Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ((90)Y) and a medium-energy beta/gamma emitter ([(177)Lu) in patients with metastatic NET refractory to conventional therapy. METHODS: A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [[(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [[(177)Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. RESULTS: Administration of tandem [(90)Y]DOTA-TATE and [[(177)Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment. CONCLUSION: The results of our study indicates that combined [(90)Y]DOTA-TATE and [(177)Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach.

Neuronal specific and non-specific responses to cadmium possibly involved in neurodegeneration: A toxicogenomics study in a human neuronal cell model.

Epidemiological data have linked cadmium exposure to neurotoxicity and to neurodegenerative diseases (e.g., Alzheimer's and Parkinson's disease), and to increased risk of developing ALS. Even though the brain is not a primary target organ, this metal can bypass the blood brain barrier, thus exerting its toxic effects. The coordination chemistry of cadmium is of strong biological relevance, as it resembles to zinc(II) and calcium(II), two ions crucial for neuronal signaling. A toxicogenomics approach applied to a neuronal human model (SH-SY5Y cells) exposed to cadmium (10 and 20 µM) allowed the identification of early deregulated genes and altered processes, and the discrimination between neuronal-specific and unspecific responses as possible triggers of neurodegeneration. Cadmium confirmed its recognized carcinogenicity even on neuronal cells by activating the p53 signaling pathway and genes involved in tumor initiation and cancer cell proliferation, and by down-regulating genes coding for tumor suppressors and for DNA repair enzymes. Two cadmium-induced stress responses were observed: the activation of different members of the heat shock family, as a mechanism to restore protein folding in response to proteotoxicity, and the activation of metallothioneins (MTs), involved in zinc and copper homeostasis, protection against metal toxicity and oxidative damage. Perturbed function of essential metals is suggested by the mineral absorption pathway, with MTs, HMOX1, ZnT-1, and Ferritin genes highly up-regulated. Cadmium interferes also with Ca2+ regulation as S100A2 is one of the top up-regulated genes, coding for a highly specialized family of regulatory Ca2+-binding proteins. Other neuronal-related functions altered in SH-SY5Y cells by cadmium are microtubules dynamics, microtubules motor-based proteins and neuroprotection by down-regulation of NEK3, KIF15, and GREM2 genes, respectively.

An improved automated one-pot synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) based on a purification by cartridges.

INTRODUCTION: O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) is an established radiotracer used for oncology investigations by Positron Emission Tomography (PET). Main limitations to its widespread use are the synthesis itself (time; cost; radiochemical yield; complexity) and a troublesome and time-consuming HPLC purification. Aim of this work was to improve the preparation overall efficiency and, most important, to achieve an efficient and reliable purification by means of disposable cartridges. METHODS: [18F]FET was synthesized by direct nucleophilic radiofluorination of O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine t-butylester (TET) followed by acid hydrolysis with HCl. Several conditions and materials were tested for the synthesis and purification step. For the latter, a number of different commercial cartridges, varying in amount, particulate size and adsorbent, were examined. Best results were obtained by a combination of STRATA-X, tC18 and QMA cartridges. RESULTS: Starting from only 5 mg of TET, up to 11 GBq of injectable solutions of [18F]FET were produced within 36 min with 54-65% radiochemical yields and radiochemical purities >99%. No D-form was observed by chiral HPLC. Chemical purity was 1-2 order of magnitude below the limits imposed by the European Pharmacopoeia's monograph on [18F]FET. A radiochemical purity decrease by radiolysis, observed only on relatively large batches of [18F]FET, was efficiently suppressed by preloading in the receiving final vial a small amount of ethanol (<2% v/v). CONCLUSIONS: By combining improvements to a known synthetic route with a novel cartridge-based purification, [18F]FET was obtained in a very efficient and reproducible way. The whole process was easily implemented on a commercial automated module presently used for [18F]FDG production. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: A few drawbacks regarding the HPLC conditions recommended in the European Pharmacopoeia were highlighted. An alternative method able to cope with them is herein proposed The simplified preparation herein described is expected to encourage a more widespread clinical use of [18F]FET.

