In Vivo Persistence of Codominant Human CD8+ T Cell Clonotypes Is Not Limited by Replicative Senescence or Functional Alteration.

T cell responses to viral epitopes are often composed of a small number of codominant clonotypes. In this study, we show that tumor Ag-specific T cells can behave similarly. In a melanoma patient with a long lasting HLA-A2/NY-ESO-1-specific T cell response, reaching 10% of circulating CD8 T cells, we identified nine codominant clonotypes characterized by individual TCRs. These clonotypes made up almost the entire pool of highly differentiated effector cells, but only a fraction of the small pool of less differentiated "memory" cells, suggesting that the latter serve to maintain effector cells. The different clonotypes displayed full effector function and expressed TCRs with similar functional avidity. Nevertheless, some clonotypes increased, whereas others declined in numbers over the observation period of 6 years. One clonotype disappeared from circulating blood, but without preceding critical telomere shortening. In turn, clonotypes with increasing frequency had accelerated telomere shortening, correlating with strong in vivo proliferation. Interestingly, the final prevalence of the different T cell clonotypes in circulation was anticipated in a metastatic lymph node withdrawn 2 years earlier, suggesting in vivo clonotype selection driven by metastases. Together, these data provide novel insight in long term in vivo persistence of T cell clonotypes associated with continued cell turnover but not replicative senescence or functional alteration.

Cáncer de laringe en pacientes menores de 40 años comparado con mayores de 40 años: análisis de pares [Laryngeal cancer in patients younger vs older than 40 years old: a matched-paired analysis].

BACKGROUND: To compare clinical and demographic data between laryngeal cancer patients younger and older than 40 years old. METHODS: Is a matched-paired study, realized from 1989 to 2002. We selected 500 laryngeal cancer patients treated in the National Cancer Institute of Mexico. Fifteen cases of patients younger than 40 years that accomplished inclusion criteria were identified, pair-matched and compared by clinical stage with 33 patients older than 40 years. We analyzed demographic factors and disease-free and Overall Survival by Kaplan-Meier method. RESULTS: We included 9 male and 6 female patients with a mean age of 34 years in contrast to a mean age of 62 years in the comparison group. Four cases in clinical stage I, none clinical stage II, 6 in stage III and 5 in stage IV were included in the younger group and compared to 8 patients in stage I, 15 in stage III and 10 in stage IV in the older group. No differences in demographic variables or lifestyle habits were found. All patients in stage I, are alive in both groups. Disease-free survival not show any differences when comparing stages III and IV (p=NS). Mean disease-free survival was 66 months and mean overall survival was 83 months in the younger group. CONCLUSION: Laryngeal carcinoma is rare in patients younger than 40 years. No gender, clinical or prognostic differences could be identified among the two groups. The prognosis of these patients seems to be only determined by the initial clinical stage.

The promoter of the gene encoding 3',5'-cyclic adenosine monophosphate (cAMP) response element binding protein contains cAMP response elements: evidence for positive autoregulation of gene transcription.

The transcriptional transactivational activities of the phosphoprotein cAMP-response element-binding protein (CREB) are activated by the cAMP-dependent protein kinase A signaling pathway. Dimers of CREB bind to the palindromic DNA element 5'-TGACGTCA-3' (or similar motifs) called cAMP-responsive enhancers (CREs) found in the control regions of many genes, and activate transcription in response to phosphorylation of CREB by protein kinase A. Earlier we reported on the cyclical expression of the CREB gene in the Sertoli cells of the rat testis that occurred concomitant with the FSH-induced rise in cellular cAMP levels and suggested that transcription of the CREB gene may be autoregulated by cAMP-dependent transcriptional proteins. We now report the structure of the 5'-flanking sequence of the human CREB gene containing promoter activity. The promoter has a high content of guanosines and cytosines and lacks canonical TATA and CCAAT boxes typically found in the promoters of genes in eukaryotes. Notably, the promoter contains three CREs and transcriptional activities of a promoter-luciferase reporter plasmid transfected to placental JEG-3 cells are increased 3- to 5-fold over basal activities in response to either cAMP or 12-O-tetradecanoyl phorbol-14-acetate, and give 6- to 7-fold responses when both agents are added. The CREs bind recombinant CREB and endogenous CREB or CREB-like proteins contained in placental JEG-3 cells and also confer cAMP-inducible transcriptional activation to a heterologous minimal promoter. Our studies suggest that the expression of the CREB gene is positively autoregulated in trans.

