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Objective: To investigate the expression of T-cell immunoglobulin and mucin domain 3 (TIM-3) on peripheral T cells of cervical carcinoma patients., Methods: Peripheral blood samples from 15 high-grade cervical squamous intraepithelial lesion (HSIL) patients, 24 cervical carcinoma patients, and 21 healthy controls were collected. TIM-3 expressions on the surface of peripheral CD4+ T cells and CD8+ T cells were analyzed with flow cytometry., Results: There was significantly lower expression of CD4+ T cells and CD8+ T cells in HSIL patients and cervical carcinoma patients compared with healthy controls. We also found that TIM-3 expression on peripheral CD4+ T and CD8+ T cells of both HSIL patients and cervical carcinoma patients was significantly increased compared to the control group. Further analyses revealed that the expression of TIM-3 on peripheral CD4+ T and CD8+ T cells significantly increased in stage III-IV cervical carcinoma patients compared to stages I-II., Conclusion: The increased expression of TIM-3 on CD4+ T cells and CD8+ T cells of patients with cervical carcinoma and HSIL suggests the potential role of TIM-3 in the development and progression of cervical carcinoma, which may be a novel therapy target for cervical carcinoma., (© 2020 S. Karger AG, Basel.)

Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-x03BA;B (NF-x03BA;B) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-x03BA;B activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models. Myosin light chain kinase (MLCK) is suggested to be associated with epithelial permeability via TNF signaling. Therefore, the relationship between epithelial MLCK expression and NF-x03BA;B activation via TNFR2 signaling on CAC development was investigated. Pro-tumorigenic cytokines such as interleukin (IL)-1β, IL-6 and macrophage inflammatory protein-2 at the lamina propria were increased in the setting of colitis and further increased in tumor tissues with upregulated epithelial TNFR2 and MLCK expressions in an animal model of CAC. The upregulated MLCK expression was also observed in TNF-stimulated colonic epithelial cells in vitro in association with the upregulation of TNFR2 but not TNFR1/TNFRSF1a/p55. Gene silencing of tnfrsf1b, but not tnfrsf1a, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. The presence of anti-TNF antibody also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results including the suppressed TNFR2 and MLCK expressions were observed by inhibiting MLCK in the epithelial cells. MLCK silencing also led to suppressed TNFR2 expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in reduced CAC development, restored TJ, and decreased pro-tumorigenic cytokines. These imply that TNF-induced NF-x03BA;B activation and MLCK expression may be a potential target for the prevention of IBD-associated carcinogenesis., (© 2016 S. Karger AG, Basel.)

With the development of new therapeutic approaches, the ultimate goal of ulcerative colitis (UC) treatment is not only clinical remission but also mucosal healing. Successful mucosal healing has been associated with a dramatic risk reduction in UC recurrence and colitis-associated cancer development, which are the most critical complications of UC. However, invasive tests such as colonoscopy and biopsy are required to evaluate mucosal healing. Therefore, frequent examinations are unsuitable for UC patients. Mucosal inflammation of the colon and prostaglandin E2 production are assumed to be correlated; therefore, we considered that prostaglandin E-major urinary metabolite (PGE-MUM; 7-hydroxy-5,11-diketotetranor-prosta-1,16-dioic acid) may be a surrogate biomarker of UC activity. In this review, we propose that PGE-MUM levels reflect the colonoscopic and histological appearance of UC, suggesting that it is a more sensitive biomarker than those previously utilized for UC-related mucosal inflammation. According to the 'organ-specific chronic inflammation-carcinoma sequence' theory, by measuring PGE-MUM periodically, it would be possible to control inflammation, with subsequent prevention of UC recurrence and colitis-associated cancer development. The measurement of urine samples for PGE-MUM - a simple, noninvasive method - can reduce the patient burden as well as medical costs, suggesting its potential for application in routine practice., (© 2016 S. Karger AG, Basel.)

Background: Helicobacter pylori (Hp) infection and gastric atrophy are both risk factors for gastric cancer. Recently it has been found that X-ray examination for gastric cancer screening does not have much effect on the detection rate for gastric cancer in Japan. A candidate for a new mass screening for gastric cancer, the ABC method, using the combination assay of Hp and serum pepsinogen, was useful for identifying the development of gastric cancer in high-risk and low-risk populations. People with higher cancer risk are recommended to receive endoscopy. The ABC method was carried out as a gastric cancer mass-screening on the initiative of Nishitokyo Medical Association in Nishitokyo city from 2011. This paper reviewed the present status of gastric cancer screening using the ABC method, including the latest results of our ongoing screening., Summary: We report results for 36,627 individuals from 2011 to 2013. Among them, 16,965 received blood examination for the ABC method. Of those, 8,083 planned to undergo endoscopic examination according to stratification of the risk for the development of gastric cancer. In fact, a total of 2,911 individuals underwent endoscopic examination. Gastric cancer was detected in 65 patients, including 52 (80%) diagnosed with early gastric cancer. The ABC method was not organized screening but opportunistic screening. X-ray examination was the organized screening that was ongoing during the same period. Detection cost for 1 gastric cancer case using the ABC method was cheaper than the conventional X-ray screening method (¥1,267,452 vs. ¥2,807,763)., Key Messages: Although further large epidemiological studies are required, the ABC method might be positioned as an effective mass screening for gastric cancer., (© 2016 S. Karger AG, Basel.)

