Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapy.

A total of 30-50% of early breast cancer (EBC) patients considered as high risk using standard prognostic factors develop metastatic recurrence despite standard adjuvant systemic treatment. A means to better predict clinical outcome is needed to optimize and individualize therapeutic decisions. To identify a protein signature correlating with metastatic relapse, we performed surface-enhanced laser desorption/ionization-time of flight mass spectrometry profiling of early postoperative serum from 81 high-risk EBC patients. Denatured and fractionated serum samples were incubated with IMAC30 and CM10 ProteinChip arrays. Several protein peaks were differentially expressed according to clinical outcome. By combining partial least squares and logistic regression methods, we built a multiprotein model that correctly predicted outcome in 83% of patients. The 5-year metastasis-free survival in 'good prognosis' and 'poor prognosis' patients as defined using the multiprotein index were strikingly different (83 and 22%, respectively; P<0.0001, log-rank test). In a multivariate Cox regression including conventional pathological factors and multiprotein index, the latter retained the strongest independent prognostic significance for metastatic relapse. Major components of the multiprotein index included haptoglobin, C3a complement fraction, transferrin, apolipoprotein C1 and apolipoprotein A1. Therefore, postoperative serum protein pattern may have an important prognostic value in high-risk EBC.

Mutations at BRCA1: the medullary breast carcinoma revisited.

BRCA1-associated breast cancers (BRCA1-BCs) frequently harbor a high histoprognostic grade, p53 alterations, and estrogen receptor negativity. Although these parameters predict a poor outlook, the overall survival in BRCA1-BCs is equivalent to or even better than that in sporadic cases. These features are reminiscent of what is observed for breast carcinoma of the medullary type, a high-grade tumor with a particular favorable course. To explore a possible relationship between this phenotype and BRCA1 mutations, we first compared 32 BRCA1-BCs and 200 consecutive cases of breast cancer without familial history for the prevalence of typical medullary breast carcinoma (TMC) using the criteria given by Ridolfi et al. [R. Ridolfi et al, Cancer (Phila.), 40: 1365-1385, 1977]. Second, we searched for BRCA1 mutations in a set of 18 cases of TMC, using denaturing gradient gel electrophoresis and Cleavase fragment length polymorphism scanning. Six of 32 (19%) BRCA1-BCs were of the TMC type, compared to 0 of 200 controls (P < 0.0001). Among the 18 TMCs, 2 BRCA1 nonsense mutations were found. This corresponds to almost 7 times the contribution of BRCA1 mutations in the general population. Two additional missense mutations were identified. Together, these results suggest that, although TMC and BRCA1-BCs are not strictly coincidental, an important connection between the two populations does exist.

Detection of gastrin mRNA in fresh human colonic carcinomas by reverse transcription-polymerase chain reaction.

To investigate the hypothesis that gastrin might be synthesized by tumour tissues in cancer of the colon, samples from six human colon tumours, one hepatic metastasis, four normal colonic mucosal samples and two antral and one fundic gastric mucosal samples from nine patients were analysed to determine whether gastrin mRNA was present. RNA was extracted from surgical specimens by ultracentrifugation on a CsCl cushion, purified using the guanidinium thiocyanate method, reverse-transcribed and amplified by polymerase chain reaction. Gastrin mRNA was detected in each colonic carcinoma sample (including the hepatic metastasis), while no such signal was observed in normal colon biopsies. Positive and negative controls (gastric antrum and fundus respectively) gave the expected results. In each of the positive samples, the chemiluminescent revelation of amplified products after Southern blotting corresponded to gastrin mRNA without the intron. These findings demonstrate the ability of primary and metastatic human colonic tumours to produce gastrin mRNA. Since malignant cell lines have been reported to produce gastrin peptide, and since gastrin receptors were present in some cases, our results support the idea that gastrin may be involved in an autocrine mechanism.

Systematic association of PAP and PSA determinations to bone scintigraphy in prostatic cancer.

