Pierre Levillain

Inflammation in Benign Prostatic Hyperplasia: Correlation With Prostate Specific Antigen Value

PURPOSE We attempted to identify morphological parameters of benign prostatic hyperplastic inflammation that correlate with pre-biopsy prostate specific antigen (PSA) concentrations. MATERIALS AND METHODS Patients undergoing prostate biopsy at our department were prospectively studied between January 1995 and January 1996. preoperative blood and 24-hour urine samples were measured for PSA. Biopsy samples harboring exclusively benign prostatic tissue were graded on a 4-point scale for inflammation (0-no inflammatory cells, 1-scattered inflammatory cell infiltrate, 2-nonconfluent lymphoid nodules and 3-large inflammatory areas with confluence of infiltrate) and aggressiveness (0-no contact between inflammatory cells and glandular epithelium; 1-contact between inflammatory cell infiltrate and glandular epithelium; 2-clear but limited, that is less than 25% of the examined material, glandular epithelium disruption, and 3-glandular epithelium disruption on more than 25% of the examined material). RESULTS A total of 66 patients with exclusively benign prostatic tissue on prostate biopsies was analyzed. Difference between inflammation graded groups was not significant when considering serum or urinary PSA. There was a significant correlation between aggressiveness grading and serum PSA (rho = 0.51, p < 0.0001), whereas aggressiveness grading and urinary PSA did not correlate (rho = -0.06, p = 0.6). CONCLUSIONS Prostatic subclinical inflammation is not associated with high urinary PSA. Unless associated with glandular epithelial disruption, density of prostatic interstitial inflammatory cell infiltrate is not significantly correlated with serum PSA concentration. We believe that this issue should be considered when interpreting a prostate biopsy.

Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter

Background Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Discussion Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer

BACKGROUND Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated. PATIENTS AND METHODS Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT). RESULTS A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01). CONCLUSIONS These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.

Risk Factors for Recurrent Nodular Goiter after Thyroidectomy for Benign Disease: Case-control Study of 244 Patients

Surgery for recurrent nodular goiter is associated with a significant risk of parathyroid and recurrent laryngeal nerve (RLN) morbidity. Total thyroidectomy for benign disease is assessed. The aim of this study was to evaluate the risk factors for recurrence and the morbidity associated with reoperation. From 1969 to 1996 a total of 4334 thyroidectomies were performed, of which 122 were for recurrent nodular goiter (group I: 116 women, 6 men). A matched case-control study of 122 patients operated on for nonrecurrent multinodular goiter was performed (group II: 112 women, 10 men). Age, family history, initial surgery, pathology, and morbidity were compared in the two groups by ċ2 test, Fisher’s exact test, and the Mantel-Haenszel test. The mean age was 39.88 years in group I and 47.89 years in group II. There was no statistical difference in relation to the extent of thyroidectomy or morbidity after initial surgery. Statistical differences were identified regarding age (p = 0.000002) and the multinodular nature of the initial goiter (p = 0.005). Bilaterality and family history were less significant (p = 0.09 and p = 0.08, respectively). Temporary RLN palsy and temporary hypoparathyroidism were higher in group I (12.3% vs. 5.7%, p = 0.0737; 10.6% vs. 1.7%, p = 0.00337). Permanent RLN palsy was found in 0.8% in group I and in none in group II (p = 0.5, NS). Young age and multiple nodules at initial surgery are risk factors for recurrence. A higher rate of temporary morbidity was demonstrated after surgery for recurrent goiter. Total thyroidectomy for multinodular goiter is advisable.

SERUM-TO-URINARY PROSTATE SPECIFIC ANTIGEN RATIO: ITS IMPACT IN DISTINGUISHING PROSTATE CANCER WHEN SERUM PROSTATE SPECIFIC ANTIGEN LEVEL IS 4 TO 10 NG./ML.

