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Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)–GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to evaluate how cumulative burden of clinically relevant, self‐reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. Methods: The authors invited 5925 5‐year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self‐reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30‐year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30‐year MCC, and compared the ranking to levels of care according to existing risk stratifications. Results: At median 18.5 years after 5‐year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30‐year MCC = 0.79; 95% confidence interval [CI], 0.74–0.85 vs. 30‐year MCC = 0.29; 95% CI, 0.25–0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30‐year MCC often did not correspond with levels of care in existing risk stratifications. Conclusions: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity. Survivors of childhood cancer experience a high cumulative burden of clinically relevant outcomes. Choices for survivorship care should extend beyond primary tumor and treatment parameters and should also consider including the current morbidity of childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Context: During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects. Objective: To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes. Methods: Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin. Results: We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99). Conclusion: Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasoneinduced state of acute leptin resistance might play a role. [ABSTRACT FROM AUTHOR]

Small functional pituitary tumors can cause severely disabling symptoms and early death. The gold standard diagnostic approach includes laboratory tests and MRI, with or without inferior petrosal sinus sampling (IPSS). In up to 40% of patients, however, the source of excess hormone production remains unidentified or uncertain. This excludes patients from surgical, Gamma Knife, and CyberKnife therapy and adversely affects overall cure rates. We here assess the diagnostic yield of O -(2-[ 18 F]fluoroethyl)-l-tyrosine ([ 18 F]FET) PET/MRI for detection of small functional pituitary tumors in these patients. Methods: This retrospective analysis included patients with Cushing disease (CD) but prior negative or inconclusive MRI results who underwent [ 18 F]FET PET/MRI between February 1, 2021, and December 1, 2022. PET/MR images and MR images alone were evaluated by experienced nuclear radiologists, neuroradiologists, or radiologists. Postoperative tissue analysis (when performed) was used as a reference standard to assess diagnostic metrics (i.e., sensitivity and positive predictive value). Results were also compared with previously obtained MR images, preceding IPSS, and clinical or biochemical follow-up. Results: Twenty-two patients (68% female; mean age ± SD, 48 ± 15 y; range, 24-68 y) were scanned. All patients showed a clear metabolic focus on [ 18 F]FET PET, whereas reading of the MRI alone yielded a suspected lesion in only 50%. Fifteen patients underwent surgery directed at the [ 18 F]FET-positive focus. Tissue analysis confirmed a pituitary adenoma/pituitary neuroendocrine tumor of the corticotroph cell type (TPIT lineage) in 10 of 15 and a pituicytoma in 1 of 15, rendering a sensitivity of 100% and a positive predictive value of 73%. Lateralization was more accurate with [ 18 F]FET PET/MRI than with IPSS in 33%. Twelve of 16 (75%) patients who received surgical, Gamma Knife, or CyberKnife therapy after [ 18 F]FET PET/MRI reached short-term remission. Conclusion: [ 18 F]FET PET/MRI shows a high diagnostic yield for localizing small functional pituitary tumors. This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease, particularly those with repeated negative or inconclusive MRI results with or without IPSS., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)