Anti-PSMA 124I-scFvD2B as a new immuno-PET tool for prostate cancer: preclinical proof of principle.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer-related death in the Western population. The use in oncology of positron emission tomography/computed tomography (PET/CT) with emerging radiopharmaceuticals promises accurate staging of primary disease, restaging of recurrent disease and detection of metastatic lesions. Prostate-specific membrane antigen (PSMA) expression, directly related to androgen-independence, metastasis and progression, renders this tumour associate antigen a good target for the development of new radiopharmaceuticals for PET. Aim of this study was to demonstrate in a preclinical in vivo model (PSMA-positive versus PSMA-negative tumours) the targeting specificity and sensitivity of the anti-PSMA single-chain variable fragment (scFv) labelled with 124I. METHODS: The 124I-labeling conditions of the antibody fragment scFvD2B were optimized and assessed for purity and immunoreactivity. The specificity of 124I-scFvD2B was tested in mice bearing PSMA-positive and PSMA-negative tumours to assess both ex-vivo biodistribution and immune-PET. RESULTS: The uptake fraction of 124I-scFvD2B was very high on PSMA positive cells (range 75-91%) and highly specific and immuno-PET at the optimal time point, defined between 15 h and 24 h, provides a specific localization of lesions bearing the target antigen of interest (PSMA positive vs PSMA negative tumors %ID/g: p = 0.0198 and p = 0.0176 respectively) yielding a median target/background ratio around 30-40. CONCLUSIONS: Preclinical in vivo results of our immuno-PET reagent are highly promising. The target to background ratio is improved notably using PET compared to SPECT previously performed. These data suggest that, upon clinical confirmation of sensitivity and specificity, our anti-PSMA 124I-scFvD2B may be superior to other diagnostic modalities for PCa. The possibility to combine in patients our 124I-scFvD2B in multi-modal systems, such as PET/CT, PET/MR and PET/SPECT/CT, will provide quantitative 3D tomographic images improving the knowledge of cancer biology and treatment.

Genome scan implicates adhesion biological pathways in secondary leukemia.

The genetic risk factors for etoposide-induced leukemia with MLL translocations remain largely unknown. To identify genetic risk factors for and novel characteristics of secondary leukemia, we profiled 116,204 single nucleotide polymorphisms (SNPs) in germline and paired leukemic cell DNA from 13 secondary leukemia/myelodysplasia cases and germline DNA from 13 matched and 156 unmatched controls, all with acute lymphoblastic leukemia treated with etoposide. We analyzed global gene expression from a partially overlapping cohort. No single locus was altered in most cases. We discovered 81 regions of loss of heterozygosity (LOH) in leukemic blasts and 309 SNPs whose allele frequencies differed in cases vs controls. Candidate genes were prioritized on the basis of genes whose SNPs or expression differentiated cases from controls or showed LOH or copy number change in germline vs paired blast DNA from the 13 cases. Three biological pathways were altered: adhesion, Wnt signaling and regulation of actin. Validation experiments using a genome scan for etoposide-induced leukemogenic MLL chimeric fusions in 15 HapMap cell lines also implicated genes involved in adhesion, a process linked to de novo leukemogenesis. Independent clinical epidemiologic and in vitro genome-wide approaches converged to identify novel pathways that may contribute to therapy-induced leukemia.

Genome-wide approach to identify risk factors for therapy-related myeloid leukemia.

Using a target gene approach, only a few host genetic risk factors for treatment-related myeloid leukemia (t-ML) have been defined. Gene expression microarrays allow for a more genome-wide approach to assess possible genetic risk factors for t-ML. We assessed gene expression profiles (n=12 625 probe sets) in diagnostic acute lymphoblastic leukemic cells from 228 children treated on protocols that included leukemogenic agents such as etoposide, 13 of whom developed t-ML. Expression of 68 probes, corresponding to 63 genes, was significantly related to risk of t-ML. Hierarchical clustering of these probe sets clustered patients into three groups with 94, 122 and 12 patients, respectively; 12 of the 13 patients who went on to develop t-ML were overrepresented in the latter group (P<0.0001). A permutation test indicated a low likelihood that these probe sets and clusters were obtained by chance (P<0.001). Distinguishing genes included transcription-related oncogenes (v-Myb, Pax-5), cyclins (CCNG1, CCNG2 and CCND1) and histone HIST1H4C. Common transcription factor recognition elements among similarly up- or downregulated genes included several involved in hematopoietic differentiation or leukemogenesis (Maz, PU.1, ARNT). This approach has identified several genes whose expression distinguishes patients at risk of t-ML, and suggests targets for assessing germline predisposition to leukemogenesis.

