Traitement médical des tumeurs endocrines digestives

Gastroenteropancreatic neuroendocrine tumors constitute a highly heterogeneous group of tumors with very different prognoses. It is important to distinguish between the well-differentiated neuroendocrine tumors (carcinoid tumors affecting the gastrointestinal tract and pancreatic endocrine tumors), which generally progress slowly, and the poorly differentiated endocrine tumors, which are characterized by being aggressive and of rapid progression. The treatment of the poorly differentiated forms is essentially based on chemotherapy, although prognosis remains poor. The well-differentiated forms require a more complex approach – depending on the site of the primary tumor, staging, the resectability of the lesions, and disease spread – and should therefore be defined within a multidisciplinary setting. The treatment of choice remains surgical excision of the primary tumor and metastases. No additional treatment has been demonstrated to be effective. For functional tumors, symptomatic treatment with a somatostatin analog for carcinoid tumors or a protein pump inhibitor for gastrinoma must be started rapidly to reduce the complications related to hormone secretion. For metastatic disease or for tumors that are not amenable to complete resection, several options can be proposed: careful monitoring, chemoembolization of liver metastases, systemic chemotherapy, or enrollment in therapeutic protocols offering targeted therapies. Stepwise introduction of these various therapies prolongs survival, even in metastatic disease.     

Classification et aspects anatomopathologiques des tumeurs endocrines digestives

Gastrointestinal and pancreatic endocrine tumors GIPET are rare and represent only 2 % of malignant tumors. Beyond their common features, endocrine tumors are characterized by a marked diversity, which results from the large functional, structural and embryological heterogeneity of normal endocrine cells. Despite the rational basis for predicting prognosis provided by the WHO classification, there is no reliable means of predicting the clinical course of patients with gastrointestinal and pancreatic endocrine tumors. The current criteria used for the definition of the tumor grade remain unsatisfactory. According to the WHO classification system, pathologists vary significantly in their reporting of endocrine tumors. Recently, the European Neuroendocrine Tumour Society (ENETS) has proposed a TNM (tumor–node–metastasis) classification for gastrointestinal and pancreatic endocrine tumors. The use of this classification is considered simple and valuable. It is hoped that the combination of WHO classification, with anatomical staging systems TNM, and possibly incorporating molecular features of gastrointestinal and pancreatic endocrine tumors will provide clinicians with effective means of classification and prognostication of patients with these tumors.     

Somatostatin analogs in the management of gastrointestinal tumors

Experience with SMS 201-995 (Sandostatin), a somatostatin analog, in the treatment of endocrine active gastrointestinal tumors is reviewed. Best immediate results were obtained in vipomas and insulinomas but a scape phenomenon was frequently observed. A positive and persistent effect was recorded in a case of nesidioblastosis. It was striking that good clinical control could be obtained in some instances despite insufficient suppression of hormone secretion by the tumor. This finding suggests peripheral actions of somatostatin and SMS independently of its primary effect on hormone release.     

Performances de la TEP-TDM à la 6-Fluoro-[18F]-L-Dihydroxyphénylalanine (FDOPA) et de l’imagerie radiologique conventionnelle dans la prise en charge des patients avec maladie tumorale endocrine dont le primitif est inconnu

