Chemotherapy for post-menopausal women with early breast cancer seems not to result in clinically significant changes in thyroid function.

OBJECTIVE: Adjuvant chemotherapy is often indicated in patients diagnosed with early breast cancer (EBC). Among others, weight gain is one of the observed side effects of both chemotherapy and other cancer treatments; however, the mechanism is not well-described. In this study, we aimed to assess thyroid function before and shortly after the course of chemotherapy for EBC. METHODS: This is a prospective cohort study of women diagnosed with EBC. The main outcome was the thyroid function and body weight before and after completing chemotherapy. Secondary outcomes were the presence of thyroid autoantibodies and treatment radiation dosage. We included 72 patients treated with adjuvant chemotherapy, whereas 59 patients also received supraclavicular locoregional radiotherapy. Triple-negative breast cancer (BC) patients receiving chemoimmunotherapy were excluded. RESULTS: After the chemotherapy, we observed an increase in thyroid-stimulating hormone (p = 0.03) and a decrease in free-thyroxine (p = 0.0006), with no significant weight change. The prevalence of autoimmune thyroiditis was low. On average 3 months post-chemo, we found no statistically significant difference in the thyroid function of women treated versus not treated with supraclavicular locoregional radiotherapy. CONCLUSIONS: Although statistically significant changes in thyroid hormones were observed, this study suggests no obvious clinically significant changes in thyroid function in women with early BC after the course of chemotherapy. The decrease in thyroid function was not related to autoimmunity, non-thyroidal illness, radiotherapy, or high-dose corticosteroids. Further studies with a longer follow-up of thyroid function after adjuvant chemotherapy and supraclavicular locoregional radiotherapy are needed.

Long-term pituitary function and functional and patient-reported outcomes in severe acquired brain injury.

OBJECTIVE: Assessment of posttraumatic hypothalamic-pituitary dysfunctions is expected to be the most relevant assessment to offer patients with severe intracranial affection. In this study, we aim to investigate the prevalence of hypopituitarism in patients with severe acquired traumatic brain injury (TBI) compared with nontraumatic brain injury (NTBI) and to relate pituitary insufficiency to functional and patient-reported outcomes. DESIGN: This is a prospective study. METHODS: We included patients admitted for inpatient neurorehabilitation after severe TBI (N = 42) and NTBI (N = 18). The patients underwent a pituitary function assessment at a mean of 2.4 years after the injury. Functional outcome was assessed by using Functional Independence Measure and Glasgow Outcome Scale-Extended (both 1 year after discharge from neurorehabilitation) and patient-reported outcome was assessed by using Multiple Fatigue Inventory-20 and EQ-5D-3L. RESULTS: Hypopituitarism was reported in 10/42 (24%) patients with TBI and 7/18 (39%) patients with NTBI (P = .23). Insufficiencies affected 1 axis in 14/17 (82%) patients (13 hypogonadotropic hypogonadism and 1 growth hormone [GH] deficiency) and 2 axes in 3/17 (18%) patients (1 hypogonadotropic hypogonadism and GH deficiency, and 2 hypogonadotropic hypogonadism and arginin vasopressin deficiency). None had central hypoadrenalism or central hypothyroidism. In patients with both TBI and NTBI, pituitary status was unrelated to functioning and ability scores at 1 year and to patient-reported outcome scores at a mean of 2.4 years after the injury. CONCLUSION: Patients with severe acquired brain injury may develop long-term hypothalamus-pituitary insufficiency, with an equal occurrence in patients with TBI and NTBI. In both types of patients, mainly isolated deficiencies, most commonly affecting the gonadal axis, were seen. Insufficiencies were unrelated to functional outcomes and patient-reported outcomes, probably reflecting the complexity and heterogeneous manifestations in both patient groups.

Peripheral blood mononuclear cells exhibit increased mitochondrial respiration after adjuvant chemo- and radiotherapy for early breast cancer.

