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Background: Tumor-derived cytokines play a significant role in the progression of head and neck squamous cell carcinoma (HNSCC). Targeting proteins, such as tristetraprolin (TTP), that regulate multiple inflammatory cytokines may inhibit the progression of HNSCC. However, TTP's role in cancer is poorly understood. The goal of the current study was to determine whether TTP regulates inflammatory cytokines in patients with HNSCC., Methods: TTP messenger RNA (mRNA) and protein expression were determined by quantitative real-time-polymerase chain reaction (Q-RT-PCR) and Western blot analysis, respectively. mRNA stability and cytokine secretion were evaluated by quantitative RT-PCR and enzyme-linked immunoadsorbent assay, respectively, after overexpression or knockdown of TTP in HNSCC. HNSCC tissue microarrays were immunostained for interleukin-6 (IL-6) and TTP., Results: TTP expression in HNSCC cell lines was found to be inversely correlated with the secretion of IL-6, vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE(2) )(.) Knockdown of TTP increased mRNA stability and the secretion of cytokines. Conversely, overexpression of TTP in HNSCC cells led to decreased secretion of IL-6, VEGF, and PGE(2) . Immunohistochemical staining of tissue microarrays for IL-6 demonstrated that staining intensity is prognostic for poor disease-specific survival (P = .023), tumor recurrence and development of second primary tumors (P = .014), and poor overall survival (P = .019)., Conclusions: The results of the current study demonstrated that down-regulation of TTP in HNSCC enhances mRNA stability and promotes secretion of IL-6, VEGF, and PGE(2) . Furthermore, high IL-6 secretion in HNSCC tissue is a biomarker for poor prognosis. In as much as enhanced cytokine secretion is associated with poor prognosis, TTP may be a therapeutic target to reduce multiple cytokines concurrently in patients with HNSCC., (Copyright © 2011 American Cancer Society.)

Background: Autoimmunity is clearly linked with hematologic malignancies, but less is known about autoimmunity and alimentary tract cancer risk, despite the specific targeting of alimentary organs and tissues by several autoimmune diseases. The authors therefore conducted the first systematic evaluation of a broad range of specific autoimmune diseases and risk for subsequent alimentary tract cancer., Methods: On the basis of 4,501,578 US male veterans, the authors identified 96,277 men who developed alimentary tract cancer during up to 26.2 years of follow-up. By using Poisson regression methods, the authors calculated relative risks (RRs) and 95% confidence intervals., Results: A history of autoimmune disease with localized alimentary tract effects generally increased cancer risks in the organ(s) affected by the autoimmune disease, such as primary biliary cirrhosis and liver cancer (RR, 6.01; 95% confidence interval [CI], 4.76-7.57); pernicious anemia and stomach cancer (RR, 3.17; 95% CI, 2.47-4.07); and ulcerative colitis and small intestine, colon, and rectal cancers (RR, 2.53; 95% CI, 1.05-6.11; RR, 2.06; 95% CI, 1.70-2.48; and RR, 2.07; 95% CI, 1.62-2.64, respectively). In addition, a history of celiac disease, reactive arthritis (Reiter disease), and systemic sclerosis all were associated significantly with increased risk of esophageal cancer (RR, 1.86-2.86). Autoimmune diseases without localized alimentary tract effects generally were not associated with alimentary tract cancer risk, with the exception of decreased risk for multiple alimentary tract cancers associated with a history of multiple sclerosis., Conclusions: These findings support the importance of localized inflammation in alimentary tract carcinogenesis. Future research is needed to confirm the findings and improve understanding of underlying mechanisms by which autoimmune diseases contribute to alimentary tract carcinogenesis., (Published 2010 by the American Cancer Society.)

Background: The authors prospectively evaluated the late gastrointestinal (GI) and genitourinary (GU) toxicity and prostate-specific antigen (PSA) control of magnetic resonance imaging (MRI)-guided brachytherapy used as salvage for radiation therapy (RT) failure., Methods: From October 2000 to October 2005, 25 men with a rising PSA level and biopsy-proven, intraprostatic cancer at least 2 years after initial RT (external beam in 13 men and brachytherapy in 12 men) who had favorable clinical features (Gleason score < or =7, PSA < 10 ng/mL, negative pelvic and bone imaging studies), received MRI-guided salvage brachytherapy to a minimum peripheral dose of 137 gray on a phase 1/2 protocol. Estimates of toxicity and cancer control were calculated using the Kaplan-Meier method., Results: The median follow-up was 47 months. The 4-year estimate of grade 3 or 4 GI or GU toxicity was 30%, and 13% of patients required a colostomy and/or urostomy to repair a fistula. An interval < 4.5 years between RT courses was associated with both outcomes with a hazard ratio of 12 (95% confidence interval [95% CI], 1.4-100; P = .02) for grade 3 or 4 toxicity and 25 (95% CI, 1.1-529; P = .04) for colostomy and/or urostomy. PSA control (nadir +2 definition) was 70% at 4 years., Conclusions: The current results indicated that MRI-guided salvage brachytherapy in men who are selected based on presenting characteristics and post-failure PSA kinetics can achieve high PSA control rates, although complications requiring surgical intervention may occur in 10% to 15% of patients. Prospective randomized studies are needed to characterize the relative cancer control and toxicity after all forms of salvage local therapy.

