Dysphagia, hypothyroidism, and osteoradionecrosis after radiation therapy for head and neck cancer.

OBJECTIVES: To analyze the long-term side effects of radiation therapy (RT) for head and neck cancer (HNC). METHODS: Retrospective chart analysis of all 688 HNC patients treated during 2010-2015 at Turku University Hospital, Finland. All patients who survived for more than a year after RT/chemoRT were included (n = 233). Intensity modulated RT (IMRT) with standard fractionation was applied in each case. RESULTS: One hundred and six patients (45%) reported persisting dysphagia, for which neck RT increased risk. Definitive neck RT to high-risk volume did not increase late toxicity risks compared to elective neck RT. Radiation-induced hypothyroidism (29%, n = 67) was more common among younger patients and females. Osteoradionecrosis (12%, n = 29) was more common in the oral cavity cancer group (20.7%, n = 92) compared to all other subsites. CONCLUSIONS: Late toxicities of RT for HNC are common. Age, gender, tumor subsite, and neck RT affect susceptibility to long-term side effects. LEVEL OF EVIDENCE: 4.

The relationship between diurnal cortisol secretion and climacteric-related symptoms.

OBJECTIVES: Chronic stress, also associated with climacteric-related symptoms, may influence cortisol secretion. We studied cortisol metabolism in peri- and postmenopausal women with diverse climacteric-related symptoms. STUDY DESIGN AND MAIN OUTCOME MEASURES: The study population was 35 women, aged 45-70 years. Plasma cortisol levels were measured from blood samples collected every 20 min over 24 h. Urinary cortisol was analysed from 24-hour urine collections. Climacteric-related symptoms (vasomotor, sleep, depressive, anxiety, cognitive, sexual, menstrual, and somatic) were evaluated with the Women's Health Questionnaire (WHQ). Associations between cortisol variables (24-hour, night, day, maximum, minimum, morning baseline, cortisol awakening response (CAR), area under the curve, slope, and 24-hour urinary cortisol) and the symptoms were first examined with a correlation analysis. Then, the women were divided into two groups according to their climacteric symptomatology, and differences in cortisol variables between the groups were investigated. Diurnal cortisol curves by symptomatology were also analyzed visually. RESULTS: In the correlation analysis, more frequent vasomotor symptoms were associated with a higher CAR (rs = 0.37, p = 0.039) and lower 24-hour urinary cortisol excretion (rs= -0.45, p = 0.012), and more frequent depressive symptoms were associated with a higher minimum cortisol level (rs = 0.33, p = 0.0498). When the women were divided into two groups, women with more frequent vasomotor (p = 0.012) or somatic symptoms (p = 0.021) had a lower 24-hour urinary cortisol excretion than less symptomatic women. CONCLUSIONS: Although previous studies have reported associations between climacteric-related symptoms and cortisol secretion, these two factors were not substantially interrelated in our study.

Obesity-associated intestinal insulin resistance is ameliorated after bariatric surgery.

AIMS/HYPOTHESIS: The intestine is the main site for glucose absorption and it has been suggested that it exhibits insulin resistance. Bariatric surgery has been shown to reverse insulin resistance and type 2 diabetes, but its effects on human intestinal metabolism are unknown. Our aim was to evaluate the effects of insulin on intestinal glucose metabolism before and after bariatric surgery. METHODS: Twenty-one morbidly obese individuals undergoing bariatric surgery and ten age-matched healthy individuals were recruited and intestinal and skeletal muscle glucose uptake (GU) was measured using [(18)F]fluoro-2-deoxyglucose and positron emission tomography at fast and during hyperinsulinaemia. MRI was used as anatomical reference. Obese participants were studied again 6 months postoperatively. RESULTS: In contrast to healthy individuals, insulin had no effect on intestinal GU in obese participants with or without diabetes, suggesting that intestinal insulin resistance is present early in morbid obesity. Postoperatively, jejunal GU increased in line with whole-body and muscle GU. Postoperative GU values in the intestine correlated with whole-body insulin sensitivity, indicating that the intestinal mucosa may reflect the overall glycaemic state and potentially mediate obesity-associated insulin resistance. CONCLUSIONS/INTERPRETATION: This study shows that insulin is a potent stimulator of GU in the healthy intestine and that intestinal insulin resistance is ameliorated after bariatric surgery. In our study, obese individuals had intestinal insulin resistance regardless of their glycaemic status. Persistent changes in intestinal glucose metabolism are likely to influence both local processes in the gut and systemic glucose homeostasis.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients.

BACKGROUND & AIMS: Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS: Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS: Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS: This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

Planar scintigraphy with 123I/99mTc-sestamibi, 99mTc-sestamibi SPECT/CT, 11C-methionine PET/CT, or selective venous sampling before reoperation of primary hyperparathyroidism?

