The Effect of Thyrotropin Suppression on Survival Outcomes in Patients with Differentiated Thyroid Cancer: A Systematic Review and Meta-Analysis.

Background: Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. Methods: We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (≥18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Results: Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; I2 = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; I2 = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; I2 = 0%). Significant study heterogeneity was noted for primary outcomes. Conclusion: TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings. Registration: PROSPERO #252396.

Using Fuzzy Mathematical Model in the Differential Diagnosis of Pancreatic Lesions Using Ultrasonography and Echographic Texture Analysis.

Malignant tumors of the pancreas are the fourth leading cause of cancer-related deaths. This is mainly because they are often diagnosed at a late stage. One of the challenges in diagnosing focal lesions in the pancreas is the difficulty in distinguishing them from other conditions due to the unique location and anatomy of the organ, as well as the similarity in their ultrasound characteristics. One of the most sensitive imaging modalities of the pancreas is endoscopic ultrasonography. However, clinicians recognize that EUS is a difficult and highly operator-dependent method, while its results are highly dependent on the experience of the investigator. Hybrid technologies based on artificial intelligence methods can improve the accuracy and objectify the results of endosonographic diagnostics. Endoscopic ultrasonography was performed on 272 patients with focal lesions of the pancreatobiliary zone, who had been treated in the surgical section of the Kursk Regional Clinical Hospital in 2014-2023. The study utilized an Olympus EVIS EXERA II video information endoscopic system, along with an EU-ME1 ultrasound unit equipped with GF UM160 and GF UC140P-AL5 echo endoscopes. Out of the focal formations in the pancreatobiliary zone, pancreatic cancer was detected in 109 patients, accounting for 40.1% of the cases. Additionally, 40 patients (14.7%) were diagnosed with local forms of chronic pancreatitis. The reference sonograms displayed distinguishable focal pancreatic pathologies, leading to the development of hybrid fuzzy mathematical decision-making rules at the South-West State University in Kursk, Russian Federation. This research resulted in the creation of a fuzzy hybrid model for the differential diagnosis of chronic focal pancreatitis and pancreatic cancer. Endoscopic ultrasonography, combined with hybrid fuzzy logic methodology, has made it possible to create a model for differentiating between chronic focal pancreatitis and pancreatic ductal adenocarcinoma. Statistical testing on control samples has shown that the diagnostic model, based on reference endosonograms of the echographic texture of pancreatic focal pathology, has a confidence level of 0.6 for the desired diagnosis. By incorporating additional information about the contours of focal formations obtained through endosonography, the reliability of the diagnosis can be increased to 0.9. This level of reliability is considered acceptable in clinical practice and allows for the use of the developed model, even with data that is not well-structured.

Early short-term effects on catecholamine levels and pituitary function in patients with pheochromocytoma or paraganglioma treated with [177Lu]Lu-DOTA-TATE therapy.