Niosomal approach to brain delivery: Development, characterization and in vitro toxicological studies.

The majority of active agents do not readily permeate into brain due to the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Currently, the most innovative and promising non-invasive strategy in brain delivery is the design and preparation of nanocarriers, which can move through the brain endothelium. Niosomes can perform brain delivery, in fact polysorbates, can act as an anchor for apolipoprotein E from blood plasma. The particles mimic LDL and interact with the LDL receptor leading to the endothelial cells uptake. The efficacy of niosomes for anticancer therapeutic applications was correlated to their physicochemical and drug delivery properties. Dimensions and ζ-potential were characterized using dynamic light scattering and asymmetric flow-field fractionation system. Lipid bilayer was characterized measuring the fluidity, polarity and microviscosity by fluorescent probe spectra evaluation. Morphology and homogeneity were characterized using atomic force microscopy. Physicochemical stability and serum stability (45% v/v fetal bovine and human serum) were evaluated as a function of time using dynamic light scattering. U87-MG human glioblastoma cells were used to evaluate vesicle cytotoxicity and internalisation efficiency. From the obtained data, the systems appear useful to perform a prolonged (modified) release of biological active substances to the central nervous system.

CA 15.3 determination in patients with breast cancer: clinical utility for the detection of distant metastases.

In 81 healthy women, 26 pregnant women, 25 patients with fibrocystic disease and 144 breast cancer patients, the overall diagnostic sensitivity and specificity of the CA 15.3 test was 27 and 97%, respectively. The positive and negative predictive values were 93 and 43%. In 150 node-negative patients taking part in a chemoprevention trial CA 15.3 was assayed at baseline and every 4 months for a median follow-up of 24 months (range 4-48). In these patients, 5 had local recurrences, 1 had a regional recurrence, 9 had distant metastases and 3 developed cancer in the contralateral breast. Among the patients with recurrences, those with distant metastases showed the highest ratio of CA 15.3 increase (8/9); in local and regional recurrences, this ratio was lower (2/6). The patients with contralateral breast cancer had no significant increase in CA 15.3. Patients in whom metastases were detected showed an increase in CA 15.3 4-48 months before clinical or instrumental detection of the metastases.

Prospective evaluation of fluorine-18-FDG PET in presurgical staging of the axilla in breast cancer.

METHODS: The presurgical, noninvasive staging of axillary nodes for metastases was prospectively investigated in 68 patients who were diagnosed with primary breast cancer using PET with 18F-fluorodeoxyglucose (FDG). Four patients had bilateral nodules; therefore, the total number of evaluable cases was 72. Visual analyses of attenuation-corrected PET images and standardized uptake values (SUVs) of FDG uptake in carcinomas were compared with histopathological surgical findings. The SUV distribution differences between carcinomas with and without axillary metastases were evaluated by means of statistical and receiver operating characteristics analyses. RESULTS: PET correctly classified 64 of the 72 cases; four false-positive and four false-negative PET results were found. The overall sensitivity, specificity and accuracy of PET for axillary metastases were 85%, 91% and 89%, respectively. With respect to the clinical axillary stage of the patients (TNM, or tumor-node-metastasis, classification), we obtained the following results: N0 patients, sensitivity = 70%, specificity = 92%, accuracy = 86%; N1a patients, sensitivity = 85.5%, specificity = 100%, accuracy = 95%; and N1b-2 patients, sensitivity = 100%, specificity = 67%, accuracy = 87%. The median SUV in carcinomas with axillary metastases (4.6) was significantly higher than that in carcinomas without metastases (2.9), but there was a great SUV overlap between the two groups (interquartile ranges = 2.7-7.2 and 1.9-4.5, respectively). Analysis of the receiver operating characteristics curve showed that a high sensitivity of SUV in predicting axillary metastases was associated with a very low specificity and vice versa. With the best SUV cutoff value of 2.9, the sensitivity and specificity were 74% and 56%, respectively. CONCLUSION: PET showed good overall diagnostic accuracy in the detection of axillary metastases (86%). The very high accuracy (95%) in N1a patients is of particular importance. False-negative PET findings, however, can be encountered. SUVs of breast carcinoma cannot predict the spread of the disease to the axilla, even if higher values are often associated with axillary metastases. Any decision on the use of PET in the presurgical staging of breast cancer should be incorporated into a more general debate on axillary management. In selected patients with a very low probability of axillary metastases (T1a), in whom axillary surgery can already be avoided according to data from follow-up studies, 18F-FDG PET could be proposed as a noninvasive imaging modality to improve the diagnosis of axillary relapses.