IntroductionDespite the extensive diagnostic work-up performed by conventional morphologic and functional imaging in patients with endocrine metastatic malignancies, the primary tumor remains often unknown. Knowledge of the primary tumor improves patients’ management in case of metastatic disease, and allows curative surgical debulking. At present, few studies have focused on the detection of the primary lesion.AimsTo retrospectively assess the FDOPA PET/CT accuracy in the detection of primary endocrine tumors and to evaluate the incremental value of FDOPA PET/CT over conventional imaging.Patients and methodsFourteen patients with biopsy-proven or clinically and biologically suspected endocrine tumors underwent FDOPA PET/CT. Results were compared with conventional imaging, and related to a pathologic or follow-up gold standard.ResultsFDOPA PET/CT detected the primary tumor in four out of 14 patients. Conventional imaging detected the primary tumor in three out of 14 patients. The association of FDOPA PET/CT and morphologic imaging allowed the identification of five out of 14 primary tumors. On an organ-based analysis, FDOPA PET/CT detected more metastasis than morphologic imaging (respective sensitivities of 92% and 58%).ConclusionIn our study, FDOPA PET/CT seemed more sensitive than conventional imaging for the detection of primary endocrine tumors and metastatic spread assessment. Physiological pancreatic uptake hampers FDOPA PET/CT accuracy for the detection of islet cell primary malignancies. Moreover, some pathologic characteristics of the endocrine phenotype, such as cellular differentiation, may influence FDOPA tumoral uptake.     

Manifestations cliniques et diagnostic échoendoscopique des tumeurs endocrines digestives

Gastroenteropancreatic endocrine tumors are rare and need a multidisciplinary approach. Some of them are only found in the pancreas: insulinomas, glucagonomas and VIPomas wether other are located in the duodenum or in the small intestine. Clinical presentation depends on the site of the primary tumor and whether they are functioning tumors. Best known functioning tumors are those secreting gastrin with the so-called Zollinger–Ellison syndrome. Endoscopic ultrasonography is not used in the first place. It is particularly sensitive for identification of small tumor like pancreatic insulinomas and in the context of MEN1. Fine-needle aspiration may give diagnosis but also prognosis informations.     

Surgical treatment of neuroendocrine tumours of the pancreas

Gastro-entero-pancreatic (GEP) endocrine tumours can originate from various pancreatic islet cells, from endocrine cells of the gastric and duodenal mucosa, or from APUD cells of neuroectodermal origin in the gastrointestinal tract. They are benign when smaller than 2 cm, but larger tumours are generally malignant. Surgery is the only method for the curative treatment of GEP tumours. A diagnosed and localised tumour is an absolute indication for radical surgery. Conservative medical treatment may be indicated only in an inoperable condition, but in this case tumour reduction surgery is suggested. In the last 15 years 22 patients with pancreatic neuroendocrine tumours were treated without any mortality. Except for two of them, the surgical therapy was curative.     

Simultaneous transfer of tumorigenic and metastatic phenotypes by transfection with genomic DNA from a human cutaneous squamous cell carcinoma

High-molecular-weight genomic DNA isolated from a human cutaneous squamous cell carcinoma (AS) was assayed for its ability to induce tumorigenic transformation of NIH 3T3 cells. Subcutaneous injection of NIH 3T3 cells cotransfected with DNAs from AS tumor and pSV2-neo plasmid not only induced tumors at the site of injection, but also metastasized spontaneously to the lungs in 100% of nude mice injected. DNA isolated from a representative primary tumor and a metastasis was again used in a second round of transfection. Injection of secondary transfectants into nude mice again resulted in induction of both subcutaneous tumors and spontaneous long metastases. Southern blot hybridization with ras-specific probes revealed that DNA from both primary tumors and metastases induced by AS tumor DNA contained highly amplified Ha-ras oncogene. Furthermore, DNAs from secondary tumors and metastases induced by DNA from a primary tumor and a metastasis also contained similar highly amplified Ha-ras oncogene. These results suggest that the amplified Ha-ras oncogene may be responsible for induction of both tumorigenic and metastatic phenotypes in NIH 3T3 cells transfected with DNA from AS tumor.     

