Breast cancer is a major health problem as well as scientifically poorly understood. Our knowledge of breast cancer is however rapidly progressing in several directions. First, genomic studies are establishing a new molecular classification of breast cancers. Molecular subtypes have been identified and are being associated with the histoclinical forms of breast cancers. Second, genetic alterations are discovered and classified, generating new potential therapeutical targets. Third, mammary stem cells have been identified in the normal mammary epithelium. Their altered counterparts have been identified in tumors and are being characterized. These combined studies allow a new integrated cellular and molecular definition of breast cancers and a conceptual basis that will help the management of the disease.

Multiple endocrine neoplasia type 2 (MEN2) is an hereditary disease with a prevalence of 1/5000. Three phenotypic variants have been identified: MEN2A associates medullary thyroid carcinoma (MTC) to pheochromocytoma in about 20-50% of cases and to primary hyperparathyroidism in 5-20% of cases; MEN2B associates MTC to pheochromocytoma in 50% of cases, to marphanoid habitus and to mucosal and digestive ganglioneuromatosis whereas in familial isolated medullary thyroid carcinoma (FMTC), the other components of the disease are absent. In MEN2, natural history of the disease and a common embryologic origin (neural crest) may explain the phenotypes observed in the organ involved, beginning from the stage of hyperplasia to adenoma and cancer. MEN2 is an inherited autosomal dominant disease with a complete penetrance, related to germline mutation in the proto-oncogene RET. MTC represent the most frequent circumstance of diagnosis. Pheochromocytoma and HPT may reveal the disease unfrequently and are systematically associated to undiagnosed MTC which is present yet. Analysis of the RET gene allows to confirm the diagnosis of MEN2 by identifying the causal germline mutation. Management of MEN2 patients include thyroidectomy associated to cervical central and bilateral lymph nodes dissection for MTC, unilateral adrenalectomy for unilateral pheochromocytoma or bilateral adrenalectomy when both glands are involved, and selective resection of pathologic parathyroid glands for HPT. Familial genetic screening detects at risk subjects who will develop the disease and allows to manage them at the earliest stage of the disease by perform early or prophylactic thyroidectomy such giving them the best chance of cure. Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC, thus pointing the necessity of a complete thyroid surgery for index cases with MTC and the earliest thyroidectomy for screened at risk subjects.

Clinical implications associated with polymorphisms in drug-metabolizing genes involved in the chemotherapy of colorectal cancers (5-flurorouracil, oxaliplatin and irinotecan) are reviewed.

Large-scale genomic studies based on DNA microarrays improve our understanding of the pathophysiology of cancers. The use of these research findings to improve diagnosis, prognosis and treatment is the current challenge of research in genomics.

Gene alterations which have been implicated in colorectal carcinogenesis are characterized by three major mechanisms: chromosomal instability, microsatellite instability, and epigenetic mechanisms (i.e., CpG island hypermethylation). Progress in understanding of these genetic and epigenetic instabilities has led to advances in the individualization and characterization of more homogeneous sub-groups of colorectal tumors with regard to progression, prognosis and response to therapy.

Papillary and follicular carcinomas of the thyroid are differentiated carcinomas developed from the follicular epithelium, that keep some of its morphological and functional characteristics. Their increased incidence is related to an improved screening. Thyroid carcinoma usually presents as a thyroid nodule. Only 5% of nodules are malignant and fine needle biopsy is the most accurate tool for their diagnosis. Initial treatment is standardized and includes a total thyroidectomy with central lymph node dissection in case of papillary carcinoma, that is followed by the administration of a large activity of radioiodine in case of incomplete surgery, distant metastases or high risk factors. Papillary carcinomas of less than 1 cm in diameter, when unifocal and intra-thyroid are treated with surgery only, and radioiodine is not indicated. Thyroxine treatment is given to all patients. The majority of patients are cured, as demonstrated by the work-up performed at 1 year (undetectable serum thyroglobulin following stimulation with recombinant human TSH and normal neck ultrasonography). Subsequent follow-up is yearly with serum Tg and TSH determinations that is maintained within the normal range. In the other patients, other tests may be indicated, starting with the administration of a large activity of radioiodine. In these patients, serum TSH should be decreased to a low level.

5-fluorouracil, (5-FU) is an antimetabolite used in many types of cancers. It has a narrow therapeutic index. More than 80% of administered 5-FU is detoxified in 5-fluoro-5,6-dihydrouracil (5-FUH2) by an enzyme: dihydropyrimidine dehydrogenase (DPD). Half life increased with DPD deficiency. Thus, patients presenting a partial or profound DPD deficiency have an increased risk of severe or lethal toxicity. DPD deficiency was estimated between 3 to 5% in the normal population. Different approaches have been developed: Pharmacogenetic on the DPD gene or pharmacologic measuring DPD activity. More than 30 mutations have been reported on this gene. The more common mutation is the slice-site mutation IVS14+1G>A. Analysis of the various mutations allowed to identify a population at risk with a DPD deficiency. DPD activity is determined in peripheral blood mononuclear cells. This assay offers the capability of identifying individuals who are completely deficient in DPD activity and those who are partially deficient. Assays to detect DPD deficiency are not used as a screening test to prevent 5-FU toxicity.

