Carcinoma of an unknown primary: are EGF receptor, Her-2/neu, and c-Kit tyrosine kinases potential targets for therapy?

Carcinomas of an unknown primary site (CUP) are heterogeneous tumours with a median survival of only 8 months. Tyrosine kinase inhibitors are promising new drugs. The aim of this study was to determine the expression of EGF-receptor, Her-2/neu, and c-Kit tyrosine kinases in CUP. Paraffin-embedded specimens were obtained from 54 patients with a CUP who were included in the GEFCAPI 01 randomised phase II trial. Immunohistochemistry was performed using the Dako autostainer with antibodies directed against HER-2/neu protein, EGFR protein, and c-Kit protein (CD117). EGFR expression was found in 36 out of 54 samples (66%). In contrast, Her-2/neu overexpression and c-Kit positivity were only detected in 4 and 10% of patients, respectively. No significant association was found between the expression of the tyrosine kinase receptors and prognosis. EGFR expression was significantly associated with response to cisplatin-based chemotherapy: the response rates were 50 and 22% in patients with EGFR-positive tumours and EGFR-negative tumours, respectively (P<0.05). This study shows that EGFR is frequently expressed in CUP. This finding may prompt clinical trials investigating EGFR inhibitors in this setting. In contrast, c-Kit expression and Her-2/neu overexpression occur infrequently in CUP. EGFR expression was correlated to tumour chemosensitivity.

[2002 Standards, Options and Recommendations: good practice for the management and shipment of histological and cytopathological cancer specimens]. / Standards, Options et Recommandations 2002 bonnes pratiques de l'acheminement et de la prise en charge initiale d'un prélèvement en anatomie et cytologie pathologiques en cancérologie (rapport intégral).

CONTEXT: The Standards, Options and Recommendations (SOR) collaborative project was initiated in 1993 by the Federation of the French Cancer Centres (FNCLCC), with the 20 French Regional Cancer Centres, several French public university and general hospitals, as well as private clinics and medical speciality societies. Its main objective is the development of serviceable clinical practice guidelines in order to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review, followed by critical appraisal by a multidisciplinary group of experts. Draft guidelines are produced, then validated by specialists in cancer care delivery. OBJECTIVES: Produce clinical practice guidelines for the management and shipment of histological and cytopathological cancer specimens using the methodology developed by the Standards, Options and Recommendations project. METHODS: The FNCLCC designated the group of experts. Available data were collected by a search of Medline and lists selected by experts in the group. A first draft of the guidelines was written, then validated by independent reviewers. RESULTS: The main recommendations are: 1/ High-quality transmission of information between professionals is essential to the management of cancer specimens in order to assure high-quality diagnosis and evaluation of prognostic factors; 2/ Written procedures concerning sample shipment, handling, storage, registration, tracking and fixation exist; these procedures, as well as the necessary shipping material, will be sent to all clinical services involved; 3/ When possible, fresh, unfractionated, oriented surgical samples will be submitted to the same histological and cytopathological laboratory; 4/ Samples collected for extemporaneous examination, freezing or cell culture must be shipped immediately under appropriate storage conditions; 5/ Once frozen, samples can be stored in a deep freezer at temperatures of -80 degrees C or below, or kept in liquid nitrogen; 6/ Fixing tissues shortly after sample collection is essential to prevent cell lysis; 7/ Computerised systems will be used to assure correct specimen registration and tracking in histological and cytopathological laboratories.

[Standards, options and recommendations for the composition of anatomic and surgical pathology reports or cytopathology reports in oncology]. / Standards, Options et Recommandations pour la rédaction d'un compte rendu d'anatomie et cytologie pathologiques en cancérologie.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop practice guidelines according to the definitions of the Standards, Options and Recommendations project for the content of the anatomic and surgical pathology or cytopathology reports in field of oncology. METHODS: Data were identified either by searching on Medline or via members of the expert groups personal references lists. When the guidelines were defined, the document was submitted to 49 independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the composition of the anatomic and surgical pathology or cytopathology reports in oncology are 1/ The reports must contain the identification of the pathologist, of the patient and of the specimen, a gross description for the surgical specimen, eventually a microscopic description, the diagnosis, all the elements essential for establishing the prognosis and for the clinical care, and a conclusion. 2/ The reports could contain some comments. 3/ The reports must be brief, precise, clear, homogeneous and ideally standardised, in order to be comprehensible for all the clinicians and the pathologists.

[HER2 gene amplification assay: is CISH an alternative to FISH?]. / Recherche de l'amplification du gène HER2: la CISH est-elle une alternative à la technique FISH?

