Epidemiological profile of neuroendocrine tumors in adults in Brazil.

Objective: Neuroendocrine tumors (NETs) are a set of diseases that originate from neuroendocrine cells, which comprises a diffuse endocrine system present in various organs of the body. These tumors are more frequent in the gastrointestinal tract (70%) and the bronchopulmonary system (20%-30%). A NET incidence rate of 1-5 per 100,000 inhabitants has been estimated for several European countries and the USA employing 20 years of data. However, no comprehensive studies on this rare neoplasm are available in Brazil. In this context, the aim of this study was to characterize the epidemiological NET profile in the country. Materials and methods: This is a retrospective descriptive observational study based on data from Hospital Cancer Records available at the Brazilian National Cancer Institute and the São Paulo Oncocentro Foundation. Demographic, clinical and treatmentrelated variables were analyzed from selected cases employing descriptive statistics. Results and Conclusion: A total of 15,859 cases were identified, most occurring in males (53.4%) and in individuals under 65 years old (63.3%). Small cell carcinoma was the most frequent histological type (46.7%). Bronchopulmonary tumors were the most frequent NETs, followed by pancreatic tumors, with cases mostly concentrated in high complexity centers in the Brazilian Southeast and treated mainly with surgery and chemotherapy, with over half of the patients diagnosed in advanced stages of the disease.

Neutrophil to lymphocyte ratio as a prognosis biomarker of PRRT in NET patients.

PURPOSE: Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE is a palliative therapeutic option for advanced Neuroendocrine Tumors (NETs). Prognostic factors can predict long-term outcomes and determine response to therapy. Among those already explored, biomarkers from full blood count, including neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) has shown value for other solid tumors and for NETs patients submitted to other forms of therapy. However, its relation to PRRT response and patients' prognosis is still to be determined. METHODS: Medical records from 96 patients submitted to PRRT between 2010 and 2017 were reviewed, median NLR and PLR were calculated from baseline flood blood count and dichotomized as high or low. Progression-free survival (PFS) and Overall Survival (OS) were calculated. RESULTS: NLR and PLR median values were 1.8 and 123, respectively. Patients with low NLR had a significantly longer OS (estimated median of 77.5 months, 95% CI: 27.3-127.7) when compared to patients with high NLR (estimated median of 47.7 months, 95% CI: 34.7-60.8); p = 0.04. Patients with low NLR had a trend toward a longer median PFS when compared to patients with high NLR [estimated medians of 77 months (95% CI: 27.3-127.7), and 47.7 months, (95% CI: 34.7-60.7)], respectively, p = 0.08. CONCLUSION: Patients with advanced-stage NET with NLR higher than 1.8 have worse long term clinical outcomes after PPRT. Larger studies are needed to validate the optimal cutoff for this biomarker.

Dual origin of vertebral artery and intimal relationship with spontaneous artery dissection: a case report and systematic review.

Dual origin of the vertebral artery (VA) is an uncommon anatomical variation. We describe a case of duplication origin at right vertebral artery (RVA) found incidentally in one elderly patient on investigation for cerebral aneurysm. Angiogram study showed a pseudoaneurysm at V4 segment of the RVA associated with embryological anatomy. The authors performed a systematic review of the similar cases reported worldwide.

Is there a role for peptide receptor radionuclide therapy in medullary thyroid cancer?

BACKGROUND: Medullary thyroid cancer (MTC) is a rare but potentially life-threatening disease with limited therapeutic options. As a neuroendocrine tumor, MTC expresses somatostatin receptors, and therefore, somatostatin-labeled radiopharmaceuticals could be used to treat patients with MTC. OBJECTIVE: The aims of this study were to evaluate tumor shrinkage after Lu-DOTATATE treatment, to analyze the impact on quality of life as accessed by the SF-36 questionnaire, and to demonstrate a possible prognostic role for In-DTPA-octreotide uptake in patients with MTC. PATIENTS AND METHODS: Patients with progressive MTC underwent evaluation using In-DTPA-octreotide. Patients who demonstrated In-DTPA-octreotide uptake were treated with 4 cycles of 200 mCi of Lu-DOTATATE and were evaluated using CT scans over 8 to 12 months of treatment. RESULTS: Of the 16 patients initially enrolled, 9 (56.25%) had lesions that were observed in the In-DTPA-octreotide scans and were eligible for therapy with Lu-DOTATATE. Three patients had a partial response, 3 patients were classified as having stable disease and, 1 patient had a progressive disease. All responders indicated improvement in quality of life 6 to 12 months after therapy. CONCLUSIONS: Treatment with Lu-DOTATATE seems to be an alternative therapy for somatostatin receptor-positive tumors, with very mild adverse effects and quality-of-life improvement, at least during a short-term period. Further studies are needed to determine long-term benefits and to identify which patients are more likely to respond to this modality of therapy.

