SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018).

NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.

SEOM Clinical Guideline of management of soft-tissue sarcoma (2016).

Soft-tissue sarcomas are uncommon and heterogeneous tumors of mesenchymal origin. A soft-tissue mass that is increasing in size, greater than 5 cm, or located under deep fascia are criteria for suspicion of sarcoma. Diagnosis, treatment, and management should preferably be performed by a multidisciplinary team in reference centers. MRI and lung CT scan are mandatory for local and distant assessment. A biopsy indicating histological type and grade is needed previous to the treatment. Wide surgical resection with tumor-free tissue margin is the primary treatment for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not likely of being improved with reexcision. Neoadjuvant and adjuvant chemotherapy improve survival in selected cases, usually in high-grade sarcomas of the extremities. In the case of metastatic disease, patients with exclusive lung metastasis could be considered for surgery. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. New drugs have shown activity in second-line therapy and in specific histological subtypes.

SEOM Clinical Guideline for gastrointestinal sarcomas (GIST) (2016).

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, and this disease has served as a paradigmatic model for successful rational development of targeted therapies. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. The Spanish Society of Medical Oncology (SEOM) guidelines provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

Detection of mycobacterium avium subsp. paratuberculosis in a cattle/pudu interface / Detecção de mycobacterium avium subsp. paratuberculosis em uma interface gado/pudu

Mycobacterium avium subsp. paratuberculosis (Map) is the etiological agent of paratuberculosis. In Chile, information about Map isolation from both domestic ruminant and wildlife species has been accumulating, but it has to be extended to other species. The present study focuses specifically on one wild grazing species, the pudu (Pudu puda), one of the less known South American deer considered an endangered species that shares pastures with cattle in southern Chile, where the greatest part of the country's dairy cattle population is located. Convenient samples from 3 pudus were collected from one dairy farm where Map infection had previously been confirmed in cattle. All three pudus shed the bacterium in feces and the isolates are the same type of Map as described for cattle. This study represents the first case report of Map isolation in the pudu captured from the wild. It is also the first documented association between a Map-infected dairy herd and free-ranging wildlife species, such as pudu in the Los Ríos region, Chile. Since interspecies transmission of Map and other pathogens from livestock to pudu has already been demonstrated, the results from this study suggest that this free-ranging wildlife specie, inhabiting a dairy district in southern Chile, might represent another case of spillover host.

O agente etiológico da paratuberculose é o Mycobacterium avium subsp. paratuberculosis (Map). No Chile, já foi gerada informação do isolamento do Map em ruminantes domésticos e em algumas espécies selvagens, porém essa informação deve ser expandida a outras espécies. O presente estudo está focado na espécie selvagem herbívora, o Pudu (Pudu puda), que é considerado um dos cervos menos conhecidos da América do Sul, e que está em extinção. Essa espécie compartilha as pastagens com o gado no sul do Chile, local do país onde está concentrada a maior parte do rebanho leiteiro. Foram obtidas amostras de 3 pudus de uma fazenda de gado leiteiro, onde previamente havia sido confirmada a infecção por Map em bovinos. Os três pudus eliminavam a bactéria nas fezes, e os isolados fecais foram do mesmo tipo do Map relatado para os bovinos. Este estudo representa o primeiro relato de caso de isolamento do Map em pudu em vida silvestre. Também é a primeira associação documentada entre um rebanho leiteiro infectado com Map e a infecção de uma espécie silvestre de vida livre, tal como o pudu na região de Los Ríos, no Chile. A transmissão interespécies do Map, do mesmo modo que de outros patógenos de ruminantes para o pudu, já foi demonstrada, assim os resultados deste estudo sugerem que essa espécie de vida extensiva, que habita a mesma região leiteira no sul do Chile, pode representar mais um caso de repercussão ao hospedeiro.