Prostate-specific antigen (PSA) was compared to prostatic acid phosphatase (PAP) in patients with prostatic cancer suspected to have bone metastases. Bone scans were classified according to metastatic skeletal involvement. The sensitivity of PSA in predicting the presence of metastatic disease (68%) was better than that of PAP (53%). Specificity was 79% for PSA and 90% for PAP. Thirty-five patients had a positive PSA level and a normal scintigraphy (false-positive); 14 of them had only endoscopic prostate resection. Thirty-eight patients underwent a further exploration 3-18 months later. PSA level during disease was correlated to scintigraphy in 32 of 38 patients.

[Clinical importance of the determination of the hydrophobic forms of serum carcinoembryonic antigen (CEA) in metastatic cancer of the colon]. / Intérêt clinique de la détermination des formes hydrophobes de l'antigène carcinoembryonnaire (ACE) sérique dans les cancers métastatiques du côlon.

Thirty-four patients with metastatic colon cancer were treated with 5 fluorouracil and folinic acid. The follow-up of disease was evaluated by tomodensitometric CT-scan analysis and by serum CEA determination. In addition, a study of the different CEA molecular forms separated by Triton X114 partitioning, immunoprecipitation and immunoblotting was completed. Concerning the aqueous phase, no relationship appeared between the pattern of CEA species and the outcome of chemotherapy. Opposingly, the analysis of the hydrophobic phase gave results closely correlated to chemotherapeutic response. In 19/34 patients, the hydrophobic CEA forms were absent or weakly expressed; out of these patients, 16/19 underwent a successful response to chemotherapy regimen. Opposingly, all of the remaining 15 patients expressing high levels of hydrophobic CEA species were non-responders. The present study thus gives new means for predicting the outcome of 5 fluorouracil-folinic acid chemotherapy by screening the molecular CEA forms expressed in the serum of patients with metastatic colon cancer.

[Pilot study of screening of prostate cancer by the assay of prostate specific antigen in occupational milieu]. / Etude pilote de dépistage du cancer de la prostate par le dosage de l'antigène spécifique de la prostate en milieu professionnel.

The goal of this study was to confirm the capacity of occupational medicine to become involved in cooperative screening programs with a dosage of the PSA (Prostate Specific Antigen) determined by immunoradiometric assay. Two thousands and five hundred seventy three salaried workers in the building sector, between 50 and 65 years old, participated in this investigation. Thirty seven individual ie 1.4% had a PSA level above or equal to 10 micrograms/l. Among them, 35 were checked within three months and 17 were found to have a persistently elevated PSA level. In this subgroup 15 pathologies including two cancers were found. We observed a great variability in the results of PSA determination in the groups of individuals whose initial assay level was above or equal to 10 micrograms/l. The linear correlation coefficient between the two assays (on the same individual), carried out at a six week interval on average, was low (r = 0.52 for N = 35). In our series, 3.5% of patients followed up had undergone a rectal examination less than a year previously. Occupational medicine seems to be an efficient setting for screening intervention. However, the people mainly concerned by our study, (salaried workers seen through the physicians interviewed) did not seem very aware of this type of action.

[Serum gastrin levels in colorectal cancers. Evolution after treatment]. / La gastrinémie dans les cancers colorectaux. Devenir après traitement.

Increased basal serum gastrin level has been described in patients presenting with colorectal cancer. The aim of this work was to study the evolution of serum gastrin levels after cancer treatment. We measured basal serum gastrin levels before and 1 to 2 months after treatment in 15 patients (7 men, 8 women; mean age: 61.6 years). There were 3 malignant polyps, 4 Dukes A, 3 Dukes B, 4 Dukes C and 1 Dukes D colonic cancers. Treatment included 3 endoscopic polypectomies, 2 laser photodestructions, and 10 surgical resections, Mean basal gastrin level after treatment (49.07 +/- 12.65 mIU/l) was significantly lower (P less than 0.002) than before treatment (104.47 +/- 26.98 mIU/l). In the 2 patients treated by laser therapy, recurrences were associated with reincreasing serum gastrin levels. These results suggest an "autocrine" secretion of gastrin.