Objective: To evaluate the usefulness of measuring serum CEA, CA19-9, and CYFRA 21-1 levels for the diagnosis and monitoring of bladder cancer., Materials and Methods: Serum levels of CEA, CA19-9, and CYFRA 21-1 were measured in 85 patients with bladder cancer. The absolute level of each marker and the positive rate were compared with the clinical stage and histological grade of the tumor. Changes of the markers were assessed in patients with or without disease progression, and the correlations between survival and positivity/negativity of these markers were also evaluated., Results: A higher serum level of CYFRA 21-1 was significantly correlated with higher tumor stage (p < 0.01) and higher grade (p < 0.05). In contrast, serum CEA and CA19-9 levels did not differ significantly among each stage and grade. The CYFRA 21-1 level increased significantly along with disease progression (from 7.33 ± 13.3 to 55.9 ± 127 ng/ml, p < 0.01). Patients who were positive for CYFRA 21-1 had significantly worse disease-specific survival (p < 0.0001, log rank test)., Conclusion: Serum CYFRA 21-1 seems to be a marker of advanced- and high-grade urothelial carcinoma of the bladder. It is useful for monitoring this disease and for predicting the prognosis. In contrast, the clinical usefulness of CEA and CA19-9 as tumor markers was not demonstrated., (Copyright © 2011 S. Karger AG, Basel.)

Objectives: To analyze the distribution of HLA alleles and HLA microsatellite alleles in Croatian patients with testicular carcinoma, compare it with that of healthy controls and investigate whether the polymorphism within the HLA region could be associated with the development of testicular cancer., Methods: Genomic DNA was isolated from the peripheral blood of 24 patients with testicular germ cell tumors (TGCT). Patients and controls were typed for HLA class I and class II polymorphism by the PCR-SSO method. Nine HLA microsatellites were analyzed by PCR and electrophoresis in an automated sequencer., Results: No significant deviation in the distribution of frequencies at HLA class I alleles was observed between patients and controls. Among HLA class II alleles, a statistically significant increase in the frequency of the HLA-DPB1*1701 allele was found among patients. The frequency of the HLA-DRB1*07-DQA1*0201-DQB1*0202 haplotype was increased in patients in comparison to the controls. Analysis of HLA microsatellites showed an increased frequency of D6S291-3 allele (p(corr) = 0.0455, OR = 3.05) among patients., Conclusions: The observed association of the disease and the DPB1*1701 allele as well as with the D6S291-3 allele suggests that this part of the HLA region might be involved in the pathogenesis of TGCT. Our data provide a basis for further studies about the correlation between the HLA region and testicular cancer., (Copyright © 2011 S. Karger AG, Basel.)

Background: Hepatoid carcinoma is a rare, primary neoplasm of the ovary characterized by histologic, immunobistochemical and analytical evidence of hepatic differentiation. Reflecting the rarity of this entity, few cytologic descriptions are available., Case: A 65-year-old woman presented with an abdominopelvic mass, peritoneal implants and elevated levels of CA-125 and a-fetoprotein (AFP). Cytologic examination of the ascitic fluid revealed cellular samples of polygonal cells in trabecular and papillary groups. Neoplastic cells were predominantly monomorphous, but some groups exhibited marked cellular atypia. A few trabecular groups showed peripheral endothelial rimming. Histologically, the neoplasm had evident hepatocellular differentiation, with a solid, trabecular growth of polygonal, eosinophilic cells with well-defined boundaries. The cells were immunoreactive with keratins, AFP and HepPar1. Retrospectively, HepPar1 was tested in cytologic samples, with a positive result., Conclusion: As occurs with other hepatocellular neoplasms, the hepatic differentiation that characterizes this unusual neoplasm may not be easily recognizable in effusion samples. However, there are some features that, in addition to an elevated AFP value, may help to suggest the diagnosis. A predominant trabecular arrangement with occasional endothelial rimming and HepPar1 immunoreactivity, consistent with hepatic differentiation, are unusual in common surface epithelial ovarian tumors.

A case of sarcomatoid carcinoma of the bladder is reported herein. Immunohistochemical staining with human pancytokeratin antibody was negative, while vimentin staining was strongly positive, suggesting a diagnosis of sarcoma of the bladder. Further immunohistochemical analysis revealed positivity for AE1/AE3 cytokeratins, permitting a correct diagnosis of sarcomatoid carcinoma of the bladder. It can be difficult to distinguish between sarcomatoid carcinoma, undifferentiated carcinoma and sarcoma, particularly if the biopsy specimens are of small size. In rare cases, sarcomatoid tumors may express epithelial markers different from those revealed by human pancytokeratin staining., (Copyright 2002 S. Karger AG, Basel)

Background: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC., Methods: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5-6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-alpha, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined., Results: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3x) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible., Conclusion: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.

Using serologic and molecular methods, 45 nasopharyngeal carcinoma (NPC) patients were typed for HLA class I and class II and were compared to 100 unrelated normal Tunisians. Our results showed that the antigen frequency of HLA-B13 and allelic frequencies of DRB1*03, DRB1*15 were significantly higher in the NPC patients than in the control group (15.5 vs. 4; 26.4 vs. 11.5, and 14.4 vs. 6.5%, respectively) probably indicating a positive association with NPC. Moreover, we observed that HLA-A23 was absent in our NPC sample and was present in 18% of normal controls, and HLA-DRB1*11 was less frequent among the patients compared to the controls (5.5 vs. 14%) suggesting a protective effect of this association with NPC., (Copyright 2001 S. Karger AG, Basel)

