No description available.

<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.

The purpose of the thesis was to investigate if integrity promoting care improves functions in demented patients over time. The Erikson (1982) theory of ”eight stages of man” was used as a basis for training of staff in a three-month intervention study (I-VI) at a nursing home ward. A collective living unit where staff had had support in the performance of the delivery of care was also evaluated and compared with a nursing home in a long-term study (VII). Patients, relatives, staff, and the environments were investigated. Cerebrospinal fluid concentrations of somatostatin increased, and reduction of distractability, anxiety and confusion was seen in the intervention group (I) in contrast to controls. In the collective living group (VII) EEG activities indicated a reduction of supposed dementia induced changes. Better motor and social ability, some improved intellectual ability, more alertness and reduced signs of depression were seen (I, II, VII). Patients expressed more autonomy (IV, VII) and initiatives (II-VII) and showed a lot of competence (V) in conversations. Five patients (V) showed patterns of behaviour which seemed to reflect life-long characteristics in spite of their severe dementia. The improvement in the patients' functions can be attributed to the physical environment and the integrity promoting care, since the medical treatment of the patients remained unchanged. In the thesis medical, psychological, and nursing sciences were connected in a complementary process. The results were congruent, and indicate that patients in the care of staff who had had training and support, declined less than controls. / <p>S. 1-61: sammanfattning, s. 63-184: 7 uppsatser</p> / digitalisering@umu

Les travaux de cette thèse ont porté sur le contrôle des neurones à GHRH dans des conditions physiologiques et pathologiques. Le but étant de caractériser les mécanismes cellulaires et moléculaires impliqués dans le fonctionnement ou dérégulations du réseau de neurones à GHRH. Ces neurones sont les principaux stimulateurs de la libération de l’hormone de croissance (GH). Nous avons d’abord montré que l’axe de la croissance et de l’appétit peuvent être régulés indépendamment au niveau de l’hypothamus. En effet, la ghréline, seule hormone produite par le tractus gastro-intestinal et connue pour stimuler la libération de GH en agissant principalement sur les neurones GHRH, stimule ces derniers de manière uniquement directe. Ces effets sont indépendants de ceux qu’elle exerce sur les neurones voisins à NPY, orexigéniques. De plus, la ghréline et les GHS (agonistes sélectifs du récepteur de la ghréline) ne changent pas le mode de décharge électrique des neurones à GHRH ni ne les synchronise. Enfin, ces effets ne présentent pas de dimorphisme sexuel. Dans un second temps, la somatostatine, principal inhibiteur de l’axe GH, induit un rythme d’activité électrique des neurones à GHRH médié par les récepteurs de sous-type SST1 et SST2. Ces effets sont donc temps-dépendants, et aussi sexuellement dimorphiques. Ils sont probablement impliqués dans la modulation de la pulsatilité ultradienne de la libération de GH. Enfin, après un traumatisme crânien, nous observons un déficit de la libération de GH qui apparaît tôt et est soutenu, comme ceux observés chez l’humain. Aucune inflammation ni changement histologique n’a été observe dans l’hypophyse. Cependant, l’inflammation, impliquant une réaction tanycytaire, microgliale, astrocytaire, est présente dans le noyau arqué et l’éminence médiane (EM), ou sont respectivement présents les corps cellulaires et terminaisons des neurones à GHRH. Ceci est lié à des changements morpho-fonctionnels de l’EM (augmentation perméabilité, rupture des barrières tanycytaires). Aucun changement n’a été observé dans le noyau périventriculaire, où sont localisés les neurones à somatostatine. Enfin, les propriétés électriques passives des neurones à GHRH ne sont pas modifiées. En conclusion, une dérégulation de leur activité au niveau des terminaisons nerveuses doit expliquer les défauts posttraumatiques de libération de GH. / The works of this thesis were interested in the control of the hypothalamic GHRH neurons in physiological and pathological conditions. The goal was to clarify the molecular and cellular mechanisms involved in the control or impairments of GHR neuronal network functions. These neurons are the main stimulators of the GH release. We first showed that the hypothalamic growth axis could be regulated independently from the feeding network. Indeed, GHRH neurons are directly stimulated by ghrelin, which is the only hormone produced by the gastrointestinal tract known to stimulate the GH release through acting mainly on GHRH neurons. These effects are independent from its orexigenic effects exerted on the neighbourings NPY neurons. In addition, ghrelin and GHS (synthetic ghrelin receptor agonists) don’t change neither the firing rate of GHRH neurons, nor synchronize them. These effects are not gender-dependant; by contrast, Somatostatin, the major GH axis inhibitor, generates a sexual dimorphic and rhythmic inhibition of the GHRH neurons electrical activity mediated by its SST1 and SST2 receptors subtypes. These effects are so time-dependant direct and indirect effects and can probably be involved in the generation of the ultradian rhythm of the GH release. After a traumatic brain injury, we found an early and sustained deficiency of the GH release, like those observed in human. No pathological changes are visible in the pituitary gland. Inflammation occurs at the arcuate nucleus, and mainly at the median eminence levels; it involves a strong astrocyte reaction, tanycytes, and microglial and (or) infiltrated immune cells activations. These changes elicit morpho-functional impairments of the median eminence, permeability and leakage of the tanycyte barrier between the blood, CSF and Arc; at the opposite, nothing occur at the periventricular level, where are located SST neurons. Neither the number of GHRH neurons, neither their passive electrophysiological properties changed. Impairments of the activities of the GHRH nerve terminals, maybe associated to impairments of their regulated activity, must explain a GH deficiency.