[Acromegaly and sleep apnea syndrome (author's transl)]. / Acromégalie et apnée du sommeil.

Acromegaly associated with a Sleep Apnea Syndrome has but exceptionally been reported. Polygraphic recordings of sleep have been carried out in parallel with the determination of pituitary hormonal secretions, during the nycthemeral period before and after surgical treatment of the adenoma. There appears a Sleep Apnea Syndrome of the predominant obstructive type; the Apnea index is: 57 (N less than or equal to 4); the hypnogram is considerably jagged, with more than a thousand wakings and changes in the sleep stages, due to a great number of apneas. The deep slow sleep never occurs: no stages 3 and 4. The physiological peak of G.H. secreted in the beginning of the deep slow sleep thus does not appear in the Sleep Apnea Syndrome. The existence of a "false negative" criteria of a cured Acromegaly must be taken into consideration. The Sleep Apnea Syndrome must be differentiated from Narcolepsy and the usual Pickwickian syndrome. The Sleep Apnea Syndrome and Acromegaly seem to be two separate diseases, each one evolving independently. The cure of Acromegaly has not led to the cure of the Sleep Apnea Syndrome and the latter has not prevented the clinical and biological cure of Acromegaly. This may be an argument in favor of the independence of Acromegaly towards some hypothalamic structures.

[Impact of recent oncogenetic progress on the management of high risk breast cancer patients: the example of BRCA1 and BRCA2 genes]. / Impact des récents progrès en oncogénétique sur la prise en charge des sujets à haut risque de cancer du sein: l'exemple des gènes BRCA1 et BRCA2.

Evidence is mounting that hereditary breast cancers and sporadic cases harbor distinct clinical and morphological patterns that are thought to be linked to different natural histories. BRCA1-associated breast cancers appear as high grade, poorly differentiated, highly proliferating, and frequently estrogen receptor negative tumors. Surprisingly, despite these features usually associated with a poor outlook, no decrease in the overall survival is observed in hereditary cases. These elements may be of valuable help in the design of strategies in the medical management of cancer prone individuals.

[Action of 5-hydroxytryptophan on serum thyreostimulin and prolactin in primary hypothyroidism (author's transl)]. / Action du 5 hydroxytryptophane sur les taux plasmatiques de thyréostimuline et de prolactine dans l'hypothyroïdie primitive et chez le sujet normal.

Orally 5 HTP has significantly decreased serum TSH level in eight patients with primary non treated hypothyroidism, but not in five normal subjects. Serum T4 et T3 levels did not change and serum PRL did not increase in the two groups. These results indicate a possible inhibitory action of 5 HT on TSH regulation. Action of 5 HT on PRL has not been defined here.

[Study of 2 markers, keratin and neuron-specific enolase, in bronchial cancers]. / Etude de 2 marqueurs, la kératine et la NSE dans les cancers bronchiques.

In an immunohistochemical study 31 patients with bronchial cancer (squamous cell 9, large cell 4, small intermediate cell 11 and oat cell 7) were investigated for keratin and NSE. Keratin seems to be a valuable marker since only oat cell cancers and 45% of small intermediate cell cancers were negative. In contrast, marking with NSE seems to be non-discriminating. The low value of NSE as marker was confirmed by 133 serum NSE assays performed in 39 bronchial cancer patients. Although NSE values were significantly higher in oat cell cancer, in any given patient serum assays can, at best, detect relapses.

[What is the role of the correspondence of free PSA/total PSA in the staging of local prostate cancer? Series of 50 radical prostatectomy cases]. / Le rapport PSA libre/PSA total a-t-il sa place dans la stadification du cancer localisé de la prostate? A propos d'une série de 50 prostatectomies radicales.

