Human GH-secreting tumors are heterogenous regarding their basal secretory activity and response to GH-releasing factor (GRF). We have investigated whether such different secretory properties could be accounted for by alterations of intracellular mechanisms occurring at the calcium level. Basal free intracellular calcium concentrations ([Ca2+]i) and Ca2+ responses to GRF were studied in single cells cultured from fragments of five GH-secreting pituitary adenomas. We used the microspectrofluorimetric method and indo-1 as the fluorescent probe. The cell populations cultured from the tumors of patients A and C showed increased hormone secretion in response to GRF in vitro, whereas cultures from patients B, D, and E were unresponsive to the peptide. Basal [Ca2+]i measured in the five cell populations ranged from 82 +/- 18 to 118 +/- 27 nM. A 10-sec application of 10 nM GRF induced an increase in [Ca2+]i in 60% and 54% of A and C cells, respectively. In the nonresponsive cell populations, the number of calcium responses to GRF was lower, 26% (B cells), 5% (D cells), and 10% (E cells). Two principal responses types were observed: 1) an initial increase in [Ca2+]i, followed by a sustained plateau phase lasting for more than 200 sec; and 2) a monophasic peak of increased [Ca2+]i lasting approximately 1 min before returning to baseline levels. GRF responses were totally suppressed in the absence of Ca2+ ions in the external medium. Sixteen to 30% of the cells cultured from four of the five tumors showed spontaneous fluctuations of [Ca2+]i. These spontaneous Ca2+ transients were suppressed in Ca(2+)-free medium. The number of cells exhibiting such Ca2+ transients decreased with time in culture. Basal hormone secretion was higher in cultures from patient D, in which no spontaneous Ca2+ transients were observed in any of the 72 studied cells, and in cultures from patients E, in which only 16% of cells were spontaneously active. We conclude that 1) in human responsive somatotrophs, the involvement of Ca2+ in GRF stimulus-secretion coupling mechanisms is apparently similar to that described in somatotrophs of other species; 2) the lack of a secretory response to GRF observed in some tumors may result from impairment of Ca2+ responsiveness in either cell recruitment or response amplitude and/or duration; and 3) spontaneous rhythmic Ca2+ activity is apparently dissociated from basal hormone secretion in some of these tumor cells.
Resume Les carcinomes ovariens hereditaires represententenviron 10 % des 4 500 nouveaux carcinomes ovariensannuels. Ils sont generalement lies a des mutations sur lesgenesBRCA(1ou2)ou,aunmoindredegre,surceuximpli-ques dans le syndrome HNPCC. En raison d’un depistageinsuffisamment efficace a ce jour, et du haut risque pources femmes de developper cette redoutable maladie, il estrecommande, apres consultation d’oncogenetique, de proce-der des que possible a une annexectomie bilaterale prophy-lactique. Toutefois, certaines n’acceptent pas les consequen-ces de cette castration precoce, specialement dans les cas oule traitement substitutif ne peut etre delivre. Ce faisant, elless’exposent a un risque croissant avec le temps de voir sedevelopper cette maladie. Des donnees recentes, issues del’examen precis des specimens d’annexectomie prophylac-tique, ont revele une frequence anormale d’anomalies histo-logiques developpees au niveau des trompes alors que lesovaires sont normaux. Une comprehension nouvelle de lapathogenese des carcinomes ovariens fait desormais jouerun role central a la trompe de Fallope, en particulier a sonextremite terminale le pavillon ou fimbria, dans la survenuedes carcinomes de haut grade sereux pelviens, de loin lesplus frequents chez ces femmes a risque hereditaire. D’oul’idee de tester dans le cadre d’une etude controlee, pourcelles qui seraient reticentes a la realisation de l’annexecto-mie bilaterale dans la crainte des effets secondaires d’unemenopause precoce, l’efficacite d’une chirurgie prophylac-tique limitee dans un premier temps a l’exerese des deuxtrompes, en attendant la menopause naturelle pour effectuerl’ovariectomie bilaterale complementaire.Mots cles Chirurgie prophylactique annexielle · MutationBRCA · Pathogenese des carcinomes ovariens · Carcinomesereux pelvien · Trompe de Fallope · FimbriectomieradicaleAbstract Hereditary ovarian carcinomas represent 10% ofcases of the around 4,500 yearly ovarian cancers in France.They principally consist of high-grade serous carcinomas.They are especially observed in mutation carriers on genesBRCA1 or 2 and, at a lesser degree, on genes of the heredi-tary non-polyposis colorectal cancer (HNPCC) syndrome.Due to the absence of an effective screening method for thishighly lethal disease, laparoscopic prophylactic adnexec-tomy is strongly recommended as soon as possible, after agenetic counselling session. However, not all women acceptthe outcomes of an early menopause, especially if a substi-tutive treatment is contra-indicated. Recent data obtainedfrom the thorough examination of risk-reducing salpingo-oophorectomy (RRSO) specimens highlight the pivotal roleof the Fallopian tube in the pathogenesis of most ovariancarcinomas, especially its fimbrial end for the high-gradeserous subtype, so frequent with mutation carriers. Thus,for these at-risk women, reluctant to RRSO, the idea of atemporary prophylactic surgery, limited to a bilateral radicalfimbriectomy until oophorectomy at menopause, is being
The effect of GH-RH in the intra-cytosolic free Ca2+ concentration was studied in GH3 cells. To this end, we have used microspectrofluorimetry performed on single cells. We show that 60% of cells respond to a brief application of 100 nM GH-RH by an increase of their [Ca2+]i (mean increase 100% over basal values). This response which is blocked by calcium channel inhibitors results from an increased influx of Ca2+ ions from the external medium.
Glassy cell carcinoma (GCC) is a rare and aggressive type of adenoSquamous cervical carcinoma.It affects patients at a younger age compared to the general population of patients with cervical cancer.The five-year survival is inferior to that of the other histological types.The treatment is not standardized.Radiation therapy with concomitant chemotherapy is associated with a better local control and improves oncological results.The authors report here the clinical histories of two patients with an early GCC and a desire of fertility preservation treated with radical trachelectomy with an early recurrence.They conclude that considering the rarity and aggressivity of this histological type, and the lack of evidence in the literature for its management, it would be prudent to consider GCC at an early stage as a contraindication for a radical trachelectomy.
