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Purpose: Preoperative iodine therapy in toxic nodular goiter (TNG) is discouraged as iodine may cause aggravation of hyperthyroidism. We aimed to examine if a short course of iodine treatment is safe to administer in TNG. Methods: Patients with TNG (n=20) and subclinical to mild hyperthyroidism (free (f)T4 <30 pmol/L) without complicating illnesses were included in this pre-post-intervention study at Karolinska University Hospital. All participants received Lugol's solution 5%, three oral drops thrice daily for 10 days. Heart rate, TSH, fT4, fT3 concentrations were collected before (day 0) and after treatment (day 10). Thyroid hormone concentrations were also measured at two time points during treatment to discover aggravations of hyperthyroidism. ThyPRO39se, a quality-of-life questionnaire, was filled out day 0 and day 10. Differences in heart rate, thyroid hormone concentrations, and quality-of-life before and after treatment were compared. Adverse reactions were reported. Results: The median age was 63.5 years. Female to male ratio 19:1. FT4 and fT3 concentrations decreased (both p<0.001), and TSH concentration increased (p<0.001) after 10 days of treatment. There was no difference in heart rate. No aggravations of thyrotoxicosis were noticed in any of the participants. ThyPRO39se scores improved on three scales, including hyperthyroid symptoms, while the remaining scale scores were unchanged. Mild and transient symptoms related to or possibly related to treatment were observed in six participants. Conclusion: A short course of Lugol's solution improved thyroid hormone concentrations, reduced patient-reported hyperthyroid symptoms and was safe in TNG. Lugol's solution might be an option for preoperative treatment in TNG. Clinical trial registration: https://www.clinicaltrials.gov, identifier NCT04856488.
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Bocio Nodular , Yoduros , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Bocio Nodular/tratamiento farmacológico , Bocio Nodular/sangre , Hipertiroidismo/tratamiento farmacológico , Yoduros/administración & dosificación , Calidad de Vida , Hormonas Tiroideas/sangreRESUMEN
Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here, we re-analyzed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and from analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in six PCC cases. Three of these were constitutional, and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak or negative staining. Reduced CACNA1H gene expression was especially pronounced in PCC compared to aPGL and in PPGL with cluster 2 kinase signaling phenotype. Furthermore, CACNA1H levels correlated with HIF1A and HIF2A. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles, determined by mass spectrometry, as well as a shift in the membrane potential where maximum calcium currents were observed, as determined by electrophysiology. The findings suggest the involvement of CACNA1H/CaV3.2 in pheochromocytoma development and establish a potential link between the etiology of adrenomedullary and adrenocortical tumor development.
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Neoplasias de las Glándulas Suprarrenales , Regulación hacia Abajo , Feocromocitoma , Feocromocitoma/genética , Feocromocitoma/metabolismo , Humanos , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Femenino , Masculino , Animales , Persona de Mediana Edad , Adulto , Ratas , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Células PC12RESUMEN
PURPOSE: Tumor classification is a key component in personalized cancer care. For soft-tissue and bone tumors, this classification is currently based primarily on morphology assessment and IHC staining. However, these standard-of-care methods can pose challenges for pathologists. We therefore assessed how whole-genome and whole-transcriptome sequencing (WGTS) impacted tumor classification and clinical management when interpreted together with histomorphology. EXPERIMENTAL DESIGN: We prospectively evaluated WGTS in routine diagnostics of 200 soft-tissue and bone tumors suspicious for malignancy, including DNA and RNA isolation from the tumor, and DNA isolation from a peripheral blood sample or any non-tumor tissue. RESULTS: On the basis of specific genomic alterations or absence of presumed findings, WGTS resulted in reclassification of 7% (13/197) of the histopathologic diagnoses. Four cases were downgraded from low-grade sarcomas to benign lesions, and two cases were reclassified as metastatic malignant melanomas. Fusion genes associated with specific tumor entities were found in 30 samples. For malignant soft-tissue and bone tumors, we identified treatment relevant variants in 15% of cases. Germline pathogenic variants associated with a hereditary cancer syndrome were found in 22 participants (11%). CONCLUSIONS: WGTS provides an important dimension of data that aids in the classification of soft-tissue and bone tumors, correcting a significant fraction of clinical diagnoses, and identifies molecular targets relevant for precision medicine. However, genetic findings need to be evaluated in their morphopathologic context, just as germline findings need to be evaluated in the context of patient phenotype and family history.