The HER2 proto-oncogene encodes a transmembrane protein, which is considered to function as a growth factor receptor. Overexpression of this protein found by immunohistochemistry in about 20% of infiltrating breast carcinomas, has a predictive value of response to treatment by trastuzumab, an anti-HER2 humanized monoclonal antibody. Search for HER2 gene amplification is necessary to adapt the immunohistochemical technique quality and also in the cases of delicate analysis or weak overexpression. It is usually carried out by Fluorescence In Situ Hybridization (FISH). A more recent hybridization technique, named CISH because of its chromogenic revelation is an alternative method, which gives highly correlated results with FISH. We present details of this technique, which may be more familiar for the pathologists than FISH, because reading analysis is similar to that of immunohistochemical staining.

[2001 Standards, Options and Recommendations: practice guidelines for difficult diagnoses in surgical pathology or cytopathology in cancer patients]. / Standards, Options et Recommandations 2001 bonnes pratiques pour la conduite à tenir devant une lésion de diagnostic anatomocytopathologique difficile en cancérologie.

CONTEXT: The Standards, Options and Recommendations (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. OBJECTIVES: To elaborate practice guidelines for difficult diagnoses in surgical pathology or cytopathology in cancer patients. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers. RESULTS: The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are:

Study of implantable calcium phosphate systems for the slow release of methotrexate.

The authors prepared and studied systems implantable in bone, for the slow release of an antineoplasic agent, methotrexate (MTX). The systems were made by compaction of a powdered mixture of an apatitic deficient calcium phosphate, dextran and various amounts of MTX. Used as a matrix, this calcium phosphate has outstanding adsorption and compaction properties. It is an osteoconductor and biodegradable. The in vitro study carried out on these systems showed that the release of MTX with time is slow and prolonged due to the phenomena of adsorption/desorption of MTX onto deficient apatite. The composition of the implants changed with time towards that of stoichiometric apatite. The in vivo pilot study was performed by implantation in the external femoral condyle of rabbits. A pharmacokinetic study revealed that the circulating concentration of MTX in the blood was always below toxic levels. Twenty percent of the initial MTX remained in the implants after 7 days. A study of the biocompatibility and bioreactivity showed no local necrosis at any time, while implants degraded and new bone formed simultaneously. These implantable systems seem appear suitable for use immediately.

[Cost-effectiveness in diagnosis and treatment of carcinomas of unknown primary origin]. / Analyse Coût/efficacité de la prise en charge diagnostique et thérapeutique des carcinomes d'origine indéterminée.

The aim was to compare, in terms of cost-effectiveness, two diagnostic strategies for finding out the primary site of tumors revealed by metastasis, adopting the hospital's perspective. The observed strategy reflected the usual practices of doctors at the Regional Cancer Center in Toulouse (France), and was based on a sample of 202 patients of this Center. The standardized strategy, which reflected limited diagnostic investigation, was simulated using the same sample of patients to whom we applied the recommendations of local experts. In the low assumption regarding the effectiveness of the standardized strategy, the observed strategy compared to the standardized one raised the life expectancy from 407 to 418 days at an incremental cost of $US 1,236 per patient (1996 values). In this case, one day of additional life induced a cost of $US 112 per patient. In the high assumption, the incremental effectiveness was null and the incremental cost was $US 1,236 per patient. In conclusion, the effectiveness of the observed strategy as compared to the standardized strategy was highly questionable, given that the patients' quality of life was not taken into account.

[Standards, options and recommendations: practice guidelines for difficult diagnosis in surgical pathology or cytopathology in cancer patients]. / Standards, options et recommandations: conduite a tenir devant une lésion de diagnostic anatomo-cyto-pathologique difficile en cancérologie.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993 is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of the Standards, Options and Recommendations project for difficult diagnoses in surgical pathology or cytopathology in cancer patients. METHODS: Data were identified by searching Medline and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 71 independent reviewers. RESULTS: The main recommendations to prevent and reduce the number of difficult diagnoses in surgical pathology or cytopathology are: 1) The development of quality insurance programs with use of written procedures in each pathology laboratory (standard). 2) The knowledge of clinical data in order to explain surgical pathology or cytopathology results (standard). 3) The availability of complementary patient informations (radiologic data . . .) can be useful to explain surgical pathology or cytopathology results (option). The main recommendations to detect lesions associated with difficult diagnosis in surgical pathology or cytopathology are: 1) Tumor types known as potential difficult diagnosis in surgical pathology or cytopathology should be reviewed by a second pathologist. 2) The systematic second reviewing for every case is expensive but has to be done when the difficulty is know (sarcoma, lymphoma . . .) by experienced pathologists. The main recommendations to solve difficult diagnosis in surgical pathology or cytopathology are: 1) Block recuts, use of special techniques (immunocytohistochemistry and molecular biology), additional data from clinicians, second opinion by a local pathologist, or new specimen can be required for establishing the diagnosis (options). 2) Outside second opinion by expert pathologist has to be considered once the other steps did not allow to establish surgical or cytopathology diagnosis (recommendations, expert agreement).

Carcinocythemia as the single extension of breast cancer: report of a case and review of the literature.