Activation of local and systemic anti-tumor immune responses by ablation of solid tumors with intratumoral electrochemical or alpha radiation treatments

Cancer, the most devastating chronic disease affecting humankind, is treated primarily by surgery, chemotherapy, and radiation therapy. Surgery and radiotherapy are mainly used for debulking the primary tumor, while chemotherapy is the most efficient anti-metastatic treatment. To control better metastatic cancer, the host immune system should be stimulated. Yet, successful specific stimulation of the immune system against tumors was seldom achieved even in antigenic tumors. Our working hypothesis is that aggressive in situ tumor ablation can release tumor antigens and danger signals, which will enhance anti-tumor T cell responses resulting in the destruction of residual malignant cells in primary tumors and distant metastases. We developed two efficient in situ ablation treatments for solid cancer, which can be used to destroy the primary tumors and stimulate anti-tumor immune responses. The first treatment, electrochemical ablation, is applied through intratumoral electrodes, which deliver unipolar-pulsed electric currents. The second treatment, diffusing alpha-emitters radiation therapy (DaRT), is based on intratumoral ²²⁴Ra-loaded wire(s) that release by recoil its daughter atoms. These short-lived alpha-emitting atoms spread in the tumor and spray it with lethal alpha particles. It was confirmed that these treatments effectively destroy various malignant animal and human primary solid tumors. As a consequence of such tumor ablation, tumor-derived antigenic material was released and provoked systemic T cell-dependent anti-tumor immunological reactions. These reactions conferred protection against a secondary tumor challenge and destroyed remaining malignant cells in the primary tumor as well as in distant metastases. Such anti-tumor immune responses could be further amplified by the immune adjuvant, CpG. Electrochemical ablation or DaRT together with chemotherapy and immunostimulatory agents can serve as treatment protocols for solid metastatic tumors and can be applied instead of or in combination with surgery.     

The Intersection of Inheritance and Metastasis: The Role and Implications of Germline Polymorphism in Tumor Dissemination

Metastasis is an enormously complex process that involves both spatial and temporal barriers. Metastatic cells must not only acquire all of the characteristics of a primary tumor, but additionally must be capable of invasion, survival during transit and in the secondary site, interact productively with a novel microenvironment and proliferate to form a clinically relevant lesion 1. Adding complexity to the process is the fact that it can be years or even decades after diagnosis of the primary tumor before the secondary tumors are apparent. A number of models have been proposed to explain the origins of metastasis. However, while all of the models can account for some aspects of the experimental observations, suggesting they may be at least in part true, none adequately explain all of the data. This implies that the existing models are likely to be too simplistic and additional factors must be considered to adequately account for existing and newly emerging data.     

外周原始神经外胚叶肿瘤/Ewing's肉瘤的研究进展

外周原始神经外胚叶肿瘤(p PNET,peripheral primitive neuroectodermal tumor)/Ewing's肉瘤(Ewing's Sarcoma,ES)是一类罕见的高度恶性软组织肿瘤,好发于儿童和青年,5年生存率仅20%-30%,高侵袭性生长,易远处转移,易复发,预后不佳。诊断主要依靠病理,手术联合放化疗是主要的治疗方式,分子靶向治疗药物的出现给本病带来了新的希望,但疗效仍需进一步临床资料的验证。目前临床上对本病认识仍不足。本文就p PNET/ES的生物学行为,诊断,治疗和预后的研究进展作一综述,并展望p PNET/ES的研究方向。     

Significance of Lymph Node Metastasis in Cancer Dissemination of Head and Neck Cancer

Lymph node metastasis (LNM) in many solid cancers is a well-known prognostic factor; however, it has been debated whether regional LNM simply reflects tumor aggressiveness or is a source for further tumor dissemination. Similarly, the metastatic process in head and neck cancer (HNC) has not been fully evaluated. Thus, we aimed to investigate the relative significance of LNM in metastatic cascade of HNC using functional imaging of HNC patients and molecular imaging in in vivo models. First, we analyzed ¹⁸Fluorodeoxyglucose positron emission tomography (PET) parameters of 117 patients with oral cancer. The primary tumor and nodal PET parameters were measured separately, and survival analyses were conducted on the basis of clinical and PET variables to identify significant prognostic factors. In multivariate analyses, we found that only the metastatic node PET values were significant. Next, we compared the relative frequency of lung metastasis in primary ear tumors versus lymph node (LN) tumors, and we tested the rate of lung metastasis in another animal model, in which each animal had both primary and LN tumors that were expressing different colors. As a result, LN tumors showed higher frequencies of lung metastasis compared to orthotopic primary tumors. In color-matched comparisons, the relative contribution to lung metastasis was higher in LN tumors than in primary tumors, although both primary and LN tumors caused lung metastases. In summary, tumors growing in the LN microenvironment spread to systemic sites more commonly than primary tumors in HNC, suggesting that the adequate management of LNM can reduce further systemic metastasis.     

