocrit (Hct), and platelet (Plt) counts at 1 year in 50 patients who had received ≥250 mCi RAI. We did not find a significant change in white blood cell count (WBC). Approximately 60% of patients who developed anemia had concomitant WBC and Plt abnormalities. RAI dose, number of treatments, and age at diagnosis did not confer a higher risk of bone marrow suppression. CONCLUSION: High cumulative activities of RAI administered under dosimetric guidance are associated with a small but statistically significant decreases in Hb, Hct, and Plt counts. The clinical implications of these changes, if any, are unclear. The benefits obtained with high doses of RAI, when indicated, are likely to outweigh the minimal hematologic risks observed in the present study.

Positron emission tomography for response assessment in desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumors (DSRCT) typically have a large stromal component and often are extensively disseminated in the peritoneal cavity at diagnosis. These factors contribute to difficulty in quantifying response to chemotherapy using RECIST or WHO criteria. This study compares the overall disease response to chemotherapy by fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) in patients with DSRCT. METHODS: We conducted a retrospective chart review of 7 patients with DSRCT who were imaged by FDG-PET and CT at diagnosis and after 3 cycles of chemotherapy. Response to chemotherapy was graded according to EORTC metabolic response guidelines and RECIST. RESULTS: All tumors demonstrated some decrease in SUVmax (51%±21%) and longest diameter (23%±8%) with chemotherapy. The best response achieved by FDG-PET was a partial response in 6 patients and by CT was a partial response in 1 patient. Measured response was concordant between the 2 modalities in 2 patients. CONCLUSIONS: In this small series response measurement by FDG-PET did not always correlate with response measurement by CT. A greater decrease in metabolic activity as compared with size was seen in all patients. Further studies are needed to define the role of FDG-PET in assessing early response of DSRCT to chemotherapy.

Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy.

PURPOSE: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. EXPERIMENTAL DESIGN: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. RESULTS: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. CONCLUSIONS: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.

Assessment of salivary gland function after 177Lu-PSMA radioligand therapy: Current concepts in imaging and management.

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.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Bone scans, bisphosphonates, and a lack of acute changes within the mandible.

PURPOSE: The etiology of osteonecrosis of the jaw is poorly understood, but preferential mandibular uptake of intravenous bisphosphonates (IVBPs) has been implicated. We examined this association within a prospective study assessing the effect of IVBPs on radionuclide bone scanning. PATIENTS AND METHODS: Women with at least 3 osseous breast metastases on bone scanning and previous IVBP use within 8 weeks were eligible for the present study. After the first clinically indicated bone scan, the patients received zoledronic acid within 72 hours and underwent a second bone scan within another 72 hours. The regions of interest on the bone scan were read in triplicate, and the mean count per pixel was calculated for the mandible (C(M)), left femur (C(FL)), right femur (C(FR)), and thigh (C(B)). The mandibular bone turnover (MBT) was quantified as the ratio of (C(M) - C(B))/(C(F) - C(B)), where C(F) = (C(FL) + C(FR)/2). The MBT was compared before and after IVBP use. RESULTS: A total of 10 patients were enrolled (median age 51 years, range 40 to 71); none had known osteonecrosis of the jaw. Of the 10 patients, 8 had paired bone scans available for analysis. The previous zoledronic acid exposure was 48.6 mg (range 24 to 148) for a median of 13 months (range 6 to 35). The baseline mean MBT ratio was 2.33 (range 0.88 to 4.22). After IVBP administration, the mean MBT ratio was statistically unchanged at 2.23 (range 1.05 to 3.09). The MBT had declined in 4 patients and increased in 4. Only 1 patient had had an MBT of less than 1.0 before IVBP use, and no patient had an MBT ratio of less than 1.0 after IVBP use. CONCLUSIONS: The mandibular region appears to be a site of increased uptake of technetium-99m bound to methylene diphosphonate-technetium. Acute changes in bisphosphonate binding in the mandible were not observed in our patients receiving chronic IVBP therapy.

Doubled-haploid production in chickpea (Cicer arietinum L.): role of stress treatments.

