No evidence for PML-RARa bcr1 fusion gene in colorectal cancer

Colorectal cancer is the third most prevalent cancer and a leading cause of cancer death. Metastatic colorectal cancer patients are treated with anti-EGFR monoclonal antibodies in combination with chemotherapy; however, the efficiency is only 10-20% of such patients. An increasing amount of data has demonstrated that response to anti-EGFR therapies is confined to patients with KRAS and BRAF wild type tumors but still some of these patients are non responders to this treatment. The presence of oncogenic deregulation of different members of EGFR downstream signaling or crosstalk molecules could predict the lack of response in these patients. In this study, 40 wild type KRAS and BRAF colorectal tumors were analyzed to elucidate whether PML-RARa bcr1 fusion gene may play a role in colorectal carcinogenesis. Specifically we want to determine if this fusion could be responsible for the inability to respond to anti-EGFR monoclonal antibodies. Here, for the first time it is reported, that PML-RARa bcr1 fusion is not responsible for colorectal tumor development and also, this translocation is not predicting the lack of efficacy of anti-EGFR therapies in wild type KRAS and BRAF colorectal cancer patients. These results also suggest that PML-RARa is unlikely to be a promising target for adjuvant therapy in colorectal cancer patients.     

Autoantibodies against the tumour-associated antigen GA733-2 in patients with colorectal carcinoma

The tumour-associated antigen (TAA) GA733-2 is expressed as a non-secreted surface molecule on the majority of human colorectal carcinoma cells. The antigen has been used as a target for passive and active immunotherapy during the last decade. To determine the incidence of autoantibodies against this antigen, sera from 1068 patients with colorectal carcinoma were analysed for naturally occurring IgG antibodies against the baculovirus-produced GA733-2E protein. A total of 14.5% of the patients had IgG antibodies against the antigen. In 519 patients, sera were collected at the time of diagnosis and 15% of those patients had anti-GA733-2E IgG antibodies. There was a tendency to a higher frequency of patients with antibodies among those in the advanced Dukes stages: 11% in stage A and 32% in stage D respectively (P = 0.06). Antibodies could be detected for up to 10 years after the diagnosis. Patients with Crohn's disease or colitis ulcerosa (n = 20) did not elicit anti-GA733-2E antibodies. No healthy control donor (n = 45) had detectable antibodies against the antigen. The specificity of GA733-2E-reactive serum IgG was indicated by significant inhibition of mAb17-1A (originally used to define GA733-2) binding to the GA733-2E antigen. Sera of positive patients bound to the GA733-2-expressing human colorectal carcinoma cell line, SW948. No significant correlation was found between the presence of antibodies and survival in the present patient population. However, the high incidence of autoantibodies against this tumour antigen in colorectal carcinoma patients confirms its antigenicity in humans and supports the use of the GA733-2 antigen as a target for immunotherapy. Received: 25 May 1998 / Accepted: 26 November 1998     

Missense mutations in hMLH1 associated with colorectal cancer

One of the most prevalent hereditary syndromes associated with colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC). The inherited gene defects in HNPCC have been shown to reside in DNA mismatch repair genes, mostly hMSH2 or hMLH1. Most HNPCC patients are heterozygous with regard to the relevant mismatch repair gene; they have one normal and one mutated allele, and mismatch repair in normal somatic cells is functional. Cancer predisposition in HNPCC is believed to be associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair. This gives rise to DNA microsatellite instability (MSI), an increased somatic mutation rate, and eventually, to the accumulation of mutations in genes involved in colorectal carcinogenesis. In support of this theory, colorectal tumors in HNPCC patients and in mice deficient for hMSH2 or hMLH1 show MSI. Here, we describe two missense mutations in hMLH1 exon 16 associated with colorectal cancer. Interestingly, the tumors do not show MSI. This raises some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations and these will be missed if an MSI test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggests that the mechanism involved in carcinogenesis could be different from that generally hypothesized.     