Background: MUC1 is aberrantly expressed on a variety of epithelial tumors. We have reported that MUC1 plays important roles in separation from primary site, invasion into the stromal tissue, and protection from immune responses. The aim of this study is to determine the precise binding of MUC1 to intercellular adhesion molecule 1 (ICAM-1) that accelerates the cancer metastasis., Methods: A cell aggregation assay between MUC1 cDNA transfectants and ICAM-1 expressing cells was employed. An anti-MUC1 antibody, anti-ICAM-1 antibody or synthetic peptide of MUC1 core protein was added to the assay to inhibit the cell aggregation., Results: MUC1 transfectants showed a significantly higher aggregation rate compared to the control cells. This aggregation was further enhanced by the inhibition of O-glycan biosynthesis. It was inhibited by either an anti-MUC1 antibody recognizing the tandem repeat domain of MUC1 core protein or an anti-ICAM-1 antibody identifying domain 1. It was also inhibited by a synthetic MUC1 peptide of 40 amino acids corresponding to two tandem repeats., Conclusions: The results revealed that a tandem repeat domain of MUC1 mucin core protein binds to domain 1 of ICAM-1, suggesting a potential role of MUC1- ICAM-1 interaction in the metastasis of epithelial tumors., (Copyright 2001 S. Karger AG, Basel)

We investigated micrometastasis in lymph nodes by detecting carcinoembryonic antigen (CEA) mRNA. A total of 400 lymph nodes obtained from 21 patients with esophageal carcinoma were examined by CEA-specific reverse transcription-polymerase chain reaction (RT-PCR). Serial sections of positive lymph nodes were reexamined histologically and immunohistologically. Twenty-seven lymph nodes of 11 patients were diagnosed as being positive by conventional histologic examination. CEA-mRNA positivity was found in 18 of 21 patients. Among 373 histologically negative nodes, 79 (21.2%) were positive for CEA mRNA. Of these, micrometastasis was detected in 2 by histological reexamination and in 11 by immunohistochemical staining using cytokeratin antibody. Two of 6 RT-PCR-positive patients (33.3%) had recurrent disease. Four of 11 patients (36.4%) whose nodal involvement was discovered by routine histological examination also had recurrent cancer. CEA-specific RT-PCR detected micrometastasis in lymph nodes at a higher rate than histological or immunohistochemical analysis of serial sections. Since the incidence of CEA-mRNA positivity is high in the lymph nodes of esophageal cancer patients except for those with early cancer, these patients should be treated with adjuvant therapy., (Copyright 2000 S. Karger AG, Basel)

Objective: Detecting malignant cells in the setting of reactive mesothelium can be difficult. Several techniques have been tried but without widespread acceptance. Sialosyl-Tn (STn) is an aberrantly glycosylated precursor of the MN blood group antigen frequently expressed in carcinomas and dysplastic epithelium. We investigated the STn monoclonal antibody for its clinical utility as an isolated stain to discriminate benign mesothelium from malignant cells., Study Design: Cell block material from 72 cases of body cavity fluids were immunostained for STn using the avidin-biotin complex method without antigen retrieval. Slides were incubated overnight at 4 degrees C in a humidified chamber., Results: Strong immunoreactivity was noted in 31/40 (77%) carcinomatous cases. Only moderate staining was noted in 1 of 28 (4%) benign effusions and weak staining in 5 (18%) additional benign cases. Specificity was 100%, sensitivity 78%, positive predictive value 100% and negative predictive value 76%. No staining was noted in four noncarcinomatous malignant effusions., Conclusion: STn may have diagnostic value in this cytologic setting as part of a diagnostic panel but not as an isolated stain.

In a previous study, we obtained a novel monoclonal antibody (F1 alpha-75) directed against a synthetic mucin antigen termed F1 alpha, and demonstrated that this antigen was expressed in a high percentage (80.2%; 89/111) of gastric carcinomas. In the present study, we compared the expression of F1 alpha with that of sialyl-Tn antigen, a mucin antigen similar to F1 alpha, in 54 human early gastric carcinomas, intestinal metaplasia and adenomatous polyps of the stomach to determine how differences in the expression of these antigens correlated with gastric carcinogenesis. The rate of expression of F1 alpha in early gastric carcinoma tissues, 81.5%, was higher than that of sialyl-Tn antigen, 57.4%. No correlation was found between the rate of expression and histological type, depth of cancerous invasion or lymph node metastasis. Sialyl-Tn antigen was extensively expressed in 77.5% of specimens of complete intestinal metaplasia and in 78.6% of those of incomplete intestinal metaplasia; however, the expression of F1 alpha in those specimens was rare and sporadic, with rates of only 25.0 and 27.7%, respectively. In adenomatous polyps, the rate of expression of F1 alpha is 6.25% and that of sialyl-Tn antigen is 43.8%. Our findings indicate that F1 alpha is a more specific antigen for gastric cancer than sialyl-Tn antigen, and that F1 alpha is an antigen associated with carcinogenesis of the stomach.

Since 1967, about 40 cases of digital necrosis associated with neoplasia have been reported. We report a new case of digital necrosis associated with an ovarian carcinoma and with a lupus-like syndrome. Immunologic cross-reactivity to tumoral antigen could explain the lupus-like syndrome.