Involvement of signaling molecules in the prediction of response to imatinib treatment in metastatic GIST patients.

Imatinib therapy has undoubtedly contributed to the treatment of metastatic gastrointestinal stromal (GIST) tumors that were previously untreatable. However, disease progression during treatment with tyrosine kinase inhibitors remains an issue in clinical practice not fully explained by KIT and PDGFRA mutation status. We investigated the role of three important signaling molecules (insulin-like growth factor 1 receptor [IGF1R], protein kinase C-θ [PKCθ], and Raf kinase inhibitor protein [RKIP]) that have been implicated in GIST pathogenesis as potential biomarkers for prediction of response to imatinib treatment. We retrospectively reviewed 76 patients with metastatic GIST submitted to imatinib treatment between 2002 and 2007, and analyzed 63 of them. Insulin-like growth factor 1, total PKCθ, phosphorylated PKCθ, and RKIP immunohistochemical expression were correlated with objective response to imatinib treatment and progression-free and overall survival. Median follow-up was 31.2 mo (95% confidence interval, 26.3-36.1 mo). There was a statistically significant association between IGF1R expression and type of response to imatinib treatment (P = 0.05)-that is, higher IGF1R expression was related to lower objective response. However, IGF1R higher expression did not affect progression-free and overall survival. Insulin-like growth factor 1, but not PKCθ and RKIP, emerges as a potential biomarker for prediction of response to imatinib treatment in metastatic GISTs. Validation studies are warranted.

Tumor estromal gastrointestinal: análise de 146 casos do centro de referência do Instituto Nacional do Câncer - INCA / Gastrointestinal stromal tumor: analysis of 146 cases of the center of reference of the National Cancer Institute - INCA

OBJETIVO: Avaliar os resultados do tratamento de GIST no INCA. MÉTODOS: Análise retrospectiva de todos os casos de GIST tratados no INCA no período de 1997 a 2009. RESULTADOS: Analisamos 146 pacientes, com média de idade de 44,5 anos e predomínio do sexo feminino. O principal sintoma foi dor abdominal. Tivemos ocorrência de segundo primário em 22 por cento dos casos e na imuno-histoquímica, 92 por cento foram positivos para CD117. A localização mais frequente foi estômago e predominou o grupo de alto risco. A cirurgia foi R0 (extenso) em 70 por cento e os principais sítios de metástases foram fígado e peritônio. A sobrevida global foi, respectivamente, em dois e cinco anos de 86 por cento e 59 por cento. Houve significante diferença entre a sobrevida global (p=0,29) do grupo de alto risco versus os demais. CONCLUSÃO: Os nossos pacientes apresentam-se principalmente sob forma de doença de alto risco com repercussão óbvia na sobrevida. O uso de Imatinib melhorou a sobrevida dos pacientes com doença metastática e recidivada. Devemos estudar seu uso no cenário de adjuvância e neoadjuvancia visando melhorar os índices do grupo de alto risco. A criação de centros referenciais é uma necessidade para o estudo de doenças pouco frequentes.

OBJECTIVE: To evaluate the treatment of GIST in INCA. METHODS: We conducted a retrospective analysis of all cases of GIST treated at INCA in the period from 1997 to 2009. RESULTS: We analyzed 146 patients with a mean age of 44.5 years and female predominance. The main symptom was abdominal pain. We observed the occurrence of a second primary tumor in 22 percent of cases and 92 percent of the immunohistochemistry exams were positive for CD117. The most frequent location was in the stomach and the high-risk group was predominant. Surgery was considered R0 (extensive) in 70 percent of the cases and the main sites of metastases were liver and peritoneum. Overall survival in two and five years was, respectively, 86 percent and 59 percent. There was a significant difference between overall survival (p = 0.29) of the high-risk group versus the other. CONCLUSION: Our patients presented mainly in the form of high-risk disease, with obvious impact on survival. The use of imatinib improved survival of patients with recurrent and metastatic disease. We should study its use in the setting of adjuvant and neoadjuvant therapy to improve results of the high risk group. The creation of reference centers is a need for the study of rare diseases.