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Genómica , Sarcoma , Humanos , Sarcoma/genética , Sarcoma/diagnóstico , Sarcoma/patología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Genómica/métodos , Neoplasias Óseas/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Adulto Joven , Perfilación de la Expresión Génica , Anciano de 80 o más Años , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , Adolescente , Biomarcadores de Tumor/genética , Estudios Prospectivos , Niño , Secuenciación Completa del Genoma/métodosRESUMEN
The parathyroid cell is a vital regulator of extracellular calcium levels, operating through the secretion of parathyroid hormone (PTH). Despite its importance, the regulation of PTH secretion remains complex and not fully understood, representing a unique interplay between extracellular and intracellular calcium, and hormone secretion. One significant challenge in parathyroid research has been the difficulty in maintaining cells ex vivo for in-depth cellular investigations. To address this issue, we introduce a novel platform for parathyroid cell transplantation and noninvasive in vivo imaging using the anterior chamber of the eye as a transplantation site. We found that parathyroid adenoma tissue transplanted into the mouse eye engrafted onto the iris, became vascularized, and retained cellular composition. Transplanted animals exhibited elevated PTH levels, indicating a functional graft. With in vivo confocal microscopy, we were able to repetitively monitor parathyroid graft morphology and vascularization. In summary, there is a pressing need for new methods to study complex cellular processes in parathyroid cells. Our study provides a novel approach for noninvasive in vivo investigations that can be applied to understand parathyroid physiology and pathology under physiological and pathological conditions. This innovative strategy can deepen our knowledge on parathyroid function and disease.
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Calcio , Neoplasias de las Paratiroides , Ratones , Animales , Glándulas Paratiroides/diagnóstico por imagen , Glándulas Paratiroides/patología , Hormona Paratiroidea , Neoplasias de las Paratiroides/diagnóstico por imagen , Neoplasias de las Paratiroides/patologíaRESUMEN
PURPOSE: This study aimed to investigate the relationship between Lugol iodine treatment in a rescue setting and surgical outcomes in Graves' disease patients. METHODS: The retrospective register-based cohort study included 813 patients who had undergone primary total thyroidectomy with a primary diagnosis of Graves' disease (ICD-code E05.0) at Karolinska University Hospital in Stockholm, Sweden, between January 2008 and December 2015. Of 813 patients, 33 (4.1%) were given Lugol iodine before surgery and the remaining, the non-Lugol group, did not. The study's primary outcomes were post-operative calcium treatment day 1, calcium and vitamin D supplements at discharge and follow-up. Secondary outcomes were laryngeal nerve damage and bleeding (defined as re-operation). RESULTS: Differences were found between the Lugol and non-Lugol groups in the treatment of calcium day 1 (45.5% vs 26.7%, p = 0.018), at discharge (36.4% vs. 16.2%, p = 0.002) and vitamin D supplements at discharge (36.4% vs. 19.1%, p = 0.015) as surrogate variables for hypocalcemia post-operatively. No differences could be seen at 4-6 weeks and six-months follow-up. There were no differences between the Lugol and non-Lugol groups in terms of operation time, laryngeal nerve damage, and bleeding. CONCLUSION: Patients in our cohort undergoing thyroidectomy due to Graves' disease pre-operatively treated with Lugol iodine as a rescue therapy had a higher risk of experiencing short term post-operative hypocalcemia.
