VEGF, VEGF165b and EG-VEGF expression is specifically related with hormone profile in pituitary adenomas.

Vascular endothelial growth factor (VEGF), its inhibitory splice variant, VEGF165b and Endocrine Gland derived VEGF (EG-VEGF) have a controversial role in pituitary gland. We aim to study VEGF, VEGF165b and EG-VEGF expression in pituitary adenomas. A significant correlation was found between growth hormone (GH) and VEGF secretion (P=0.024). For prolactinomas, VEGF and prolactin expression, had a P-value of 0.02 for Kendall coefficient and a P-value of 0.043 for the Spearman coefficient. VEGF-mRNA amplification was detected in both tumor cells and folliculostellate cells. VEGF165b was positive in 16.66% of pituitary adenomas. EG-VEGF was significantly correlated with prolactin (P=0.025) and luteinizing hormone (P=0.028). Our data strongly support VEGF, VEGF165b and EG-VEGF as important players of pituitary adenomas tumorigenesis. Particular hormonal milieu heterogeneity, special vascular network with an unusual reactivity to tumor growth correlated with variability of VEGF, VEGF165b and EG-VEGF secretion may stratify pituitary adenomas in several molecular groups with a direct impact on therapy and prognosis.

Origin of renal cell carcinomas.

Cancer is a heritable disorder of somatic cells: environment and heredity are both important in the carcinogenic process. The primal force is the "two hits" of Knudson's hypothesis, which has proved true for many tumours, including renal cell carcinoma. Knudson et al. [1, 2] recognised that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumour-suppressor genes. Their observations (i.e., that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation) led them to propose a two-hit theory of carcinogenesis. Furthermore, Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumours would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumours would develop late in life and in a unifocal manner [3, 4]. The kidney is affected in a variety of inherited cancer syndromes. For most of them, both the oncogene/tumour-suppressor gene involved and the respective germline mutations have been identified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. Families with hereditary predisposition to cancer continue to provide a unique opportunity for the identification and characterisation of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal cell carcinoma, and genes associated with five of these syndromes have been already identified: VHL, MET, FH, BHD and HRPT2. Few cancers have as many different types of genetic predisposition as renal cancer, although to date only a small proportion of renal cell cancers can be explained by genetic predisposition.

Pathologic features of renal cortical tumors.

Our better understanding of the morphologic spectrum of renal cortical tumors has resulted in a clinically more relevant classification of these tumor types. We now recognize that "granular cell" and "sarcomatoid" renal cell carcinoma are only nonspecific descriptors, and that such features are seen in a variety of types of renal tumors. The authors believe that the recently gained knowledge about molecular-driven antigen expression will play an important role in the characterization, development, and evaluation of targeted therapies in kidney cancer in the coming years.

Origin of renal cell carcinomas

Cancer is a heritable disorder of somatic cells: environment and heredity are both important in the carcinogenic process. The primal force is the "two hits" of Knudson's hypothesis, which has proved true for many tumours, including renal cell carcinoma. Knudson et al. [1, 2] recognised that familial forms of cancer might hold the key to the identification of important regulatory elements known as tumour-suppressor genes. Their observations (i.e., that retinoblastoma tend to be multifocal in familial cases and unifocal in sporadic presentation) led them to propose a two-hit theory of carcinogenesis. Furthermore, Knudson postulated that patients with the familial form of the cancer would be born with one mutant allele and that all cells in that organ or tissue would be at risk, accounting for early onset and the multifocal nature of the disease. In contrast, sporadic tumours would develop only if a mutation occurred in both alleles within the same cell, and, as each event would be expected to occur with low frequency, most tumours would develop late in life and in a unifocal manner [3, 4]. The kidney is affected in a variety of inherited cancer syndromes. For most of them, both the oncogene/tumour-suppressor gene involved and the respective germline mutations have been identified. Each of the inherited syndromes predisposes to distinct types of renal carcinoma. Families with hereditary predisposition to cancer continue to provide a unique opportunity for the identification and characterisation of genes involved in carcinogenesis. A surprising number of genetic syndromes predispose to the development of renal cell carcinoma, and genes associated with five of these syndromes have been already identified: VHL, MET, FH, BHD and HRPT2. Few cancers have as many different types of genetic predisposition as renal cancer, although to date only a small proportion of renal cell cancers can be explained by genetic predisposition (AU)

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Non-functioning pituitary adenomas infrequently harbor G-protein gene mutations.