Molecular diagnostics and personalized medicine in oncology: Challenges and opportunities

Increasing evidence demonstrates that target‐based agents are active only in molecularly selected populations of patients. Therefore, the identification of predictive biomarkers has become mandatory to improve the clinical development of these novel drugs. Mutations of the epidermal growth factor receptor (EGFR) or rearrangements of the ALK gene in non‐small‐cell lung cancer, and BRAF mutations in melanoma are clear examples of driver mutations and predictive biomarkers of response to treatment with specific inhibitors. Predictive biomarkers might also identify subgroups of patients that are not likely to respond to specific drugs, as shown for KRAS mutations and anti‐EGFR monoclonal antibodies in colorectal carcinoma. The discovery of novel driver molecular alterations and the availability of drugs capable to selectively block such oncogenic mechanisms are leading to a rapid increase in the number of putative biomarkers that need to be assessed in each single patient. In this respect, two different approaches are being developed to introduce a comprehensive molecular characterization in clinical practice: high throughput genotyping platforms, which allow the detection of recognized genetic aberrations in clinical samples, and next generation sequencing that can provide information on all the different types of cancer‐causing alterations. The introduction of these techniques in clinical practice will increase the possibility to identify molecular targets in each individual patient, and will also allow to follow the molecular evolution of the disease during the treatment. By using these approaches, the development of personalized medicine for patients with cancer will finally become possible. J. Cell. Biochem. 114: 514–524, 2013. © 2012 Wiley Periodicals, Inc.     

MuSK Myasthenia Gravis IgG4 Disrupts the Interaction of LRP4 with MuSK but Both IgG4 and IgG1-3 Can Disperse Preformed Agrin-Independent AChR Clusters

A variable proportion of patients with generalized myasthenia gravis (MG) have autoantibodies to muscle specific tyrosine kinase (MuSK). During development agrin, released from the motor nerve, interacts with low density lipoprotein receptor-related protein-4 (LRP4), which then binds to MuSK; MuSK interaction with the intracellular protein Dok7 results in clustering of the acetylcholine receptors (AChRs) on the postsynaptic membrane. In mature muscle, MuSK helps maintain the high density of AChRs at the neuromuscular junction. MuSK antibodies are mainly IgG4 subclass, which does not activate complement and can be monovalent, thus it is not clear how the antibodies cause disruption of AChR numbers or function to cause MG. We hypothesised that MuSK antibodies either reduce surface MuSK expression and/or inhibit the interaction with LRP4. We prepared MuSK IgG, monovalent Fab fragments, IgG1-3 and IgG4 fractions from MuSK-MG plasmas. We asked whether the antibodies caused endocytosis of MuSK in MuSK-transfected cells or if they inhibited binding of LRP4 to MuSK in co-immunoprecipitation experiments. In parallel, we investigated their ability to reduce AChR clusters in C2C12 myotubes induced by a) agrin, reflecting neuromuscular development, and b) by Dok7- overexpression, producing AChR clusters that more closely resemble the adult neuromuscular synapse. Total IgG, IgG4 or IgG1-3 MuSK antibodies were not endocytosed unless cross-linked by divalent anti-human IgG. MuSK IgG, Fab fragments and IgG4 inhibited the binding of LRP4 to MuSK and reduced agrin-induced AChR clustering in C2C12 cells. By contrast, IgG1-3 antibodies did not inhibit LRP4-MuSK binding but, surprisingly, did inhibit agrin-induced clustering. Moreover, both IgG4 and IgG1-3 preparations dispersed agrin-independent AChR clusters in Dok7-overexpressing C2C12 cells. Thus interference by IgG4 antibodies of the LRP4-MuSK interaction will be one pathogenic mechanism of MuSK antibodies, but IgG1-3 MuSK antibodies will also contribute to the reduced AChR density and neuromuscular dysfunction in myasthenia patients with MuSK antibodies.     

Can the Tumor Deposits Be Counted as Metastatic Lymph Nodes in the UICC TNM Staging System for Colorectal Cancer?

Objective

The 7th edition of AJCC staging manual implicitly states that only T1 and T2 lesions that lack regional lymph node metastasis but have tumor deposit(s) will be classified in addition as N1c, though it is not consistent in that pN1c is also an option for pT3/T4a tumors in the staging table. Nevertheless, in this TNM classification, how to classify tumor deposits (TDs) in colorectal cancer patients with lymph node metastasis (LNM) and TDs simultaneously is still not clear. The aim of this study is to investigate the possibility of counting TDs as metastatic lymph nodes in TNM classification and to indentify its prognostic value for colorectal cancer patients.

