RESUMEN
A coupled global aerosol-carbon-climate model is applied to assess the impacts of aerosol physical climate change on the land ecosystem services gross primary productivity (GPP) and net primary productivity (NPP) in the 1996-2005 period. Aerosol impacts are quantified on an annual mean basis relative to the hypothetical aerosol-free world in 1996-2005, the global climate state in the absence of the historical rise in aerosol pollution. We examine the separate and combined roles of fast feedbacks associated with the land and slow feedbacks associated with the ocean. We consider all fossil fuel, biofuel and biomass burning aerosol emission sources as anthropogenic. The effective radiative forcing for aerosol-radiation interactions is -0.44 W m-2 and aerosol-cloud interactions is -1.64 W m-2. Aerosols cool and dry the global climate system by -0.8 °C and -0.08 mm per day relative to the aerosol-free world. Without aerosol pollution, human-induced global warming since the preindustrial would have already exceeded the 1.5 °C aspirational limit set in the Paris Agreement by the 1996-2005 decade. Aerosol climate impacts on the global average land ecosystem services are small due to large opposite sign effects in the tropical and boreal biomes. Aerosol slow feedbacks associated with the ocean strongly dominate impacts in the Amazon and North American Boreal. Aerosol cooling of the Amazon by -1.2 °C drives NPP increases of 8% or +0.76 ± 0.61 PgC per year, a 5-10 times larger impact than estimates of diffuse radiation fertilization by biomass burning aerosol in this region. The North American Boreal suffers GPP and NPP decreases of 35% due to aerosol-induced cooling and drying (-1.6 °C, -0.14 mm per day). Aerosol-land feedbacks play a larger role in the eastern US and Central Africa. Our study identifies an eco-climate teleconnection in the polluted earth system: the rise of the northern hemisphere mid-latitude reflective aerosol pollution layer causes long range cooling that protects Amazon NPP by 8% and suppresses boreal NPP by 35%.
Asunto(s)
Cambio Climático , Conservación de los Recursos Naturales , Ecosistema , Aerosoles/químicaRESUMEN
Sunitinib treatment leads to improvement in progression-free survival in patients with advanced pancreatic neuroendocrine tumours (pNETs). However, limited data exist regarding the effectiveness, safety and tolerability in clinical practice. We present the results of the first detailed pNET cohort analysis since sunitinib was approved. Patients with advanced, differentiated pNET treated with sunitinib were retrospectively analysed. All patients had progressive disease before start of sunitinib treatment. Twenty-one patients, with a median age of 64 years (range 28-78), were included in this study. Nineteen patients could be analysed for treatment effectiveness. Twelve (57%) patients exhibited either a partial response (1 patient) or stable disease (11 patients) according to the RECIST criteria. The median progression-free survival was 7.0 months (95% CI 3.0-12.0); the probability of being event-free at 6 months was 52.6% (95% CI 28.4-72.1). Potential influencing factors as Ki-67 index, age or duration of disease did not show significant correlations with the response to sunitinib therapy. Considering the differences in patients' characteristics, sunitinib in daily practice showed effectiveness parameters similar to the phase III trial.
Asunto(s)
Antineoplásicos/uso terapéutico , Indoles/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pautas de la Práctica en Medicina , Pirroles/uso terapéutico , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Tumores Neuroendocrinos/secundario , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Sunitinib , Resultado del TratamientoRESUMEN
Background: Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). Objective: The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. Design and methods: A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Results: Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Conclusion: Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. Significance statement: The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.