BACKGROUND: Mutations of the genes encoding the alpha subunit of the stimulatory G protein (Gs) and of the inhibiting Gi2 protein (GNAS1 and GNAI2 genes, respectively) have been described in various endocrine neoplasias, including pituitary tumors. AIM: To search for mutations of GNAS1 and GNAI2 in a continuous series of non-functioning pituitary adenoma (NFPA) patients neurosurgically treated. SUBJECTS AND METHODS: The surgical samples of 22 patients who have been defined and characterized on a clinical, biochemical, histological, and immunohistochemical point of view have been processed for investigating the presence of the above mutations by PCR amplification of the hot spots exons 8 and 9 of GNAS1, and exons 5 and 6 of GNAI2, followed by direct sequencing. Moreover, the promoter region of GNAI2, in order to assess the prevalence of single nucleotide polymorphisms (SNP), was investigated in the same series. RESULTS: A CGT>TGT mutation at codon 201 of GNAS1 gene in a single case of NFPA was found, but no mutation of GNAI2A was demonstrated. CONCLUSIONS: This finding suggests and confirms that G-protein mutations are rare and not crucial in NFPA development. Additionally, we found a silent SNP at codon 318 in the promoter of the Gi2alpha gene in one out of the 22 NFPA.

Different DNA ploidy patterns for the differentiation of common subtypes of renal tumors.

OBJECTIVES: The common subtypes of renal tumors are conventional or clear cell carcinoma, papillary carcinoma, chromophobe carcinoma and oncocytoma. Each subtype has its distinct histogenesis and clinical evolution. DNA ploidy is viewed as a marker of gross genomic aberrations. The aim of this study is to evaluate the DNA ploidy in the common subtypes of renal tumors to increase our understanding of renal tumor biology and to broaden clinical application of DNA ploidy. METHODS: 38 renal tumor samples (13 clear cell RCCs, 12 papillary RCCs, 7 chromophobe RCCs, and 6 oncocytomas) were studied. Five biopsies of different parts of each fresh tumor were subjected to a flow cytometric analysis of DNA ploidy. RESULTS: All tumors except one papillary RCC generated interpretable DNA histograms. Flow cytometric analysis of oncocytomas showed the diploid pattern (29/30 frequencies) while the chromophobe RCC never showed the diploid pattern (0/55 frequencies) (p<0.01). 3/7 chromopbobe RCCs possessed the hypodiploid stemline. The hypodiploid stemline appeared neither in conventional RCCs (0/63 frequencies) nor in papillary RCCs (0/50 frequencies). The diploid pattern was dominant in conventional and papillary RCCs. 10/13 (76.9%) of clear cell RCCs and 9/11 (81.8%) of papillary RCCs possessed a homogeneous DNA ploidy pattern while only 1/7 (14.3%) has a homogeneous DNA ploidy pattern. 6/7 chromophobe RCCs had multiple aneuploid stemlines. CONCLUSIONS: Flow cytometric analysis reveals that conventional and papillary RCCs are more homogeneous than chromophobe RCC. Each subtype of renal tumors possesses a specific DNA ploidy pattern. The analysis of DNA ploidy is useful for the differentiation of common subtypes of renal tumors in morphologically difficult cases.

High frequency of serum DNA alterations in renal cell carcinoma detected by fluorescent microsatellite analysis.