Hepatic metastases from the spindle cell variant of medullary thyroid carcinoma: report of a case with diagnosis by fine needle aspiration biopsy.

BACKGROUND: The liver is a common site of neuroendocrine tumors (NTs) metastatic from primaries in the gastrointestinal tract, pancreas, biliary system and lungs. Medullary thyroid carcinoma (MTC) is also a potential source of metastases of NTs. Their metastases to the liver are frequent and can appear several years after the primitive tumor. Although a wide variety of cytomorphologic features are normally exhibited by MTC in smears, a spindle-shaped cell pattern can predominate, complicating the correct interpretation of a metastasis. CASE: A 63-year-old man presented with multiple liver nodules two years after a total thyroidectomy for MTC. Fine needle aspiration biopsy smears of the liver revealed neoplastic cells occurring in loose groupings or lying singly, most of them with a spindle shape and elongated nucleus with the characteristic "salt and pepper" chromatin pattern of a neuroendocrine tumor. Cytoplasmic dendritic processes and intranuclear inclusions were frequently seen. The cytomorphologic features of the tumor were essentially the same as those of the primary MTC. Immunoreactivity for calcitonin confirmed the diagnosis. CONCLUSION: In fine needle aspiration biopsy of liver masses, knowledge of the spindle pattern of the NT is important in order to achieve a correct diagnosis when metastases are the first manifestation of an occult primary tumor. Among neuroendocrine tumors, MTC must be included in the differential diagnosis.     

Secreted Gaussia Luciferase as a Biomarker for Monitoring Tumor Progression and Treatment Response of Systemic Metastases

Background

Currently, only few techniques are available for quantifying systemic metastases in preclinical model. Thus techniques that can sensitively detect metastatic colonization and assess treatment response in real-time are urgently needed. To this end, we engineered tumor cells to express a naturally secreted Gaussia luciferase (Gluc), and investigated its use as a circulating biomarker for monitoring viable metastatic or primary tumor growth and their treatment responses.

Methodology/Principal Findings

We first developed orthotopic primary and metastatic breast tumors with derivative of MDA-MB-231 cells expressing Gluc. We then correlated tumor burden with Gluc activity in the blood and urine along with bioluminescent imaging (BLI). Second, we utilized blood Gluc assay to monitor treatment response to lapatinib in an experimental model of systemic metastasis. We observed good correlation between the primary tumor volume and Gluc concentration in blood (R² = 0.84) and urine (R² = 0.55) in the breast tumor model. The correlation deviated as a primary tumor grew due to a reduction in viable tumor fraction. This was also supported by our mathematical models for tumor growth to compare the total and viable tumor burden in our model. In the experimental metastasis model, we found numerous brain metastases as well as systemic metastases including bone and lungs. Importantly, blood Gluc assay revealed early growth of metastatic tumors before BLI could visualize their presence. Using secreted Gluc, we localized systemic metastases by BLI and quantitatively monitored the total viable metastatic tumor burden by blood Gluc assay during the course of treatment with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2.

Conclusion/Significance

We demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors. Blood Gluc activity not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments.     