Introdução: A acromegalia é uma doença rara, caracterizada pela produção aumentada de hormônio do crescimento, causada geralmente por um adenoma hipofisário, ocasionando uma série de comorbidades como apneia do sono e resistência insulínica que acarretam um aumento na mortalidade e redução da expectativa de vida. Objetivo: O objetivo deste estudo foi avaliar o impacto da terapêutica da apneia do sono com um dispositivo de pressão positiva contínuas nas vias aéreas (CPAP) e avaliar o impacto desta terapêutica na resistência insulínica pela realização do clamp euglicêmico hiperinsulinêmico (CEH). Pacientes: De 156 acromegálicos regularmente atendidos na unidade de Neuroendocrinologia do HC-FMUSP, foram selecionados 12 indivíduos com apneia do sono de moderada a grave em uso de análogos da somatostatina (AS). Método: Os pacientes foram randomizados em dois grupos com seis integrantes. O grupo A iniciou o tratamento com CPAP, e o grupo B, um adesivo dilatador nasal com efeito de placebo. A avaliação basal incluiu a polissonografia, determinação do GH, IGF-1, HbA1c, ácidos graxos livres, lípides, CEH, bem como os índices de resistência periférica à insulina (HOMA, HOMA2 e QUICKI). Após 3 meses de tratamento, os pacientes foram reavaliados pelos mesmos exames, sendo trocado o tratamento entre os grupos e feita nova avaliação, após mais 90 dias. Resultados: Analisando os resultados finais de todos os pacientes que fizeram uso do CPAP, foi observada uma redução significante na resistência periférica à insulina, verificada pelo índice de sensibilidade derivado do clamp (ISCLAMP, pré e pós- CPAP, 3,83 versus 6,11, p=0,032). Esta redução não foi observada no grupo que fez uso do adesivo nasal (ISCLAMP, pré e pós-adesivo, 5,53 versus 5,19, p=0,455). Não houve diferença significante nos níveis de lípides, HbA1c nem nos índices de resistência periférica à insulina. Conclusão: O tratamento da apneia do sono moderada a grave com CPAP, em pacientes acromegálicos em uso de AS, levou a uma redução da resistência periférica à insulina aferida pelo CEH, dado não observado por meio dos índices HOMA, HOMA2 e QUICKI / Introduction. Acromegaly is a rare disease, characterized by the production of high GH levels usually by pituitary adenoma leading to comorbidities as sleep apnea and insulin resistance, bringing increase of mortality and life span reduction. Objective: This study aims to assess the impact of treatment of sleep apnea with a continuous positive air pressure device (CPAP) on the insulin resistance by performing the hyperinsulinemic euglycemic clamp (HEC). Patients: From 156 acromegalic patients regularly attended on Neuroendocrine Unit of the Hospital das Clínicas, University of São Paulo Medical School, 12 subjects on somatostatin analogs (SA) harboring moderate to severe sleep apnea were selected. Methods: Patients were randomized in two groups of six subjects. Group A started treatment with CPAP while group B started treatment using a nasal dilator adhesive with placebo effect. Basal assessment included polysomnography, determination of GH, IGF-1, HbA1c, free fat acids, lipids assays, HEC as well as insulin resistance indexes (HOMA, HOMA2 and QUICKI). Patients were reevaluated after three months of treatment by the same tests and then the treatment was switched between groups with new assessment 90 days later. Results: A significant reduction on insulin resistance determined by the clamp derived sensibility index was observed after assessing the final data of all patients on CPAP (SICLAMP, pre and post CPAP, 3,83 versus 6,11, p=0,032). This reduction was not seen in the nasal dilator adhesive group (SICLAMP, pre and post adhesive, 5,53 versus 5,19, p=0,455). There was no significant difference on lipids, HbA1c or on peripheral insulin resistance indexes. Conclusion: CPAP treatment of acromegalic patients on AS with moderate to severe sleep apnea leaded to significant reduction on peripheral insulin resistance assessed by the HEC. HOMA, HOMA2 and QUICK did not detect this data