Detection of Mycobacterium avium subsp. paratuberculosis in a cattle/pudu interface / Detecção de Mycobacterium avium subsp. paratuberculosis em uma interface gado/pudu

Mycobacterium avium subsp. paratuberculosis (Map) is the etiological agent of paratuberculosis. In Chile, information about Map isolation from both domestic ruminant and wildlife species has been accumulating, but it has to be extended to other species. The present study focuses specifically on one wild grazing species, the pudu (Pudu puda), one of the less known South American deer considered an endangered species that shares pastures with cattle in southern Chile, where the greatest part of the country's dairy cattle population is located. Convenient samples from 3 pudus were collected from one dairy farm where Map infection had previously been confirmed in cattle. All three pudus shed the bacterium in feces and the isolates are the same type of Map as described for cattle. This study represents the first case report of Map isolation in the pudu captured from the wild. It is also the first documented association between a Map-infected dairy herd and free-ranging wildlife species, such as pudu in the Los Ríos region, Chile. Since interspecies transmission of Map and other pathogens from livestock to pudu has already been demonstrated, the results from this study suggest that this free-ranging wildlife specie, inhabiting a dairy district in southern Chile, might represent another case of spillover host.(AU)

O agente etiológico da paratuberculose é o Mycobacterium avium subsp. paratuberculosis (Map). No Chile, já foi gerada informação do isolamento do Map em ruminantes domésticos e em algumas espécies selvagens, porém essa informação deve ser expandida a outras espécies. O presente estudo está focado na espécie selvagem herbívora, o Pudu (Pudu puda), que é considerado um dos cervos menos conhecidos da América do Sul, e que está em extinção. Essa espécie compartilha as pastagens com o gado no sul do Chile, local do país onde está concentrada a maior parte do rebanho leiteiro. Foram obtidas amostras de 3 pudus de uma fazenda de gado leiteiro, onde previamente havia sido confirmada a infecção por Map em bovinos. Os três pudus eliminavam a bactéria nas fezes, e os isolados fecais foram do mesmo tipo do Map relatado para os bovinos. Este estudo representa o primeiro relato de caso de isolamento do Map em pudu em vida silvestre. Também é a primeira associação documentada entre um rebanho leiteiro infectado com Map e a infecção de uma espécie silvestre de vida livre, tal como o pudu na região de Los Ríos, no Chile. A transmissão interespécies do Map, do mesmo modo que de outros patógenos de ruminantes para o pudu, já foi demonstrada, assim os resultados deste estudo sugerem que essa espécie de vida extensiva, que habita a mesma região leiteira no sul do Chile, pode representar mais um caso de repercussão ao hospedeiro.(AU)

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) 2014.

GEP-NENs are a challenging family of tumors of growing incidence and varied clinical management and behavior. Diagnostic techniques have substantially improved over the past decades and significant advances have been achieved in the understanding of the molecular pathways governing tumor initiation and progression. This has already translated into relevant advances in the clinic. This guideline aims to provide practical recommendations for the diagnosis and treatment of GEP-NENs. Diagnostic workup, histological and staging classifications, and the different available therapeutic approaches, including surgery, liver-directed ablative therapies, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are briefly discussed in this manuscript. Clinical presentation (performance status, comorbidities, tumor-derived symptoms and hormone syndrome in functioning tumors), histological features [tumor differentiation, proliferation rate (Ki-67), and expression of somatostatin receptors], disease localization and extent, and resectability of primary and metastatic disease, are all key issues that shall be taken into consideration to appropriately tailor therapeutic strategies and surveillance of these patients.

Second primary malignancies in patients with neuroendocrine tumors.

PURPOSE: An association between neuroendocrine tumors (NETs) and second primary malignancies (SPMs) has been reported. We have examined the incidence and etiology of SPMs in patients with NETs included in the Neuroendocrine Tumor Association of Andalusia (ATNEA) Registry. METHODS: Data on 111 patients were collected. Sex, age, NET site, chromogranin A levels, neuropeptide secretion and disease stage were compared between NETs with and without SPMs. RESULTS: SPMs were present in 21 patients (18.9 %): five colorectal tumors, four non-small-cell lung cancers, three gastric cancers, two tumors in the small intestine, one hepatocarcinoma, two ovarian tumors, one breast adenocarcinoma, one hypernephroma, one bladder cancer, and one neuroblastoma. SPMs were present in 18 % of patients with a gastrointestinal NET and 22 % of those with a non-gastrointestinal NET. SPMs were found in 23 % of patients with elevated levels of serum chromogranin A, compared to 17 % of patients with normal levels, and in 22 % of patients with functional tumors, compared to 11 % of those with non-functional tumors. Finally, SPMs were observed in 24 % of patients with a local or locoregional tumor but in only 13 % of those with a metastatic tumor. No other differences between patients with and without SPMs were observed. CONCLUSIONS: The percentage of patients with SPMs in the ATNEA Registry is similar to those reported in other series. In our registry, patients with functional NETs and local/locoregional tumors have higher probability of SPMs. The low number of patients, selection bias and other etiologic factors of SPMs may have influenced our results.