Extragastrointestinal stromal tumors (EGIST): a series of case reports.

BACKGROUND/AIM: Gastrointestinal stromal tumors (EGIST) are mesenchymal tumors which may originate in sites outside the gastrointestinal tract with clinico-pathological and molecular profiles similar to GISTs. Here is a series of case reports from The National Cancer Institute (INCA) about this rare type of tumor. METHODOLOGY: We retrospectively analyzed 142 patients with a diagnosis of GIST who were treated at INCA between 1997 and 2009, among which 9 were confirmed as having EGIST. RESULTS: We identified 9 patients with a diagnosis of EGIST, 7 of which (77.8%) were female patients with an average age of 56.8 (36-81) years. All patients were symptomatic, with abdominal pain present in 55% of cases. The tumors were located in the pancreas (n=2), in the retroperitoneum (n=3), and in the mesocolon, in the mesentery of the small intestine, in the spleen and in the pelvis (all n=1), respectively. The average tumor size was 18(8.5-27)cm. Immunohistochemistry revealed CD 117 positive in 100% of cases and CD34 positive in 62.5%. Five patients were treated surgically, three of which were submitted to R0 resection. Among those patients, all recurred after 31, 23 and 17 months respectively, and the most frequent sites were the liver and the peritoneum. Out of these three recurrences, two were "rescued" surgically (66%). Five patients were given imatinib (three patients considered unresectable, one submitted to R2 resection and another patient with recurrent disease not amenable to surgery) two patients did not receive any treatment due to compromised clinical conditions. The average overall survival was 26.4 (04-114) months. CONCLUSION: The occurrence of EGIST is extremely rare and little is known about their actual origin. They manifest through bulky masses, which compromise the prognosis. Aggressive surgical intervention is the most effective treatment associated with the use of imatinib, and a strict followup is necessary due to high recurrence rates.

Gastrointestinal stromal tumor: analysis of 146 cases of the center of reference of the National Cancer Institute--INCA.

OBJECTIVE: To evaluate the treatment of GIST in INCA. METHODS: We conducted a retrospective analysis of all cases of GIST treated at INCA in the period from 1997 to 2009. RESULTS: We analyzed 146 patients with a mean age of 44.5 years and female predominance. The main symptom was abdominal pain. We observed the occurrence of a second primary tumor in 22% of cases and 92% of the immunohistochemistry exams were positive for CD117. The most frequent location was in the stomach and the high-risk group was predominant. Surgery was considered R0 (extensive) in 70% of the cases and the main sites of metastases were liver and peritoneum. Overall survival in two and five years was, respectively, 86% and 59%. There was a significant difference between overall survival (p = 0.29) of the high-risk group versus the other. CONCLUSION: Our patients presented mainly in the form of high-risk disease, with obvious impact on survival. The use of imatinib improved survival of patients with recurrent and metastatic disease. We should study its use in the setting of adjuvant and neoadjuvant therapy to improve results of the high risk group. The creation of reference centers is a need for the study of rare diseases.

Extragastrointestinal Stromal Tumors (EGIST): a series of case reports

Gastrointestinal stromal tumors(EGIST) are mesenchymal tumors whichmay originate in sites outside the gastrointestinal tract with clinico-pathological and molecular profilessimilar to GISTs. Here is a series of case reports from The National Cancer Institute (INCA) about this rare type of tumor.

Colorectal GISTs: from presentation to survival. An analysis of 13 cases.

This papers is a retrospective analysis of all cases of colorectal GIST treated at our institution. Considering the increased interest in this pathology, in 2008, we recently established a unit supported by Novartis in our department to research and treat GIST. Since then, there was a dramatic increase in the referral of this type of tumor to our center. Before initiating our research group, we had the permission of the ethics committee and the medical directors to study and publish the analysis of our cases. Now, we have a cohort of 98 patients treated during the last 10 years and from that, we selected all cases of Colorectal GIST's. They numbered 13 cases. We performed an analysis of these cases from the presentation to the results of treatment.

Occurrence of other tumors in patients with GIST.