The concept that the major histocompatibility complex (MHC) plays an important role in the pathogenesis of nasopharyngeal cancer (NPC) in several ethnic groups has gained increased attention during the last 15 years. Earlier studies have suggested that an increased risk of NPC is associated with specific phenotypes of human leukocyte antigens (HLA). The present study was performed to examine the association of HLA specificities and haplotypes with NPC in a Greek population. In a genotypical study of 53 patients, a significant association between the haplotype HLA-B5DR11 and NPC was found, mainly in patients > 45 years. Also, the above haplotype was significantly associated with longer disease-free interval. HLA-B5 and HLA-B5DR11 were more often seen among patients with squamous cell histology than among those with the undifferentiated type. These results suggest that MHC loci are probably implicated in the pathogenesis and outcome of NPC in Greek patients.

CYFRA 21-1 is a new tumor marker using two different monoclonal antibodies which recognize the divergent epitope on the N- or C-terminal region of domain 2 of cytokeratin 19 fragment, respectively. In this study, we investigated the relationship between levels of CYFRA 21-1 and survival duration, as well as the efficacy of chemotherapy associated with changes in CYFRA 21-1. Serum samples were obtained from 87 patients with nonoperable lung cancer (35 cases with squamous-cell carcinoma, 33 with adenocarcinoma, 3 with large-cell carcinoma, and 16 with small-cell carcinoma). The cutoff point was set at 3.5 ng/ml. In a CYFRA 21-1 assay, significantly more patients with squamous-cell carcinoma and adenocarcinoma were positive compared to patients with small-cell and large-cell carcinomas (p = 0.0017). Following chemotherapy, blood levels of CYFRA 21-1 decreased significantly in responders versus nonresponders (p = 0.0246). A significant correlation was noted between survival periods and pretreatment levels of CYFRA 21-1 (p = 0.0036). The present study suggests that CYFRA 21-1 might be useful as a possible indicator of survival and therapeutic effect for lung cancer.

Objective: Natural killer (NK) cells are cells of undefined lineage that are capable of lysing certain tumor cell lines in vitro. Determination of NK cell percent (NK%) in effusions by flow cytometry could aid in the detection of malignancies., Study Design: Over a six-month period at the Houston Veterans Affairs Medical Center, fresh effusions were routinely processed for cytology, and a portion was submitted for lymphocyte immunophenotyping using the FACScan and a panel including CD16/CD56 for NK cells. Seventy fluids (42 pleural, 28 peritoneal) from 62 men were examined., Results: NK cell percents were markedly increased in 15 cases (29-68%, mean 45.5) and low in 55 (2-20%, mean 8). Fourteen of the 15 cases with increased NK% were positive for carcinoma (93%), while 54/55 cases with low ones were negative for carcinoma (98%). Mesotheliomas, lymphomas and leukemias had low NK%., Conclusion: Using the Mann-Whitney U test, an increase in NK% predicts metastatic carcinoma with a P level of < .00001.

Objective: To use an instant cytologic diagnostic method to examine touch imprints of nasopharyngeal (NP) biopsies. This method aimed to ensure the adequacy of biopsied specimens for histologic examination. This paper describes the morphologic findings of NP lesions examined by this method., Study Design: Imprints were made from NP biopsies from patients suspicious for nasopharyngeal carcinoma (NPC). These imprints were air dried, stained with Diff-Quik and examined immediately. The adequacy of the specimens was assessed, and the findings of the imprints were interpreted as positive-, negative- or suspicious for NPC. Repeat biopsies and cytologic studies were done as indicated. In selected cases, immunocytochemical staining was done to identify cells on the imprints. Histologic examination of the biopsied specimens served as the control., Results: With this method we could interpret the imprints within five minutes of their receipt and determine if repeat biopsy was needed. In benign lesions, the imprints often contained many cells, most mature and reactive lymphocytes. These cells and the numerous lymphoglandular bodies (fragments of lymphoid cytoplasm) intermingled with the ciliated and squamous epithelial cells. In cases of NPC, the appearance was discrete, or clusters of, carcinoma cells or naked nuclei. They were less cellular than those of benign lesions. The lymphocytes were markedly depleted. Cells of dubious lineage were identified by the additional use of immunocytochemical studies., Conclusion: Cytologic examination of imprints of NP biopsies helps to determine the adequacy of the specimen for histologic examination. It is a rapid, practical method with high diagnostic accuracy.

In 44 ovarian cancers, CD44 variant (CD44v) expression was investigated immunohistochemically using a variant-specific polyclonal antibody. Patients with CD44v-positive carcinomas had a significantly shorter disease-free survival than patients with CD44v-negative tumors. Overall survival was also significantly reduced for stages III and IV of the International Federation of Gynecology and Obstetrics. Furthermore, a highly significant inverse correlation was observed between CD44v expression and preoperative platelet count. Urinary neopterin concentration, a marker of cell-mediated immunostimulation, did not differ between CD44v-positive and -negative ovarian cancer patients. Moreover, in seven ovarian carcinoma cell lines, modulation of CD44v expression was analyzed by living cell radioimmunoassay. Interferon-alpha, interferon-gamma, tumor necrosis factor, transforming growth factor-beta, all-trans retinoic acid and cisplatin did not affect CD44v expression.