PURPOSE Benign prostatic hyperplasia (BPH) was shown to be associated with high concentrations of urinary prostate specific antigen (PSA). We investigated the serum-to-urinary PSA ratio in patients undergoing prostate biopsy to assess its efficacy in enhancing serum PSA specificity in the detection of prostate carcinoma. MATERIALS AND METHODS From November 1995 through January 1996 consecutive patients undergoing prostate biopsy were prospectively included in the study. Serum and urine PSA levels were measured at our laboratory with the Tandem-R assay. Samples were drawn 24 hours before prostate biopsy and at a distance from prostatic manipulation or ejaculation. RESULTS We studied 73 patients with BPH and 57 with prostate cancer. Differences between BPH and prostate cancer were statistically significant considering serum PSA or serum-to-urinary PSA ratios. In the 50 patients with a serum PSA of 4.0 to 10.0 ng./ml. (35 with BPH and 15 with prostate cancer) the differences between prostate cancer and BPH were still significant only when considering serum-to-urinary PSA ratio. Receiver operating characteristic curves showed that serum-to-urinary PSA ratio was a better predictor of prostate cancer than serum PSA. CONCLUSIONS Our results suggest that the serum-to-urinary PSA ratio may be useful in distinguishing BPH from prostate cancer, particularly in the diagnostic gray zone of serum PSA between 4.0 and 10.0 ng./ml.

Granulomatous hepatitis due to combination of amoxicillin and clavulanic acid

SummaryWe report the case of a patient with amoxicillinclavulanic acid-induced hepatitis with histologic multiple granulomas. This type of lesion broadens the spectrum of liver injury due to this drug combination, mainly represented by a benign cholestatic syndrome. The association of granulomas and eosinophilia favor an immunoallergic mechanism. As penicillin derivatives and amoxicillin alone are known to induce such types of lesions, the amoxicillin component, with or with-out a potentiating effect of clavulanic acid, might have a major role.

Prognostic molecular markers with no impact on decision-making: the paradox of gliomas based on a prospective study

This study assessed the prognostic value of several markers involved in gliomagenesis, and compared it with that of other clinical and imaging markers already used. Four-hundred and sixteen adult patients with newly diagnosed glioma were included over a 3-year period and tumour suppressor genes, oncogenes, MGMT and hTERT expressions, losses of heterozygosity, as well as relevant clinical and imaging information were recorded. This prospective study was based on all adult gliomas. Analyses were performed on patient groups selected according to World Health Organization histoprognostic criteria and on the entire cohort. The endpoint was overall survival, estimated by the Kaplan–Meier method. Univariate analysis was followed by multivariate analysis according to a Cox model. p14ARF, p16INK4A and PTEN expressions, and 10p 10q23, 10q26 and 13q LOH for the entire cohort, hTERT expression for high-grade tumours, EGFR for glioblastomas, 10q26 LOH for grade III tumours and anaplastic oligodendrogliomas were found to be correlated with overall survival on univariate analysis and age and grade on multivariate analysis only. This study confirms the prognostic value of several markers. However, the scattering of the values explained by tumour heterogeneity prevents their use in individual decision-making.

Allelic loss on chromosomes 2q21 and 19p 13.2 in oxyphilic thyroid tumors

Hürthle thyroid tumors are characterized by frequent numerical chromosomal aberrations, including aneuploidy or polyploidy, losses and gains of some chromosomal regions and DNA fragmentation. In recent years, great attention has been paid to the combined analysis of morphologic and genetic features of oxyphilic tumors and to the elucidation of their pathogenesis. We analyzed for loss of heterozygosity (LOH) of the candidate regions for TCO (thyroid tumor with cell oxyphilia) and NMTC1 (nonmedullary thyroid carcinoma 1), 2 loci already mapped on chromosomes 19p13.2 and 2q21, respectively. Matched normal and tumor DNA samples from 70 patients with sporadic oxyphilic thyroid tumors and 20 with sporadic follicular tumors were subjected to microsatellite analysis using 10 markers on 19p13.2 and 6 markers on 2q21. This approach led us to the observation of a more significant LOH in oxyphilic than in follicular tumors. Allelic loss in tumor samples was evenly distributed in both 19p13.2 and 2q21 regions, in accordance with the established linkage of TCO and NMTC1 for inherited tumors. In order to investigate the possible contribution of both susceptibility loci in oxyphilic tumors, the family that led to the original mapping of TCO locus was reanalyzed for the markers in the 2q21 region. This led to the exclusion of linkage with the NMTC1 locus and to the refutation of the digenic inheritance hypothesis at least in this family.

