Clinical value of immunoscintigraphy in colorectal carcinoma patients: a prospective study.

Fifty-seven patients with suspected CEA-producing tumors were studied prospectively by radioimmunoscintigraphy (RIS) using a 123I-labeled anti-CEA monoclonal antibody (MAb) (essentially the F(ab')2 or Fab fragments) and emission computed tomography (ECT). Results of RIS were compared to those of a comprehensive diagnostic study. Final diagnosis was based on surgery, biopsy and autopsy (n = 39) or follow-up findings (n = 18). Three groups of patients were defined: Group A with suspected primary tumors (n = 11), Group B with probable (n = 19) and Group C with questionable (n = 27) tumor relapse. Eighty-eight per cent, 93% and 71% of the anatomic regions studied were correctly identified as being involved, and 97%, 97%, and 87% as being free from tumor in Groups A, B, and C, respectively. In the 27 patients from Group C with no definite diagnosis of relapse, and in whom diagnosis was most difficult, 38 tumor sites were involved. Of these, 21 were detected by both prospective RIS and repeated comprehensive study, six by RIS only and seven by conventional methods only. Four sites remained undetected by both approaches. Ten of the 21 lesions were detected by RIS more than 1 mo earlier than by any other method. Among the seven tumor sites detected by other diagnostic modalities only, three were identified at the time of RIS and four became positive more than 6 mo later. Overall diagnosis was entirely correct in 30, partially correct in 16 and incorrect in six patients studied. RIS with ECT and 123I-labeled anti-CEA MAb allows early detection of recurrence or metastasis of colorectal cancer. It thus contributes to reduced delay between diagnosis and treatment.

Detection of recurrence of large-bowel carcinoma by radioimmunoassay of circulating carcinoembryonic antigen (C.E.A.).

The usefulness and limitations of the carcinoembryonic antigen (C.E.A.) radioimmunoassay for the evaluation of tumour resection and for the detection of tumour relapse were studied in patients with large-bowel carcinoma. The level of plasma-C.E.A. was determined before any treatment in a group of 101 patients with histologically proven adenocarcinoma of the colon and rectum. 71% of all patients and 63% of cases with localised tumour (Dukes A and B) had a preoperative C.E.A. value of 5 ng. per ml. or higher. This limit was reached by only 1 of 90 apparently healthy, non-smoking blood-donors. Among 45 patients for whom a complete tumour resection was reported, all patients except 5 showed a drop of C.E.A. to normal values after surgery. The 5 patients whose C.E.A. did not fall to below 5 ng. per ml. showed a subsequent rise in C.E.A. level and were all found later to have a tumour relapse. The results indicate that an incomplete drop of circulating C.E.A. level one month after surgery has a bad prognostic significance. 22 of these patients were followed up by repeated C.E.A. radioimmunoassay for several months after surgery. 8 showed a progressive increase in C.E.A. levels preceding clinical diagnosis of tumour relapse by two to ten months. 6 other patients showed a moderate increase in C.E.A. levels, suggesting a tumour relapse not yet clinically detectable. The remaining 8 patients showed no increase in C.E.A. level above 5 ng. per ml. and no clinical symptoms of relapse. The results demonstrate that relapses of colon and rectum carcinoma can be detected by increased C.E.A. levels months before the appearance of any clinical evidence.

External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study.

BACKGROUND: We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. METHODS: For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1-2 prostatic adenocarcinoma with WHO histological grade 3 or T3-4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0-2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. FINDINGS: Between May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1-12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3-29·7) in the radiotherapy-alone group and 47·7% (39·0-56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33-0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9-47·5) in patients receiving radiotherapy alone and 58·1% (49·2-66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45-0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2-37·5) and 10·3% (5·1-15·4), respectively (HR 0·38, 95% CI 0·24-0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment. INTERPRETATION: In patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.

Antibody-dependent cell-mediated cytolysis of human colon carcinoma cells induced by specific antisera against carcinoembryonic antigen.

Antibody-dependent lymphocyte cytotoxicity against human colon carcinoma cells grown in vitro was demonstrated with rabbit anti-carcinoembryonic antigen (CEA) antisera and normal human lymphocytes. The same antisera produced no tumor cell lysis in a complement-dependent cytotoxicity test. The specificity of the reaction was demonstrated by the inhibition of antibody-dependent lymphocyte cytotoxicity after the addition of increasing amounts of purified CEA to the antiserum and by the fact that only tumor cell lines expressing CEA on their surface were lysed. Antibody-dependent lymphocyte cytotoxicity was also observed against two colon carcinoma cell lines that expressed Blood Group A antigen, using a human serum containing anti-Blood Group A antibodies of the immunoglobulin G class. This reaction was specifically inhibited by absorption with Blood Group A red cells, whereas the anti-CEA-dependent cytotoxicity was not inhibited by absorption with red cells of different blood groups.

Carcinome de Merket: (r)évolution [Merkel cell carcinoma: (r)evolution].