BACKGROUND: Adjuvant chemo- and radiotherapy cause cellular damage to tumorous and healthy dividing cells. Chemotherapy has been shown to cause mitochondrial respiratory dysfunction in non-tumorous tissues, but the effects on human peripheral blood mononuclear cells (PBMCs) remain unknown. AIM: We aimed to investigate mitochondrial respiration of PBMCs before and after adjuvant chemo- and radiotherapy in postmenopausal patients with early breast cancer (EBC) and relate these to metabolic parameters of the patients. METHODS: Twenty-three postmenopausal women diagnosed with EBC were examined before and shortly after chemotherapy with (n = 18) or without (n = 5) radiotherapy. Respiration (O2 flux per million PBMCs) was assessed by high-resolution respirometry of intact and permeabilized PBMCs. Clinical metabolic characteristics and mitochondrial DNA (mtDNA) content of PBMCs (mtDN relative to nuclear DNA) were furthermore assessed. RESULTS: Respiration of intact and permeabilized PBMCs from EBC patients significantly increased with adjuvant chemo- and radiotherapy (p = 6 × 10-5 and p = 1 × 10-7 , respectively). The oxygen flux attributed to specific mitochondrial complexes and respiratory states increased by 17-43% compared to before therapy initiation. Similarly, PBMC mtDNA content increased by 40% (p = 0.002). Leukocytes (p = 0.0001), hemoglobin (p = 0.0003), and HDL cholesterol (p = 0.003) concentrations decreased whereas triglyceride (p = 0.01) and LDL (p = 0.02) concentrations increased after treatment suggesting a worsened metabolic state. None of the metabolic parameters or the mtDNA content of PBMCs correlated significantly with PBMC respiration. CONCLUSION: This study shows that mitochondrial respiration and mtDNA content in circulating PBMCs increase after adjuvant chemo- and radiotherapy in postmenopausal patients with EBC. Besides the increased mtDNA content, a shift in PBMC subpopulation proportions towards cells relying on oxidative phosphorylation, who may be less sensitive to chemotherapy, might influence the increased mitochondrial respiration observed iafter chemotherapy.

Influence of the anti-oestrogens tamoxifen and letrozole on thyroid function in women with early and advanced breast cancer: A systematic review.

INTRODUCTION: Breast cancer (BC) is a common type of cancer in women. Advances in therapy options have resulted in higher overall survival rates but side effects of cancer treatment are increasingly in the spotlight. The beneficial effects of anti-oestrogen therapy with tamoxifen and letrozole in the prevention of BC recurrence are well documented. While the most common side-effects of this therapy are well-defined, less is known about its effects on thyroid function. In women treated for early BC, an average of 1-5 kg weight gain has been observed after treatment with chemotherapy/anti-oestrogens. We aim to evaluate the current knowledge on the side effects of tamoxifen and letrozole treatments on thyroid function, followed by its potential influence on the observed weight gain. METHODS: We searched PubMed and found 16 publications on thyroid function and tamoxifen treatment in pre- and post-menopausal women with early- and advanced BC, whereas five publications on letrozole treatment in post-menopausal women with advanced BC. RESULTS: According to the current literature, there is an overall tendency towards a mild and transient thyroid dysfunction, that is, subclinical hypothyroidism in tamoxifen-treated patients. Only one publication reported further significant changes in thyroid hormones beyond one year of tamoxifen treatment. No significant changes in thyroid function have been observed among letrozole-treated patients. CONCLUSION: Tamoxifen-treated patients can develop mild and transient thyroid dysfunction within the first 12 months, yet further significant changes in thyroid function beyond one year of tamoxifen treatment have been reported in a single study. There is no evidence of thyroid dysfunction in letrozole-treated patients. Current literature does not focus on subclinical hypothyroidism as a possible cause of weight gain in patients with BC. Subgrouping of BC patients and studies with a longer observation of thyroid hormones and weight changes during and after anti-oestrogen treatment are needed to further elucidate how anti-oestrogens affect thyroid function.

Bacteremia and urogenital infection with Actinomyces urogenitalis following prolonged urinary retention.

A case of bacteremia with the fastidious bacteria Actinomyces urogenitalis following lengthy urinary retention is reported in a sixty-year-old man. In 2013, the first case of bacteremia due to A. urogenitalis was presented, secondary to a tubo-ovarian abscess following transvaginal oocyte retrieval. To the best of our knowledge, this is the first male bacteremic episode involving A. urogenitalis related to a urinary tract focus. The patient had no prior urogenital medical history. Extensive susceptibility testing was done on isolates from urinary and blood cultures. The organism exhibited fluoroquinolone resistance but was susceptible to most other antibiotics used in the treatment of urinary infections. Due to its unusual growth requirements infections with A. urogenitalis are most likely an underdiagnosed entity.

Reversible Albumin-Binding GH Possesses a Potential Once-Weekly Treatment Profile in Adult Growth Hormone Deficiency.