Carcinocythemia (carcinoma cell leukemia) has been previously described as a rare, late and dramatic event occurring in widespread tumoral disease. We report a case of carcinocythemia occurring in a patient with a particularly indolent breast cancer. When a large amount of circulating tumor cells (CTC) appeared in the blood smears, neither visceral macrometastases nor massive bone marrow infiltration could be detected. We isolated CTC to perform cell cycle analysis and to study the expression of adhesion molecules. A fraction of the CTC was proliferating in the bloodstream but we detected no relevant anomaly of adhesion properties in the CTC. A post-mortem biopsy disclosed an exclusive sinusoidal infiltration of the liver. We propose that in this case, carcinocythemia resulted from the release of CTC from the visceral microcirculation where the proliferation occurred.

[Clear cell soft tissue sarcoma. Clinical, histopathological and prognostic study of 36 cases]. / Sarcome à cellules claires des tissus mous. Etude clinique, histopathologique et évolutive de 36 cas.

Thirty six cases of clear cell sarcoma of soft tissue are reported. The median age was 44 years (5 to 80 years). The principal sites were the foot (11 cases), the hand and wrist (7 cases) and the knee (6 cases). The architecture was fascicular with lobular arrangement of cells delimited by delicate fibrous septa intimately bound to tendons or aponeuroses. Tumoral cells were round or fusiform with abundant clear cytoplasm sometimes epithelioid with round nuclei and prominent nucleoli. The mitotic rate was evaluated to 9/10 HPF. S100 protein was expressed in 33/36 cases and HMB45 marked 29/31 cases, without expression of cytokeratin. Three-year and 5-year survival rate were respectively 72% and 62%. Prognosis factors for global survival were efficiency of initial treatment with distal location and necrosis and FNCLCC grade. The distinction of clear cell sarcoma from metastatic melanoma is important because of the difference of prognosis.

[Standards, Options and Recommendations (SOR) for drafting of anatomic and surgical pathology reports or cytopathology reports in oncology]. / Standards, Options et Recommandations (SOR) pour la rédaction d'un compte rendu d'anatomie et de cytologie pathologiques en cancérologie.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop practice guidelines according to the definitions of the Standards, Options and Recommendations project for the content of the anatomic and surgical pathology or cytopathology reports in field of oncology. METHODS: Data were identified either by searching on Medline or via members of the expert groups personal references lists. When the guidelines were defined, the document was submitted to 49 independent reviewers, and to the medical committees of the 20 French Cancer Centres. RESULTS: The main recommendations for the drafting of the anatomic and surgical pathology or cytopathology reports in oncology are: 1) The reports must contain the identification of the pathologist, of the patient and of the specimen, a gross description for the surgical specimen, eventually a microscopic description, the diagnosis, all the elements essential for establishing the prognosis and for the clinical care, and a conclusion. 2) The reports could contain some comments. 3) The reports must be brief, precise, clear, homogeneous and ideally standardised, in order to be comprehensible for all the clinicians and the pathologists.

In vivo patterns of Bcl-2 family protein expression in breast carcinomas in relation to apoptosis.

The expression of the pro-apoptotic proteins (Bax, Bak) and anti-apoptotic proteins (Bcl-2, Bcl-X, Mcl-1) was studied by immunohistochemistry in 110 invasive ductal breast carcinomas. The results were correlated with tumour grade, expression of oestrogen receptor (ER) and p53 protein, and the apoptotic index by combined morphology, immunohistochemistry, and a terminal UTP nick end labelling (TUNEL) procedure. Overall, Bcl-2, Bcl-X, Mcl-1, Bax, Bak, ER, and p53 were detected in 62, 75, 68, 75, 60, 68 and 26 per cent of the cases respectively, but at different levels in each case. A high apoptotic index was correlated with high tumour grade (p<0.001), overexpression of p53 (p<0.001), Bak expression (p<0.001), and low expression of Bcl-2 (p<0.001) and ER (p<0.001). No correlation was found between the apoptotic index and Bax, Bcl-X, and Mcl-1 immunostaining results. The expression of Bcl-2 and Bcl-X was correlated to that of ER. Overall, the results of this study strongly suggest that Bcl-2 and Bak expression is critical in regulating apoptosis in breast carcinomas.

Ex vivo discrimination between normal and pathological tissues in human breast surgical biopsies using bioimpedance spectroscopy.

Ex vivo bioimpedance data measured on normal and cancerous female breast tissues are reported. They clearly show that the electrical properties of normal tissues, surrounding tissues, and carcinoma are different. These differences lie in the conductivity, in the characteristic frequency (frequency of the maximum of the imaginary part of the bioimpedance), and also in the shape of the Bode plots. Modeling using an R-S-Zcpe model is reported as well as indexes extracted from the real and imaginary parts of the bioimpedance. Even if a classification of the different types of tissues remains a difficult task and leads to much less precise diagnosis than microscopic examination, the electrical behavior of mammary tissue could be used to develop a noninvasive technique for early breast cancer detection.