Merkel Cell Carcinoma (CCM) is an aggressive cutaneous tumor of the elderly, which has become the second cause of mortality linked to skin cancer. This has led clinicians and scientists to devote more time to the study of this rare tumor, announcing to a revolution in our understanding, diagnosis and therapy of this cancer. We present here these recent advances, which illustrate the exponential growth of knowledge in the medical field, drawing comparisons with more frequent cancers such as melanoma and squamous cell carcinoma.

Radiation therapy duration influences overall survival in patients with cervical carcinoma.

OBJECTIVE: This article analyses the influence of treatment duration on survival in patients with invasive carcinoma of the cervix treated by radical radiation therapy. METHOD: Three hundred and sixty patients with FIGO stage IB-IIIB carcinoma of the cervix were treated in Lausanne (Switzerland) with external radiation and brachytherapy as first line therapy. Median therapy duration was 45 days. Patients were classified according to the duration of the therapies, taking 60 days (the 75th percentile) as an arbitrary cut-off. RESULTS: The 5-year survival was 61% (S.E. = 3%) for the therapy duration group of less than 60 days and 53% (S.E. = 7%) for the group of more than 60 days. In terms of univariate hazard ratio (HR), the relative difference between the two groups corresponds to a 50% increase of deaths (HR = 1.53, 95% CI = 1.03-2.28) for the longer therapy duration group (P = 0.044). In a multivariate analysis, the magnitude of estimated relative hazards for the longer therapies are confirmed though significance was reduced (HR = 1.52, 95% CI = 0.94-2.45, P = 0.084). CONCLUSION: These findings suggest that short treatment duration is a factor associated with longer survival in carcinoma of the cervix.

Detection of colorectal carcinoma by emission-computerized tomography after injection of 123I-labeled Fab or F(ab')2 fragments from monoclonal anti-carcinoembryonic antigen antibodies.

This clinical study was based on experimental results obtained in nude mice grafted with human colon carcinoma, showing that injected 131I-labeled F(ab')2 and Fab fragments from high affinity anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAb) gave markedly higher ratios of tumor to normal tissue localization than intact MAb. 31 patients with known colorectal carcinoma, including 10 primary tumors, 13 local tumor recurrences, and 21 metastatic involvements, were injected with 123I-labeled F(ab')2 (n = 14) or Fab (n = 17) fragments from MAb anti-CEA. The patients were examined by emission-computerized tomography (ECT) at 6, 24, and sometimes 48 h after injection using a rotating dual head scintillation camera. All 23 primary tumors and local recurrences except one were clearly visualized on at least two sections of different tomographic planes. Interestingly, nine of these patients had almost normal circulating CEA levels, and three of the visualized tumors weighed only 3-5 g. Among 19 known metastatic tumor involvements, 14 were correctly localized by ECT. Two additional liver and several bone metastases were discovered by immunoscintigraphy. Altogether, 86% of the tumor sites were detected, 82% with F(ab')2 and 89% with Fab fragments. The contrast of the tumor images obtained with Fab fragments suggests that this improved method of immunoscintigraphy has the potential to detect early tumor recurrences and thus to increase the survival of patients. The results of this retrospective study, however, should be confirmed in a prospective study before this method can be recommended for the routine diagnosis of cancer.

Immunogenicity of the carcinoembryonic antigen derived peptide 694 in HLA-A2 healthy donors and colorectal carcinoma patients.

Carcinoembryonic antigen (CEACAM5) is commonly overexpressed in human colon cancer. Several antigenic peptides recognized by cytolytic CD8+ T-cells have been identified and used in colon cancer phase-I vaccination clinical trials. The HLA-A*0201-binding CEA(694-702) peptide was recently isolated from acid eluted MHC-I associated peptides from a human colon tumor cell line. However, the immunogenicity of this peptide in humans remains unknown. We found that the peptide CEA(694-702) binds weakly to HLA-A*0201 molecules and is ineffective at inducing specific CD8+ T-cell responses in healthy donors. Immunogenic-altered peptide ligands with increased affinity for HLA-A*0201 were identified. Importantly, the elicited cytolytic T lymphocyte (CTL) lines and clones cross-reacted with the wild-type CEA(694-702) peptide. Tumor cells expressing CEA were recognized in a peptide and HLA-A*0201 restricted fashion, but high-CEA expression levels appear to be required for CTL recognition. Finally, CEA-specific T-cell precursors could be readily expanded by in vitro stimulation of peripheral blood mononuclear cell (PBMC) from colon cancer patients with altered CEA peptide. However, the CEA-specific CD8+ T-cell clones derived from cancer patients revealed low-functional avidity and impaired tumor-cell recognition. Together, using T-cells to demonstrate the processing and presentation of the peptide CEA694-702, we were able to corroborate its presentation by tumor cells. However, the low avidity of the specific CTLs generated from cancer patients as well as the high-antigen expression levels required for CTL recognition pose serious concerns for the use of CEA694-702 in cancer immunotherapy.