CONTEXT: NNC0195-0092 is a reversible, albumin-binding GH derivative, developed for once-weekly administration. OBJECTIVES: The objective of the study was to evaluate safety, local tolerability, pharmacodynamics, and pharmacokinetics of multiple, once-weekly doses of NNC0195-0092, compared with daily GH. DESIGN AND SETTING: This was a phase 1, randomized, open-label, active-controlled, multiple-dose, dose-escalation trial. PATIENTS: Thirty-four GH-treated adult subjects (male, n = 25) with GH deficiency participated in the study. INTERVENTIONS AND MAIN OUTCOME MEASURES: Subjects were sequentially assigned into four cohorts of eight subjects, randomized within each cohort (3:1) to once-weekly NNC0195-0092 (n = 6) for 4 weeks (0.02, 0.04, 0.08, and 0.12 mg/kg) or daily injections of Norditropin NordiFlex (n = 2) for 4 weeks with a dose replicating the pretrial dose of somatropin. A safety assessment was performed prior to initiating treatment at the next dose level of NNC0195-0092. Daily GH treatment was discontinued 14 days before the trial start. Blood samples were drawn for assessment of safety, pharmacokinetics, pharmacodynamics (IGF-1 and IGF-binding protein-3) profiles, and immunogenicity studies. RESULTS: Numbers of adverse events were similar at the dose levels of 0.02, 0.04, and 0.08 mg/kg NNC0195-0092 vs daily injections of Norditropin NordiFlex, whereas the number of adverse events was greater at the highest dose level of NNC0195-0092 (0.12 mg/kg). NNC0195-0092 (area under the curve[0-168h]) and peak plasma concentration) increased in a dose-dependent manner, and a dose-dependent increase in IGF-1 levels was observed. IGF-1 profiles were elevated for at least 1 week, and for the 0.02-mg/kg and 0.04-mg/kg NNC0195-0092 doses, the observed IGF-1 levels were similar to the levels for the active control group. CONCLUSION: Four once-weekly doses of NNC0195-0092 (dose range 0.02-0.12 mg/kg) administered to adult patients with GH deficiency were well tolerated, and IGF-1 profiles were consistent with a once-weekly treatment profile. No clinically significant safety and tolerability signals causally related to NNC0195-0092 were identified, nor were any immunogenicity concerns revealed.

Truncated somatostatin receptor 5 may modulate therapy response to somatostatin analogues--Observations in two patients with acromegaly and severe headache.

BACKGROUND: Somatotropinomas have unique "fingerprints" of somatostatin receptor (sst) expression, which are targets in treatment of acromegaly with somatostatin analogues (SSAs). However, a significant expression of sst is not always related to the biochemical response to SSAs. Headache is a common complaint in acromegaly and considered a clinical marker of disease activity. SSAs are reported to have an own analgesic effect, but the sst involved are unknown. PATIENTS AND METHODS: We investigated sst expression in two acromegalic patients with severe headache and no biochemical effects of octreotide, but a good response to pasireotide. We searched the literature for determinants of biochemical and analgesic effects of SSAs in somatotropinomas. RESULTS: Case 1 had no biochemical or analgesic effects of octreotide, a semi-selective SSA, but a rapid and significant effect of pasireotide, a pan-SSA. Case 2 demonstrated discordance between analgesic and biochemical effects of octreotide, in that headache disappeared, but without biochemical improvement. In contrast, pasireotide normalized insulin-like growth factor 1. Both adenomas were sparsely granulated and had strong membranous expressions of sst2a in 50-75% and sst5 in 75-100% of tumor cells. The truncated sst5 variant TMD4 (sst5TMD4) showed expression in 20-57% of tumor cells. CONCLUSIONS: A poor biochemical response to octreotide may be associated with tumor expression of a truncated sst5 variant, despite abundant sst2a expression, suggesting an influence from variant sst5 on common sst signaling pathways. Furthermore, unrelated analgesic and biochemical effects of SSAs supported a complex pathogenesis of acromegaly-associated headache. Finally, assessment of truncated sst5 in addition to full length sst could be important for a choice of postoperative SSA treatment in somatotropinomas.

Early endocrine alterations reflect prolonged stress and relate to 1-year functional outcome in patients with severe brain injury.

