Ines Donangelo

Expression of retinoblastoma protein in human growth hormone-secreting pituitary adenomas

The retinoblastoma gene (RB1) is a tumor-suppressor gene in chromosomal region 13q14.2. Its role in the pathogenesis of pituitary tumors has not been fully clarified. Some studies have shown that losses in this chromosomal region are related to aggressive tumor behavior, although the retinoblastoma protein (pRB) is still expressed. Conversely, lack of expression of pRB was observed in one fourth of GH-secreting pituitary adenomas (GH-tumors). In order to further study the expression of pRB in GH-tumors, we evaluated this protein in 49 tumors from patients with acromegaly (20 noninvasive, 25 invasive, and 4 with no information) and 8 normal pituitaries using immunohistochemistry (IHC). Nuclear staining for pRB ranged from 0 to 90% (median 40%) in the tumors and from 40 to 80% (median 58%) in normal pituitaries. In 10 tumors (20% of total) the adenomatous cells were negative (5 cases) or had very low labeling (5 cases) for pRB. Sixty three percent (31/49) of the tumors showed staining in 10–80% of the cells and in 16% (8/49) of the cases >80% of the adenomatous cells were positive for pRB. The expression of pRB was not different in invasive and noninvasive tumors. In conclusion, pRB is underexpressed in a subgroup of GH-tumors, and this may represent an early event in the pathogenesis of this tumor subtype.

Diagnóstico e tratamento da acromegalia no Brasil

Acromegaly is a disabling and disfiguring illness, which, if not adequately controlled, decreases life expectancy. Cardiovascular and respiratory complications represent the main causes of death in acromegalic patients. Nowadays, the diagnosis is made following the guidelines reported in the 2000 consensus: Failure of GH to suppress to less than 1ng/mL and an increased IGF-1. Progress in all therapeutic modalities has been made, allowing biochemical disease control in more patients. Previous studies demonstrated that achieving safe GH levels (mean GH <2.5ng/mL) and normal IGF-1 decreases mortality rate to normal. In 2002, the guidelines for management of acromegaly were published which encompass, many times, a multidisciplinary approach. In this article, we critically evaluate what is available in Brazil that allows us to follow the guidelines established in the diagnosis and treatment consensus.

Optic pathways tuberculoma mimicking glioma: case report.

BACKGROUND Optochiasmatic tuberculomas are very rare lesions. They can occur with concomitant tuberculous meningitis, and pulmonary tuberculosis or as the only manifestation of the disease. The authors present a case of optic pathways tuberculoma with radiologic appearance simulating an optic pathways glioma. CASE DESCRIPTION We report a case of a 20-year-old man with mental retardation due to anoxic encephalopathy who developed a sudden bilateral amaurosis. He also presented with diabetes insipidus, panhypopituitarism, right proptosis, and chemosis. Computed tomography (CT) and magnetic resonance imaging (MRI) showed an enhancing lesion in the optochiasmatic region extending to both optic nerves, with a mass in the right orbit, mimicking an optic pathways glioma. There was no other evidence of systemic involvement of the tuberculosis. The lesion was explored through a right pterional transylvian approach with opening of the optic canal and orbital roof, and a biopsy and an internal decompression were performed. Histopathological studies demonstrated a granulomatous lesion with central caseous necrosis with acid-fast bacilli. The patient improved after treatment with tuberculostatic drugs, but vision recovery could not be achieved. CONCLUSIONS Visual compromise in tuberculosis is associated with hydrocephalus, optical neuritis or tuberculomas involving the optic pathways. Reviewing the literature on tuberculomas of the optochiasmatic area, we could not find any other case with such extensive involvement of the optic pathways that was radiologically suggestive of an infiltrating glioma. Histopathological studies remain crucial in the diagnosis of intrinsic expansive processes of the optochiasmatic region.