This is the first report on the production of double-haploid chickpea embryos and regenerated plants through anther culture using Canadian cultivar CDC Xena (kabuli) and Australian cultivar Sonali (desi). Maximum anther induction rates were 69% for Sonali and 63% for CDC Xena. Under optimal conditions, embryo formation occurred within 15-20 days of culture initiation with 2.3 embryos produced per anther for CDC Xena and 2.0 embryos per anther for Sonali. For anther induction, the following stress treatments were used: (1) flower clusters were treated at 4 degrees C for 4 days, (2) anthers were subjected to electric shock treatment of three exponentially decaying pulses of 50-400 V with 25 microF capacitance and 25 Omega resistance, (3) anthers were centrifuged at 168-1,509g for 2-15 min, and finally (4) anthers were cultured for 4 days in high-osmotic pressure (563 mmol) liquid medium. Anthers were then transferred to a solid embryo development medium and, 15-20 days later, embryo development was observed concomitant with a small amount of callus growth of 0.1-3 mm. Anther-derived embryos were regenerated on plant regeneration medium. Electroporation treatment of anthers enhanced root formation, which is often a major hurdle in legume regeneration protocols. Cytological studies using DAPI staining showed a wide range of ploidy levels from haploid to tetraploid in 10-30-day-old calli. Flow cytometric analysis of calli, embryos and regenerated plants showed haploid profiles and/or spontaneous doubling of the chromosomes during early regeneration stages.

Enchondroma of Tibia as Potential False-positive Finding on 68Ga-DOTATOC PET/CT Scan.

A 70-year-old man with a history of carcinoid tumor of small bowel was referred for Ga-DOTATOC study to evaluate the extent of disease. PET/CT scan revealed known metastatic disease in the liver, with other sites of involvement including pancreas, peritoneum, and bones. In addition, moderately intense uptake was noted in proximal right tibia and further correlation on CT showed metaphyseal lesion with "rings and arcs" calcification suggestive of enchondroma. This case highlights the possibility of overexpression of somatostatin receptors in enchondromas, which has been little explored in literature.

Thyroid Cancer Brain Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.

PURPOSE: Brain metastases (BMs) in patients with differentiated thyroid cancer (DTC) are rare but associated with poor prognosis. We examined risk factors for overall survival (OS) in this population and explored the pattern of genomic alterations. METHODS: Single-institution, retrospective review of all patients with DTC from January 2000 to November 2016 identified 79 patients for analysis. Multiple prognostic factors, including age, gender, distal metastasis (DM), diagnosis time, DM sites, BM diagnosis time, BM number and size, genomic sequencing data, craniectomy, external beam radiation therapy, and kinase inhibitor therapies, were evaluated. Univariate and multivariate analyses were performed. RESULTS: Median survival after BM was 18 months. One- and 3-year survival rates were 63% and 33%, respectively. Univariate analysis identified 4 covariates correlated with prolonged survival: time between DTC diagnosis and BM for less than 3 years (P = 0.01), time from initial DM diagnosis to BM for 22 months or less (P = 0.03), 3 BM sites or fewer (P = 0.002), and craniectomy (P = 0.05). Multivariate model revealed 3 variables associated with OS: DTC diagnosis to BM time of less than 3 years (P = 0.04), craniectomy (P = 0.06), and patients with fewer than 3 BM sites (P = 0.06). The majority of patients with BM had a telomerase reverse transcriptase promoter mutation, However, mutational status was not an independent predictor of survival. CONCLUSIONS: For BM from DTC, time interval between DTC diagnosis and BM, number of BM sites, and craniectomy were independently associated with OS. Further studies are needed to define the role of genomic mutations in advanced cancer.

Thyroid Cancer Bone Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort.

Bone metastasis (BM) in differentiated thyroid cancer (DTC) is the second most common site of metastasis after lung. Bone metastases are associated with worse prognosis in DTC. In this study, we examined risk factors for overall survival in patients with BM and for the first time explore the pattern of genomic alterations in DTC BM. PATIENTS AND METHODS: A Health Insurance Portability and Accountability Act (HIPAA) compliant, institutional review board-approved retrospective evaluation of the medical record was performed for all patients treated at a single institution for thyroid cancer over a 16-year period. Seventy-four patients met inclusion criteria. Multiple prognostic factors including age, sex, genes, radioactive iodine, and radiation or kinase inhibitor therapies were analyzed. Univariate and multivariate analyses were performed. RESULTS: Treatment with external beam radiation was found to significantly increase survival (P = 0.03). The 5-year survival rate was 59% and median survival was 92 months. Patients who developed bone metastasis earlier tend to live longer (P = 0.06). The presence of TERT and BRAF mutations did not significantly worsen the prognosis (P = 0.10). CONCLUSION: Patients with DTC can benefit from early treatment with external beam radiation therapy, especially those who develop bone metastasis within 3 years of primary TC diagnosis. Kinase inhibitor treatment tended to prolong survival but not in a statistically significant manner. Sex, age, and TERT or BRAF genetic mutations did not significantly affect the prognosis.

Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers.

CONTEXT: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN: This was a pilot trial that enrolled from June 2014 to January 2016. SETTING: Academic cancer center. PATIENTS: Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). CONCLUSIONS: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.