Immunohistochemical detection, regulation and antiproliferative function of G-protein-coupled receptor kinase 2 in thyroid carcinomas

TSH, via its G-protein-coupled receptor, activates cell growth of both benign and malignant thyroid tumors. G-protein-coupled receptors (GR) kinase 2 (GRK2) has been reported to regulate the TSH receptor but its role in cancer is unknown. To determine a possible function for GRK2 in the growth process of thyroid cancers, we analysed its expression in normal and tumoral thyroid tissues and studied thyroid cancer cell line proliferation after GRK2 overexpression. Thirty one thyroid tissues, including 16 non-medullary thyroid cancers and 15 adjacent normal tissues, were analysed by immunohistochemistry. Five paired tissues were also studied by western blotting for the GRK2 enzymatic activity. Immunohistochemical staining showed an increase in GRK2 in thyroid cancers including papillary, follicular, and anaplastic types, compared with their adjacent normal tissues. Immunoblot analysis and GRK2 enzymatic activity measurement confirmed immunohistochemical study. TSH and TSH in association with insulin or IGF-I stimulated GRK2 protein accumulation in normal human thyroid cells in primary culture. The TSH effect on the GRK2 expression was mimicked by forskolin. After GRK2 overexpression in two poorly differentiated thyroid cell lines, all the clones showed a significant reduction in cell proliferation, ranging from 28 to 65% inhibition compared with vector alone after 96-h culture. In conclusion, thyroid mitogenic factor-stimulated GRK2 accumulation may explain, in part, high GRK2 levels in differentiated carcinoma, because TSH, insulin, or IGF-I is known to be involved in the thyroid cancer progression. Surprisingly, instead of stimulating, GRK2 reduced cell proliferation revealing a new role for this kinase in the growth of thyroid cancers.

Histology of familial thyroid tumours linked to a gene mapping to chromosome 19p13.2

This paper describes the pathology of thyroid tumours showing an autosomal mode of inheritance linked to a gene that maps to chromosome 19p13.2. All the affected members from the family (seven males and two females; mean age 23 years) were clinically euthyroid and presented with nodular goitre; tumour recurrence after thyroidectomy was observed in four. In four of the five patients studied, the tumours were multifocal, bilateral well demarcated or encapsulated and composed of follicles, papillae, trabeculae/solid areas (often resembling hyalinizing trabecular adenoma of the thyroid) or an admixture, formed by cells with pale to intense cytoplasmic eosinophilia. A diagnosis of multiple adenomatous goitre was made in the thyroidectomy specimen from two patients, while the other two patients showed, in addition to multiple adenomas, a co‐existent oxyphil papillary carcinoma. The fifth patient had an oxyphil cell carcinoma. All tumours were of follicular cell origin as shown by immunocytochemistry. Less than a third of the benign tumours and all three carcinomas showed a variable number of neoplastic cells diffusely immunostained for mitochondria. Histological findings of a ‘multiple adenomatous goitre’, non‐endemic ‘multinodular goitre’ or multiple neoplasms of follicular cell origin with the morphology of those described here, particularly in young patients, should alert the pathologist and physician to the possibility of an inherited trait, with its implications for family screening. The tumours are usually benign and well demarcated but because of multicentricity and consequently increased risk of recurrence and/or progression to carcinoma, total thyroidectomy should be advocated. Copyright