Teste agudo com octreotide subcutâneo como preditor de resposta ao tratamento com octreotide LAR

Os analogos da somatostatina sao muito utilizados no tratamento da acromegalia. Com o objetivo de determinar o valor do teste agudo (TA) com octreotide subcutâneo (SC) como preditor da resposta ao tratamento com octreotide LAR®, analisamos os dados de 20 pacientes. Para o TA, amostras de sangue foram colhidas antes e duas horas apos a administracao de octreotide SC para a dosagem de GH. Os niveis de GH antes e apos o TA foram 21,9 (2,3-143,4) e 3,1ng/mL (0,3-61,3), respectivamente. Foi considerado controle de doenca: GH< 2,5ng/mL e IGF-I normal em algum momento durante o tratamento. A sensibilidade, especificidade e os valores preditivos positivo e negativo do TA foram 0,9, 0,6, 0,69 e 0,86 para reducao de 75% do GH no teste. Concluimos que, em nossa casuistica, um decrescimo de 75% dos niveis de GH no TA teve um bom poder discriminatorio entre pacientes com maior e menor chance de resposta ao tratamento.

Tumor deletion mapping of chromosomal region 13q14 in 43 growth hormone secreting pituitary adenomas

Previous studies have reported allelic loss in chromosomal region 13q14 in pituitary tumors. However, the role of RB1 in this region has not been clarified. We performed a tumor deletion map of chromosomal region 13q14 with pituitary adenomas and matched blood samples of 43 patients with acromegaly. Twenty-one patients had non-invasive tumors, 19 had invasive tumors, and in 3 this information was not available. Results showed loss of heterozygosity in at least one microsatelite marker of region 13q14 in 12% (5 of 43) of the somatotropinomas. Retention of marker D13S1325, telomeric to RB1, suggests that the putative tumor suppressor gene is located centromeric to this region, which includes RB1 locus. The participation of RB1 was excluded in four of the five cases because retinoblastoma protein was shown to be positive in these tumors in our previous study. Allelic loss occurred in similar frequency in invasive and noninvasive adenomas. In summary, we confirmed the participation of chromosomal region 13q14 in a subset of GH-secreting adenomas with no regard to tumor grade. RB1 was not implicated, suggesting the participation of another tumor suppressor gene in this region during the first steps of somatotropinoma development.

Bases moleculares dos adenomas hipofisários com ênfase nos somatotropinomas

This review describes the molecular basis of pituitary adenomas with emphasis on GH-secreting tumors (somatotropinomas). The roles of tumor suppressor genes (such as RB1 and MEN-1) and oncogenes (such as gsp and PTTG) in tumor initiation and promotion are discussed. The characterization of these molecular markers may contribute to the understanding of tumor behavior, helping in the therapeutical management. However, despite recent advances, the sequence of genetic abnormalities participating in the pathogenesis of these adenomas is not completely known.

Dependency and analgesia related to treatment with subcutaneous octreotide in patients with growth hormone-secreting tumors.

OBJECTIVE To describe three patients diagnosed with somatotropinomas in whom the analgesic effect of octreotide was observed, along with dependency to the drug. METHODS These patients had pituitary macroadenomas treated with transphenoidal surgery and pituitary radiotherapy, and received high daily doses (>900 microg/day) of subcutaneous octreotide because of persistent high levels of growth hormone and insulin-like growth factor I (IGF-I). RESULTS Headache occurred prior to drug administration in all three cases, with relief soon after. We also observed tolerance to octreotides analgesic and anti-secretory actions (one patient), craving for the drug (two patients), withdrawal syndrome (one patient), and drug abuse (one patient). CONCLUSION Dependency syndrome may occur when high doses of octreotide are used, sometimes leading to drug abuse. Tolerance to the growth hormone anti-secretory effect of the drug may encourage physicians to increase doses to levels at which drug dependency has been observed. Sustained release somatostatin analogs may represent a solution to this problem.