Objective: To analyze longitudinally the basal natural killer cell activity in patients with invasive cervical carcinoma, the natural cytotoxicity was related to the most important known prognostic factors, and evaluated with respect to the clinical outcome of cervical disease., Materials and Methods: Forty-six patients with histologically proven invasive cervical carcinoma treated and followed at the Institute of Gynecology and Obstetrics, Ancona University, Salesi Hospital, were consecutively recruited from 1989 to 1992 and included into the study. For immunologic investigation, natural killer cell activity and peripheral blood T-lymphocyte subsets were tested before primary treatment and during the follow-up period, every 6 months. Natural killer activity was determined by target cell retention of the fluorescent dye carboxyfluorescein diacetate; the K 562 cell line was used as target cells., Results: A significant inverse relationship was observed between natural killer activity and disease stage (p = 0.001); patients with stage IV disease had the lowest level of natural cytotoxicity. The reduction of natural cytotoxicity was not accompanied by any alteration of lymphocyte distribution. The longitudinal analysis showed an increase of natural killer activity after surgical removal of the tumor, persisting during the follow-up, but all the 9 patients who recurred showed, at the time of disease recurrence, a significant decrease of their natural cytotoxic potential., Conclusion: Natural killer cell activity seems to be a functional index of immune status, significantly related to the stage and the clinical outcome of disease.

Elevated serum CA125 levels may be caused by any condition which produces peritoneal irritation as well as by the presence of various malignancies. This report of a case with atypical presentation of tubo-ovarian abscess and CA125 level of 1,160 U/ml serves to re-emphasize cautious operative planning in patients desirous of reproductive capability in the face of findings highly consistent with probable malignancy. This is the highest reported serum CA125 level in a reproductive age woman with well-documented reversible benign disease.

One of the more difficult challenges in cytopathology may be distinguishing malignancy from reactive conditions in effusions. Furthermore, it is frequently impossible to determine the primary site of the tumor on the basis of cellular morphology alone. In the present study we sought to construct a panel of antibodies that might distinguish carcinoma of the ovary from other metastatic tumor types as well as aid in the distinction between benign and malignant effusions. One hundred twenty-four cases of effusions (80 malignant and 44 benign) were examined with seven monoclonal antibodies (MAbs) (Ber-EP4, OV-TL3, OV-TL23, ID-3, SH9, H23 and D-14). Sensitivities for the seven MAbs ranged from 11% to 75%, with specificity of 43-100%. No single antibody could reliably distinguish carcinoma from reactive conditions, but Ber-EP4 combined with H23 detected 87% of malignant effusions, with a false-positive rate of 2%. Although these antibodies did not differentiate ovarian carcinoma from other types of malignancies, when used together they are highly accurate in distinguishing benign from malignant effusions.

An enzyme-linked immunosorbent assay (ELISA) which uses a recombinant truncated form of the Epstein-Barr virus (EBV) membrane antigen gp350/250 has been developed and used to measure human IgA antibody responses to that antigen. From comparisons with conventional immunofluorescence assays (IFA) for measuring IgA antibody responses to EBV viral capsid antigens, the ELISA shows comparable specificity and is approximately 4-fold more sensitive. Since IgA antibodies to EBV indicate a high risk of developing nasopharyngeal carcinoma (NPC), the described ELISA, which is more sensitive and objective than IFA, has potential for use in the diagnosis of NPC and for large-scale screening to identify individuals at risk for the development of this disease.

Density gradient centrifugation was applied to isolate cell subsets from tumor cyst and ascitic fluid in eight patients with ovarian serous carcinoma. A comparison of cellular composition and immunologic reactivity of cells from the cysts and from ascitic fluid in each patient was performed. Some differences in density profiles were found, but in each case the consistency of morphologic cell forms in the primary tumor and ascites was documented. Immunophenotypic analyses of isolated cellular fractions using polyclonal and monoclonal antibodies against ovarian carcinoma-associated antigens showed significant immunologic intratumoral heterogeneity. However, there was a similarity of antigen expression in cells from the primary tumors and ascitic fluids. Our study indicated that morphologic and antigenic characterization of a given tumor could be determined in a single representative sample of ascitic fluid.

Data are presented on AB0 and RhD blood groups in 186 patients suffering from carcinoma of cervix uteri and 274 controls from Delhi, India. A strong association is observed between carcinoma patients and blood group A, and a slightly weaker association with blood group B. There is no significant association with RhD blood group. The available data in other populations confirm the association with AB0 blood group.

The phenotypic distribution and immune reactivity of T lymphocyte subpopulations from peripheral blood of 50 patients with urological cancer were determined. Included were 36 patients with bladder transitional cell carcinoma, 7 patients with renal cell carcinoma and 7 patients with prostatic carcinoma. Thirty-eight age-matched patients with benign urological disease served as controls. A depression in immune competence was found in the group of male patients with infiltrating bladder cancer. In more than 50% of the patients with infiltrating bladder carcinoma, the T helper (CD4) subset was reduced with a concomitant inversion in the CD4/CD8 ratio and impairment in the T cell function as determined by the ability to proliferate upon phytohemagglutinin and concanavalin stimulation. Patients with superficial bladder carcinoma, as well as those with renal cell carcinoma had an immune profile similar to that of the control group. The group of patients with prostatic carcinoma had higher mean CD4/CD8 ratios than the control group, resulting from decreased suppressor/cytotoxic cells. Our results have indicated that the characterization of T cell subset and lymphocyte activity correlated well with the histopathologic state of patients with bladder carcinoma. Thus, the determination of the CD4/CD8 ratio may prove a valuable method for monitoring patients with bladder carcinoma, in addition to serial urine cytology, random urothelial biopsies and flow cytometry.