Methods and Results

In this retrospective study, 513 cases of colorectal cancer with LNM were reviewed. We proposed a novel pN (npN) category in which TDs were counted as metastatic lymph nodes in the TNM classification. Cancer-specific survival according to the npN or pN category was analyzed using Kaplan-Meier survival curves. Univariate and multivariate analyses were performed to indentify significant prognostic factors. Harrell''s C statistic was used to test the predictive capacity of the prognostic models. The results revealed that the TD was a significant prognostic factor in colorectal cancer. Univariate and multivariate analyses uniformly indicated that the npN category was significantly correlated with prognosis. The results of Harrell''s C statistical analysis demonstrated that the npN category exhibited a superior predictive capacity compared to the pN category of the 7th edition TNM classification. Moreover, we also found no significant prognostic differences in patients with or without TD in the same npN categories.

Conclusions

The counting of TDs as metastatic lymph nodes in the TNM classification system is potentially superior to the classification in the 7th edition of the TNM staging system to assess prognosis and survival for colorectal cancer patients.     

Comparative Subpopulation Analysis of Plasma Exosomes from Cancer Patients

Pre-selection of tumor exosomes from a total pool of circulating microvesicles is an important stage required to increase sensitivity and specificity of the developing methods for diagnostics of oncological diseases. In this study, universal proteins characterized by increased expression in plasma exosomes have been identified in patients with colorectal cancer, head and neck squamous cell carcinomas, and lung cancer. The use of antibodies against major exosomal proteins will help to develop a simple and high-performance method of affinity isolation of tumor exosomes.     

Antiphospholipid antibodies and acute-phase response in non-metastatic colorectal cancer patients.

AIM: To investigate the plasma levels and prevalence of the most common antiphospholipid antibodies, as well as their relationships with several plasma markers of inflammation, in order to characterize some aspects of cancer thrombophilia. MATERIALS AND METHODS: Eighty-three cancer patients with non-metastatic colorectal solid tumors and 94 control subjects were tested for the presence of IgG/IgM/IgA anti-cardiolipin and anti-Beta2-glycoprotein I antibodies and of several acute-phase reactants, i.e., fibrinogen, factor VIII:C and C4b-binding protein. RESULTS: In cancer patients the plasma levels of the acute-phase reactants and the IgA/IgG anti-cardiolipin and IgA anti-Beta2- glycoprotein I antibodies were significantly higher; the acute-phase reactants were significantly correlated with anti-cardiolipin antibodies; the prevalence of antiphospholipid antibodies was not significantly higher. CONCLUSIONS: In patients with non-metastatic colorectal cancer the acute-phase response is associated with antiphospholipid generation. This could represent a further pathogenetic mechanism for the short-term post-surgery thrombotic complications of patients with colorectal cancer.     

Serum antibodies to EpCAM in healthy donors but not ulcerative colitis patients

Purpose: The gastrointestinal carcinoma-associated antigen epithelial cell adhesion molecule (EpCAM) has been a target for passive and active immunotherapy of gastrointestinal carcinoma patients. The antigen is expressed by both tumor and normal tissues. The immunogenicity of EpCAM in colorectal cancer patients has been described previously. The purpose of this study was to evaluate humoral and cellular immune responses of healthy individuals and ulcerative colitis patients to EpCAM and to relate immune responses to colonic tissue expression of EpCAM. Methods: An inhibition radioimmunoassay was used to detect anti-EpCAM serum antibodies. Anti-EpCAM antibodies of a healthy donor were expressed by phages and sequenced. ³H-thymidine incorporation assay was used for detection of lymphoproliferative responses to stimulation with EpCAM. EpCAM tissue expression was determined by immunohistochemistry. Results: We detected anti-EpCAM serum antibodies in 4 of 10, and EpCAM-specific lymphoproliferation responses in 1 of 10 healthy volunteers. The majority of anti-EpCAM antibodies derived from a healthy donor were germline-encoded. In contrast, none of the 23 patients with ulcerative colitis showed serum antibodies to EpCAM (P=0.005). Antigen expression was greatly reduced and altered in ulcerative colitis patients, whereas colon from healthy individuals and uninvolved colon of colorectal cancer patients expressed high levels of EpCAM. Conclusion: The results of these studies suggest an association between EpCAM antibody production and colonic EpCAM expression in healthy individuals and patients with ulcerative colitis. Decreased and altered colonic EpCAM expression in ulcerative colitis patients may be related to the disease induction, based on the previously demonstrated adhesion function of this molecule. Healthy individuals with anti-EpCAM immune responses and high risk for developing colorectal carcinoma are prime candidates for prophylactic immunization against EpCAM.Emma E. Furth and Jian Li contributed equally     

Patient Delay in Colorectal Cancer Patients: Associations with Rectal Bleeding and Thoughts about Cancer