Lack of tissue-specificity of mucin markers in a lung-cancer model - biochemical approach.

Mucin-associated epitopes are recognized by monoclonal antibodies in the immunometric assays used for the diagnosis and monitoring of cancer. The recently developed new assays measure mucins as tumor markers, assuming that each mucin is associated with a particular tumor site, i.e. CA 15.3 and MCA with breast cancer, CA 125 with ovarian cancer, CA 19.9 and CA 195 with colon and pancreatic cancer. These associations are based on the frequency and the intensity of expression of the single markers for a certain organ. However, this theoretical organ specificity is not absolute, since the mucins are expressed also by tumors other than those mentioned above and they may also be present in inflammatory conditions and in normal tissues. These observations were confirmed by the present study, which used an experimental model consisting of a pool of 20 lung tissue samples (10 normal and 10 cancer). The tissue concentrations of the mucins MCA, CA 15.3, CA 125, CA 19.9, and of the glycoprotein CEA, were measured both in malignant tissue samples and in their normal counterparts. The marker levels were detected by immunometric assays in mucin fractions separated from the tissue extract by chromatographic methods. The comparison of the chromatographic profiles and the evaluation of the mucin levels in normal and malignant lung tissue specimens confirmed the absence of tissue specificity of these biochemical parameters. Recent developments in molecular biology and the discovery of genes coding for several apomucins may open new perspectives towards the understanding of the mechanisms regulating mucin pathways.

Reliability of immunoradiometric assays for sex-hormone binding globulin, androstenedione, 17-Beta estradiol and tumor-markers cea and cb15.3 to assess the biological response of megestrol-acetate treatment in patients with advanced breast-cancer.

This study evaluated the effect of megestrol acetate administration on the serological assessment of some sex steroid hormones in women with advanced hormone-sensitive breast cancer. The serum levels of 17-beta estradiol, androstenedione and sex hormone binding globulin (SHBG) were measured by means of radioimmunometric assays, before and during drug administration. A significant suppressive effect on SHBG and androstenedione levels in comparison with the baseline values was reached in 100% (40/40) and 51% (20/39) of patients, respectively, after two months of therapy; by contrast, 17-beta estradiol levels showed an increase above the baseline levels in 18 out of 22 patients. These findings might be explained on the basis of a possible interference in vivo of megestrol acetate metabolites particularly in the estradiol assay, since a direct influence of the solubilized megestrol acetate was not observed in vitro. The hormone levels generally did not shaw any relationship with the course of the disease, so their serial determinations do not seem to be useful to assess the clinical status or evaluate response to therapy. In our group of patients, CEA and CA15.3 serum determinations were also carried out to monitor the efficacy of treatment. CEA and CA15.3 levels reflected the course of the disease in 58.9% (23/39) and 65.8% (25/38) of patients, respectively. The two tumor markers displayed a similar sensitivity in detecting cancer progression (64% CEA and 63% CA15.3), but CA15.3 seemed to have a better diagnostic value in evaluating the response to therapy and signalling tumor relapse.