RESUMEN
Treatment of patients with undifferentiated and histologically confirmed neuroendocrine tumors (NET) usually includes chemotherapeutic intervention. This retrospective study evaluated the outcome of 2 such chemotherapies. 18 patients (11 males; age 56.2 ± 2.5) with proven progressive disease were enrolled (mean Ki-67 34 ± 5%). Patients were treated from 2005 to 2007 with regimen A (carboplatin, etoposide, paclitaxel), and from 2007 to 2009 with regimen B (cisplatin, etoposide). This change was due to low tolerability of regimen A. The standard imaging procedure was computed tomography. 8 patients underwent treatment with regimen A (mean 3.3 ± 0.7 courses). Due to severe side effects, 3 patients had their therapy prematurely discontinued. The treatment responses of 6 patients who received more than 1 course were: 0% complete response (CR), 17% partial response (PR), 50% stable disease (SD), and 33% progressive disease (PD). The median progression free survival (PFS) was 6.7 months (range 3.2-10.0). In contrast, 12 patients received regimen B (mean 3.8 ± 0.4 courses), and none of them dropped out because of side effects. The overall responses were: 0% CR, 17% PR, 42% SD, and 42% PD. The median PFS was 6.3 months (range 2.8-26.4). The response rates of both regimes were not statistically different. Patients who were treated with regimen B demonstrated comparable PFS and less severe side effects than patients who received regimen A. However, patients need to be aware of the relatively short PFS time. In order to improve therapeutic outcome of patients with progressive undifferentiated NET, new therapeutic approaches and larger multi-center studies are needed.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Diferenciación Celular , Progresión de la Enfermedad , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Pheochromocytomatosis is defined as a multifocal cell dissemination limited to the operatively opened space with no signs of distant metastasis. After primary adrenalectomy due to a pheochromocytoma this is a rare and underrecognized manifestation of a tumor recurrence. Between 2010 and 2019 a total of 5 patients with the presentation of pheochromocytomatosis were treated in this center. Clinical and survival data were compared to 12 patients with a metastasized pheochromocytoma. Patients presenting with pheochromocytomatosis showed a better but not significant overall survival (136.8 vs. 107 months). Furthermore, patients with pheochromocytomatosis presented more often with a noradrenaline secretion type. Tumor recurrence in the pheochromocytomatosis group occurred on average 69.2 months after the initial diagnosis and was therefore much later than in patients with distant metastases from a pheochromocytoma (39 months, pâ¯= 0.13). This article outlines this special manifestation of recurrence of a pheochromocytoma based on this patient collective. Besides technical operative aspects there appears to be evidence for tumor-specific factors that promote the development of pheochromocytomatosis. Importantly, it seems that all patients with a pheochromocytoma should receive lifelong aftercare and that patients should be closely monitored during the first 5 years after surgery.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/cirugía , Feocromocitoma/cirugía , Adrenalectomía , Humanos , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
Unstimulated early morning cortisol has been suggested as a first line parameter to assess adrenal function in patients with suspected secondary adrenal insufficiency. The measurement of basal salivary cortisol (BSaC) instead of basal serum cortisol (BSeC) offers some advantages, such as painless sampling and the determination of the free hormone. The objective of this study was to evaluate the diagnostic value of BSeC and BSaC in comparison to the insulin tolerance test (ITT). Seventy-seven patients with hypothalamic-pituitary disease and 184 healthy controls were enrolled. ITT were performed in patients, and BSeC as well as BSaC levels were measured in patients and controls. Upper and lower thresholds (with >or=95% specificity either for adrenal sufficiency or adrenal insufficiency) were calculated by ROC analysis both for BSeC and BSaC. The ITT identified 41 patients as adrenal insufficient and 36 patients as adrenal sufficient. Upper and lower cutoffs were 470 and 103 nmol/l for BSeC, and 21.1 and 5.0 nmol/l for BSaC, respectively. Thereby, basal cortisol allowed a highly specific diagnosis (i.e., similar to the ITT result) in either 23% (BSeC) or 27% (BSaC) of patients. We suggest the determination of unstimulated early morning cortisol as first-line screening method for the diagnosis of secondary adrenal insufficiency. If upper and lower cutoffs are used, dynamic testing could be obviated in about one fourth of cases. Due to its easy and painless collection BSaC may be preferable to BSeC.
Asunto(s)
Insuficiencia Suprarrenal/diagnóstico , Técnicas de Diagnóstico Endocrino , Hidrocortisona , Insulina/análisis , Saliva/química , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Hidrocortisona/sangre , Insulina/metabolismo , Masculino , Persona de Mediana Edad , Saliva/metabolismoRESUMEN
Ghrelin is a peptide thought to be involved in the regulation of appetite. Furthermore, significant effects on the release of growth hormone (GH) and ACTH were demonstrated. Contributing to the physiological relevance of this hormone, we investigated the expression of ghrelin and its receptor (GHS-R) in several normal human tissues. RNA samples (BD Biosciences) underwent one-step TaqMan Real-Time RT-PCR. Immunohistochemistry was performed on paraffin-embedded tissues using specific primary antibodies against ghrelin and its receptor. Relevant ghrelin mRNA levels were detected in all human tissues with the highest levels in stomach, pituitary, and small intestine. By immunohistochemistry, ghrelin peptide expression was detectable in reproductive and endocrine organs (ovary, anterior pituitary, adrenal gland), and organs of the gastrointestinal tract (stomach, pancreas). GHS-R1a mRNA expression was demonstrated in 10 of 24 human organs analyzed with the highest levels in pituitary, adrenal gland, and spinal cord. Expression of the receptor peptide was detected by immunohistochemistry in endocrine and reproductive organs (anterior pituitary, thyroid, pancreas, testis), parts of the CNS (cerebrum, cerebellum), and in single cells of bone marrow. Expression of both ghrelin and its receptor in endocrine and reproductive organs may indicate new endocrine or paracrine mechanisms of regulation in these tissues.