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.

Testing mouse mammary tumor virus superantigen as adjuvant in cytotoxic T-lymphocyte responses against a melanoma tumor antigen.

Cytotoxic T cells represent a powerful strategy for antitumor treatment. Depending on the route of injection, an important role for CD4 T cell-mediated help was observed in the induction of this response. For this reason, we investigated whether induction of a CTL response to the HLA-A2-restricted immunodominant peptide melanoma antigen Melan-A was improved by using rVVs expressing the CTL-defined epitope alone or in combination with an SAg. In the latter case, the few infected dendritic cells simultaneously presented an SAg and an antigen, i.e., peptide. Here, we show that the anti-Melan-A response was efficiently induced but not significantly improved by coexpression of the SAg.

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.

Follow-up of optic pathway gliomas in children with neurofibromatosis type 1.

Optic pathway gliomas (OPG) are found in about 15% of patients with neurofibromatosis Type 1 (NF-1). The natural history of OPG is not yet well documented. Treatment in cases with growing tumors is still controversial. Twenty-one patients with NF-1 and OPG, diagnosed over a 20-year period, and followed neuroradiologically and ophthalmologically for at least two years, were reevaluated. The diagnosis of OPG was made at a mean age of 7.1 years (range 0-14.5 years); six children were asymptomatic, 15 were symptomatic. The mean follow-up was 9.0 years (2.0-18.5 (years). In eight initially operated or biopsied patients (three optic nerve and five chiasmal gliomas) tumor regrowth was found in one patient without progression on subsequent follow-up. Improvement of visual acuity occurred in one child after operation of a large suprasellar tumor and deterioration in one patient after biopsy of a chiasmal glioma. The neuroradiological follow-up of the 13 not-operated and not-radiated patients (four optic nerve and nine chiasmal gliomas) was stable in 10, progressive in three, resulting in visual loss in one patient. In 11 children (52%) a second tumor outside the optic pathway was found at a mean age of 4.0 years after the diagnosis of an OPG. Until now they are mostly asymptomatic. Second site tumors were operated in two children because of rapid tumor growth, one child died of a brainstem tumor. OPG are a frequent complication in children with NF-1, appearing within the first decade.(ABSTRACT TRUNCATED AT 250 WORDS)

Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity.

Shedding of intercellular adhesion molecule 1 (ICAM-1) is believed to play a role in tumor cell resistance to cell-mediated cytotoxicity. However, the mechanism whereby ICAM-1 is shed from the surface of tumor cells remains unclear. In this study, we have addressed the possibility that matrix metalloproteinases are implicated in ICAM-1 shedding. Our observations suggest a functional relationship between ICAM-1 and matrix metalloproteinase 9 (MMP-9) whereby ICAM-1 provides a cell surface docking mechanism for proMMP-9, which, upon activation, proteolytically cleaves the extracellular domain of ICAM-1 leading to its release from the cell surface. MMP-9-dependent shedding of ICAM-1 is found to augment tumor cell resistance to natural killer (NK) cell-mediated cytotoxicity. Taken together, our observations propose a mechanism for ICAM-1 shedding from the cell surface and provide support for MMP involvement in tumor cell evasion of immune surveillance.

Adult-type rhabdomyosarcoma: analysis of 57 cases with clinicopathologic description, identification of 3 morphologic patterns and prognosis.