Purpose: While there are reports of treatment-related endocrine disruptions and catecholamine surges in pheochromocytoma/paraganglioma (PPGL) patients treated with [177Lu]Lu-DOTA-TATE therapy, the spectrum of these abnormalities in the immediate post-treatment period (within 48 hours) has not been previously evaluated and is likely underestimated. Methods: The study population included patients (≥18 years) enrolled in a phase 2 trial for treatment of somatostatin receptor (SSTR)-2+ inoperable/metastatic pheochromocytoma/paraganglioma with [177Lu]Lu-DOTA-TATE (7.4 GBq per cycle for 1 - 4 cycles). Hormonal measurements [adrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH), free thyroxine (FT4), follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, growth hormone, prolactin], catecholamines, and metanephrines were obtained on days-1, 2, 3, 30, and 60 per cycle as per trial protocol, and were retrospectively analyzed. Results: Among the 27 patients (age: 54 ± 12.7 years, 48.1% females) who underwent hormonal evaluation, hypoprolactinemia (14.1%), elevated FSH (13.1%), and elevated LH (12.5%) were the most frequent hormonal abnormalities across all 4 cycles combined. On longitudinal follow-up, significant reductions were noted in i. ACTH without corresponding changes in cortisol, ii. TSH, and FT4, and iii. prolactin at or before day-30 of [177Lu]Lu-DOTA-TATE. No significant changes were observed in the gonadotropic axis and GH levels. Levels of all hormones on day-60 were not significantly different from day-1 values, suggesting the transient nature of these changes. However, two patients developed clinical, persistent endocrinopathies (primary hypothyroidism: n=1 male; early menopause: n=1 female). Compared to day-1, a significant % increase in norepinephrine, dopamine, and normetanephrine levels were noted at 24 hours following [177Lu]Lu-DOTA-TATE dose and peaked within 48 hours. Conclusions: [177Lu]Lu-DOTA-TATE therapy is associated with alterations in endocrine function likely from radiation exposure to SSTR2+ endocrine tissues. However, these changes may sometimes manifest as clinically significant endocrinopathies. It is therefore important to periodically assess endocrine function during [177Lu]Lu-DOTA-TATE therapy, especially among symptomatic patients. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03206060?term=NCT03206060&draw=2&rank=1, identifier NCT03206060.

Differential Diagnosis of Pancreatic Cancer and Chronic Pancreatitis According to Endoscopic Ultrasonography Based on the Analysis of the Nature of the Contours of Focal Formations Based on Fuzzy Mathematical Models.

One of the key echographic signs of focal pathology of the pancreas is the presence of formation contours and their nature. Endoscopic ultrasonography has a unique ability to visualize the echographic texture of the pancreatic parenchyma, and also allows you to assess in detail the boundaries and nature of the contours of the tumor formations of the organ due to the proximity of the ultrasound sensor. However, the differential diagnosis of focal pancreatic lesions remains a difficult clinical task due to the similarity of their echosemiotics. One of the ways to objectify and improve the accuracy of ultrasound data is the use of artificial intelligence methods for interpreting images. Improving the quality of differential diagnosis of focal pathology of the pancreas according to endoscopic ultrasonography based on the analysis of the nature of the contours of focal formations using fuzzy mathematical models.

Method for Determining the Body's Level of Protection According to Oxidant Status in Assessing the Influence of Industrial Risk Factors on Health.

This work aims at improving the quality of health assessments, specifically under the influence of occupational risk factors. For this purpose, additional informative indicators are utilized in prognostic and diagnostic models. The models are used to characterize the level of body protection based on oxidative status. A quantitative method is proposed to assess the body's level of protection by means of the levels of lipid peroxidation and antioxidant activity, which characterize the body's oxidative status. A mechanism is developed for integrating the proposed method into prognostic and diagnostic decision rules. The developed rules are in the form of mathematical models used to synthesize hybrid fuzzy decision rules, which are then used to quantify the level of body protection (LBP) against external risk factors, based on the use of protection level functions in terms of lipid peroxidation and antioxidant activity. A mechanism for embedding LBP into predictive and diagnostic decision rules has been proposed. The proposed method is used to predict the occurrence and development of coronary heart disease in railroad locomotive drivers. It was found that to improve the predicting and diagnosing of diseases caused by external pathogenic factors, quantitative assessments of LBP, determined by oxidative status, can be implemented. It has been established that the use of the protection level indicator in predictive decision rules makes it possible to increase the efficiency of the prediction while simultaneously increasing its accuracy.

Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for 131I Administration.