Asunto(s)
Glándulas Endocrinas/metabolismo , Tracto Gastrointestinal/metabolismo , Expresión Génica , Ghrelina/metabolismo , Ovario/metabolismo , Receptores de Ghrelina/metabolismo , Testículo/metabolismo , Glándulas Endocrinas/química , Femenino , Tracto Gastrointestinal/química , Ghrelina/genética , Humanos , Inmunohistoquímica , Masculino , Ovario/química , Receptores de Ghrelina/genética , Testículo/químicaRESUMEN
An undiagnosed pheochromocytoma may result in life-threatening consequences. The diagnosis of pheochromocytoma is based on the overproduction of catecholamines. Highly sensitive biochemical assays are essential to avoid false-negative results. Determinations of 24-h urinary epinephrine and norepinephrine levels are established diagnostic tools. However, they may be falsely negative in patients with a biochemically-silent or periodically-secreting pheochromocytoma. Metanephrines, which are metabolites of catecholamines, have been suggested as an alternative diagnostic tool. Urinary metanephrines are determined by high-pressure liquid chromatography (HPLC) in an increasing number of laboratories, whereas plasma metanephrines measured by HPLC are available in specialised centres only. The different HPLC methods may be cost- and time-intensive. Immunoassays such as radio- or enzyme-immunoassays may be alternative procedures. Measurement of metanephrines instead of catecholamines by either technique improved the diagnostic accuracy for the diagnosis of pheochromocytomas. Determination of plasma free metanephrines demonstrated a higher accuracy than their urinary counterparts. The use of immunoassays may be an alternative to the laborious HPLC, although the method needs to be evaluated in more detail.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Inmunoensayo/métodos , Metanefrina/orina , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/orina , Humanos , Inmunoensayo/economía , Metanefrina/sangre , Feocromocitoma/sangre , Feocromocitoma/orinaRESUMEN
An adrenal incidentaloma is an adrenal mass detected on imaging that was not performed for suspected adrenal disease. The prevalence is approximately 3% and increases up to 10% in older people. The risk of malignancy and a hormone excess have to be evaluated. Approximately 15% of incidentalomas harbor an overproduction of hormones, in particular primary aldosteronism (Conn's syndrome), hypercortisolism (Cushing's syndrome) and pheochromocytoma. Primary aldosteronism is the main cause of endocrine hypertension. It is characterized by an overproduction of aldosterone usually due to a unilateral adenoma or an idiopathic, often bilateral hyperplasia. The aldosterone to renin ratio is an established screening parameter for the diagnosis. If the ratio is elevated a confirmatory test, e.â¯g. saline infusion test, should follow. Usually an adrenal venous catheter has to be used to discriminate between unilateral and bilateral aldosterone overproduction. In the case of unilateral overproduction an adrenalectomy is recommended, otherwise treatment is carried out with an aldosterone antagonist. For the diagnosis of an adrenal Cushing's syndrome a dexamethasone suppression test and a suppressed or in the lower limit of normal ACTH is required. The rare pheochromocytoma is a catecholamine-producing tumor. The diagnosis is carried out by determination of metanephrines in plasma or in 24â¯h urine samples. Unilateral adrenal tumors leading to clinically significant hormone excess or tumors with suspicion of malignancy should be surgically removed. A minimally invasive adrenalectomy is normally the method of choice in patients with a unilateral adrenal tumor <6â¯cm and without local tumor invasion. In unilateral, clearly benign, non-functioning, small adrenal tumors (<4â¯cm) surgery is not required.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Síndrome de Cushing , Hiperaldosteronismo , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Anciano , Anciano de 80 o más Años , Síndrome de Cushing/etiología , Humanos , Hiperaldosteronismo/etiologíaRESUMEN
Chorion, placental membranes, and embryo all arise from the same fertilized oocyte; therefore, chorionic cells are presumed to reflect fetal chromosome status. Progenitor cells of the embryo are selected from the blastocyst, however, at a very early stage of development. If mitotic nondisjunction were to occur in one of the blastocyst cells destined to become trophoblast, the resultant abnormal cell line would be restricted to extraembryonic tissues. Indeed, chromosome mosaicism confined to the placenta has been found repeatedly in diagnostic chorionic villus sampling, and occasionally in third trimester placentas. Cytogenetically abnormal placental cells are morphologically and perhaps functionally abnormal. Such aberrations might result in deficient oxygen or nutrient supply to the fetus, causing intrauterine growth retardation (IUGR). To investigate this hypothesis we studied chorion and cord blood samples after delivery from 11 confirmed IUGR pregnancies. A minimum of 10 cells were analyzed from each cord blood and chorion specimen (mean number of cells from cord blood = 27; from chorion = 17). None of the cases showed true mosaicism for a hyperdiploid line. We conclude from this preliminary study that few, if any, cases of IUGR are likely to be due to chorionic mosaicism.