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Enfermedad de Graves , Sistema de Registros , Tiroidectomía , Humanos , Tiroidectomía/efectos adversos , Femenino , Enfermedad de Graves/cirugía , Enfermedad de Graves/tratamiento farmacológico , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Resultado del Tratamiento , Yoduros/uso terapéutico , Yoduros/administración & dosificación , Anciano , Hipocalcemia/epidemiología , Hipocalcemia/etiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios de Cohortes , Vitamina D/uso terapéutico , Vitamina D/administración & dosificación , Calcio/uso terapéuticoRESUMEN
BACKGROUND: Substantial disparities in the utilization of parathyroidectomy for primary hyperparathyroidism have been reported. This study aimed to analyse regional variations in parathyroidectomy incidence with respect to the patient's disease burden and socioeconomic status. METHODS: A population-based case-control study included all patients with primary hyperparathyroidism who underwent parathyroidectomy in Sweden between 2008 and 2017 and 10 matched controls. Data on demographic and socioeconomic variables, co-morbidities and drug prescriptions were collected from relevant national registers. Conditional logistic regression was used to analyse predictors of parathyroidectomy. RESULTS: A total of 8626 patients with primary hyperparathyroidism (77% women) underwent parathyroidectomy during the study interval. The annual incidence of parathyroidectomy was 9.0 per 100 000 persons. The annual age-adjusted regional incidences of parathyroidectomy varied between 3.3 and 16.9 operations per 100 000 inhabitants. Except for a small underrepresentation of patients with lower education, no effect of socioeconomic variables was observed. Compared with matched controls, the parathyroidectomy group had increased odds ratios of having developed classical symptoms of primary hyperparathyroidism and being prescribed medication against cardiovascular disorders and psychiatric illness at the time of parathyroidectomy. Increased risks of kidney stones and osteoporosis were observed 5 years before parathyroidectomy. Patients with primary hyperparathyroidism selected for parathyroidectomy from regions with a low incidence of operations had a higher prevalence of kidney stones, osteoporosis and hypertension, as well as larger adenomas and higher calcium levels at the time of parathyroidectomy compared with patients in high-incidence regions. CONCLUSION: The considerable variation in parathyroidectomy seems more likely associated with different clinical thresholds for detection of primary hyperparathyroidism and referral to surgery than socioeconomic disparities.
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Hiperparatiroidismo Primario , Cálculos Renales , Osteoporosis , Humanos , Femenino , Masculino , Suecia , Estudios de Casos y ControlesRESUMEN
The relationships between parathyroid hormone (PTH) secretion and parathyroid cell membrane potential, including the identities and roles of K+ channels that regulate and/or modulate membrane potential are not well defined. Here we have used Western blot/immunohistochemistry as well as patch-clamp and perifusion techniques to identify and localize specific K+ channels in parathyroid cells and to investigate their roles in the control of membrane potential and PTH secretion. We also re-investigated the relationship between membrane potential and exocytosis. We showed that in single human parathyroid cells K+ current is dependent on at least two types of Ca2+-activated K+ channels: a small-conductance Ca2+-activated K+ channel (KSK) and a large-conductance voltage and Ca2+-activated K+ channel (KBK). These channels were sensitive to specific peptide blocking toxins including apamin, charybdotoxin, and iberiotoxin. These channels confer sensitivity of the membrane potential in single cells to high extracellular K+, TEA, and peptide toxins. Blocking of KBK potently inhibited K+ channel current, and KBK was shown to be expressed in the plasma membrane of parathyroid cells. In addition, when using the capacitance technique as an indicator of exocytosis, clamping the parathyroid cell at -60 mV prevented exocytosis, whereas holding the membrane potential at 0 mV facilitated it. Taken together, the results show that human parathyroid cells have functional KBK and KSK channels but the data presented herein suggest that KBK/KSK channels likely contribute to the maintenance of the membrane potential, and that membrane potential, per se, modulates exocytosis independently of [Ca2+]i.