Rectal bleeding is considered to be an alarm symptom of colorectal cancer. However, the symptom is seldom reported to the general practitioner and it is often assumed that patients assign the rectal bleeding to benign conditions. The aims of this questionnaire study were to examine whether rectal bleeding was associated with longer patient delays in colorectal cancer patients and whether rectal bleeding was associated with cancer worries. All incident colorectal cancer patients during a 1-year period in the County of Aarhus, Denmark, received a questionnaire. 136 colorectal cancer patients returned the questionnaire (response rate: 42%). Patient delay was assessed as the interval from first symptom to help-seeking and was reported by the patient. Patients with rectal bleeding (N = 81) reported longer patient intervals than patients without rectal bleeding when adjusting for confounders including other symptoms such as pain and changes in bowel habits (HR = 0.43; p = 0.004). Thoughts about cancer were not associated with the patient interval (HR = 1.05; p = 0.887), but more patients with rectal bleeding reported to have been wondering if their symptom(s) could be due to cancer than patients without rectal bleeding (chi² = 15.29; p<0.001). Conclusively, rectal bleeding was associated with long patient delays in colorectal cancer patients although more patients with rectal bleeding reported to have been wondering if their symptom(s) could be due to cancer than patients without rectal bleeding. This suggests that assignment of symptoms to benign conditions is not the only explanation of long patient delays in this patient group and that barriers for timely help-seeking should be examined.     

Effect of BRAF V600E mutation on tumor response of anti-EGFR monoclonal antibodies for first-line metastatic colorectal cancer treatment: a meta-analysis of randomized studies

Anti-EGFR monoclonal antibodies (anti-EGFR MoAbs) in metastatic colorectal cancer (mCRC) treatment are still not effective in all patients. This study aimed to evaluate the relationship between BRAF V600E mutation and the tumor response of anti-EGFR MoAbs for first-line treatment in mCRC patients. We searched the MEDLINE and EMBASE databases, using the key words that included colorectal cancer, cetuximab, panitumumab, and BRAF mutation and retrieved 445 articles. Among them four were included in the systematic review. Relative risks (RRs) with 95 % confidence intervals (CI) for response rate were calculated. BRAF mutation carriers had worse ORR than non-carriers in mCRC patients with KRAS wild-type in first-line treatment whether adding anti-EGFR MoAb to chemotherapy or not (RR = 0.43, [95 % CI 0.16–0.75]; RR = 0.38, [95 % CI 0.20–0.73]). But in the unselected patients whose KRAS mutation were unknown, BRAF mutation carriers had similar ORR whether adding cetuximab to chemotherapy or not (RR = 0.45, [95 % CI 0.18–1.09]; RR = 0.57, [95 % CI 0.15–2.23]). In BRAF mutation carriers adding anti-EGFR MoAb to chemotherapy was similar to chemotherapy alone whether in patients with wild-type KRAS or unselected patients (RR = 1.61, [95 % CI 0.57–4.47]; RR = 0.71, [95 % CI 0.18–2.77]). But in the BRAF mutation non-carriers, adding anti-EGFR MoAb produced a clear benefit in response rate than chemotherapy alone and this advantage was restricted to KRAS wild-type patients (RR = 1.48, [95 % CI 1.28–1.71]). BRAF mutation decreases tumor response in first-line treatment whether cetuximab was given or not in patients with KRAS wild-type, and anti-EGFR MoAb produces a clear benefit in response rate in patients with BRAF and KRAS wild-type.     

Antibodies against Myelin Lipids in Multiple Sclerosis

Development of immunopathological responses in the central nervous system (CNS) is one of the key events in the pathogenesis of multiple sclerosis (MS). Humoral immune responses with formation of antibodies against the components of the myelin sheath play an important role. However, the targets for antibodies, their contribution to the development of pathologic process, and stages of the disease where they play the most important role are still not quite clear. In this study, we investigated the frequency of detection of antibodies against myelin glycolipids in MS and their relationship with clinical features of the disease. The results of the study showed that patients with MS demonstrate a trend towards more frequent detection of antibodies against glycolipids and sulfatide in blood serum, being especially pronounced in patients with secondary progressive course. Antibodies against GM1 ganglioside were detected significantly more frequently in patients with secondary progressive MS as compared to patients with remitting course and healthy volunteers. These results are indicative of the fact that antibodies to lipids may participate in the development of demyelinating and neurodegenerative processes in MS and be the markers of disease progression. Further development of the concept of the mechanisms of humoral response to myelin lipids in MS and identification of the most significant antibody targets will facilitate the development of new approaches to prediction of disease course and discovery of new targets for immunomodulating therapy.     