To date there are no reliable serological markers for renal cell carcinoma (RCC). We applied fluorescent microsatellite analysis (MSA) to detect serum DNA alterations in patients with RCC. Fresh tumour, peripheral blood and serum specimens from 60 consecutive patients treated for malignant renal tumours (n= 53 RCC and n= 7 non-RCC) were prospectively collected. After DNA extraction, we performed MSA with a total of 9 markers from the chromosomal regions 3p, 5q, 7p, 7q, 9p, 13q, 17p and 17q to identify tumour specific serum DNA alterations in Group I (n= 53 RCC); 11 additional markers were used in the first 23 RCCs (Group II) in order to increase sensitivity; and 20 healthy controls were investigated with 10 markers. Besides the histomorphological diagnosis the RCCs were genetically stratified according to the "Heidelberg Classification" of renal tumours. Detection of allelic imbalance and loss of heterozygosity (LOH) was carried out on an automated laser sequencer. In Group I we identified serum DNA alterations in 74% (39/53) of cases. When applying 20 markers, the sensitivity was elevated to 87% (20/23) in Group II. Investigating 20 healthy controls with 10 markers, the method rendered 85% specificity. The highest incidence of alterations was detected for chromosomal regions 3p and 5q. The presence of serum DNA alteration was not associated with tumour nuclear grade but exhibited a trend towards advanced stages (p = 0,044). In RCC, the microsatellite analysis has a high sensitivity in the detection of serum DNA alterations when a sufficient number of markers from various chromosomal regions are used. Advanced tumours tend to express serum DNA alterations more frequently.

Two cases of acromegaly in a family.

We report two cases of acromegaly due to pituitary adenoma without any other endocrinopathy in a family. The patients had high plasma GH and were improved by transsphenoidal adenomectomy. Acromegaly is usually a clinical syndrome of sporadic nonfamilial occurrence. The familial occurrence of acromegaly not associated with multiple endocrine neoplasia is very rare. Our patients are unlikely to be associated with the multiple endocrine neoplasia type 1 syndrome. Here we describe two patients with acromegaly, a father and his daughter, and review familial cases reported.

Familial pituitary adenoma--report of four cases from two unrelated families.

The authors report four cases of familial pituitary adenomas from two unrelated families. No clinical or biochemical evidence of multiple endocrine neoplasia, type I (MEN-I) was demonstrated. Detailed study of the family trees disclosed no other family members affected by MEN-I. Familial occurrence of pituitary adenomas unassociated with MEN-I is rare.

[Familial occurrence of pituitary adenoma (author's transl)].

The familial occurrence of brain tumors are exceedingly rare except in cases with phacomatosis. We encountered pituitary adenomas in two sisters of a family, so far presenting no evidence of multiple endocrine adenomatosis (MEA). Case 1, K. O. a 26-year-old woman was admitted to our Hospital on September 10, 1970 with visual acuity and field disturbance, irregular menstruation and acromegaly. Neurological examination: Her visual acuity was Vd 0.6 and Vs 0.3, visual field was bitemporal hemianopsia, and ther was papilledema bilaterally. She had left exophthalmos and left abducens palsy. Roentgenogram of the skull, brain scanning, cerebral angiogram, pneumoencephalogram suggested the presence of a pituitary tumor. On Sep. 17, 1970, through a left frontotemporal craniotomy the tumor was removed subtotally. The pathological diagnosis was pituitary adenoma (chromophobe). Case 2, M. T. a 31-year-old woman, sister of case 1, was admitted to the Hospital on September 19, 1973, with mild headache, left visual field disturbance and amenorrhea. She had a child, and a past history of pulmonary tbc. Neurological examination: Her visual acuity was Vd 1.2 and Vs 0.03, and visual field of the right eye was temporal lower quandrant anopsia. There was optic nerve atrophy in the left eye. Plain X-ray craniogram, brain scanning, cerebral angiogram and pheumoencephalogram suggested the presence of a pituitary tumor. On Sep. 28, 1973, a right frontal craniotomy was performed. The tumor tissue with capsule was removed subtotally. The pathological diagnosis was pituitary adenoma (mixed type). In the literatures about familial brain tumors with histological diagnosis, glioma and glioblastoma are common, meningioma is relatively rare. Pituitary adenoma with no evidence of MEA is exceedingly rare. The two sisters presented in this paper, have no evidence of hyperparathyroidism, pancreas adenoma and peptic ulcer. So, we consider, at present, these cases should not be field in MEA.