Five antibodies, 2D.1 (pan-leukocyte), AE-1,3 (anti-keratin), B72.3 (anti-carcinoma), ME 1-14 (alpha-chondroitin sulfate proteoglycan) and polyclonal S-100 protein (P-S100), were tested to determine if this panel could be used immunocytochemically to differentiate melanoma from nonmelanoma. A total of 161 cases were evaluated: 145 fine needle aspirates of various body sites and 16 effusions, consisting of 52 melanomas, 41 adenocarcinomas, 11 squamous cell carcinomas, 14 undifferentiated carcinomas, 8 small cell carcinomas, 8 miscellaneous carcinomas, 8 primary central nervous system (CNS) tumors, 7 lymphomas/leukemias, 4 sarcomas and 8 benign effusions. The 52 melanomas were stained by ME 1-14 (in 31 cases) and by P-S100 (in 39 cases), but not by B72.3, AE-1,3 or 2D.1. The 82 carcinomas reacted with P-S100 (in 25 cases), B72.3 (in 37 cases), AE-1,3 (in 68 cases) and 2D.1 (in 1 case), but not with ME 1-14. Lymphomas were stained only by 2D.1 (5 of 7 cases). The eight primary CNS tumors reacted solely with ME1-14 (in 3 cases) and P-S100 (in 3 cases). The eight benign effusions exhibited staining by ME 1-14 (in 1 case), P-S100 (in 1 case), AE-1,3 (in 3 cases) and 2D.1 (in 8 cases), but not by B72.3. Thirty-six cases (including 11 melanomas) failed to stain with any antibody. In summary, 41 of 52 melanomas and 4 of 8 CNS tumors stained with ME1-14, P-S100 or both and were negative for B72.3, AE-1,3 and 2D.1. Only 2 of 101 other nonmelanomas exhibited this pattern. Thus, this panel distinguishes melanoma from other neoplastic and nonneoplastic processes in the majority of cases.

Previous work of ours has demonstrated that a significant amount of natural killer (NK) activity variance after surgery in stage I and II breast cancer patients could be accounted for by both the estrogen receptor (ER) status of the tumor and by social factors, namely, perceived social support and seeking social support as a general coping strategy. As considerable evidence has accumulated that social support in both animal and human populations may have survival value, we sought to test the reliability of this regression model, using coping and perceived support factor values obtained at 3 months after surgery to account for concurrent follow-up NK activity in this serially assessed group of patients. It was found that the most significant variable predicting NK activity at follow-up was tumor ER concentration, with higher NK activity associated with ER- status. In addition, seeking social support as a coping strategy, as well as the perceived quality of support, also entered the model to account for a significant amount of NK activity variance (multivariate F = 5.25, p less than 0.001). If, as the literature suggests, NK activity is relevant to breast cancer control, and since ER- tumors have a worse prognosis, we suggest here that perhaps such tumors are resistant to control by NK cells because they lack the ability to attract an accumulation of effector cells to the tumor site, or because blocking factors at the site of the tumor prevent local tumor control at the site of action. The finding related to social support also replicates results from an independent sample of breast cancer patients. This finding, taken together with other evidence that this social variable is associated with longer survival in breast cancer populations, underscores the potential importance of this social support variable. Our findings also suggest one possible immunological variable involved, with potential clinical significance, for this patient population.

In 40 patients with urinary bladder tumours we compared the results of the immune profile, obtained by means of cutaneous tests with dinitrochlorobenzene (DNCB), and the infiltration of immunocompetent cells in the histological pattern after transurethral tumour resection. It was noted that the more the tumour had infiltrated, the less was it possible to immunize with DNCB or to achieve an immunocyte infiltration in the tumour. According to the classification of the WHO there was a positive reaction in 56-67% and a correlating immunocyte infiltration in 50-73%.

Monoclonal antibodies B 6.2, B 72.3 and B 1.1, reactive against tumor-associated antigens of human breast cancer, have been tested on histologic sections of paraffin blocks from 49 cases of breast cancer and from 13 cases of mammary dysplasia. The results have shown that: (a) the three monoclonal antibodies recognize different antigenic determinants of the cancer cells; (b) monoclonal antibodies B 6.2 and B 1.1 recognize antigens which are frequently expressed in cancer cells; (c) the antigen recognized by monoclonal antibody B 72.3, at the concentrations used, is less frequently expressed in tumors, while it seems to be selective for the apical cell border and luminal secretions of apocrine metaplastic lobules or cysts occurring in mammary dysplasia; (d) intracytoplasmic expression of the antigens is observed only in cancer cells, with rare exceptions; (e) tumor cell populations are heterogeneous in respect to the expression of the antigens detected by the monoclonal antibodies tested; (f) the antigens detected are unrelated to the tumor histotype; (g) the frequency of axillary lymph nodal metastases is not influenced by the presence or intensity of antigenic expression in the primary tumors; but (h) in metastatic tumor cell populations the antigenic expression is higher than in primary tumors. This fact suggests some relationship between tumor metastatization and the expression of antigens recognized by the monoclonal antibodies tested.

Blood group antigens and carcinoembryonic antigen (CEA) were sought in the tissues of 37 bladder tumor cases using enzyme antibody method. A correlation (p less than 0.01) was found between the extinction of ABO (H) and progressive malignant states of the tumor or invasion stage. Significant correlation (p less than 0.05) was observed between the presence of CEA and the invasion stage. The state of the T antigen, however, did not reflect the malignancy grade or invasion stage. The states of ABO (H) and CEA significantly reflected (p less than 0.05) the prognosis, as did the malignancy grade and invasion stage, while the state of the T antigen did not correlate with the prognosis. Although there was a correlation (p less than 0.01) between the extinction of ABO (H) blood group antigens and the presence of CEA, the state of T antigen did not significantly correlate with ABO (H) antigen or CEA. From what has been mentioned, the search for intratissue ABO (H) antigens and CEA is important and will provide a useful auxiliary means in diagnosing biopsy specimens.