Asunto(s)
Corion/ultraestructura , Retardo del Crecimiento Fetal/genética , Mosaicismo , Ploidias , Adulto , Muestra de la Vellosidad Coriónica , Femenino , Sangre Fetal , Humanos , Linfocitos/ultraestructura , EmbarazoRESUMEN
5 Human somatostatin receptor subtypes (sst1-5) mediate the antisecretory and antiproliferative effects of somatostatin. We examined somatostatin receptor protein expression in 28 human normal tissues. Immunostaining was performed with specific polyclonal antibodies for sst1-5. Staining pattern and distribution of ssts were evaluated. Anterior pituitary was positively stained for all 5 ssts. Pancreatic islets exhibited a positive staining for sst1-3 and sst5. Adrenal cortex expressed all 5 receptor subtypes, while the medulla was positive for sst3 and sst5 only. The thyroid expressed sst5 only, limited to single interfollicular cells. All 5 ssts were detected in the ovary, limited to luteinized granulosa cells of the corpus luteum. In the testis, sst2A was detected in the basal parts of the tubules, while sst5 was positively stained in the luminal parts. Sst1 was found in Leydig cells only. Stomach was positively stained for all 5 ssts. Investigation of the kidney revealed differential expression, with sst2A being found in the glomerules. The tubules expressed all 5 ssts. In the bone marrow cells of the granulocytopoiesis expressed sst2A only. The cerebellum expressed sst5 in a certain cell type, representing presumably Purkinje cells, while sst2A was stained in intercellular fibers. The expression of somatostatin receptor subtypes in a variety of human normal tissues may indicate a physiological role in these organs. Somatostatin analogues may offer new diagnostic and therapeutic implications for tumours related to these tissues. However, treatment of defined tumours with somatostatin analogues may also alter other normal tissues.
Asunto(s)
Corteza Suprarrenal/metabolismo , Islotes Pancreáticos/metabolismo , Adenohipófisis/metabolismo , Receptores de Somatostatina/metabolismo , Corteza Suprarrenal/citología , Femenino , Células de la Granulosa/citología , Células de la Granulosa/metabolismo , Humanos , Inmunohistoquímica , Islotes Pancreáticos/citología , Masculino , Especificidad de Órganos , Adenohipófisis/citología , Isoformas de Proteínas/metabolismo , Testículo/citología , Testículo/metabolismo , Glándula Tiroides/citología , Glándula Tiroides/metabolismoRESUMEN
Adrenal pheochromocytomas are neoplasms characterized by catecholamine excess. Determination of metanephrines by high-pressure liquid chromatography has been well established for the diagnosis of pheochromocytomas, demonstrating high sensitivity and specificity. This study evaluates the diagnostic value of newly available enzyme immunoassays for metanephrines in plasma and urine. Chromogranin A was studied as a potential additional diagnostic tool. Spontaneous blood samples and 24-h urine samples were collected in 149 subjects, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas, 30 nonfunctioning adrenal masses, 15 patients with essential hypertension and 42 healthy normotensive volunteers. Plasma and urinary metanephrine and normetanephrine as well as chromogranin A were determined and putative thresholds were calculated by ROC analysis. Plasma free normetanephrine was found to be the best single parameter