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Calcio , Canales de Potasio , Humanos , Potenciales de la Membrana , Calcio/metabolismo , Péptidos/metabolismo , ExocitosisRESUMEN
Abnormalities of the insulinlike growth factor 2 (IGF2)H19 locus with the overexpression of IGF2 are frequent findings in adrenocortical carcinoma (ACC). The present study assessed the expression of RNAs and microRNAs (miRNAs/miRs) from the IGF2H19 locus using PCRbased methods in ACC and adrenocortical adenoma (ACA). The results were associated with proteomics data. IGF2 was overexpressed in ACC, and its expression correlated with that of miR4833p and miR4835p hosted by IGF2. The downregulated expression of H19 in ACC compared to ACA correlated with miR675 expression hosted by H19. Several proteins exhibited an inverse correlation in expression and were predicted as targets of miR4833p, miR4835p or miR675. Subsets of these proteins were differentially expressed between ACC and ACA. These included several proteins involved in mitochondrial metabolism. Among the mitochondrial respiratory complexes, complex I and IV were significantly decreased in ACC compared to ACA. The protein expression of NADH:ubiquinone oxidoreductase subunit C1 (NDUFC1), a subunit of mitochondrial respiratory complex I, was further validated as being lower in ACC compared to ACA and normal adrenals. The silencing of miR4835p increased NDUFC1 protein expression and reduced both oxygen consumption and glycolysis rates. On the whole, the findings of the present study reveal the dysregulation of the IGF2H19 locus and mitochondrial respiration in ACC. These findings may provide a basis for the further understanding of the pathogenesis of ACC and may have potential values for diagnostics and treatment.
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Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Carcinoma Corticosuprarrenal , MicroARNs , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/patología , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Complejo I de Transporte de Electrón/metabolismo , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , MicroARNs/genética , NAD/metabolismo , UbiquinonaRESUMEN
Background: The ATP-sensitive K+ (K(ATP)) channel is found in a variety of tissues extending from the heart and vascular smooth muscles to the endocrine pancreas and brain. Common to all K(ATP) channels is the pore-forming subunit Kir6.x, a member of the family of small inwardly rectifying K+ channels, and the regulatory subunit sulfonylurea receptor (SURx). In insulin secreting ß-cells in the endocrine part of the pancreas, where the channel is best studied, the K(ATP) channel consists of Kir6.2 and SUR1. Under physiological conditions, the K(ATP) channel current flow is outward at membrane potentials more positive than the K+ equilibrium potential around -80 mV. However, K(ATP) channel kinetics have been extensively investigated for inward currents and the single-channel kinetic model is based on this type of recording, whereas only a limited amount of work has focused on outward current kinetics. Methods: We have estimated the kinetic properties of both native and cloned K(ATP) channels under varying ionic gradients and membrane potentials using the patch-clamp technique. Results: Analyses of outward currents in K(ATP) and cloned Kir6.2ΔC26 channels, alone or co-expressed with SUR1, show openings that are not grouped in bursts as seen for inward currents. Burst duration for inward current corresponds well to open time for outward current. Conclusions: Outward K(ATP) channel currents are not grouped in bursts regardless of membrane potential, and channel open time for outward currents corresponds to burst duration for inward currents.