Ex vivo localization and immunohistochemical detection of sentinel lymph node micrometastasis in patients with colorectal cancer can upgrade tumor staging

ABSTRACT: BACKGROUND: It is not clear if sentinel lymph node (SLN) mapping can improve outcomes in patients with colorectal cancers. The purpose of this study was to determine the prognostic values of ex vivo sentinel lymph node (SLN) mapping and immunohistochemical (IHC) detection of SLN micrometastasis in colorectal cancers. METHODS: Colorectal cancer specimens were obtained during radical resections and the SLN was identified by injecting a 1% isosulfan blue solution submucosally and circumferentially around the tumor within 30 min after surgery. The first node to stain blue was defined as the SLN. SLNs negative by hematoxylin and eosin (HE) staining were further examined for micrometastasis using cytokeratin IHC. RESULTS: A total of 54 patients between 25 and 82 years of age were enrolled, including 32 males and 22 females. More than 70% of patients were T3 or above, about 86% of patients were stage II or III, and approximately 90% of patients had lesions grade II or above. Sentinel lymph nodes were detected in all 54 patients. There were 32 patients in whom no lymph node micrometastasis were detected by HE staining and 22 patients with positive lymph nodes micrometastasis detected by HE staining in non-SLNs. In contrast only 7 SLNs stained positive with HE. Using HE examination as the standard, the sensitivity, non-detection rate, and accuracy rate of SLN micrometastasis detection were 31.8% (7/22), 68.2% (15/22), and 72.2%, respectively. Micrometastasis were identified by ICH in 4 of the 32 patients with HE-negative stained lymph nodes, resulting in an upstaging rate 12.5% (4/32). The 4 patients who were upstaged consisted of 2 stage I patients and 2 stage II patients who were upstaged to stage III. Those without lymph node metastasis by HE staining who were upstaged by IHC detection of micrometastasis had a significantly poorer disease-free survival (p = 0.001) and overall survival (p = 0.004). CONCLUSION: Ex vivo localization and immunohistochemical detection of sentinel lymph node micrometastasis in patients with colorectal cancer can upgrade tumor staging, and may become a factor affecting prognosis and guiding treatment.     

Protection from infection or disease? Re-evaluating the broad immunogenicity of inactivated SARS-CoV-2 vaccines

How do we measure vaccine efficacy? The strictest but also easiest parameter to determine vaccine efficacy is its ability to block infection. Indeed, if a vaccine is able to block infection, this necessarily follows that it will also prevent both disease development and viral transmission. As a consequence, antibodies, specifically neutralising antibodies, have been used as the “gold standard” correlate of protection to measure SARS-CoV-2 vaccine efficacy, given their ability to block infection. Since SARS-CoV-2 infects cells by the binding of its spike protein to the host ACE-2 receptor, a vaccine that is able to induce a large quantity of antibodies able to block the interaction between the ACE-2 receptor and spike protein should theoretically be highly efficacious. Given this “antibody-centric” method of evaluating of a vaccine, it is clear why spike mRNA vaccines have to date been regarded the most effective COVID-19 vaccine in the market.     

Antiangiogenic peptides and proteins: from experimental tools to clinical drugs

The formation of a 'tumor-associated vasculature', a process referred to as tumor angiogenesis, is a stromal reaction essential for tumor progression. Inhibition of tumor angiogenesis suppresses tumor growth in many experimental models, thereby indicating that tumor-associated vasculature may be a relevant target to inhibit tumor progression. Among the antiangiogenic molecules reported to date many are peptides and proteins. They include cytokines, chemokines, antibodies to vascular growth factors and growth factor receptors, soluble receptors, fragments derived from extracellular matrix proteins and small synthetic peptides. The polypeptide tumor necrosis factor (TNF, Beromun) was the first drug registered for the regional treatment of human cancer, whose mechanisms of action involved selective disruption of the tumor vasculature. More recently, bevacizumab (Avastin), an antibody against vascular endothelial growth factor (VEGF)-A, was approved as the first systemic antiangiogenic drug that had a significant impact on the survival of patients with advanced colorectal cancer, in combination with chemotherapy. Several additional peptides and antibodies with antiangiogenic activity are currently tested in clinical trials for their therapeutic efficacy. Thus, peptides, polypeptides and antibodies are emerging as leading molecules among the plethora of compounds with antiangiogenic activity. In this article, we will review some of these molecules and discuss their mechanism of action and their potential therapeutic use as anticancer agents in humans.     