Fate of Mycobacterium avium subsp. paratuberculosis after application of contaminated dairy cattle manure to agricultural soils.

Details regarding the fate of Mycobacterium avium subsp. paratuberculosis (basonym, Mycobacterium paratuberculosis) after manure application on grassland are unknown. To evaluate this, intact soil columns were collected in plastic pipes (lysimeters) and placed under controlled conditions to test the effect of a loamy or sandy soil composition and the amount of rainfall on the fate of M. paratuberculosis applied to the soil surface with manure slurry. The experiment was organized as a randomized design with two factors and three replicates. M. paratuberculosis-contaminated manure was spread on the top of the 90-cm soil columns. After weekly simulated rainfall applications, water drainage samples (leachates) were collected from the base of each lysimeter and cultured for M. paratuberculosis using Bactec MGIT ParaTB medium and supplements. Grass was harvested, quantified, and tested from each lysimeter soil surface. The identity of all probable M. paratuberculosis isolates was confirmed by PCR for IS900 and F57 genetic elements. There was a lag time of 2 months after each treatment before M. paratuberculosis was found in leachates. The greatest proportions of M. paratuberculosis-positive leachates were from sandy-soil lysimeters in the manure-treated group receiving the equivalent of 1,000 mm annual rainfall. Under the higher rainfall regimen (2,000 mm/year), M. paratuberculosis was detected more often from lysimeters with loamy soil than sandy soil. Among all lysimeters, M. paratuberculosis was detected more often in grass clippings than in lysimeter leachates. At the end of the trial, lysimeters were disassembled and soil cultured at different depths, and we found that M. paratuberculosis was recovered only from the uppermost levels of the soil columns in the treated group. Factors associated with M. paratuberculosis presence in leachates were soil type and soil pH (P < 0.05). For M. paratuberculosis presence in grass clippings, only manure application showed a significant association (P < 0.05). From these findings we conclude that this pathogen tends to move slowly through soils (faster through sandy soil) and tends to remain on grass and in the upper layers of pasture soil, representing a clear infection hazard for grazing livestock and a potential for the contamination of runoff after heavy rains.

Phase I/II study of gefitinib and capecitabine in patients with colorectal cancer.

OBJECTIVE: The objectives of this phase I/II study were to determine the maximum tolerated dose (MTD), characterise the principal toxicities in the phase I part and assess the efficacy in the phase II part of gefitinib, an oral selective inhibitor of the epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer (CRC). METHODS AND PATIENTS: Patients with advanced CRC were treated with gefitinib administered daily for 21 days and capecitabine administered twice daily for 14 days of a 21-day cycle. The dose levels of gefitinib (mg) and capecitabine (mg/m(2) bid) assessed were 250/1000 and 250/ 1250. An expanded cohort was enrolled at the MTD to better characterise toxicity and efficacy. A total of 32 previously treated patients were accrued. In the phase I part 10 subjects were treated, with one dose-limiting toxicity. Overall 26 patients were treated at the MTD of the combination, which was gefitinib 250 mg/day and capecitabine 1250 mg/m(2) twice daily. RESULTS: The most frequent treatment-related adverse events included asthenia, diarrhoea, nausea, rash and anorexia. The incidence profile was very similar in phases I and II. No objective responses were documented but 53% of the patients achieved stable disease as best response to therapy. CONCLUSIONS: Capecitabine 1250 mg/m(2) twice daily 14 of 21 days and gefitinib at 250 mg/day can be safely administered in combination. The combination is relatively well tolerated. There were no objective responses, although an interesting stabilisation rate was documented, in previously treated advanced CRC patients.