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Surgery is the cornerstone of gastrointestinal stromal tumor (GIST) treatment, and adjuvant therapy with imatinib has improved survival for high-risk tumors. The use of imatinib preoperatively has been increasing, but efficacy and impact on patient outcomes have not been formally investigated. This is a retrospective study from a single-center cohort of patients diagnosed with GIST and treated with neoadjuvant imatinib at Karolinska University Hospital in Stockholm, Sweden over a 20-year period. Eighty-four patients diagnosed with GIST and treated with neoadjuvant imatinib were identified and included. Tumors were located throughout the whole gastrointestinal tract but most frequently in the stomach (n = 29; 35%) and the small intestine (n = 30; 36%), followed by the rectum (n = 12; 14%) and the gastroesophageal junction (n = 10; 12%). The tumors were large (mean 10.5 cm) and decreased after treatment (mean 7.6 cm). Main indications for neoadjuvant imatinib were tumor size or anatomical location. None of the patients with stomach tumors and four patients with tumors near the gastroesophageal junction underwent gastrectomy. Three patients with tumors in the small intestine underwent pancreaticoduodenectomy, whereas seven patients with rectal tumors underwent rectal amputation. After surgery, 94% (n = 79) of the tumors had R0-resection. About one-fourth experienced local relapse or distant metastasis. In conclusion, neoadjuvant imatinib can reduce tumor size and prevent high morbidity due to more extensive surgery, or at least reduce the extent of the surgery, especially for tumors in the stomach or small intestine.
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Antineoplásicos , Tumores del Estroma Gastrointestinal , Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib/uso terapéutico , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/patología , Derivación y Consulta , Estudios RetrospectivosRESUMEN
BACKGROUND: Hypocalcemia is one of the most common complications of thyroidectomy, and vitamin D deficiency has been found to be an independent risk factor. Sweden is located north of the 55th latitude, resulting in a significant seasonal variation in sun exposure, thereby large variation in the naturally occurring levels of vitamin D. This study aimed to determine if there is a correlation between season of surgery and post-thyroidectomy hypocalcemia. METHODS: We conducted a retrospective register-based observation study on patients who had undergone total thyroidectomy during 2008-2015. In total, 7125 patients operated in Swedish facilities were identified via the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery (SQRTPA). Patients operated during February-April were included in the dark group and patients operated during August-October were included in the bright group. Further stratification was made on the indication for surgery. The primary outcome was post-operative calcium treatment due to hypocalcemia, defined as having received calcium orally or intravenously before discharge. RESULTS: The risk of receiving post-operative calcium treatment was significantly lower in the bright group (29.7%) compared to the dark group (35.1%), with a relative risk of 0.846 (P < 0.001). This correlation held true if the indication for surgery was goiter or thyrotoxicosis. For malignancy, there was no significant difference between the groups. CONCLUSION: In this cohort, total thyroidectomy performed during August-October was associated with a lower rate of calcium treatment given post-operatively when compared to total thyroidectomy performed during February-April. This would indicate a decreased risk of post-operative hypocalcemia if surgery was carried out after the brighter season.
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ATP-sensitive K+ (KATP) channels couple cellular metabolism to electrical activity in many cell types. Wild-type KATP channels are comprised of four pore forming (Kir6.x) and four regulatory (sulfonylurea receptor, SURx) subunits that each contain RKR endoplasmic reticulum retention sequences that serve to properly translocate the channel to the plasma membrane. Truncated Kir6.x variants lacking RKR sequences facilitate plasma membrane expression of functional Kir6.x in the absence of SURx; however, the effects of channel truncation on plasma membrane orientation have not been explored. To investigate the role of truncation on plasma membrane orientation of ATP sensitive K+ channels, three truncated variants of Kir6.2 were used (Kir6.2ΔC26, 6xHis-Kir6.2ΔC26, and 6xHis-EGFP-Kir6.2ΔC26). Oocyte expression of Kir6.2ΔC26 shows the presence of a population of inverted inserted channels in the plasma membrane, which is not present when co-expressed with SUR1. Immunocytochemical staining of intact and permeabilized HEK293 cells revealed that the N-terminus of 6xHis-Kir6.2ΔC26 was accessible on both sides of the plasma membrane at roughly equivalent ratios, whereas the N-terminus of 6xHis-EGFP-Kir6.2Δ26 was only accessible on the intracellular face. In HEK293 cells, whole-cell electrophysiological recordings showed a ca. 50% reduction in K+ current upon addition of ATP to the extracellular solution for 6xHis-Kir6.2ΔC26, though sensitivity to extracellular ATP was not observed in 6xHis-EGFP-Kir6.2ΔC26. Importantly, the population of channels that is inverted exhibited similar function to properly inserted channels within the plasma membrane. Taken together, these data suggest that in the absence of SURx, inverted channels can be formed from truncated Kir6.x subunits that are functionally active which may provide a new model for testing pharmacological modulators of Kir6.x, but also indicates the need for added caution when using truncated Kir6.2 mutants.