OBJECTIVE: Severe brain injury may increase the risk of developing acute and chronic hypopituitarism. Pituitary hormone alterations developed in the early recovery phase after brain injury may have implications for long-term functional recovery. The objective of the present study was to assess the pattern and prevalence of pituitary hormone alterations 3 months after a severe brain injury with relation to functional outcome at a 1-year follow-up. DESIGN: Prospective study at a tertiary university referral centre. METHODS: A total of 163 patients admitted to neurorehabilitation after severe traumatic brain injury (TBI, n=111) or non-TBI (n=52) were included. The main outcome measures were endocrine alterations 3.3 months (median) after the brain injury and their relationship to the functioning and ability of the patients at a 1-year follow-up, as measured by the Functional Independence Measure and the Glasgow Outcome Scale-Extended. RESULTS: Three months after the injury, elevated stress hormones (i.e. 30 min stimulated cortisol, prolactin and/or IGF1) and/or suppressed gonadal or thyroid hormones were recorded in 68 and 32% of the patients respectively. At 1 year after the injury, lower functioning level (Functional Independence Measure) and lower capability of performing normal life activities (Glasgow Outcome Scale-Extended) were related to both the elevated stress hormones (P≤0.01) and the reduced gonadal and/or thyroid hormones (P≤0.01) measured at 3 months. CONCLUSION: The present study suggests that brain injury-related endocrine alterations that mimic secondary hypogonadism and hypothyroidism and that occur with elevated stress hormones most probably reflect a prolonged stress response 2-5 months after severe brain injury, rather than pituitary insufficiency per se. These endocrine alterations thus seem to reflect a more severe disease state and relate to 1-year functional outcome.

Impact of acute exercise on antioxidant enzymes activity and lipid status in blood of patients with hypertension.

BACKGROUND/AIM: Many studies support the hypothesis that oxidative stress is involved in the pathogenic process of a variety of diseases including hypertension. In humans, hypertension is also considered a state of oxidative stress that can contribute to the development of arteriosclerosis and other hypertension-induced organ damage. The aim of this study was to evaluate an influence of acute physical exercise on antioxidative enzymes activity and lipid status in patients with hypertension. METHODS: Fourty patients with hypertension and 20 age-matched controls were included in the study. To assess an influence of acute exercise on lipids and antioxidative enzymes activity the following parameters were determined at rest and immediately after the acute cardiopulmonary exercise cycloergometer test: triglycerides (TG), total cholesterol, low density cholesterol (LDL), oxidised LDL cholesterol (OxLDL), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and plasminogen activator inhibitor (PAI). RESULTS: In basal condition, hypertensive patients compared to the control group had increased, but not significantly, level of Ox LDL (88.61 +/- 14.06 vs 79.00 +/- 29.26 mmol/L), PAI (3.06 +/- 0.56 vs 2.6 +/- 0.35 U/mL) and activity of GSH-Px (50.22 +/- 15.20 vs 44.63 +/- 13.73 U/g Hb). After acute exercise test, there was significantly greater level of Ox LDL (79.0 +/- 29.26 vs 89.3 +/- 29.07 mmol/L; p < 0.05) only in the control group. GSH-Px activity was significantly decreased only in hypertensive patients after acute exercise (50.22 +/- 15.2 vs 42.82 +/- 13.42 U/g Hb; p < 0.05), but not in the controls. CONCLUSION: No significantly elevated Ox LDL, GSH-Px and PAI-1 levels were found in hypertensive patients during basal condition in comparison with healthy subjects. Decreased GSH-Px activity was associated with those in acute exercise only in hypertensive patients. It could be an important indicator of deficiency of physiological antioxidative defense mechanism in hypertensive patients during an acute exercise.

[Exercise-induced oxidative stress and antioxidant enzyme activity in type 2 diabetic patients with and without diastolic dysfunction and hypertension].

INTRODUCTION: Antioxidant systems are important factors affecting the oxidation of lipoproteins and thereby the progression of atherosclerotic disease. It has been suggested that physical activity might maintain and promote the antioxidant defence capacity against the oxidative stress. Left ventricular dysfunction (LVDD) and hypertension are more common in subjects with diabetes mellitus (DM) type 2. OBJECTIVE: To evaluate the oxidative stress in patients with DM type 2, particularly with LVDD and hypertension and to determine the influence of acute exercise training on the investigated parameters. METHODS: To assess the oxidative stress of patients, we determined the following antioxidative parameters: triglycerides (TG), total cholesterol, low density cholesterol, OxLDL cholesterol, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), plasminogen activator-type 1 (PAI-1) which were measured at rest and immediately after the acute bout of the cardiopulmonary exercise cycle ergometer test. RESULTS: In basal conditions, diabetic patients had a significant increase of TG (3.12 +/- 1.09 vs 1.74 +/- 0.9 mmol/l; p < 0.01), OxLDL cholesterol (84.73 +/- 16.9 vs 79.00 +/- 29.26 mmol/l; p < 0.05) and SOD enzyme activity (913.38 +/- 120.36 vs 877.14 +/- 153.18; p < 0.05) compared to controls. During the acute exercise test, there were significantly greater levels of OxLDL (84.73 +/- 16.90 vs 92.33 +/- 23.29 mmol/l; p < 0.05) in study patients. SOD significantly increased in both groups during exercise, in diabetic patients (913.38 +/- 120.36 vs 921.50 +/- 130.03 U/g Hb; p < 0.05) and in controls (877.14 +/- 153.18 vs 895.00 +/- 193.49 U/g Hb; p < 0.05). GSH-Px significantly increased only in diabetic patients after acute exercise (45.04 +/- 11.19 vs 51.81 +/- 15.07 U/g Hb; p < 0.01), but not in controls. PAI significantly decreased during the exercise test only in healthy subjects (2.60 +/- 0.35 vs 2.22 +/- 0.65; p < 0.05). Type 2 diabetic patients with cardiovascular complications (LVDD and hypertension) had a significant increase of GSH-Px activity (47.10 +/- 7.37 vs 54.52 +/- 11.97 U/g Hb; p < 0.01). CONCLUSION: Elevated enzyme levels are associated with exercise in type 2 diabetic patients. We suggest that it could be a compensatory mechanism to prevent free radical tissue damage. We hypothesize that a physical training programme induces the enhancement of muscular and liver antioxidant enzymes and reduces the oxidative stress.