Adult-type rhabdomyosarcoma (RMS) has been classically defined as a pleomorphic sarcoma with desmin expression occurring in adult patients. To reevaluate this entity, we analyzed a series of 57 cases using immunohistochemistry for desmin, myogenin, alpha smooth muscle actin, h-caldesmon, pankeratin AE1/AE3, epithelial membrane antigen (EMA), S100 protein, CD34, MDM2, and CDK4. In this series, there were 36 men and 21 women aged from 22 to 87 years (median: 59). Tumors were mainly located in the lower limbs (27 cases), trunk wall (15 cases), and upper limbs (10 cases). Most tumors were deeply located (51/54) with a size from 1 to 30 cm (median: 8 cm). Cases were classified in 3 histologic categories: spindle cell RMS (25 cases), pleomorphic RMS (16 cases), and mixed type (16 cases). Forty-one tumors were grade 3 and 16 grade 2. Immunohistochemistry showed that every case was positive for desmin and myogenin. Alpha smooth muscle actin was positive in 21%, pankeratin AE1/AE3 in 20%, and CD34 in 13.2%. Treatment modalities and follow-up were available in 46 cases. Median follow-up was 60.9 months. Eight patients developed a local recurrence and 16 a distant metastasis with a 5-year overall survival rate of 52.6% and a 5-year metastasis-free survival of 62.9%. The only predictive factor for metastasis was histologic grade. In conclusion, adult-type RMS is a rare sarcoma occurring mainly in the extremities and trunk wall with 2 main histologic patterns, spindle cell, and pleomorphic patterns, which represent the end of the spectrum of a single entity.

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.

Place de la laparoscopie dans le traitement du cancer de l'endomètre [Laparoscopy in the management of endometrial cancer]

Les récents progrès de la laparoscopie ont modifié l'approche chirurgicale des patientes atteintes d'un cancer de l'endomètre. Le centre Swissendos Fribourg en collaboration avec l'AGO (Groupe de travail pour la gynécologie oncologique) et l'AGE (Groupe de travail pour la gynécologie endoscopique) ont entrepris d'élaborer un consensus basé sur l'évidence pour la pratique de la laparoscopie dans le traitement du cancer de l'endomètre. L'objectif a été de définir une approche propre à la Suisse en fournissant aux praticiens une aide à la prise en charge. Recent advance in laparoscopy have changed the surgical approach of endometrial cancer patients. The Swissendos Center, Fribourg, in collaboration with AGO (Groupe de travail pour la gynécologie oncologique) and AGE (groupe de travail pour la gynécologie endoscopique) have established a consensus based on the available evidence for the use of laparoscopy in the management of patients with endometrial cancer The main objective was to define Swiss clinical practice guidelines appropriate to the country and consistent with the needs of the physicians.

An EORTC phase I itudy of bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.

CD10 is inversely associated with nuclear factor-kappa B and predicts biochemical recurrence after radical prostatectomy.

INTRODUCTION: The cell surface endopeptidase CD10 (neutral endopeptidase) and nuclear factor-κB (NF-κB) have been independently associated with prostate cancer (PC) progression. We investigated the correlations between these two factors and their prognostic relevance in terms of biochemical (prostate-specific antigen, PSA) relapse after radical prostatectomy (RP) for localized PC. PATIENTS AND METHODS: The immunohistochemical expression of CD10 and NF-κB in samples from 70 patients who underwent RP for localized PC was correlated with the preoperative PSA level, Gleason score, pathological stage and time to PSA failure. RESULTS: CD10 expression was inversely associated with NF-κB expression (p < 0.001), stage (p = 0.03) and grade (p = 0.003), whereas NF-κB was directly related with stage (p = 0.006) and grade (p = 0.002). The median time to PSA failure was 56 months. CD10 and NF-κB were directly (p < 0.001) and inversely (p < 0.001) correlated with biochemical recurrence-free survival, respectively. CD10 expression (p = 0.022) and stage (p = 0.018) were independently associated with time to biochemical recurrence. CONCLUSION: Low CD10 expression is an adverse prognostic factor for biochemical relapse after RP in localized PC, which is also associated with high NF-κB expression. Decreased CD10 expression which would lead to increased neuropeptide signaling and NF-κB activity may be present in a subset of early PCs.

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.