Introdução: A doença de Cushing apresenta elevada morbimortalidade. Seu tratamento de escolha é a cirurgia transesfenoidal que possui resultados satisfatórios em cerca de 70% dos casos. Na doença persistente ou recorrente, reabordagem cirúrgica, radioterapia e adrenalectomia bilateral podem ser realizadas, porém, essas opções apresentam como desvantagens o desenvolvimento de hipopituitarismo e a dependência de terapia de reposição. Até o momento, nenhuma droga tem se mostrado eficaz no tratamento do corticotrofinoma. Os esquemas terapêuticos mais eficazes são os inibidores da esteroidogênese que não atuam no tumor hipofisário. Objetivos: avaliar o efeito do octreotide e da cabergolina administrados isoladamente e em associação nas concentrações urinárias de cortisol e plasmáticas de ACTH em pacientes com corticotrofinomas; correlacionar esse efeito com a expressão tumoral dos receptores SSTR2, SSTR5 e DRD2; correlacionar a expressão tumoral desses receptores através de RT-PCR quantitativa e imunohistoquímica; avaliar se o uso prévio dessas drogas altera a expressão desses receptores. Casuística e Métodos: grupo controle composto por 11 pacientes (10 mulheres e 1 homem) entre 21 e 43 anos sem tratamento prévio à neurocirurgia e um grupo tratado formado por 11 pacientes (2 homens e 9 mulheres) entre 22 e 53 anos que receberam o seguinte tratamento antes da cirurgia: coleta de três amostras de cortisol urinário e ACTH plasmático, seguida da introdução de octreotide 100 g, subcutâneo, 8/8h durante 30 dias e nova coleta de três amostras de cortisol urinário e ACTH plasmático. Em seguida, iniciou-se a cabergolina 0,5 mg via oral 3 vezes na semana durante 30 dias com nova coleta de três amostras de cortisol urinário e ACTH plasmático. A seguir, o octreotide era associado por mais 30 dias com nova coleta de três amostras de cortisol urinário e ACTH plasmático. Resultados: Os valores de cortisol urinário apresentaram queda significante após o uso de cabergolina isolada (P = 0,016) e em associação ao octreotide (P = 0,012). A eficácia do tratamento combinado não foi maior que a da cabergolina isolada. Os valores de ACTH plasmático não revelaram diferença significante durante o tratamento e não se correlacionaram com os valores de cortisol. A média de expressão do mRNA do gene DRD2 foi maior no grupo tratado (1,170 ± 0,417) quando comparada ao grupo controle (0,776 ± 0,252) (P = 0,036). Houve dissociação entre os conteúdos de mRNA e da proteína desse receptor. Não foi possível analisar a expressão do mRNA do gene SSTR5, pois o tratamento das amostras com DNAse causou degradação do RNA. A imunorreatividade para SSTR5 esteve presente em todos os pacientes e não foi alterada pelo tratamento prévio. Não houve diferença estatística na expressão do gene SSTR2 entre os grupos controle (1,253 ± 0,511) e tratado (1,267 ± 0,386) bem como diferença significante da imunoexpressão do SSTR2 entre os grupos. Houve correlação entre os conteúdos de mRNA e da proteína desse receptor (P = 0,021). Não houve correlação entre a expressão dos receptores analisados e a resposta ao octreotide e à cabergolina isoladamente ou em associação. Conclusões: a cabergolina isolada representa opção terapêutica na doença de Cushing persistente ou recorrente. A associação de octreotide na dose estudada por 30 dias não foi mais eficiente em reduzir o cortisol urinário. A resposta a essas drogas não está relacionada à expressão dos receptores SSTR2, SSTR5 e DRD2 / Introduction: The Cushings disease presents high morbimortality. Its treatment of choice is transsphenoidal surgery which has satisfactory results in about 70% of cases. In persistent or recurrent disease, a second transsphenoidal surgery, radiotherapy and bilateral adrenalectomy can be carried through, however, these options present disadvantages as development of hypopituitarism and lifelong dependence on hormone replacement therapy. Presently, no drug has shown efficacy in corticotrophinomas treatment. The most efficient agents are the inhibitors of steroidogenesis which have no effect at pituitary tumor. Objectives: To evaluate isolated octreotide and cabergoline effects and their association on plasma ACTH and urinary cortisol in Cushings disease patients, to correlate this effect with tumoral expression of SSTR2, SSTR5 and DRD2 receptors; to correlate tumoral expression of these receptors by quantitative RT-PCR and immunohistochemistry; to evaluate whether these drugs modifies these receptors expression. Patients and methods: control group with 11 patients (10 women and 1 man) between 21 and 43 years who underwent pituitary surgery with no prior treatment and a treated group with 11 patients (2 men and 9 women) between 22 and 53 years that received the following treatment before surgery: : after three baseline urinary cortisol samples and one plasma ACTH sample, patients received octreotide 100 g, subcutaneous 8/8h for 30 days collecting three urinary cortisol samples and one plasma ACTH. After that, cabergoline was introduced 