OBJECTIVE: To refine the pretreatment staging of localized prostate cancers. MATERIAL AND METHOD: Prospective study on 50 total prostatectomy specimens from men with apparently prostate-confined adenocarcinoma. Preoperative assay of the free PSA/total PSA ratio and analysis of this ratio according to the presence of capsular effraction, capsular invasion and positive margins. RESULTS: Significant difference of this ratio according to the presence or absence of capsular effraction (13.2% versus 18.9%), capsular invasion (12.4% versus 17.5%) and positive margins (11.6% versus 16.3%). CONCLUSION: The free PSA/total PSA ratio can be useful for staging of prostate cancer, but this needs to be confirmed by a large-scale prospective study.

Molecular study of CEBPA in familial hematological malignancies.

Familial aggregation in patients with several haematological malignancies has been described, but the genetic basis for this familial clustering is not known. Few genes predisposing to familial haematological malignancies have been identified, among which RUNX1 and CEBPA have been described as predisposing genes to acute myeloid leukemia (AML). Recent studies on RUNX1 suggest that germline mutations in this gene predispose to a larger panel of familial haematological malignancies than AML. In order to strengthen this hypothesis, we have screened CEBPA for germline mutations in several families presenting aggregation of hematological malignancies (including chronic or acute, lymphoid or myeloid leukemias, Hodgkin's or non Hodgkin's lymphomas, and myeloproliferative or myelodysplastic syndromes) with or without solid tumours. Although no deleterious mutations were found, we report two novel and rare variants of uncertain significance. In addition, we confirm that the in frame insertion c.1175_1180dup (p.P194_H195dup) is a germline polymorphism.

[Preliminary results of a new radioimmunoassay for thyroxine binding globulin (T.B.G.) (author's transl)]. / Dosage radio-immunologique de la globuline fixant la thyroxine. Résultats préliminaires--intérêt pratique.

A radioimmunoassay for the accurate measurement of T.B.G., developed by Crouzat-Reynes, was used to perform T.B.G. concentration in sera of euthyroid subjects in different clinical situations, in hypothyroid and hyperthyroid patients. In normal control, the T.B.G. concentration was not different from men and women, from young and old subjects (m = 21,1; sigma = 3,9). On the other hand, in women either pregnant (m = 51,2; sigma = 18,1) or receiving oral contraception (m = 30,1; sigma = 5,7), the T.B.G. levels were significantly higher than euthyro subjects. Cirrhosis of the liver and liver carcinoma were without apparent effect on T.B.G. levels because it was a too few number of patients and the group was too heterogeneous. In the group of hypothyroid (m = 25,9; sigma = 6,5) and hyperthyroid (m = 21,1; sigma = 5,5) patients, the T.B.G. serum concentrations were not significantly different from normal. The ratio T4/T.B.G., as I.T.L. (T4 X T3 uptake) permit to bring back in normal range T4 levels changed by extrathyroidal process; however, this ratio seems to us to be less interesting than standard I.T.L. The T.B.G. assay has not to be considered only as a substitution of T3 uptake because they do not study the same parameters.

[beta2-Microglobulin and carcino-embryonic antigen in bronchogenic carcinoma (author's transl)]. / beta2-Microglobuline et antigène carcino-embryonnaire dans les cancers bronchiques primitifs.

In a series of 52 patients with bronchogenic carcinoma serum levels of beta2-microglobulin (beta2m) and carcino-embryonic antigen (CEA) were studied. No correlation was found between the increase of beta2m (greater than 3,2 mg/l) and CEA (greater than 40 ng/l). High levels were found in 10 % of cases for CEA and in 30% of cases for beta2m. The follow-up of serum levels of beta2m and CEA was studied during the evolution of the disease through monthly assays. Upon 15 cases followed, the same dissociation between beta2m and CEA was observed.

[beta2-Microglobulin and pulmonary tuberculosis (author's transl)]. / beta2-Microglobuline et tuberculose pulmonaire.

Serum beta2-microglobulin levels, determined in 29 healthy adults were found to be 1,3 mg/l with an upper confidence limit (95%) of 2,0 mg/ml. In contrast, serum values in 101 patients with pulmonary tuberculosis were 2,1 mg/l with an upper confidence limit of 3,2 mg/l. The latter value is therefore to be taken into consideration if serum beta2m is to be used for discriminating between lung carcinoma and other pulmonary diseases.