Significance of CA72.4 in patients with colorectal cancer. Comparison with CEA and CA19.9.

CA72.4 is a new tumor-associated antigen identified by monoclonal antibodies cc49 and B72.3. Serum levels of CA72.4 were measured in patients with benign and malignant diseases. The cut-off used was 4 U/mL. CA72.4 is a highly specific marker since only 3% of 162 patients with benign diseases had elevated levels of antigen. Forty-four percent of 89 patients with colorectal cancer had elevated CA72.4 levels. Compared with CEA and CA19.9, we have found that CEA (75%) is the most sensitive marker (p less than 0.001). The simultaneous use of two or three markers did not further contribute to the evaluation of patients with colorectal cancer.     

Genome-wide allelotyping indicates increased loss of heterozygosity on 9p and 14q in early age of onset colorectal cancer.

Colorectal cancer remains a significant public health challenge, despite our increased understanding of the genetic mechanisms involved in the initiation and progression of this disorder. It has become clear that multiple mechanisms lead to the tumorigenic phenotype, with familial predisposition syndromes accounting for less than 15% of all colorectal cancers. A genome-wide scan for loss of heterozygosity (LOH) was carried out with 150 highly polymorphic markers in an effort to identify additional loci involved in colorectal tumorigenesis in DNA samples from 42 colorectal cancer patients. The results confirm earlier observations that tumor DNAs from patients with hereditary nonpolyposis colon cancer (HNPCC) either maintain heterozygosity or exhibit altered or additional alleles. DNAs from patients with early onset colorectal carcinomas (diagnosed prior to age 50) revealed a higher overall degree of LOH than DNAs from patients with sporadic colorectal cancers diagnosed later in life (after age 50). While regions on 1p, 10q and 14q are suggestive, statistical analysis of LOH at these regions failed to reach significance. However, LOH at 9p did reveal a statistically significant increase in the early onset patient group, compared to the greater than age 50 group. LOH on 9p may involve inactivation of p16/CDKN2 through aberrant DNA methylation on the remaining chromosome, resulting in a situation analogous to a homozygous deletion of p16 and providing a selective growth advantage to these cells. This marker may prove to be a useful prognostic indicator for patient stratification in the design of therapy for early onset colorectal cancer patients.     

Treatment of metastatic colorectal cancer by means of specific monoclonal antibodies conjugated with iodine-131: a phase II study

Eighteen consecutive patients with advanced and/or metastatic colorectal carcinoma have been treated with intraperitoneal administration of radiolabelled (iodine-131) monoclonal antibodies raised against different antigens associated to these kinds of tumours: anti-CEA FO23C5, anti-CEA BW494/32, anti-TAG B72.3, AUA1. The doses of isotope ranged between 21 and 150 mCi (777–5550 MBq) which delivered a radiation dose to the target tumour from 768 to 4628 cGy. Thirteen patients were previously treated with conventional regimens which consisted of chemotherapy (5-fluoracil with or without other anti-neoplastic drugs) both in adjuvant or palliative setting. Three patients are considered non-evaluable owing to concomitant chemotherapy in 2 and lack of objective parameters in 1. Out of 15 evaluable patients 2 achieved complete remission and 2 partial remission with a response rate of 26.6%. Three stable and 8 with progressive disease have also been registered. The toxicity was negligible consisting of hematologic WHO grade 1 in 7 patients, grade 2 in 1 patient and grade 3 in 1 patient, as well as hepatic WHO grade 1 in 8 and grade 2 in 2 patients. The authors conclude that this innovative way of treatment for advanced colorectal carcinoma seems to offer promising therapy; from these data, therefore, a new trial is justified employing radiolabelled MoAbs in well selected patients with metastatic or locally advanced colorectal carcinoma.     

Colorectal carcinoma antigens detected by hybridoma antibodies.

Hybridoma cells which secrete colorectal carcinoma-specific antibodies have been produced and used to study the antigenic structure of these tumor cells. Nineteen antibodies have been studied in detail, and 15 of these are colorectal carcinoma specific. Only two antibodies reactive with carcinoembryonic antigen (CEA) have been discovered and five other antibodies that react with distinct epitopes on the cell surface have been defined. Several antigens with distinct molecular characteristics have been shown to exist by use of hybridoma antibodies. Six hybridoma antibodies have been shown to mediate antibody-dependent cell-mediated cytotoxicity (ADCC).