OBJECTIVE: Evaluate the presence of other tumors in cohort of patients with GIST treated at a cancer treatment referral center - INCA. METHODS: We reviewed the medical records of patients diagnosed with GIST who were treated at INCA between 1998 and 2008. Immunohistological diagnosis was confirmed by a pathologist specialized in sarcomas. Patients presenting second non-GIST tumors were identified. Age, sex, tumor location, risk groups (according to the National Institutes of Health criteria), characteristics of non-GIST tumors and treatment results were analyzed. RESULTS: Among the 101 patients diagnosed with GIST who were evaluated during the study period, 14 (13.8%) had other non-GIST tumors, 9 females (64.3%), with a median age of 68 years (10-79 years). The stomach was the location of GISTs in 8 cases (57.1%), followed by the small bowel in 4 cases (28.5%), colon and mesentery with 1 case (7.1%) each. The mean size of lesions was 4.79 cm (0.3-15 cm), with malignant potential low/very low in 7 cases (50%), intermediate in 5 cases (35.7%) and high in 2 cases (14.3%). The diagnosis of GIST was incidental in 6 cases and in one case the non-GIST tumor was incidental. The non-GIST tumors were most frequent in the stomach (adenocarcinoma), in 4 cases (28.5%) and colon/rectum (adenocarcinoma) in 4 other cases. The other sites involved were breast (ductal carcinoma), kidney (clear cell carcinoma), prostate (adenocarcinoma), endometrium (adenocarcinoma), ovary (adenocarcinoma) and adrenal (neuroblastoma), with one case each. The tumors were synchronous in 7 cases (50%). With a median follow-up after GIST resection of 41 months (2-87 months), 9 patients were alive without evidence of disease, 2 died due to GIST, 2 died due to non-GIST tumors and the remaining patient died due to postoperative complications. CONCLUSIONS: We discovered a 13.8% incidence of non-GIST tumors in a series of 101 GIST cases under our care. This association should always be considered in the management of patients with GIST.

Cirurgia Adjuvante no tratamento do tumor estromal gatrointestinal metastático: um novo conceito / Adjuvant Surgery in the treatment of metastatic gastrointestinal stromal tumor's: a new concept

Os recentes avanços no tratamento dos tumores estromais gastrointestinais (GIST) foram responsáveis pela mudança da história natural da doença. O melhor conhecimento dos mecanismos moleculares foi fundamental para o desenvolvimento de droga alvo-molecular dirigida capaz de obter resultados, até então, não alcançados em nenhum tratamento de tumor sólido. A introdução do imatinibe na prática clínica modificou não só a sobrevida dos portadores de GIST metastático, como também foi responsável por quebras de paradigmas bem estabelecidos; porém, apesar de o tratamento da doença metastática ser baseado na utilização do imatinibe, o papel do cirurgião, nesse contexto, tem sido revisado, havendo alguns indícios de que a cirurgia de resgate na doença metastática possa trazer benefícios a grupos selecionados de pacientes. Dessa forma, um novo conceito se estabelece, o da Cirurgia Adjuvante; ou seja, uma estratégia terapêutica que visa a otimizar os resultados do tratamento do GIST metastático.

What is the prognostic significance of metastatic lymph nodes in GIST?

BACKGROUND/AIMS: So many variables have been identified as prognostic factors influencing survival after curative resection in gastrointestinal stromal tumors (GIST), but the role of lymph node metastasis remains uncertain. METHODOLOGY: Twenty-nine patients with c-Kit positive gastric GIST who underwent surgical resection at the Brazilian National Cancer Institute between 1983 and 2004 were reviewed retrospectively. The prognostic significance of lymph node metastasis was investigated. The endpoints were overall survival and disease free survival. RESULTS: The median follow-up was 35 months. The 5-years estimate survival rate was 53%. Three patients presented lymph node metastasis and developed recurrence disease. Univariate analysis for overall survival identified the size >13.5cm (p = 0.01) and recurrence (p = 0.03) as prognostic factors. Size > 13.5cm and recurrence were independent factors (p = 0.01 and p = 0.03, respectively) in the multivariate analysis. Univariate analysis for disease free survival identified the size > 13.5cm (p = 0.04) and the grade (p = 0.04) as prognostic factors but, only the size > 13.5cm was an independent factor in the multivariate analysis. Lymph node metastasis had no prognostic significance for overall and disease free survival (p = 0.65 and p = 0.57, respectively). CONCLUSIONS: GIST lymph node metastasis was not related to poor survival in this study, but more studies are needed to identify the real incidence and the proper role of the GIST metastatic nodal disease.