<p>We treated 16 patients with somatostatin analogs combined with α-interferon and achieved a biochemical and/or radiological response in 56% (median duration 22 months). We consider this treatment a good alternative for patients who fail during chemotherapy or who do not want to/cannot receive cytotoxic drugs.</p><p>Thirty-six patients with neuroendocrine tumors were treated with cisplatin combined with etoposide. Of 14 patients with evaluable EPTs, 50% responded radiologically and/or biochemically (median duration 9 months). We consider this treatment useful as first-line medical treatment in aggressive EPTs or in patients failing prior chemotherapy.</p><p>Twenty-eight tumor tissues from EPTs were examined with immunohistochemistry regarding expression of somatostatin receptors (ssts) 1 to 5 on tumor cells and in intratumoral vessels. We found that sst₂ and sst₄ were highly expressed on tumor cells and in vessels. However, sst₃ and sst₅ were lacking in half of the tumor tissues and in most of the vessels. Because of the variability in sst expression, we recommend analysis of each individual’s receptor expression before starting treatment.</p><p>Endocrine pancreatic tumors (EPTs) are rare with an incidence of 4 per million inhabitants. In the majority of cases they grow slowly, but there are exceptions with very rapidly progressing malignant carcinomas. First-line medical treatment is streptozotocin combined with 5-fluorouracil.</p><p>We examined 38 tumor samples regarding expression of tyrosine kinase receptors platelet-derived growth factor receptors (PDGFRs), c-kit and epidermal growth factor receptor (EGFR). We found that the receptors were expressed in more than half of the tumor tissues. Further studies will reveal if tyrosin kinase antagonists can be part of the future treatment arsenal.</p>

We treated 16 patients with somatostatin analogs combined with α-interferon and achieved a biochemical and/or radiological response in 56% (median duration 22 months). We consider this treatment a good alternative for patients who fail during chemotherapy or who do not want to/cannot receive cytotoxic drugs. Thirty-six patients with neuroendocrine tumors were treated with cisplatin combined with etoposide. Of 14 patients with evaluable EPTs, 50% responded radiologically and/or biochemically (median duration 9 months). We consider this treatment useful as first-line medical treatment in aggressive EPTs or in patients failing prior chemotherapy. Twenty-eight tumor tissues from EPTs were examined with immunohistochemistry regarding expression of somatostatin receptors (ssts) 1 to 5 on tumor cells and in intratumoral vessels. We found that sst2 and sst4 were highly expressed on tumor cells and in vessels. However, sst3 and sst5 were lacking in half of the tumor tissues and in most of the vessels. Because of the variability in sst expression, we recommend analysis of each individual’s receptor expression before starting treatment. Endocrine pancreatic tumors (EPTs) are rare with an incidence of 4 per million inhabitants. In the majority of cases they grow slowly, but there are exceptions with very rapidly progressing malignant carcinomas. First-line medical treatment is streptozotocin combined with 5-fluorouracil. We examined 38 tumor samples regarding expression of tyrosine kinase receptors platelet-derived growth factor receptors (PDGFRs), c-kit and epidermal growth factor receptor (EGFR). We found that the receptors were expressed in more than half of the tumor tissues. Further studies will reveal if tyrosin kinase antagonists can be part of the future treatment arsenal.