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Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Membrana Celular/metabolismo , Oocitos/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Receptores de Sulfonilureas/metabolismo , Animales , Células HEK293 , Humanos , Activación del Canal Iónico , Oocitos/citología , Canales de Potasio de Rectificación Interna/genética , Receptores de Sulfonilureas/genética , Xenopus laevisRESUMEN
Metabolic adaptation to increased oxidative phosphorylation (OXPHOS) has been found in gastrointestinal stromal tumor (GIST) upon imatinib treatment. However, the underlying mechanism of imatinib-induced OXPHOS is unknown. Discovering molecules that mediate imatinib-induced OXPHOS may lead to the development of therapeutic strategies synergizing the efficacy of imatinib. In this study, we explored the role of microRNAs in regulating OXPHOS in GIST upon imatinib treatment. Using a microarray approach, we found that miR-483-3p was one of the most downregulated miRNAs in imatinib-treated tumors compared to untreated tumors. Using an extended series of GIST samples, we further validated the downregulation of miR-483-3p in imatinib-treated GIST samples by RT-qPCR. Using both gain- and loss-of-function experiments, we showed that miR-483-3p could regulate mitochondrial respiratory Complex II expression, suggesting its role in OXPHOS regulation. Functionally, miR-483-3p overexpression could rescue imatinib-induced cell death. These findings provide the molecular link for imatinib-induced OXPHOS expression and the biological role of miR-483-3p in regulating cell viability upon imatinib treatment.
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Antineoplásicos/farmacología , Complejo II de Transporte de Electrones/metabolismo , Neoplasias Gastrointestinales/metabolismo , Tumores del Estroma Gastrointestinal/metabolismo , Mesilato de Imatinib/farmacología , MicroARNs/metabolismo , Mitocondrias/enzimología , Transducción de Señal/efectos de los fármacos , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Regulación hacia Abajo/efectos de los fármacos , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mesilato de Imatinib/uso terapéutico , MicroARNs/genética , Mitocondrias/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , ARN Mensajero/genética , Transducción de Señal/genética , TransfecciónRESUMEN
Purpose: Neuroendocrine tumors of the pancreas (Pan-NETs) are usually hormonally inactive with a capacity to metastasize. Since Pan-NETs are rare, more knowledge is needed. Methods: We reviewed all patients' medical files with Pan-NET treated at a tertiary center (2006-2019). Grade 1 (G1) and grade 2 (G2) tumors were compared. The latter group was subdivided arbitrarily based on proliferation index into G2a (3-9.9%) and G2b (10-19.9%). Results: We found 137 patients (76 females, 61 males; G1 n=66, G2 n=42), the median age at diagnosis 61 years (interquartile range (IQR) 50-71), and tumor size 2 cm (1.3-5 cm). The initial surgery was performed in 101 patients. The remaining (n=36) were followed conservatively. Metastatic disease was evident in 22 patients (16%) at diagnosis while new lesions developed in 13 out of 22 patients (59%). In patients without previous metastatic disease, progressive disease was discovered in 29% of G1 vs. 55% of G2 patients (P=0.009), 47% of G2a vs. 75% of G2b patients (NS). Survival was poorer in patients with metastasis at diagnosis vs. those with local disease (P<0.001). During follow-up of 74 months, Pan-NET related death was found in 10 patients. Survival was not different between G1 vs. G2 or G2a vs. G2b, or if tumors were functional. Size ≤2 cm was associated with a better outcome (P=0.004). During the follow-up of small tumors (≤2 cm, n=36) two were resected. Conclusion: In small non-functional Pan-NETs, active surveillance is reasonable. Progressive disease was more common in G2, but survival was similar in G1, G2 and between G2 subgroups. Survival was poorer in patients with metastasis at diagnosis.
