Systems biology: perspectives on multiscale modeling in research on endocrine-related cancers.

Drawing on concepts from experimental biology, computer science, informatics, mathematics and statistics, systems biologists integrate data across diverse platforms and scales of time and space to create computational and mathematical models of the integrative, holistic functions of living systems. Endocrine-related cancers are well suited to study from a systems perspective because of the signaling complexities arising from the roles of growth factors, hormones and their receptors as critical regulators of cancer cell biology and from the interactions among cancer cells, normal cells and signaling molecules in the tumor microenvironment. Moreover, growth factors, hormones and their receptors are often effective targets for therapeutic intervention, such as estrogen biosynthesis, estrogen receptors or HER2 in breast cancer and androgen receptors in prostate cancer. Given the complexity underlying the molecular control networks in these cancers, a simple, intuitive understanding of how endocrine-related cancers respond to therapeutic protocols has proved incomplete and unsatisfactory. Systems biology offers an alternative paradigm for understanding these cancers and their treatment. To correctly interpret the results of systems-based studies requires some knowledge of how in silico models are built, and how they are used to describe a system and to predict the effects of perturbations on system function. In this review, we provide a general perspective on the field of cancer systems biology, and we explore some of the advantages, limitations and pitfalls associated with using predictive multiscale modeling to study endocrine-related cancers.

Chemoembolization of Neuroendocrine Liver Metastases Using Streptozocin and Tris-acryl Microspheres: Embozar (EMBOsphere + ZAnosaR) Study.

PURPOSE: The purpose of this prospective observational study was to evaluate the efficacy and tolerability of transarterial chemoembolization (TACE) for neuroendocrine liver metastases using a combination of streptozocin, Lipiodol, and tris-acryl microspheres. PATIENTS AND METHODS: A total of 16 men and 9 women aged 59.6 ± 11.3 years, all with predominant liver disease, underwent 54 courses of TACE using an emulsion of 1.5 g of streptozocin and 10 ml of Lipiodol. Additional embolization was performed using 300-500 µm tris-acryl microspheres. Morphological response was evaluated using the RECIST criteria on multi-detector computed tomography or MRI. Clinical efficacy was evaluated particularly in patients with carcinoid syndrome. RESULTS: The primary tumor was located in the small bowel or pancreas in 21 (84%) patients. Eleven (44%) patients presented with a carcinoid syndrome. Nineteen (76%) patients presented with more than 10 liver nodules. One delayed case of ischemic cholecystitis was treated conservatively. After a median follow-up of 36.1 months, 1 (4%) patient had a complete response, 12 (48%) patients had a partial response, and 7 (28%) patients had a stable disease corresponding to a disease control rate of 80%. All patients with carcinoid syndrome had significant improvement. Median time to progression was 18.8 months and overall survival was 100, 100, and 92% at 1, 2, and 3 years, respectively. Seven patients presented with extrahepatic progression with abdominal lymphadenopathies or metastases to the brain, ovary, adrenal gland, or lung. CONCLUSION: Optimized TACE using a combination of streptozocin, Lipiodol, and tris-acryl microspheres is effective and well tolerated.

ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma.

Papillary craniopharyngioma (PCP) is an intracranial tumor that results in high levels of morbidity. We recently demonstrated that the vast majority of these tumors harbor the oncogenic BRAF V600E mutation. The pathologic diagnosis of PCP can now be confirmed using mutation specific immunohistochemistry and targeted genetic testing. Treatment with targeted agents is now also a possibility in select situations. We recently reported a patient with a multiply recurrent PCP in whom targeting both BRAF and MEK resulted in a dramatic therapeutic response with a marked anti-tumor immune response. This work shows that activation of the MAPK pathway is the likely principal oncogenic driver of these tumors. We will now investigate the efficacy of this approach in a multicenter phase II clinical trial. Post-treatment resection samples will be monitored for the emergence of resistance mechanisms. Further advances in the non-invasive diagnosis of PCP by radiologic criteria and by cell-free DNA testing could someday allow neo-adjuvant therapy for this disease in select patient populations.

[A case report of long-term survival of endocrine cell carcinoma of the esophagus with chemo-radiation therapy].

The patient was an 84-year-old man, who was diagnosed with cT3N2 (101L, 109L) M0, stage III esophageal cancer. The tumor, immunohistochemically, was stained positive for CD56 and NSE yielding a definitive diagnosis of endocrine cell carcinoma of the esophagus. We selected chemo-radiation therapy (5-FU/CDDP and 2 Gy/day total 60 Gy) for this patient. As adjuvant chemotherapy, 7 courses of chemotherapy with 5-FU/CDDP, was performed. At 8 months from the chemo-radiation therapy, the disease was diagnosed as cCR. But two years later, lung metastasis appeared, so we started chemotherapy with docetaxel/CDDP/5-FU. After 2 courses, lung metastasis was almost disappeared. He has been survived for four years and five months after chemo-radiation. This case suggests that chemo( FP) -radiation therapy and adjuvant chemotherapy could be an effective treatment for endocrine cell carcinoma of the esophagus.