Prevalence of t(11;19)(q21;p13) Translocation in Mucoepidermoid Carcinoma of the Conjunctiva

Purpose: The genetics events occurring in the development of mucoepidermoid carcinoma of the conjunctiva have not been extensively investigated. A t(11;19)(q21;p13) translocation has been reported in more than 50% of mucoepidermoid carcinoma of the salivary glands. This translocation induces a chimeric MECT1-MAML2 protein that act as a transcription activation factor in CREB and Notch pathways. Sustained expression of MECT1-MALM2 in RKE3 cells was tumorigenic in a mouse model. The presence of this translocation has been correlated with a better prognosis in mucoepidermoid carcinoma of the salivary glands. The purpose of this study was to identify the presence or absence of this translocation in mucoepidermoid carcinoma of the conjunctiva.Methods: We retrospectively reviewed all conjunctival mucoepidermoid carcinoma cases from the pathological files of Jules Gonin Eye Hospital from 1960-2010. The relevant clinico-pathological data was obtained. The presence of the t(11;19)(q21;p13) translocation was investigated by FISH using a dual color break apart probe. 100 nuclei were evaluated in each case. Normal conjunctiva was included as a control.Results: Material for FISH analysis was available in 9 patients (11 tumors). There were 2 females and 7 males. The mean age was years 71, 4 years old. Tumors were involving the bulbar conjunctiva in 6 cases and the tarsal conjunctiva in 5 cases. In a young patient of 30 years old, mucoepidermoid carcinoma was developed in the context of Xeroderma Pigmentosum. Hybridization could successfully be performed in 8 patients (9 tumors). No disruption of the dual color fusion signal was observed in all the cases, suggesting an absence of t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma of the conjunctiva.Conclusions: Although our study encompasses only a limited number of cases due to the rarity of mucoepidermoid carcinoma of the conjunctiva, it demonstrates that a translocation commonly found in this tumor at other locations is not identified in the conjunctiva, suggesting that different mechanisms occur in the development of these tumors.

Pattern and clinical significance of cancer-testis gene expression in head and neck squamous cell carcinoma

Les cancer-testis antigènes appartiennent à la famille des antigènes tumoraux spécifiques. Ils ont montré un pouvoir immunogène chez les patients porteurs de différents cancers. En effet, ils stimulent sélectivement les lymphocytes cytotoxiques, et leur expression spécifique dans les tissus tumoraux en fait une cible idéale pour une vaccination antitumorale. Le but de cette étude est d'identifier l'expression de certains de ces antigènes, d'analyser leur valeur pronostique et de déterminer la meilleure cible antigénique pour permettre une immunothérapie spécifique dans les carcinomes épidermoïdes des voies aérodigestives supérieures. Le profil et le taux d'expression de 12 cancer-testis antigènes (MAGE-A1, MAGE-A3, MAGE-A4, MAGEA10, MAGE-C2, NY-ESO-1, LAGE-1, SSX-2, SSX-4, BAGE, GAGE-1/2, GAGE-3/4) et de 3 autres antigènes tumoraux spécifiques (PRAME, HERV-K-MEL, NA-17A) ont été évalués par RT-PCR sur 57 échantillons de cancers ORL primaires. Les paramètres tumoraux et cliniques ont été prospectivement collectés afin de corréler ces données avec le résultat de nos investigations immunobiologiques. Quatre-vingt-huit pour cent des tumeurs expriment au moins 1 antigène. Une co-expression de 3 gènes ou plus est détectée chez 59% des patients. MAGE-A4 (60%), MAGE-A3 (51%), PRAME (49%) et HERV-K-MEL (42%) sont les gènes le plus fréquemment exprimés. Ils sont totalement absents des muqueuses saines avoisinantes. La présence de MAGE-A et NY-ESO-1 à la surface des cellules a été vérifiée par immunohistochimie. Nos analyses statistiques ont permis d'identifier une diminution de la survie liée au cancer chez les patients porteurs d'une tumeur exprimant de multiples cancer-testis antigènes et notamment MAGE-A4 dont l'expression indépendante d'autres éléments cliniques s'associe statistiquement à un taux de survie diminué. Nos résultats ont permis d'identifier un rôle pronostique de l'expression des gènes associés aux tumeurs dont l'expression est apparemment liée à un phénotype de malignité plus élevé. Cette constatation, corroborée par l'identification parallèle d'un infiltrat lymphocytaire spécifique confirme l'utilité potentielle de certains cancer-testis antigènes comme cible pour une immunothérapie ciblée dans les carcinomes des voies aérodigestives supérieures

Urologie."Revisitons la prostate!" [Urology. Trends in prostatic diseases in 2012].

This article discusses the management of prostate disease and new therapeutic approaches as a result from epidemiological and physiopathological links between benign prostatic hyperplasia and erectile dysfunction.