Numerous toxic side-effects, sometimes severe, are regularly reported in patients treated with 5-fluorouracil, and oral fluoropyrimidines, UFT and capecitabine, in metastatic and adjuvant setting. These toxic effects are due to a large interindividual variability of the metabolism, mainly depending on dihydropyrimidine dehydrogenase activity (DPD), the major enzyme of the catabolism of fluoropyrimidines. Thus, the patients with a DPD deficiency are at high risk of early severe acute toxicity, with this kind of drug. These toxic side-effects are potentially lethal. DPD deficiency frequencies, partial or complete, are about 3-5% and 0.2% respectively. They are most often due to a gene polymorphism. Different techniques for the detection of DPD deficiency before treatment have been reported: phenotypic, such as the plasma ratio of dihydrouracil/uracil, or genotypic, such as the detection of DPD gene variants, deleterious for enzyme activity. The pretherapeutic detection of DPD deficiency would permit to avoid almost every early acute toxic side-effects. We must emphasize that it is not merely a genetic result, since the detection of a deficiency most often does not contra-indicate the use of a fluoropyrimidine, but it must be combined with therapeutic advice.

Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT). MTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Diagnosis is usually made by a solitary nodule often associated to nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form and in about 30% of case as a familial form as a part of multiple endocrine neoplasia syndrome, an hereditary dominant inherited disease related to germline mutation of the proto-oncogene RET. Both biological (CT) and genetic (RET) markers allows the optimal diagnosis and treatment of MTC; the former allows screening and early diagnosis of MTC by routinely CT measurements in nodular thyroid diseases that make the adequate and complete surgery required to be performed. The former leads to diagnose familial MTC and to identify at risk subjects in whom early or prophylactic surgery may be performed. Treatment of MTC is based on the complete surgical resection: total thyroidectomy associated to central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be associated to other systemic treatments: as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appears as possible valuable therapeutic options for the future. Prognosis of MTC is mainly related to both the stage of the disease and the extend of the initial surgery. Ten-year survival is about 80% when the patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery.

We present the experience of the Citadelle Hospital (Liege, B) in the diagnosis, treatment and follow-up of medulloblastoma in children. A retrospective study of 10 cases of medulloblastoma was performed. Five years after diagnosis, the event-free survival was 77%.

Recent development of interphase fluorescence in situ hybridization (FISH) allows analysis on non-proliferant plasma cells. We describe the most frequent genetic abnormalities in multiple myeloma and their prognostic value.

This case-report studies the clinical, radiological, anatomopatholo-gical and therapeutic aspects of peripheral primitive neuroectodermal tumours (PNET). PNET are neoplasms with a similar histology to tumours in the Ewing family. Diagnosis requires histopathology, immunohistochemistry and cytogenetic studies. To our knowledge, this rare tumour has never been reported in the mesocolon (our case). The treatment, which is usually similar to that for Ewing's sarcoma is complex and has not yet been codified, which is another difficult aspect of this disease with a poor prognosis.

Pituitary adenomas can occur in a familial context, or they can be isolated cases, sometimes due to a predisposing syndrome. In multiple endocrine neoplasia type 1, they often associate with a mutation of the menin gene, a tumor-suppressing gene. A new germinal mutation predisposing to the development of multiple endocrine neoplasias has recently been identified in MENI-negative subjects on the gene CDKN1B encoding for p27(kip1)protein. Carney Complex syndrome--a rare disease--is in more than 60% of the cases linked to the inactivation mutation of a gene located on 17q22-24 that encodes the regulatory subunit 1 of protein kinase A, PRKARIA. Isolated familial pituitary adenomas represent 1.9 to 3.2% of the population of subjects presenting a pituitary adenoma. Low penetrance non-sense mutations, Q14X, IVS3-IG>A and R304X, in 11q12-11q13 region encoding AIP protein, (Aryl hydrocarbon receptor Interacting Protein), have been described by Vierimaa et al, in Finish patients with pituitary adenoma predispositions.

In 20% of cases, central nervous system cavernomas are an autosomal dominant familial disease. In these cases, lesions are multiple and one or more parents suffer of the same affection. Three genes (CCM 1, 2 and 3) have been identified since 1999, two on chromosome 7 (one on each arm) and one on the short arm of chromosome 3. The role of these genes in normal cerebral angiogenesis is unknown today. In clinical practice, molecular tests may be useful in some situations: 1) in sporadic cases with a unique lesion, molecular test should not be performed since these cases are not genetic; 2) in patients with multiple lesions who have an affected relative, the genetic nature of the disease is obvious and molecular tests are useful only for genetic counseling; 3) in sporadic cases with multiple lesions and no known affected relative, molecular tests can establish the genetic nature of the disease and be useful for genetic counseling.

Since the advent of modern neuroimaging (MRI) cerebral cavernomas are usually diagnosed "in vivo". In this paper we describe the data which improved our knowledge of the disease: 1) nosologically, cerebral cavernomas belong to the group of cerebral vascular hamartomas which can be associated between themselves ("mixed" lesions); 2) hemodynamically, the annual risk of hemorrhage increases after a first bleeding and in deep located lesions (brainstem); 3) association between cavernomas and developmental venous anomalies may be observed; the later on must be left in place at operation; 4) immunocytochemical studies (PCNA) show that cavernomas should be considered more as a benign vascular tumor than as a malformation; 5) familial forms (20%) are characterized by multiple locations and "de novo" lesions; 6) better understanding of the natural history of cavernomas, which is a dynamic lesion, leads to broader surgical indications (no alternative treatment).