[Chemoperfusion and embolization in the treatment of liver metastases]. / Chemoperfusion und -embolisation von Lebermetastasen.

Presentation of techniques and procedures for regional chemotherapy in the treatment of unresectable liver metastases from different primary tumors as a modality of interdisciplinary therapy management. Such transarterial therapy methods include hepatic arterial infusion (HAI), transarterial chemoembolization (TACE), chemoembolization with cytostatic-loaded microspheres (DEBs), transarterial embolization (TAE) and selective internal radiation therapy (SIRT). Regional chemotherapy procedures in the treatment of liver metastases represent a minimally invasive treatment option that can be successfully combined with surgical resection and/or radiofrequency (RFA), laser-induced thermotherapy (LITT), microwave ablation (MWA). These procedures allow optimization of the local control rate with strictly intrahepatic processes and lead to increased survival rates without any quality of life restriction.

Is adjuvant therapy with streptozotocin and 5-fluorouracil useful after resection of liver metastases from digestive endocrine tumors?

BACKGROUND: In patients with digestive endocrine tumors (DET) and liver metastases (LM) surgical resection is the only curative treatment. However, 5-year recurrence occurs in 50-80% of patients in the literature. The effect of adjuvant chemotherapy (CT) on relapse-free survival (RFS) and overall survival (OS) is unknown. AIM: To assess the safety and the efficacy of systemic adjuvant CT with streptozotocin and 5-fluorouracil (5-FU) following LM resection in patients with DET. PATIENTS AND METHODS: Between 1996 and 2006, 52 consecutive patients (23 males, median age 54 years [21-69]) underwent surgery for LM of well-differentiated DET in our center. The primary tumor was resected. After R0 resection of LM, patients were considered for adjuvant CT if the primary tumor was pancreatic, if LM was >or=10, or if the patient was <50 years old, in patients with other primary tumors. Twenty-nine patients received adjuvant CT and 23 were in the observation group. Adjuvant CT included 4 postoperative courses of i.v. streptozotocin-5-FU (500 and 400 mg/m(2), respectively, daily for 5 days every 42 days). RFS, OS and toxicity were evaluated. Log rank and chi-square analysis were used to identify prognostic factors. RESULTS: Median post-operative follow-up was 47 months (4-162). In the adjuvant CT group, all patients except one received the 4 cycles. Two patients had grade 3-4 toxicity, including 1 febrile neutropenia resulting in death. Recurrence occurred in 43% and 65% of patients in the observation and adjuvant CT groups, respectively. RFS at 3 and 5 years was 51% and 38% in the observation group and 40% and 20% in the adjuvant CT group, respectively (P = .36). In univariate analysis, the significant prognostic factors associated with RFS were the number of LM (>or=10) and synchronous LM. Administration of adjuvant CT was not correlated with RFS. OS at 3 and 5 years was 90% and 76% in the observation group and 96% and 96% in the adjuvant CT group, respectively (P = .58). CONCLUSION: RFS in patients receiving adjuvant CT was similar to that reported in the observation group and in historical cohorts without adjuvant CT. Thus, administration of streptozotocin-5-FU cannot be recommended in this indication.

Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms.

Neuroendocrine tumours (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), endocrine islets (within the thyroid or pancreas) as well as from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts. The development of somatostatin analogues (SSA) as important diagnostic and treatment tools has revolutionised the clinical management of patients with NETs. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with SSA, tumour regression is rare. Possible mechanisms when this does occur include antagonism of local growth factor release and effects, probably including activation of tyrosine and serine-threonine phosphatases, and indirect effects via anti-angiogenesis. The development of new SSA, new drug combination therapies and chimaeric molecules should further improve the clinical management of these patients, as should a more complete understanding of their mode of action.

[Immunohistochemical diagnosis by means of tyramide signal amplification]. / Immunhistokjemisk diagnostikk ved bruk av tyramid-signalamplifikasjon.

Immunohistochemistry is used for in situ detection of proteins in histological slides and is now an important diagnostic tool. Due to several methodological and biological factors, conventional immunohistochemical procedures may sometimes have too low sensitivity, especially for tracing the histogenesis of malignant tumours. A few years ago, an amplification technique was introduced which greatly increased the sensitivity of some of the commonly used immunohistochemical methods. This technique permits the use of primary antibodies in significantly lower concentrations compared with the conventional methods. Alternatively, one can keep the antibody concentration unchanged and use the enhanced sensitivity to detect scarce proteins, which are not visualised by traditional immunohistochemical procedures. We present a brief description of the technique and show some examples of its use in the diagnosis of neuroendocrine carcinomas. Tyramide signal amplification might become an important supplement for the diagnosis and classification of malignant tumours.