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Biomarcadores de Tumor/metabolismo , Antígeno Ki-67/metabolismo , Tumores Neuroendocrinos/mortalidad , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/mortalidad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Índice Mitótico , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Centros de Atención TerciariaRESUMEN
The ATP-regulated K+ channel (KATP) plays an essential role in the control of many physiological processes, and contains a ATP-binding site. Tyrosine kinase inhibitors (TKI) are commonly used drugs, that primarily target ATP-binding sites in tyrosine kinases. Herein, we used the patch-clamp technique to examine the effects of three clinically established TKIs on KATP channel activity in isolated membrane patches, using a pancreatic ß-cell line as a KATP channel source. In excised inside-out patches, the activity of the KATP channel was dose-dependently inhibited by imatinib with half-maximal concentration of approximately 9.4 µM. The blocking effect of imatinib was slow and reversible. No effect of imatinib was observed on either the large (KBK) or the small (KSK) conductance, Ca2+-regulated K+ channel. In the presence of ATP/ADP (ratio 1) addition of imatinib increased channel activity approximately 1.5-fold. Sunitinib and nilotinib were also found to decrease KATP channel activity. These findings are compatible with the view that TKIs, designed to interact at the ATP-binding pocket on the tyrosine receptor, also interact at the ATP-binding site on the KATP channel. Possibly, this might explain some of the side effects seen with TKIs.
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Células Secretoras de Insulina/metabolismo , Canales KATP/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sunitinib/farmacología , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/farmacología , Ratones , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Sunitinib/efectos adversosRESUMEN
INTRODUCTION: Hypoparathyroidism is the most common complication following thyroidectomy, and various algorithms for early detection have been suggested. The aim of this study was to evaluate the predictive value of measuring the parathyroid hormone level 2 h after thyroidectomy and whether determination of the perioperative decline in parathyroid hormone added diagnostic value. METHODS: Patients subjected to thyroidectomy for benign thyroid disorders were analyzed in (1) a retrospective register-based study (366 consecutive patients treated during 2015-2016) and (2) a prospective observational study (39 patients treated during 2018). Optimal cut-off values for postoperative parathyroid hormone and perioperative decline (%) in parathyroid hormone were determined by receiver operating characteristics and area under the curve. Sensitivity, specificity, positive and negative predictive values were calculated using cross tabulation. RESULTS: The prevalence of hypoparathyroidism the first day after thyroidectomy was higher among patients treated for hyperthyroidism (30% vs 20%; P = 0.03). The optimal cut-off level for postoperative parathyroid hormone was 1.1 pmol/L (area under the curve = 0.887, 95% confidence interval: 0.839-0.934; positive predictive value: 88%, negative predictive value: 93%) for the entire cohort. When the groups were analyzed separately, the optimal cut-off was 1.05 for the non-hyperfunctioning group and 1.55 pmol/L for the group with hyperthyroidism. Twelve months after thyroidectomy, 3% were defined as having permanent hypoparathyroidism. Measurement of parathyroid hormone decline added diagnostic value for one patient with preoperative parathyroid-hormone-elevation associated with vitamin D deficiency. CONCLUSIONS: For patients with vitamin D sufficiency, the diagnostic accuracy of a single measurement of parathyroid hormone 2 h after thyroidectomy is an excellent indicator for predicting transient hypoparathyroidism.