0,5 mg 3x/week for 30 days collecting three urinary cortisol samples and one plasma ACTH sample. Then, octreotide was associated to cabergoline for another 30 days followed by three urinary cortisol and one plasma ACTH sample. Results: Urinary cortisol concentrations significantly decreased after isolated and combined cabergoline use (P = 0,016 and P = 0,012, respectively). Combined treatment efficacy was not greater than isolated cabergoline administration. Plasma ACTH did not change statistically during treatment and did not correlate with urinary cortisol. The average of DRD2 gene expression was higher in control group (0,776 ± 0,252) in relation to treated group (1,170 ± 0,417) (P = 0,036). It had dissociation between mRNA and protein contents of this receptor. SSTR5 gene mRNA expression was not analyzed due to RNA degradation after DNAse tissue treatment. SSTR5 immunoreactivity was present in all patients and it was not modified by previous treatment. No statistic difference was observed between SSTR2 gene expression in control group (1,253 ± 0.511) and in treated group (1,267 ± 0,386). There was no significant difference in SSTR2 immunoexpression between groups. It had correlation between the mRNA and protein contents of this receptor (P = 0.021). No significant relationship was found between hormonal response to isolated and combined therapy and receptors mRNA expression levels. Conclusions: cabergoline represents therapeutical option in persistent or recurrent Cushings disease. Octreotide-cabergoline association in the studied dosage and for the period of 30 days was not more efficient in eliciting urinary cortisol reduction. The responsiveness to these drugs did not correlate to SSTR2 and DRD2 mRNA expression

<p>Multiple myeloma (MM) is an incurable B-cell malignancy mainly localized to the bone marrow. Our aim was to examine the growth- and survival-promoting role of the IGF-IR and its downstream signaling components in MM cells to identify potential targets for therapy. </p><p>Octreotide, a somatostatin analog that has been demonstrated to interfere with the actions of IGF-I, induced growth inhibition in both IL-6-dependent and IL-6-independent MM cell lines expressing the somatostatin receptors sst2, sst3 and sst5. Additionally, a slight pro-apoptotic effect could be observed in a few cell lines. In primary MM cells octreotide induced apoptosis, an effect that was abrogated by exogenously added IGF-I, but not by IL-6.</p><p>Inhibition of IGF-I signaling in Karpas 707 cells, using either the anti-IGF-IR antibody αIR3 or the PI 3-K inhibitors LY294002 and wortmannin, increased sensitivity to apoptosis induced by dexamethasone. Exogenously added IGF-I prevented dexamethasone-induced apoptosis, an effect that could partly be mimicked by the pharmacological GSK-3β inhibitors LiCl and SB415286. Thus, we suggest the GSK-3β as an important mediator of the anti-apoptotic effects of IGF-IR signaling in MM.</p><p>Using rapamycin we selectively inhibited mTOR, a phosphoprotein downstream of the IGF-IR. In MM cell lines rapamycin induced G0/G1-arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of the cyclins D2, D3 and E. Interestingly, in primary MM cells rapamycin induced apoptosis. Moreover, rapamycin potentiated dexamethasone-induced apoptosis, an effect that was associated with a downregulation of the anti-apoptotic protein survivin. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the anti-apoptotic effects of exogenously added IGF-I and IL-6, thus suggesting this drug-combination to be active also in vivo. </p><p>Two newly developed, selective IGF-I RTK inhibitors proved to be very effective in MM cell lines and in primary MM cells providing 50-90% growth inhibition within 48 h of incubation. The inhibitors induced massive apoptosis together with a prominent cell cycle arrest in the G2/M-phase. Importantly, the IGF-I RTK inhibitors downregulated the tyrosine phosphorylation of the IGF-IR β-chain but not of the insulin receptor β-chain. </p><p>In conclusion, the IGF-IR potently promotes growth and survival of MM cells. Therefore, interfering with the IGF-IR signaling pathway might be a suitable strategy to improve MM treatment.</p>