[Oxidized LDL and C-reactive protein level in relation to carotid intima-media thickness in population with risk factors for atherosclerosis].

INTRODUCTION: Elevated levels of oxidized LDL cholesterol (OxLDL) are considered to be a key factor of initiating and accelerating atherosclerosis. It promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the formation of macrophage foam cells. OBJECTIVE: To determine the relationship among OxLDL, C-reactive protein (CRP) level and carotid intima-media thickness (IMT) in population with risk factors for atherosclerosis. METHODS: The study group consisted of 125 clinically healthy, hypercholesterolaemic subjects (49.3 +/- 5.7 years; 75 females and 50 males) compared with 100 age-matched population-based control subjects. The study group was divided into two subgroups: subgroup A (the levels of LDL cholesterol > 5 mmol/L) and subgroup B (the levels of LDL cholesterol < 5 mmol/L). None of the subjects had history of cerebrovascular, ischaemic heart disease, hypertension or diabetes mellitus. Lipid profiles were measured by enzymatic methods. OxLDL was measured by using a specific monoclonal antibody, mAb4E6. CRP was measured using hemiluminescent methods (Immulite-DPC). The common carotid IMT was measured by the B-mode ultrasound. RESULTS: Compared to controls, the study group had higher levels of OxLDL (119.97 +/- 43.15 vs. 82.03 +/- 25.99 IU/L; p < 0.01) and CRP (6.20 +/- 3.55 vs. 2.68 +/- 3.04 mg/ml; p < 0.05). IMT was significantly higher in study subjects (1.14 +/- 0.38 vs. 0.72 +/- 0.24 mm; p < 0.05). We also found that, in the whole study group, IMT significantly positively correlated with OxLDL (r = 0.442; p < 0.05). We found that in the study subgroup A, IMT positively correlated with CRP (r = 0.792; p < 0.01). In controls, we found a significantly positive association between IMT and OxLDL (r = 0.781; p < 0.01) and CRP (r = 0.748; p < 0.01). CONCLUSION: The elevated levels of OxLDL and CRP are associated with higher common carotid intima-media thickness in population with risk factors for atherosclerosis.

[Lingual thyroid].

Lingual thyroid is a rare congenital malformation that occurs more frequently in the female population. It occurs because of the error in transcriptional factors, the key for the normal differentiation of thyrocyte, so the thyroid gland tissue does not descend normally down the thyroglossal duct to the final position in the neck. Due to that, it can entirely or partially remain at the base of the tongue. This is the most frequent localization of the ectopic tissue while it can remain in the sublingual, suprahyoid and infrahyoid area as well. This disease can be diagnosed in the asymptomatic phase, as well as in the phase of compensatory and manifest hypothyroidism. In the ectopic thyroid gland, all diseases of the thyroid gland can occur as in the usual localization in the neck. The authors show a 6-year old patient, who had a routine medical examination for the inflamed throat, during which a vascular tumefaction was discovered at the base of the tongue. A cyst at the base of the tongue was suspected, but additional examination showed that it was an ectopic thyroid tissue marked as a lingual thyroid gland. Diagnosis of this disease starts with the laboratory analysis of the thyroid status. The next step involves scintigraphy of the thyroid gland with technetium-pertechnetate (99mTc) or radioactive iodine (123I). The therapy of the compensatory hypothyroidism is suppressive therapy with levothyroxine and in the manifest hypothyroidism it is hormone substitution therapy with levothyroxine. Although there are recommended age-related daily doses, they should not be accepted as final, but rather prescribed according to the individual thyroid status.