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Hipocalcemia , Hipoparatiroidismo , Humanos , Hipoparatiroidismo/diagnóstico , Hipoparatiroidismo/epidemiología , Hipoparatiroidismo/etiología , Hormona Paratiroidea , Complicaciones Posoperatorias , Estudios Retrospectivos , Tiroidectomía/efectos adversosRESUMEN
PURPOSE: Sarcomas of the breast account for about 1% of all breast malignancies. The aim of this national survey was to explore etiologic and prognostic factors. METHODS: Utilizing national Swedish registers, all patients registered with mesenchymal tumors in the breast during the period 1993-2013 (n = 344) were identified and compared to up to ten age and gender matched controls. Cancer history was retrieved for cases and controls. Conditional Poisson regression models were used for calculation of odds ratios. RESULTS: Previous breast cancer was overrepresented among patients with angiosarcoma. The highest risk occurred ≥ 5 years after treatment for breast cancer (OR 73.9, 95% confidence interval, CI, 25.4-215; P < 0.001). An increase in incidence of angiosarcoma was observed during the study period (1.10, 95% CI 1.05-1.16; P < 0.001). The overall incidence of breast sarcoma increased from 1.52 to 2.04 cases per million per year. Angiosarcoma of the breast was associated with a significant excess mortality compared to age-matched controls (HR 4.65, 95% CI 3.01-7.19; P < 0.001). CONCLUSIONS: Angiosarcoma increased in incidence and displayed a more severe clinical course, with significantly shorter survival. The strong association between a history of breast cancer 5 years or more prior to the diagnosis of angiosarcoma points to radiotherapy as a contributing factor.
Asunto(s)
Neoplasias de la Mama , Neoplasias Inducidas por Radiación , Sarcoma , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etiología , Estudios de Casos y Controles , Femenino , Humanos , Pronóstico , Sarcoma/epidemiología , Sarcoma/etiología , Suecia/epidemiologíaRESUMEN
BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. METHODS: The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. RESULTS: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. CONCLUSION: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registration www.clinicaltrials.gov ; NCT: 02432846; registration date: February 22, 2016.
Asunto(s)
Antineoplásicos/uso terapéutico , Células Dendríticas/trasplante , Neoplasias Gastrointestinales/terapia , Tumores del Estroma Gastrointestinal/terapia , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trasplante HomólogoRESUMEN
Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.
Asunto(s)
Resistencia a Antineoplásicos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/metabolismo , Mesilato de Imatinib/uso terapéutico , Antimicina A/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucólisis/efectos de los fármacos , Gosipol/farmacología , Humanos , Mesilato de Imatinib/farmacología , Oligomicinas/farmacología , Biogénesis de Organelos , Fosforilación Oxidativa/efectos de los fármacos , Fenotipo , Piruvatos/farmacologíaRESUMEN
Anaplastic thyroid carcinoma (ATC) exhibits an exceedingly poor prognosis, and the current treatment options are, for most cases, palliative by nature. Few reports of long-time survivors exist, although in these patients, tumors often were limited to the thyroid and/or regional lymph nodes. We describe a 64-year-old male who developed a rapidly growing mass in the left thyroid lobe. A fine-needle aspiration biopsy (FNAB) was consistent with ATC, and the patient underwent preoperative combined chemo- and radiotherapy followed by a hemithyroidectomy. The ensuing histopathological investigation was consistent with ATC adjoined by an oxyphilic well-differentiated lesion, likely a Hürthle cell carcinoma. Tumor margins were negative, and no extrathyroidal extension was noted. Focused next-generation sequencing analysis of the primary tumor tissue identified a TP53 gene mutation but could not identify any potential druggable targets. Additional Sanger sequencing detected a C228T TERT promoter mutation. The tumor was found to be microsatellite stable and displayed PDL1 expression in 80% of tumor cells. Following a CT scan 1 month postoperatively, metastatic deposits were suspected in the lung as well as in the left adrenal gland, of which FNAB verified the latter. Remarkably, upon radiological follow-up, the disease had gone into apparent complete remission. The patient is alive and well with no signs of residual disease after 12 months of follow-up. We here summarize the clinical, histological, and molecular data of this highly interesting patient case and review the literature for possible common denominators with other patients with disseminated ATC.