with the highest sensitivity (89.5%) and speciï¬city (98.3%) using a threshold of 167 pg/ml. Analysis of the combination of plasma free metanephrines revealed a similar sensitivity with lower specificity of 90.0%. Considering both urinary parameters demonstrated a slightly higher sensitivity (92.9%) with lower specificity (77.6%). ROC analysis revealed a threshold of 215 µg/l for chromogranin A with rather low sensitivity (73.9%) and specificity (74.2%). A weak positive correlation was found between the tumor size of pheochromocytomas and plasma metanephrine (r = 0.53, p ≤ 0.05) as well as chromogranin A (r = 0.60, p ≤ 0.01). In conclusion, plasma free and urinary metanephrines measured by enzyme immunoassays are convenient and reliable parameters for the diagnosis of pheochromocytoma. In contrast, CgA demonstrated poor sensitivity and specificity.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Metanefrina/sangre , Normetanefrina/sangre , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/sangre , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/orina , Adenoma Corticosuprarrenal/sangre , Adenoma Corticosuprarrenal/diagnóstico , Adenoma Corticosuprarrenal/patología , Adenoma Corticosuprarrenal/orina , Adulto , Aldosterona/metabolismo , Cromogranina A/sangre , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Hipertensión Esencial , Femenino , Humanos , Hidrocortisona/metabolismo , Hipertensión/diagnóstico , Masculino , Metanefrina/orina , Persona de Mediana Edad , Normetanefrina/orina , Feocromocitoma/sangre , Feocromocitoma/patología , Feocromocitoma/orina , Estudios Prospectivos , Sensibilidad y Especificidad , Carga TumoralRESUMEN
INTRODUCTION: Efficacy of medical treatment in patients with 21-hydroxylase deficiency is usually monitored by measurement of 17α-hydroxyprogesterone (17OHP). Saliva instead of serum sampling offers some advantages, such as painless handling and measurement of the bioactive free hormone. This study evaluated the diagnostic validity of salivary 17OHP for monitoring medical treatment, with samples collected at 7 time points throughout a day. SUBJECTS AND METHODS: Day profiles were performed in 23 adolescents and young adults with 21-hydroxylase deficiency and 43 healthy volunteers. During each profile, saliva and serum samples for 17OHP were simultaneously collected. RESULTS: With regard to the initial day profiles, samples were pathological in 63% (saliva) and 41% (serum). After the first day profile 14 patients underwent adjustment of medical treatment, either because of highly elevated 17OHP levels or with the aim of dose reduction. When comparing the best with the first day profile fewer samples were pathological (saliva: 32% vs. 71%; p<0.05; serum: 21% vs. 47%; n. s.), while the mean hydrocortisone equivalent dose was significantly reduced (20.09 mg vs. 27.27 mg; p<0.01). In 53% of profiles with controlled salivary 17OHP levels at 0700 h, the necessity for a treatment modification became only apparent when analyzing the whole day profile. CONCLUSION: A single 0700 h value within the reference range does not allow for a reliable assessment of therapeutic efficacy. We therefore suggest 17OHP day profiles for monitoring medical treatment. In this context, saliva analysis appears to be more sensitive in identifying patients who are inadequately treated.