Grafts of the metastatic 3LL Lewis lung carcinoma result in pulmonary metastases in mouse strains which share with the tumor strain of origin (C57BL/6, H-2b) the non-H-2 background genes and the H-2D/H-2L region of the major histocompatibility complex. Lung metastases across H-2K region disparities correlated with low expression of H-2Kb-encoded molecule on the tumor cell surface. We tested whether the 3LL tumor cells lack H-2Kb private and/or public specificities by staining 3LL tumor cells and spleen cells of different recombinant mouse strains with H-2d anti-H-2b and anti-3LL antisera, respectively, following absorption of the antisera on spleen cells from various recombinant mouse strains. The data demonstrated weak expression of H-2Kb public specificities (which could represent H-2Db/H-2Kb biregional encoded molecules) and a complete lack of expression of the H-2.33 H-2Kb private specificity by 3LL tumor cells. The findings provide a possible explanation for the 3LL metastatic potential across H-2Kb region disparities.

In 37 patients with ovarian carcinoma stages Ic to IV the values of preoperatively determined tumour markers and the values of the follow-ups were examined in a trial to observe the course of the disease. The following sensitivity was recorded: Ca 125 92%, D-dimer 100%, TPA 76%, CEA 29%, CA 19-9 15%. Ca 125, D-dimer and TPA are unsuitable as follow-ups. They are also detectable in ascites.

The serum concentrations of the tumor-associated antigen SCC were determined in 62 patients with invasive carcinoma of the uterine cervix. Antigen values above 2.0 ng/ml were considered as slightly positive, and those above 4.0 ng/ml as highly positive. Pretherapeutic levels were elevated (greater than 2.0 ng/ml) in 68% of the patients with cervical carcinoma. In 49 patients with carcinoma in situ, 18% of the SCC values were above the normal range. The greatest incidence of positive SCC titers (84%) was observed in women with recurrent cervical carcinoma. Only 6.7% of women in remission had elevated titers. Five of 24 cases (21%) with invasive endometrial carcinoma had SCC values exceeding 2.0 ng/ml. Slightly positive levels of tumor antigen were seen in 1.8% (1/56) of the control subjects. Serial SCC determinations revealed a correlation with the clinical course of disease in 84%. The determination of SCC is useful for the surveillance of patients with cervical squamous cell carcinoma.

Antigens A, B, Lea, Leb, CA 12-5, CA 19-9 and CEA were prepared immunohistologically, a DNA-cytophotometry was carried out and the value of a new in vitro proliferation assay to test cytostatic drugs investigated. Material was as follows: 20 normal ovaries and 105 ovarian tumors. Blood group antigens were expressed at a high percentage from well-differentiated epithelial cells, CEA in 50% and CA 12-5 in 70% of the ovarian carcinoma. Predictions about the dignity of borderline tumors can be made with DNA-cytophotometry. The efficacy of 6 different cytostatic agents was investigated in a new in vitro proliferation assay.

An indirect immunofluorescence (IF) test on fixed cells with Evans' blue counterstain is described for all four human herpesviruses, i.e., herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Comparison with immunodiffusion (ID) for HSV-2 and with ID and complement fixation (CF) for VZV and CMV demonstrated the specificity and high sensitivity of the IF test. Also introduced is a modification of the anti-complement immunofluorescence (ACIF) test for EBV-determined nuclear antigen (EBNA), permitting simultaneous titration of antibodies to this nuclear antigen and of the anti-nuclear factor (ANF). Seroepidemiological studies of these viruses in patients with Hodgkin's disease (HD) in the Netherlands revealed the following pattern: (1) in nodular sclerosing (NS) HD there is a 4-fold (significant) elevation in antibody titer to EBV-VAC, but no elevation to EBV-EA and EBNA; (2) in mixed cellularity (MC) HD a 10-fold (significant) elevation to both EBV-VCA and EA, but no elevation to EBNA is found compared to the control groups. These patterns in NS and MC HD are different from the pattern in nasopharyngeal carcinoma (NPC) which manifests elevations in antibody titers to EBV-VCA and EA as well as to EBNA. Antibody titers to HSV, VZV and CMV are not significantly elevated in either HD or NPC.

Carcinoma-specific antibodies would be a useful tool in immunocytology of serous effusions. We tested the carcinoma-'specific' monoclonal antibody KC4 with cells obtained from pleural effusions evaluated by thoracoscopy and pleural biopsies. KC4 reacted most strongly with carcinoma cells. However, activated mesothelial cells also expressed this marker strongly. Lymphocytes stimulated with phytohemagglutinin were also stained by KC4. Thus KC4 appears to detect a proliferation antigen rather than a carcinoma-specific antigen.

Gm phenotypes and the Km(1) allotype were studied in Tunisian patients with nasopharyngeal carcinoma (NPC). A highly significant association was found between the Km(1) allotype and the NPC disease. Two rare Gm haplotypes, Gm(1, 17; 11, 15, 21) and Gm(1, 3, 5, 11), were found to be significantly increased among the NPC patients.