The Role of Respiratory Microbiota in Lung Cancer

Recently, the impact of microorganisms on tumor growth and metastasis has attracted great attention. The pathogenesis and progression of lung cancer are related to an increase in respiratory bacterial load as well as changes in the bacterial community because the microbiota affects tumors in many ways, including canceration, metastasis, angiogenesis, and treatment. The microbiota may increase tumor susceptibility by altering metabolism and immune responses, promoting inflammation, and increasing toxic effects. The microbiota can regulate tumor metastasis by altering multiple cell signaling pathways and participate in tumor angiogenesis through vascular endothelial growth factors (VEGF), endothelial cells (ECs), inflammatory factors and inflammatory cells. Tumor angiogenesis not only maintains tumor growth at the primary site but also promotes tumor metastasis and invasion. Therefore, angiogenesis is an important mediator of the interaction between microorganisms and tumors. The microbiota also plays a part in antitumor therapy. Alteration of the microbiota caused by antibiotics can regulate tumor growth and metastasis. Moreover, the microbiota also influences the efficacy and toxicity of tumor immunotherapy and chemotherapy. Finally, the effects of air pollution, a risk factor for lung cancer, on microorganisms and the possible role of respiratory microorganisms in the effects of air pollution on lung cancer are discussed.     

Assessment of tumor vascularization: immunohistochemical and non-invasive methods

Growth of solid tumors beyond a certain mass is dependent on the vascular bed from pre-existing host vasculature. The process of angiogenesis is essential not only for primary tumor growth but also for metastasis. The number of microvessels within the invasive component of a primary tumor reflects the degree of tumor angiogenesis. At present the most widely used method to assess neovascularization is the quantitation of intratumoral microvessel density (IMD) by immunohistochemical methods in which specific markers for endothelial cells are employed. In this paper we analyze the different methods used to assess IMD, as well as their advantages and potential methodological pitfalls. Several studies have shown a close correlation between IMD, tumor growth and the occurrence of metastasis, suggesting that IMD is a prognostic indicator of clinical relevance. Furthermore, preliminary studies suggest that determination of angiogenesis may predict responsiveness to some forms of conventional anticancer therapy. Although the histological microvessel density technique is the current gold standard to characterize tumor angiogenesis, it may not be the ideal tool for clinical purposes because it needs to be performed on biopsy material and does not assess the functional pathways involved in the angiogenic activity of tumors. Non-invasive assessment of tumor vascularity is possible in vivo by means of Doppler sonography, dynamic contrast-enhanced magnetic resonance imaging (MRI) and positron emission tomography (PET). These methods may be preferable to histological assay because they are non-invasive, survey the entire tumor, reflect both anatomic and physiologic characteristics, and may be useful to monitor the activity of antiangiogenic therapies.     

Pathophysiological implications of stroma pattern formation in uveal melanoma

Clinical outcome of cancer patients is mainly determined by the rate of metastasis and, also by primary tumor growth. Formation of extracellular matrix and interactions of neoplastic and non-neoplastic (host) cells in solid tumors have been shown to be essential for these processes. One result of such interactions is the outgrowth of new blood vessels from existing ones, angiogenesis, to provide the tumor tissue with oxygen and nutrients. It is assumed that the neovascular bed also facilitates the escape of metastatic cells from the primary lesions. In addition, recent reports suggested the existence of blood-conducting channels lined by melanoma cells (so-called "vascular channels") accompanied by depositions of extracellular matrix patterns in cutaneous and uveal melanoma. Since the presence of these matrix structures has been negatively associated with prognosis, we hypothesize that they play a role in melanoma outgrowth or metastasis. In this review, we will discuss the morphological and functional properties of the extracellular matrix patterns in that may underlie these clinical phenomena.     

Breast metastasis from squamous cell carcinoma of the oropharynx: a case report

Background

Breast metastases from extramammary tumors are extremely rare, the most common primary tumors being contralateral breast carcinoma, followed by lung, gynecological, gastrointestinal, melanoma, and hematological cancers. Only a few cases deriving from head and neck squamous cell carcinoma have been reported in the literature to date.