UNLABELLED: All patients with primary hyperparathyroidism should undergo localization studies before reoperation, but it is not known which method is most accurate. The purpose of this prospective study was to compare the performance of planar scintigraphy with (123)I/(99m)Tc-sestamibi, (99m)Tc-sestamibi SPECT (SPECT/CT), (11)C-methionine PET/CT, and selective venous sampling (SVS) in persistent primary hyperparathyroidism. METHODS: Twenty-one patients referred for reoperation of persistent hyperparathyroidism were included and investigated with (123)I/(99m)Tc-sestamibi, SPECT/CT (n = 19), (11)C-methionine PET/CT, and SVS (n = 18) before reoperation. All patients had been operated on 1-2 times previously because of hyperparathyroidism. The results of the localization studies were compared with operative findings, histology, and biochemical cure. RESULTS: Eighteen (86%) of 21 patients were biochemically cured. Nineteen parathyroid glands (9 adenomas, 1 atypical adenoma, and 9 hyperplastic glands) were removed from 17 patients, and 1 patient who was biochemically cured had an unclear histology result. The accuracy for localizing a pathologic parathyroid gland to the correct side of the neck was 59% (95% confidence interval [CI], 36%-79%) for (123)I/(99m)Tc-sestamibi, 19% (95% CI, 5%-42%) for SPECT/CT, 65% (95% CI, 43%-84%) for (11)C-methionine PET/CT, and 40% (95% CI, 19%-65%) for SVS (P < 0.01 for (123)I/(99m)Tc-sestamibi vs. SPECT/CT). The corresponding accuracy for the correct quadrant or more specific site was 48% (95% CI, 27%-69%) for (123)I/(99m)Tc-sestamibi, 14% (95% CI, 3%-36%) for SPECT/CT, 61% (95% CI, 39%-80%) for (11)C-methionine PET/CT, and 25% (95% CI, 9%-49%) for SVS (P < 0.02 for (123)I/(99m)Tc-sestamibi vs. SPECT/CT). In the 3 patients not cured, preoperative (123)I/(99m)Tc-sestamibi and SPECT/CT remained negative, SVS was false predictive in all, and (11)C-methionine PET/CT in 1. (11)C-methionine PET/CT accurately revealed the pathologic gland in 4 of 8 (50%) patients with a negative (123)I/(99m)Tc-sestamibi scan result, all of whom were biochemically cured after reoperation. CONCLUSION: Planar scintigraphy with (123)I/(99m)Tc-sestamibi performs well in complicated primary hyperparathyroidism and is recommended as first-line imaging before reoperation. (11)C-methionine PET/CT provides valuable additional information if (123)I/(99m)Tc-sestamibi scan results remain negative. (99m)Tc-sestamibi SPECT/CT and SVS provide no additional information, compared with the combined results of (123)I/(99m)Tc-sestamibi and (11)C-methionine PET/CT imaging.

Angiopoietin-regulated recruitment of vascular smooth muscle cells by endothelial-derived heparin binding EGF-like growth factor.

Recruitment of vascular smooth muscle cells (SMC) by endothelial cells (EC) is essential for angiogenesis. Endothelial-derived heparin binding EGF-like growth factor (HB-EGF) was shown to mediate this process by signaling via ErbB1 and ErbB2 receptors in SMCs. 1) Analysis of ErbB-ligands demonstrated that primary ECs expressed only HB-EGF and neuregulin-1. 2) Primary SMCs expressed ErbB1 and ErbB2, but not ErbB3 or ErbB4. 3) Consistent with their known receptor specificities, recombinant HB-EGF, but not neuregulin-1, stimulated tyrosine phosphorylation of ErbB1 and ErbB2 and migration in SMCs. 4) Neutralization of HB-EGF or inhibition of ErbB1 or ErbB2 blocked 70-90% of the potential of ECs to stimulate SMC migration. Moreover, 5) angiopoietin-1, an EC effector with a role in recruitment of SMC-like cells to vascular structures in vivo, enhanced EC-stimulated SMC migration by a mechanism involving up-regulation of endothelial HB-EGF. Finally, 6) immunohistochemical analysis of developing human tissues demonstrated that HB-EGF was expressed in vivo in ECs associated with SMCs or pericytes but not in ECs of the hyaloid vessels not associated with SMCs. These results suggest an important role for HB-EGF and ErbB receptors in the recruitment of SMCs by ECs and elaborate on the mechanism by which angiopoietins exert their vascular effects.

Molecular profiling of human chondrosarcomas for matrix production and cancer markers.

Chondrosarcoma is the second most common malignant bone tumor, characterized by production of abundant extracellular matrix resembling hyaline cartilage. To better understand the molecular pathogenesis of chondrosarcoma, we analyzed 12 chondrosarcomas for their production of connective tissue components and SOX9, a key regulator of normal chondrocyte differentiation. Furthermore, 10 chondrosarcoma samples were screened for additional changes in gene expression using cDNA array analysis. In Northern analysis, several tumors were found to express type II collagen mRNA at levels comparable to fetal cartilage used as a control. Interestingly, the highest levels of type II collagen mRNA were seen in 2 of the 3 grade 3 chondrosarcomas, which also exhibited the highest mRNA levels of SOX9 and "prechondrogenic" pro alpha 1(IIA) collagen. Expression of SOX9 in human chondrosarcomas is novel and suggests that chondrosarcomas originate from a multipotent stem cell committed to differentiation along the chondrogenic pathway. Results of the cDNA array analyses emphasize the heterogeneous nature of chondrosarcoma as no single transcript was systematically up- or downregulated in all tumors analyzed. Among the interesting changes observed was upregulation of decorin mRNA in 7 of the 10 tumors analyzed. Further studies are needed to determine whether decorin plays a role in the pathogenesis of chondrosarcoma. The cDNA arrays also revealed discrepancies from Northern and RNase protection analyses in transcript levels of matrix components, emphasizing the need to validate cDNA array data with other techniques.