Axillary lymph node metastases detection with nuclear medicine approaches in patients with newly diagnosed breast cancer.

Three different tracers, Tc-99m-Sesta MIBI, In-111-Pentetreotide and F-18-FDG, were evaluated in a preliminary study in three different groups of 10 breast cancer patients programmed for breast cancer resection and axillary dissection. Planar scintigraphy and single photon emission tomography (SPET) technique were used for imaging with Tc-99m-Sesta-MIBI and In-111-Pentetreotide, positron emission tomography (PET) was used for imaging with F-18-FDG. We studied 30 breast cancer patients; their clinical stage according to the TNM classification was 30 T1-T2, 1 T4 and 1 Tx (one patient had bilateral cancer and one had bifocal cancer). The lymph nodal status ranged from NO to N2 (14 NO, 16 N1, 1 N2). Tc-99m-Sesta MIBI, In-111 Pentetreotide SPET and F-18-FDG PET were randomly performed before surgery to visualize the primary tumors and to detect axillary lymph node invasion. Tc-99m-Sesta MIBI correctly visualized 10 out of 11 primary cancers in 10 patients. In-111-Pentetreotide detected 9 out of 10 primary cancers. F-18-FDG imaged all the tumors (10). As regards the axillary nodes, Tc-99m-MIBI excluded axilla involvement in 7 out of 7 negative axillae (N-), while it was positive in 2 out of 3 positive cases (N+); In-111-Pentetreotide correctly identified 7 out of 8 negative axillae (N-), while it detected 2 of 3 positive sites. F-18-FDG visualized all positive axillary lymph nodes (4 out of 4 N+ patients) and correctly excluded involvement in all negative patients (6 out of 6 N- cases). This study demonstrated that all three tracers are adequate to be proposed as tumor seeking agents with the aim of developing non-invasive diagnostic methods for pre-operative detection of axillary metastases, so that surgical dissection can be limited to selected patients. The authors discuss the advantages and disadvantages of the different radiopharmaceuticals and conclude that in centers with PET facilities F-18-FDG is the best tumor seeking agent for the evaluation of axillary status. Between Tc-99m-Sesta MIBI and In-111-Pentetreotide the former seems to present more advantages in this kind of application, considering also its lower cost and easier availability. These results encourage further study, including the simultaneous comparison of these tracers in breast cancer staging.

Clinical and endocrine effects of megestrol-acetate in women with pretreated advanced breast-cancer.

Megestrol acetate (MA) is one of the most widely used progestins in the palliation of advanced breast cancer, but its optimal dose level has yet to be defined. Forty-six women with progressive advanced disease were given MA according to a monthly loading-dose-schedule (320 mg/day orally) followed by standard-dose maintenance (160 mg/day). Most of the patients had been heavily pretreated with endocrine and/or chemotherapy; all the cases were evaluable. The response rate was 20% (95% CI: 9-31%), with 9 subjects achieving PR. The median time to response was 3 months (range 2-11), the median response duration being 3 months (range 3+-12+). After a median follow-up period of 8 months (range 7-16), only 3 of the patients achieving PR are still on treatment. No increased toxicity or potentially detrimental endocrine effects were observed and all of the patients showed good compliance to treatment. Although the loading-dose schedule used in the present series proved to be feasible, it does not appear to provide any clinical advantage over standard-dose MA treatment.

Evaluation of the soluble fragments of cytokeratin 19 (CK19) in non-small cell lung cancer (NSCLC).