Case presentation

We report a case of a 47-year-old Caucasian woman who presented to our hospital with a solitary breast lesion in the right upper external quadrant associated with multiple bone and visceral metastases. Two years before, she had undergone radical resection of a squamous cell carcinoma of the oropharynx (stage pT2, pN1), which was followed by adjuvant radiotherapy. Breast ultrasound showed a hypoechogenic tumor lesion of 4 cm in the right upper external quadrant that was associated with multiple axillary and infra-/supraclavicular adenopathies. A positron emission tomographic scan documented multiple visceral and bone metastases with a single hypermetabolic lesion of the right breast. The results of histology and immunohistochemistry were consistent with a metastasis from a squamous cell carcinoma. The patient died of acute respiratory insufficiency 1 month after her breast metastasis diagnosis and before starting any systemic antitumoral treatment.

Conclusions

Although breast metastases are extremely rare, they should be considered in any patient with a history of cancer and confirmed by histology and immunohistochemistry because they are very difficult to distinguish from other primary breast tumors based only on clinical and radiological features. There are no standardized treatment guidelines for breast metastasis management. Surgery and radiotherapy can play a role in symptom palliation, but they do not have any relevant impact on survival, the prognosis being poor, with an estimated overall survival less than 1 year from diagnosis.

     

The functional and clinical roles of osteopontin in cancer and metastasis

Osteopontin (OPN) is a secreted and integrin-binding protein that has been implicated in a number of pathologies. In this review we will focus on the functional and clinical roles of OPN in cancer and metastasis, with a particular emphasis on breast cancer. While much evidence has suggested that OPN is associated with cancer, its functional contribution to cancer remains poorly understood. Here we will review evidence for mechanisms by which OPN may act to enhance malignancy, including evidence that signaling pathways directly induced by OPN, as well as interactions with growth factor receptor pathways, can combine to activate expression of genes and functions that contribute to metastasis. OPN has been shown to be over-expressed in a variety of human tumors and is present in elevated levels in the blood of some patients with metastatic cancers. We also will discuss recent clinical evidence that suggests that OPN is not only associated with several tumor types, but that levels of OPN in cancer patients' blood or tumors may provide prognostic information.     

Mitochondria in relation to cancer metastasis: introduction to a mini-review series

This introductory article and those that follow focus on the roles that mitochondria may have in cancer metastasis (spreading) that all too frequently leads to death of cancer patients. The history of cancer dates back in time to several thousand years BC and continues to this day. Although billions of dollars have been invested, numerous cancer researchers/scientists and oncologist located at universities, hospitals, cancer centers, commercial entities (companies), and government agencies have been unable to discover ??magic bullets?? to quickly silence most cancers. That is, agents that are effective not only in eradicating the primary tumor at its site of origin, but eradicating also distant tumors that have arisen therefrom via metastatic cells. Fortunately, in recent years some researchers have obtained evidence that the mitochondria of cancer cells are involved not only in providing in part the necessary energy (ATP) to fuel their growth, but hold the secrets to their immortality, and propensity to metastasize (spread) from their original site of origin to other body locations. This introductory article, as well as those that follow, focus on the possible roles of mitochondria in cancer metastasis as well as strategies to arrest cancer metastasis based on this knowledge. Ideally, for a patient to become ??cancer free?? the anticancer agent/agents used must 1) eradicate the primary tumor at its site of origin, 2) eradicate any tumors at other body locations that have arisen via metastasis, and 3) eradicate any tumor cells that remain in the blood, i.e., circulating tumor cells. One such agent that holds promise for doing all three is the small molecule 3-bromopyruvate (3BP) discovered in the author??s laboratory by Dr. Young H. Ko near the turn of the century to be a potent anti-cancer agent [Ko et al.(2001) Can Lett 173:83?C91].