LYMPHOCYTIC THYROIDITIS IS ASSOCIATED WITH INCREASED NUMBER OF BENIGN CERVICAL NODES AND FEWER CENTRAL NECK COMPARTMENT METASTATIC LYMPH NODES IN PATIENTS WITH DIFFERENTIATED THYROID CANCER

OBJECTIVE Whether or not autoimmune thyroid disease influences the progression of differentiated thyroid cancer (DTC) remains controversial. Findings of previous studies are influenced by lead time bias and/or procedure bias selection. These biases can be reduced by studying a single-institution patient population that underwent a similar extent of surgical resection. METHODS From a cohort of 660 patients with DTC who underwent thyroidectomy, we retrospectively studied 357 patients who underwent total thyroidectomy and central compartment node dissection (CCND) for DTC between 2003 and 2013. RESULTS Forty-one percent (140/345) of study patients had lymphocytic thyroiditis (LT), and 30% (91/301) had serum positive for thyroglobulin antibody (TgAb). LT was reported in 78% of the TgAb-positive cases. Sixty percent (213/357) of cases had metastatic thyroid carcinoma in 1 or more neck lymph nodes (55% [198/357] central compartment, and 22% [77/356] lateral compartment). Patients with LT had fewer metastatic cervical lymph nodes than those with no LT (2.7 ± 4.7 vs 3.5 ± 4.8, respectively, P = .0285). Patients with positive TgAb and thyroiditis had a larger number of benign cervical lymph nodes removed than those with negative TgAb or no LT. No significant difference was observed in age, tumor size, multifocality, extrathyroidal extension, vascular invasion, or frequency of cervical lymph node metastasis between TgAb-negative and -positive cases or between cases with and without LT. CONCLUSION Lymphocytic thyroiditis is associated with fewer central neck compartment metastatic lymph nodes and a larger number of excised reactive benign cervical lymph nodes. Whether this association indicates a protective role of thyroid autoimmunity in lymph node spreading remains unclear. ABBREVIATIONS CCND = central compartment node dissection DTC = differentiated thyroid cancer HT = Hashimoto thyroiditis LT = lymphocytic thyroiditis TgAb = thyroglobulin antibody TPO = thyroid peroxidase.

Criptococose pulmonar pseudotumoral associada à síndrome de Cushing

Opportunistic infections in endogenous Cushings syndrome are associated with severe cortisol excess and carry a high mortality. Pulmonary cryptococcosis is one of these opportunistic infections and can mimic a lung neoplasm, therefore making its diagnosis difficult. We report a case of a young male with ACTH-dependent Cushings syndrome and severe hypercortisolism. The patient achieved cure after the transfenoidal surgery, but developed a febrile state. A chest computed tomography showed a pulmonary nodule that did not change in serial chest radiographs. Diagnosis of tuberculosis, fungal and bacterial infections were inconclusive, so the hypothesis of lung neoplasm became more probable. The necropsy, however, disclosed a pseudotumoral cryptococcosis. Opportunistic infections, like Cryptococcus neoformans, should be considered in patients with Cushings syndrome and a pulmonary infiltrate.

Osteogenesis imperfecta no adulto e resposta ao alendronato

Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue, due to a qualitative or quantitative abnormalities of type I collagen. Osteopenia, recurrent fractures and skeletal deformities are the hallmarks of the disease. Some patients also have blue sclera. Bisphosphonates appear to be an effective therapy in children but data on the efficacy of these drugs in adults with OI is limited. We describe a case of a thirty-year-old woman with OI and multiple fractures until puberty. During her first pregnancy bone pains relapsed, and worsened in the post-partum period. Bone markers suggested high bone turnover and the patient was started on alendronate 10mg per day. In a few months bone pain became less intense. Bone mass increased 10.8% at lumbar spine (LS) and 2.3% at femoral neck (FN) after one year, and 21.7% at LS and 10.9% at FN after three years of treatment. Our observations suggest that oral alendronate may be a good therapeutic option for adults with OI.