Asunto(s)
17-alfa-Hidroxiprogesterona/análisis , Glucocorticoides/uso terapéutico , Saliva/química , 17-alfa-Hidroxiprogesterona/sangre , Adolescente , Hiperplasia Suprarrenal Congénita/sangre , Hiperplasia Suprarrenal Congénita/diagnóstico , Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/metabolismo , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Estudios Prospectivos , Análisis de Regresión , Adulto JovenRESUMEN
OBJECTIVE: Experience with chemotherapy in patients with medullary thyroid carcinomas (MTC) is limited. This retrospective study evaluated the outcome of a combination of cyclophosphamide, vincristine, and dacarbazine ('CVD-regimen'), which has previously been suggested for treatment of malignant pheochromocytomas. METHODS: 9 patients (5 males; age 55.0 ± 4.0 years) with MTC were enrolled. Prior to chemotherapy, progressive disease was established in all patients by use of WHO criteria. On day 1 of each cycle, patients started with cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2), and dacarbazine 600 mg/m(2); on day 2, patients received dacarbazine alone (600 mg/m(2)). Treatment cycles were repeated at 21-day intervals and 6 cycles were planned for each patient. The standard imaging procedure was computed tomography, and the primary end point was the objective tumor response rate. After chemotherapy, patients were followed up until progression. RESULTS: 9 patients underwent a total of 57 cycles (mean 6.3 ± 0.3 cycles). Treatment responses were: 0% complete response, 11% partial response, 56% stable disease, and 33% progressive disease. The median progression free survival was 13.6 months (range 5.8-24.2 months). The median change (baseline vs. end of treatment) of calcitonin was -19% (range -70% to +174%). Reversible myelosuppression and moderate gastrointestinal symptoms were the most common adverse events. CONCLUSION: Although objective tumor response rates were low, the CVD regimen allowed disease stabilization for a substantial period of time and had acceptable toxicity. After initial surgery, chemotherapy may therefore be considered as a medical treatment option.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Calcitonina/sangre , Carcinoma/sangre , Carcinoma/patología , Carcinoma/secundario , Carcinoma Neuroendocrino , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Mielopoyesis/efectos de los fármacos , Estadificación de Neoplasias , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/patología , Carga Tumoral/efectos de los fármacos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
Ghrelin is a newly characterized, widely distributed peptide thought to be involved in the regulation of appetite. Significant effects on the release of growth hormone (GH) and ACTH have been demonstrated. This study compares the expression of ghrelin and its receptor (GHS-R) in various adrenal tumors and normal adrenal gland. Normal adrenal tissue was obtained after autopsy. Tissue was obtained from 13 pheochromocytomas (PHEOs), 15 cortisol-secreting adenomas (CPAs), 12 aldosterone-secreting adenomas (APAs), and 16 nonfunctional adenomas (NFAs) following laparoscopic surgery. Expression of ghrelin and GHS-R1a was investigated on RNA levels by using real-time reverse transcription polymerase chain reaction (RT-PCR) and on protein levels by using immunohistochemistry. In the seven normal adrenal glands analyzed, ghrelin mRNA levels were 12-fold lower than in stomach. Ghrelin protein expression was confirmed by immunohistochemistry. In all adrenal tumors, relevant levels of ghrelin mRNA were observed, with significantly lower expression in PHEOs and APAs than in normal adrenal gland. Ghrelin protein was detected in 0% of PHEOs, 55% of APAs, 87% of CPAs, and 54% of NFAs. GHS-R1a mRNA expression was detectable in normal adrenal gland, but the receptor protein was absent. In adrenal tumors, detectable levels of receptor mRNA were found in 38% of PHEOs, 13% of CPAs, and 25% of NFAs. GHS-R1a protein was absent in the majority of adrenal tumors. Expression of ghrelin in normal adrenal gland and adrenal tumors may indicate some unknown physiological function. The pathophysiological relevance of ghrelin expression in adrenal tumors remains to be investigated.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Glándulas Suprarrenales/metabolismo , Regulación Neoplásica de la Expresión Génica , Ghrelina/genética , Receptores de Ghrelina/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/cirugía , Adolescente , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/cirugía , Glándulas Suprarrenales/patología , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/cirugía , Adulto , Anciano , Diferenciación Celular , Cartilla de ADN , Femenino , Ghrelina/metabolismo , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Feocromocitoma/genética , Feocromocitoma/metabolismo , Feocromocitoma/cirugía , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Ghrelina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
While octreotide binds with high affinity to sst2a only, the new analogue SOM230 demonstrates high affinity for sstl, 3, and 5, in addition. We examined the immunohistochemical expression of somatostatin receptor subtypes (sst) in 7 pheochromocytomas (PHEO), 5 Conn adenomas (CONN), 9 Cushing adenomas (CUSH), 7 nonfunctioning tumors (NFA), and 4 adrenal carcinomas (CA). About one third of the PHEO were positive for sst1, 2a, and 5. Less than 30% of cells were stained in the majority of these tumors. Each of the PHEO expressed sst3 with more than 60% of cells stained. Two thirds of the NFA revealed positive staining for sst1, 2a, and 3 with less than 30% of cells affected. Sst5 was expressed in nearly all of the NFA with positive staining in 30-60% of tumor cells. Nearly all CUSH and CONN were positive for the subtypes evaluated. In the majority of these tumors, less than 30% of cells were positively stained. Fifty percent of CA expressed sst2a and 3 with positive staining in 30-100% of cells. None of them expressed sst1. Somatostatin receptors are expressed in adrenal tumors with a tumor-specific distribution pattern. This may offer new diagnostic and therapeutic possibilities.