Multiple myeloma (MM) is an incurable B-cell malignancy mainly localized to the bone marrow. Our aim was to examine the growth- and survival-promoting role of the IGF-IR and its downstream signaling components in MM cells to identify potential targets for therapy. Octreotide, a somatostatin analog that has been demonstrated to interfere with the actions of IGF-I, induced growth inhibition in both IL-6-dependent and IL-6-independent MM cell lines expressing the somatostatin receptors sst2, sst3 and sst5. Additionally, a slight pro-apoptotic effect could be observed in a few cell lines. In primary MM cells octreotide induced apoptosis, an effect that was abrogated by exogenously added IGF-I, but not by IL-6. Inhibition of IGF-I signaling in Karpas 707 cells, using either the anti-IGF-IR antibody αIR3 or the PI 3-K inhibitors LY294002 and wortmannin, increased sensitivity to apoptosis induced by dexamethasone. Exogenously added IGF-I prevented dexamethasone-induced apoptosis, an effect that could partly be mimicked by the pharmacological GSK-3β inhibitors LiCl and SB415286. Thus, we suggest the GSK-3β as an important mediator of the anti-apoptotic effects of IGF-IR signaling in MM. Using rapamycin we selectively inhibited mTOR, a phosphoprotein downstream of the IGF-IR. In MM cell lines rapamycin induced G0/G1-arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of the cyclins D2, D3 and E. Interestingly, in primary MM cells rapamycin induced apoptosis. Moreover, rapamycin potentiated dexamethasone-induced apoptosis, an effect that was associated with a downregulation of the anti-apoptotic protein survivin. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the anti-apoptotic effects of exogenously added IGF-I and IL-6, thus suggesting this drug-combination to be active also in vivo. Two newly developed, selective IGF-I RTK inhibitors proved to be very effective in MM cell lines and in primary MM cells providing 50-90% growth inhibition within 48 h of incubation. The inhibitors induced massive apoptosis together with a prominent cell cycle arrest in the G2/M-phase. Importantly, the IGF-I RTK inhibitors downregulated the tyrosine phosphorylation of the IGF-IR β-chain but not of the insulin receptor β-chain. In conclusion, the IGF-IR potently promotes growth and survival of MM cells. Therefore, interfering with the IGF-IR signaling pathway might be a suitable strategy to improve MM treatment.

Small intestinal neuroendocrine tumor (SI-NET) is the most common small bowel tumor in Europe and USA, with an annual incidence of around 0.3-1.3/100000 persons. SI-NETs are the most common type of gastroenteropancreatic NETs (GEP-NETs), and they are known for their ability to produce hormones such as tachykinins and serotonin, as well as for their favorable long-term prognosis in comparison to gastrointestinal adenocarcinoma. The overall aim of the thesis was to investigate unknown or unclear aspects of SI-NET disease, in connection with prognosis, treatment and follow-up. Paper I confirmed several known negative prognostic factors and also showed, for the first time, that para-aortal lymph node metastases and peritoneal carcinomatosis were associated with worse survival by multivariable analyses. Locoregional surgery was associated with a low post-operative mortality, and a prolonged long-term survival by multivariable analysis. In Paper II we continued to investigate peritoneal carcinomatosis and found it be a risk factor not only for death, but also for emergency re-surgery. Furthermore, genetic analyses of samples from primary tumors in patients with and without peritoneal carcinomatosis showed a difference in the DNA between these two groups. In Paper III the outcome after liver surgery and/or radiofrequency ablation of liver metastases was investigated. To summarize, no difference in survival was seen in patients treated with surgery/radiofrequency ablation in comparison with matched controls. However, a superior radiological response of liver metasases and lower U-5-HIAA values were seen in patients subjected to liver surgery and/or radiofrequency ablation compared to matched controls. Paper IV compared ultrasonography, computed tomography and 11C-5HTP-PET in the follow-up after radiofrequency ablation of NET liver metastases. The study concluded that 11C-5HTP-PET depicted all residual tumors after RFA and that it, if used, should be combined with computed tomography for easier interpretation, as RFA areas are not clearly distinguishable with 11C-5HTP-PET alone. Paper V studied gallstone complications after somatostatin analog treatment in SI-NET patients, and concluded that there was a rather high risk to be subjected to a cholecystectomy due to biliary colic, cholecystitis, cholangitis or pancreatitis after primary surgery in somatostatin analog treated patients.