This study compared the diagnostic efficacy of serum CK19 determination (Cyfra 21-1) with other tumour markers, such as CEA, SCC, NSE, TPA, in patients with resected non-small lung cancer. Tumour marker levels were tested in 90 patients with benign lung disease and at diagnosis in 72 patients with proven NSCLC, 39 squamous cell carcinoma and 33 adenocarcinoma. At presentation baseline levels of all tumor markers were significantly higher (p<0.05) in lung cancer patients than in control subjects, except for NSE. A significant increase (p<0.05) in serum concentrations was observed from stage I to stage IIIb only for Cyfra 21-1 (stage I/II, median=2.7 ng/ml; stage IIIb, median=6.3 ng/ml) and TPA (stage I/II, median=89.8 IU/ml; stage IIIb, median=170.7 IU/ml). Receiver operating characteristic (ROC) analysis was performed to evaluate the best threshold values and the global accuracy of each marker. The highest global sensitivity for NSCLC was reached by TPA (70.8%), whereas that of Cyfra 21-1 was 50%. According to tumour histology, significant difference (p<0.05) in serum levels were found only for CEA (adenocarcinomas, median=5.6 ng/ml; squamous cell carcinoma, median=3.2 ng/ml) and SCC (adenocarcinomas, median=1.0 ng/ml; squamous cell carcinoma, median=1.5 ng/ml). As regards squamous cell carcinoma histotype, the highest sensitivity was obtained by TPA (74.4% at a specificity of 62.2%) and for adenocarcinomas by CEA (78.8% at a specificity of 85.6%). Tumour marker levels were also determined during the follow-up of 10 patients. The best sensitivity in detecting relapses was shown by CEA (90%), followed by TPA (70%), SCC (50%), Cyfra 21-1 (40%) and NSE (10%), even though the CEA test displayed a high percentage of false positive results (98.1%) in patients with no evidence of disease (NED).

Pattern of mucin gene expression in normal and neoplastic lung tissues.

This work evaluates the expression in lung cancer of the most well characterized mucin genes (MUC1, MUC2, MUC3) and of the recently described MUC4 in lung tissues, to check a correlation between the expression of any particular gene and this tumor. Hybridization with synthetic oligonucleotides obtained from a part of the sequences of MUC1, MUC2, MUC3 and MUC4, was performed on blotted RNA from 18 lung cancer tissue specimens and from 10 normal tissues samples taken, when possible, from the normal lung counterpart. By means of Northern blot analysis MUC1 revealed to be the most expressed mucin gene in lung cancer, followed by MUC4; by contrast, the expression of MUC2 and MUC3 was almost undetectable in all cancer specimens. The intensity of expression of MUC1 and MUC4 was always superior in cancer tissue than in the normal counterpart. As expected, the highest reactivity for MUC1 and MUC4 expression was observed mainly in the adenocarcinoma histotype which is mucin secreting. These findings represent a contribution to the study of mucin gene pattern in lung cancer, and, in particular, indicate that MUC4, in association with the MUC1 gene, seems to be strongly expressed in this neoplastic disease.

A simple and semi-automated system for increasing the recovery of aqueous [18F] fluoride from target.

A simple semi-automated apparatus is described for rinsing the transport line from the [18F] fluoride. target to the hot-cell after recovery of aqueous [18F] fluoride. The additional activity thus recovered can then be added to that previously trapped on Dowex 1X8 (CO3=) or, alternatively, diverted to a second vial for other uses such as research, PET-camera calibration or bone investigations by PET. Inclusion of the target chamber in the rinsing procedure increased the additional recovery of activity up to ca. 15%, without a noticeable effect on the isotopic integrity of the recovered [18O]H2O.

Mucin-like carcinoma-associated antigen (MCA) in breast cancer: clinical experience at the National Cancer Institute of Milan.

Mucin-like Carcinoma-associated Antigen (MCA) is a glycoprotein belonging to the mucin family; it is defined by the monoclonal antibody b-12. Mucins represent an interesting group of tumor markers and are widely utilized in the clinical monitoring of neoplastic patients. These molecules show a certain degree of tissue specificity and MCA is preferentially associated with breast tissue. Several studies have demonstrated that patients with breast cancer usually have high MCA serum levels. In this paper the experience of the National Cancer Institute of Milan with the clinical use of MCA in breast cancer patients is reported. The observed sensitivity of the MCA test was poor in patients with early-stage disease, while it was acceptable in patients with advanced breast cancer. MCA concentrations appeared to be directly related to disease spread. A clear relationship was seen between MCA levels and lymph-nodal status. The highest MCA plasma levels were observed in patients with metastatic disease. In this group of patients the sensitivity of the test on the basis of a cut-off of 11 U/mL was 52%.