Os tumores carcinóides broncopulmonares típicos (CT) são proliferações de células neuroendócrinas. Foram consideradas como adenomas e acreditava-se que não tinham potencial para disseminação hematogênica e linfática. Porém, a ocorrência de metástase linfática e hematogênica acontece em um quinto dos indivíduos acometidos por essa patologia. A variação no comportamento clínico dos carcinóides broncopulmonares torna imperativa a realização de pesquisas que visem à melhor compreensão dessa doença. É fundamental determinar a agressividade e o risco individual da ocorrência de metástase linfática e hematogênica para que se possa oferecer um tratamento individualizado para cada binômio doente-doença. A classificação atual divide os tumores carcinóides, conforme o grau histológico de malignidade em típico e atípico, agrupando as neoplasias de acordo com o índice mitótico, relação volumétrica núcleo/citoplasma, presença ou ausência de necrose, pleomorfismo nuclear e invasão vascular. Receptores celulares na superfície externa da membrana plasmática podem ser ubiquamente expressos em diversos tipos celulares ou específicos para determinada população celular. Os receptores de somatostatina são específicos de células neuroendócrinas e também são expressos nas neoplasias desta natureza. Existem 5 tipos de receptores de somatostatina (SSTR). A interação da somatostatina (SST) com seu receptor específico provoca as inibições do ciclo celular e da angiogêsese, bem como estimula a apoptose. A meia-vida plasmática da SST é breve. Análogos com menor metabolização eram necessários. Foram desenvolvidos os análogos como octreotide e lanreotide. Estes análogos foram acoplados à radionuclídeos, possibilitando aplicação em diagnóstico, estadiamento e tratamento dos tumores neuroendócrinos. O SSTR do tipo 2 possui maior afinidade pela somatostatina. A expressão imunohistoquímica de SSTR-2 em carcinóide típicos ofereceria métodos adicionais de diagnóstico e tratamento para esta doença. Com o objetivo de demonstrar a expressão de SSTR-2 em carcinóides broncopulmonares típicos, bem como verificar se existia relação entre a expressão e ocorrência de metástase linfática 62 pacientes tiveram suas amostras de tumor submetidas ao método imunohistoquímico. Verificou-se, ademais, se a expressão de SSTR-2 e o índice de expressão imunohistoquímica eram variáveis independentes preditivas do risco de metástase linfática. A relação entre expressão de SSTR-2 e variáveis clínicas pré-operatórias também foi analisada. 36 pacientes tinham tumores que expressavam SSTR-2 (58,1%), enquanto 26 doentes tinham tumores que não expressavam SSTR-2 (41,9%). Não existiu diferença estatística significante entre a expressão de SSTR-2 e a ocorrência de metástase linfática (teste exato de Fisher, p=0,529). Também não existiram diferenças estatísticas significantes nas análises multivariadas que testaram se tanto o SSTR-2 quanto o índice de imunohistoquímica eram variáveis independentes preditivas do risco de metástase linfática. Neste estudo, os CT expressaram SSTR-2. Além disso, não existiu relação entre a ocorrência de metástase linfática e a expressão de SSTR-2. Por fim, o SSTR-2 e o índice imunohistoquímico não foram variáveis independentes do risco de metástase linfática / Typical pulmonary carcinoids are neuroendocrine cells proliferations and they were former considered lung adenomas with no hematogenic or lymphatic metastatic potential. However, it is known that up to 20% of patients develop metastatic disease. It is mandatory that new studies be developed due to the variation in clinical presentation of these patients. It is also required that the individual risk of lymphatic and hematogenic metastasis be determined in order to individualize the patients treatment. Pulmonary carcinoids are classified according to hystologic grade. The current classification includes hystologic grade, presence or absence of necrosis, nuclear pleomorphism, and vascular invasion. Somatostatin receptors (SSTR) are neuroendocrine cell specific receptors and can be detected in neuroendocrine tumors as well. There are 5 SSTRs subtypes. Somatostatin is a peptide that inhibits the cell cycle and angiogenesis as well as increases the apoptosis by binding to SSTR. The use of long-acting form of octreotide (a SST analogue) has been associated with treatment (radiolabeled somatostatin analogs) and diagnosis (OctreoScan®). Encouraging results have been obtained with the use of radiolabeled somatostain analogs yttrium-90 and Lu-177 to treat patients with neuroendocrine tumors. This study was designed to evaluate if typical bronchopulmonary carcinoid expressed Somatostatin receptor type 2 using the the immunohistochemical technique to identify Somatostatin receptor type 2. This study verified if there was relation between Somatostatin receptor type 2 expression and lymphatic metastasis. Futhermore, we verified if Somatostatin receptor type 2 and imunnohistochemistry score would be independent preditive markers to lymphatic metastasis. 62 patients were evaluated. 36 (58,1%) patients expressed Somatostatin receptor type 2 in their tumor samples whereas 26 (41,9%) patients did not express Somatostatin receptor type 2. This study did not verify significant statistical difference between SSTR-2 expression and lymphatic metastasis. Somatostatin receptor type 2 and imunnohistochemistry score were not independent preditive markers to lymphatic metastasis. There were no significant statistical differences on multivariate analyses. In conclusion this study verified that there was Somatostatin receptor type 2 expression on tumor samples studied but there was no relation between Somatostatin receptor type 2 and lymphatic metastasis. Futhermore, Somatostatin receptor type 2 and its imunnohistochemistry score were not independent preditive markers to lymphatic metastasis

The past few years have witnessed significant work being directed towards drug delivery systems with layer-by layer (LbL) technique prominently featured as one of the most sought after approach. However, majority of the studies were focused on the fabrication of microcapsules which produced numerous drawbacks resulting in reduced applicability. This has spurred research into nanocapsules which has proved to overcome most of the drawbacks that plagued microcapsules by being able to evade the reticulo-endothelial system, exhibit enhanced permeability and retention in tumours etc. The capsules fabricated by the LbL technique requires a suitable combination of cationic and anionic polyelectrolytes which ensures that it is able to effectively protect the cargo it encapsulates as well as enhance its bio-applications. With numerous advantages such as biocompatibility and biodegradability to name a few, chitosan has proved to be an ideal cationic polyelectrolyte. Thus, this thesis focuses on the various therapeutic applications of LbL fabricated chitosan based nanocapsules. The first work focuses on the targeted delivery of the somatostatin analogue, Octreotide conjugated nanocapsules to over expressed somatostatin receptors. These LbL fabricated nanocapsules composed of chitosan and dextran sulfate (CD) encapsulate the anti cancer drug, doxorubicin and are found to attain site specificity as well as enhanced anti-proliferative activity. The results indicated that the nanocapsules were biocompatible and when conjugated with octreotide was found to have an enhanced internalization into SSTR expressing cells, thereby making it a viable strategy for the treatment of tumors that has an over expression of somatostatin receptors such as pancreatic carcinoma, breast carcinoma etc. The objective of the second work was to develop an efficient drug delivery system such as CD nanocapsules for encapsulation of Ciprofloxacin in order to combat infection by Salmonella, an intracellular and intra-phagosomal pathogen. In vitro and in vivo experiments showed that this delivery system can be used effectively to clear Salmonella infection. The increased retention of ciprofloxacin in tissues delivered by CD nanocapsules as compared to the conventional delivery proved that the same therapeutic effect was obtained with reduced dosage and frequency of Ciprofloxacin administration. The third work deals with the probiotic, Saccharomyces boulardii which is found to be effective against several gastrointestinal diseases but had limited clinical application due to its sensitivity to acidic environment. However, encapsulation of S. boulardii with chitosan and dextran sulfate ensured enhanced viability and selective permeability on exposure to acidic and alkaline conditions experienced during gastro intestinal transit. The final work involves the fabrication of novel pH responsive nanocapsules composed of chitosan-heparin which facilitate the intracellular delivery of a model anti-cancer drug, doxorubicin.