The serum levels of CA 125 and CA 19-9 were determined by an immunoradiometric assay employing the monoclonal antibody OC 125 and anti-CA 19-9 antibody in 88 patients with ovarian carcinoma. When a cut-off value of CA 125 was set below 35 U/ml in the control group, serum elevated levels of CA 125 were found in 86.7% of the patients with surgically demonstrable ovarian serous cystadenocarcinoma, in 100% (4/4 cases) of clear-cell carcinoma, in 50% (2/4 cases) of endometrioid carcinoma, in 100% (5/5 cases) of undifferentiated carcinoma, and in 80% of the recurrent cases. Using a cut-off value of 37 U/ml, serum elevated levels of CA 19-9 were detected in 68.2% of mucinous cystadenocarcinoma, in 28.9% of serous cystadenocarcinoma, in 75% (3/4 cases) of metastatic ovarian carcinoma, and in 37.5% of the recurrent cases. A statistical analysis of the combination assay using CA 125, CA 19-9, tissue polypeptide antigen (TPA), immunosuppressive acidic protein (IAP), ferritin and CEA was carried out by multivariate method (discriminatory analysis) in 45 patients with ovarian carcinoma and 50 healthy subjects. As a result before treatment, positive rates of a single tumor marker were 79.7% with CA 125, 42.7% with CA-19-9, 73.1% with IAP, 61.7% with TPA, 64.3% with ferritin and 25.4% with CEA, respectively. A combination assay of these markers was useful for detecting identification of ovarian carcinoma, by which it gave a higher accuracy of ovarian cancer detection.

Sera of 120 patients, suffering from cervical cancer (CCa) of different clinical stages (stage 0: n = 27; stage I: n = 29; stage II--IV: n = 64) as well as the sera of 116 healthy individuals as control group were examined for lymphocytoxic antibodies by microlymphocytotoxicity tests, variated in incubation temperatures (15 degress -- 22 degrees -- 37 degrees C) and incubation times (30--180 minutes). At an incubation temperature of 15 degrees C cold reacting lymphocytotoxic antibodies were detected in 26 patients' sera (21.7%) and in 13 control sera (11.2%). At an incubation temperature of 22 degrees C 36 CCa-sera (30%) were positive in comparison to 11 sera of the control group (9.5%). At an incubation 37 degrees C 40 CCa-sera (33.3%) and 7 control sera (6%) were positive. Relating these results to the clinical stages of the carcinoma, the highest percentage of lymphocytotoxicity was found in the sera of patients with an early stage of the disease. Increased evidence of lymphocytotoxic antibodies in the sera of patients with cervical carcinoma supports the assumption, that various immune reactions may be involved in this disease.

Ninety-eight consecutive pleural or peritoneal effusions from 76 patients with various malignant diseases were studied by cytomorphologic evaluation and immunoperoxidase staining for carcinoembryonic antigen (CEA). Cells easily identified as mesothelial cells were always negative in the immunoperoxidase stain. Sixty-seven effusions were from patients with carcinoma. By cytomorphology, 32 of these 67 effusions contained malignant epithelial cells, 15 were suspect, and the remaining 20 were negative. By immunoperoxidase staining, 35 of the 67 effusions contained cells with a positive intracellular reaction for CEA; 13 of these were among the cytomorphologically suspect or negative cases. None of the 31 effusions from patients with nonepithelial malignancies showed positive immunostaining for CEA. A positive immunoperoxidase stain for CEA can thus be used to confirm the presence of malignant epithelial tumor cells in effusions when the cytomorphologic evaluation is uncertain or negative.

In earlier experiments it has been shown that cellular cytotoxicity of patients with prostatic carcinoma (CaP) as measured by cytolysis of EB 33 target cells correlates with the extent of their tumor lesion: a high grade of cytotoxicity was observed only when CaP was confined to gland. In order to define a possible in vivo immunological host-tumor interaction, further characterization of the type of effector cell responsible for in vitro killing has been attempted. Effector cells could be either tumor-specific sensitized T cells, K cells, macrophages or NK cells. Antibody-dependent K-cell activity could most likely be excluded, since autologous and homologous serum did not affect the extent of EB 33 killing when added to the test medium. Further separation of effector cells by nylon wool columns resulted in increased cytolysis of EB 33 target cells. This can be due either to tumor-specific T-cell-mediated mechanisms or to an increased natural killer cell activity, as macrophages and B cells were significantly removed by this measure. Separation of T and NK cells is necessary to ascertain the effector cell responsible for the in vitro killing of tumor cells derived from human CaP.

Four nasopharyngeal carcinomas (NPC) with positive Epstein-Barr virus serology were successfully grafted into athymic mice. Tumor growth could be maintained up to the 22nd passage. Strong similarity between original NPC biopsies and xenografts is demonstrated in terms of light microscopy and immunohistochemistry. Growth kinetics show an increase of tumor volume doubling time and a decrease of the labeling index after several passages. Xenografting of NPC into nude mice is evaluated as a useful in vivo tumor model for experimental NPC investigation.

The following blood cells were examined in 100 patients with invasive carcinoma of the breast and 100 control patients without malignant disease: leukocytes, lymphocytes, monocytes and different sub-populations of lymphoid cells. Lymphoid cells were characterized by E-, EA- and EAC-rosetting technique, alphanaphtyl acetate esterase activity and by the ability of latex phagocytosis. Both groups showed no significant differences. In 81 patients undergoing postoperative radiation therapy lymphocytes and lymphoid cells were reduced considerably. These changes were still evident after 12 months (6 months after completion of radiotherapy). Mainly the T lymphocytes were effected by this decrease. A negative effect of the radiation induced reduction of immune competent cells must be discussed and examined further by clinical trials.

A decrease in the frequency of HLA-A2 was noticed in 37 bronchogenic carcinoma patients studied. HLA-B8 was found to be increased in the prolonged survivors of bronchogenic carcinoma.