Context: Recombinant human thyrotropin (rhTSH) is currently not Food and Drug Administration approved for the treatment of high-risk patients with differentiated thyroid cancer (DTC). Objective: The goal of our study was to compare the outcomes in higher-risk patients with metastatic DTC prepared for radioiodine (RAI) therapy with rhTSH vs thyroid hormone withdrawal (THW). Methods: A retrospective chart review was performed of patients with metastatic DTC in follow-up at MedStar Washington Hospital Center and MedStar Georgetown University Hospital from 2009 to 2017. Patients were divided according to their preparation for RAI therapy, with assessment of progression-free survival (PFS) and overall survival (OS). Results: Fifty-five patients with distant metastases (16 men, 39 women) were prepared for RAI therapy exclusively either with rhTSH (n = 27) or with THW (n = 28). There were no statistically significant differences between the groups regarding clinicopathological features and history of RAI therapies. The median follow-up time for patients with rhTSH-aided therapies was 4.2 years (range, 3.3-5.5 years) and for patients with THW-aided therapies was 6.8 years (range, 4.2-11.6 years) (P = .002). Multivariate analysis showed that the method of thyrotropin stimulation was not associated with a difference in PFS or OS. Conclusion: As has been shown previously for low-risk DTC, this study indicates that the mode of preparation for RAI therapy does not appear to influence the outcomes of patients with metastatic DTC. PFS and OS were similar for patients with THW-aided or rhTSH-aided RAI therapies.

Fuzzy Models of Choice of Prevention Schemes for the Occurrence and Development of Gangrene of the Lower Extremities.

The study focuses on the choice of prevention schemes of the appearance and recurrence of gangrene of the lower extremities, depending on any of the degrees of confidence that the patient will have gangrene or will experience its relapse. The degree of confidence is determined using the fuzzy logic of decision making on the relevant membership functions. For each of the selected classes, an appropriate prevention scheme has been developed, the effectiveness of which was tested using the theory of measuring latent variables and the synthesis of mathematical models of their choice depending on the degree of risk of the occurrence and recurrence of lower extremities gangrene. Model statistical tests showed that compared with traditional prevention schemes the use of the proposed models can increase the rate of positive results in the absence of lower extremities gangrene and reduce the possibility of relapse (recurrent changes by 42%, risk of amputation by 35%).

Management of mitochondrial diabetes in the era of novel therapies.

Mitochondrial disorders refer to the complex group of conditions affecting energy metabolism. A number of mitochondrial disorders can lead to the development of diabetes mellitus, and mitochondrial diabetes is thought to account for up to 3% of all diabetes mellitus cases. Depending on the degree of preservation of beta cell secretory capacity and peripheral muscle insulin sensitivity, the phenotype of mitochondrial diabetes may resemble that of type 1 or type 2 diabetes. Additionally, mitochondrial diabetes may rarely present with diabetic ketoacidosis, and can be distinguished from other forms of monogenic diabetes including maturity onset diabetes of the young by the presence of multi-organ involvement, particularly pre-senile sensorineural hearing loss, maternal transmission, and later-onset diagnosis, typically affecting adults over 35 years. Various guidelines on diabetes care do not address this important subset of cases, and this diagnosis is easily missed. Additionally, there is paucity of data on tailored diabetes therapies for mitochondrial diabetes, particularly in the era of novel therapies including glucagon-like peptide-1 receptor agonist and sodium glucose co-transporter-2 inhibitors. Here, we report three patients with mitochondrial diabetes who responded well to the addition of these novel agents and propose a new treatment algorithm for this condition.

Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review.

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

Case Report: Primary Hypothyroidism Associated With Lutetium 177-DOTATATE Therapy for Metastatic Paraganglioma.

Background: Lutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited. Case Description: A 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved. Summary: We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Conclusions: Thyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.

Isolated cortical venous thrombosis after fetal demise.

Isolated cortical venous thrombosis (ICVT) occurring in the absence of dural venous thrombosis, constitutes about 2%-5% of all cerebral venous thrombosis. Its vague, non-specific presentation makes it a difficult and challenging diagnosis that needs an extensive workup especially in young patients. Outcome and prognosis depend mainly on early diagnosis and treatment. Here we discuss the clinical presentation, diagnosis and the treatment of a young woman diagnosed with ICVT with acute ischaemic venous stroke, in the setting of eclampsia and family history of coagulation disease.