The role of serum carcinoembryonic antigen (CEA) in the management of patients with colorectal carcinoma: the experience of the Istituto Tumori of Milan.

CEA determination has attained an important role in the clinical management of patients with tumors of the colorectal tract. In this paper the experience of the Istituto Tumori of Milan is reviewed and the results are discussed. Three hundred and thirty-six patients were followed after curative resection of colorectal carcinoma. The follow-up period was 15 years, from January 1975 to December 1990 (global follow-up 1358 years). In the course of follow-up 136 patients developed recurrent disease. The number of CEA determinations for each patient ranged from 1 to 37 (mean 8, total 3330). CEA levels of presurgical patients were related to the clinical stage. Among patients who developed recurrences 61% showed an increase in CEA serum levels. In 200 patients with a negative follow-up we observed only 15 cases of false-positive results.

Preliminary study on oncogene product immunohistochemistry (c-erbB-2, c-myc, ras p21, EGFR) in breast pathology.

The expression of oncogene products related to cell growth (c-erbB-2, c-myc, ras p21, EGFR) was investigated in benign (15 cases) and malignant breast lesions (20 cases) by means of immunohistochemistry using the avidin-biotin-peroxidase technique with polyclonal and monoclonal antibodies. The aim of this study was to evaluate the relationship between the staining positivity and various morphological and biological features, such as tumour type, grading, hormone receptor status and cell kinetic parameters. In benign breast lesions, as expected, the kinetic parameters were low, both for Ki-67 and LI. All the specimens showed a diploid condition (the DI being equal to 1) and we found a limited degree of immunoreactivity for all the growth factors and oncogene products. In breast cancer we studied the distribution of immunohistochemical positivity for EGFR, c-erbB-2, c-myc, ras p21 and Ki-67, which was related to age, nodal status, ER and PgR receptor status, LI, DI and histopathological grading. A significant positive correlation was found both between ras p21 expression and nodal status and ER-ICA positivity. We observed a strong correlation between LI and Ki-67 and an inverse relation between Ki-67 and ER expression. These findings suggest the importance of studying the relationship between prognostic factors which may provide preoperative prediction in the biological behaviour of breast cancer, not only on biopsy specimens, but also on fine needle aspirates.

Evaluation of cytokeratin 19 serum fragments (CYFRA 21-1) in patients with lung cancer: results of a multicenter trial.

Recently, a new immunometric assay (Cyfra 21-1) was developed to measure serum concentrations of a soluble fragment of cytokeratin subunit 19. With this method, supplied by Boehringer Mannheim (EIA Test Cyfra 21-1), an Italian multicenter trial was performed in patients with lung cancer. Cyfra 21-1 serum levels were determined in 568 normal subjects (blood donors), 607 patients with non-malignant diseases (491 respiratory diseases) and 730 patients with malignancies. In the latter group 584 had lung cancer. All these 584 patients had pathologically confirmed disease; 314 were epidermoid tumors, 166 adenocarcinomas, 88 small cell cancers and 16 large cell cancers. In the 568 healthy blood donors the mean Cyfra 21-1 value was 0.91 ng/ml (SD 0.47 ng/ml; range 0.05-2.90 ng/ml). A threshold of 1.9 ng/ml was chosen as the upper limit of normality. High levels of Cyfra 21-1 were observed in patients with chronic hepatitis (positivity rate: 17/51-33.3%) and with pancreatitis (positivity rate 5/16-31.3%). In 114 out of 491 (23.2%) patients with respiratory diseases Cyfra 21-1 showed values greater than 1.9 ng/ml. The overall sensitivity (all stages) of Cyfra 21-1 in lung cancer was 65.6% (383/584). When the histology was considered the highest positivity rates were found in patients with squamous cell tumors (226/314; 72%) followed by adenocarcinomas (105/166; 63%). In patients with SCLC the global sensitivity was 52.3% (46/88). Higher sensitivity of Cyfra 21-1 was observed from stage I to stage IV (53.9% vs 85.7%; Chi square: p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)