Background: Further optimization of dendritic cell (DC)-based vaccines is required clinically against advanced stage cancer. Given the broad range of expression levels observed in the recently defined tumor antigen EphA2 in a diverse types of cancers, especially in advanced stage or metastatic cancers, the authors evaluated the effectiveness of vaccination using DCs pulsed with EphA2-derived peptides (Eph-DCs) in a murine colon cancer model., Methods: EphA2 protein expression levels were evaluated in advanced colorectal carcinoma tissues from 10 patients by Western blot analysis. C57BL/6 mice were immunized with Eph-DCs twice weekly. Interferon gamma (IFN-gamma) ELISPOT assays were used for the analysis of CD8-positive T cells that were specific for EphA2-derived peptide. Immunized mice were challenged subcutaneously with EphA2-positive murine colorectal adenocarcinoma (MC38) mouse colon tumors or with EphA2-negative BL6 melanoma tumors. In some experiments, mice were injected with anti-CD8, anti-CD4, or antiasialo GM1 antibody to deplete corresponding lymphocyte subsets., Results: Among 10 samples of advanced colorectal carcinoma, 6 samples (60%) overexpressed EphA2. IFN-gamma ELISPOT assays revealed that EphA2-derived peptide-specific CD8-positive T cells were generated by immunization with Eph-DCs. Immunization with Eph-DCs inhibited MC38 tumor growth compared with immunization using unpulsed DCs or phosphate-buffered saline. In contrast, Eph-DC vaccination had no effect on BL6 growth. Antibody depletion studies revealed that both CD8-positive T cells and CD4-positive T cells, but not natural killer cells, played critical roles in the efficacy observed for immunizations with Eph-DCs. Eph-DC vaccines resulted in long-term antitumor immunity against a rechallenge with MC38 tumor cells., Conclusions: The current results demonstrated that Eph-DC vaccines may represent a promising preventative/therapeutic modality in the cancer setting.

Background: Adoptive cell transfer is described as an innovative and challenging option for the treatment of malignant melanoma. In the current study, the generation and expansion of telomerase-specific T-cells for adoptive cell transfer and their use in a syngeneic pancreatic carcinoma mouse model was investigated., Methods: Telomerase-specific T-cells were generated either in vitro by coculture of human lymphocytes with telomerase-peptide-pulsed dendritic cells or in vivo by injection of peptide plus adjuvant into C57BL/6 mice. Spleens were harvested after immunization and lymphocytes were expanded in the presence of feeder cells. T-cells were tested in vitro against human leukocyte antigen (HLA)-matched, telomerase-positive pancreatic carcinoma cells. Tumor-bearing (subcutaneous) mice pretreated with cyclophosphamide were injected intravenously with the expanded cells., Results: It was possible to generate and expand telomerase-specific T-cells with cytotoxic activity. The protocol did not work as well in the murine setting. However, adoptive cell transfer with murine antigen-specific T-cells delayed disease progression in tumor-bearing mice significantly., Conclusions: Generation of antigen-specific T-cells is feasible; the expansion of these cells could be accomplished without loss of function. Antigen-specific T-cells demonstrated significant cytotoxic activity in a syngeneic, subcutaneous mouse model. However, further optimization of the expansion protocol is warranted., (Copyright 2006 American Cancer Society.)

Background: The efficient detection and characterization of micrometastatic cells in the bone marrow of patients with breast carcinoma are of prognostic and therapeutic importance. The technique used must overcome the challenges that result from the small number of target cells (1 per 1 million hematopoietic cells) and the heterogeneous expression of micrometastatic cell markers. In this study, the authors assessed and improved the current methods for purifying and characterizing rare disseminated carcinoma cells., Methods: The authors developed a single-step assay that does not require density-gradient separation. This assay can be performed directly on crude human bone marrow aspirates and is based on the use of immunomagnetic beads coated with an antibody that recognizes an epithelial cell-surface epitope, the epithelial cell adhesion molecule (EpCAM). To determine the specificity of the assay, the authors evaluated bone marrow specimens from 46 control patients., Results: The novel method was highly reproducible and was capable of detecting as few as 10 carcinoma cells among 50 million hematopoietic cells. The yield was nearly 100%, with only 0.01% nonspecific cell draining. The authors found that 68 +/- 51 cells were trapped per 50 million cells in control crude aspirates and that density-gradient separation increased this number by 2-fold to 29-fold. These trapped cells expressed EpCAM, represented 1.4 x 10(-4) % of the sample, and were characterized as of hematopoietic cell origin (CD45 positive) or progenitor cell origin (CD34 positive)., Conclusions: The authors developed a highly efficient and reproducible, single-step immunomagnetic assay that may be performed directly on crude human bone marrow aspirates. The authors believe the current study is the first to demonstrate that some rare bone marrow cells (CD45-positive or CD34-positive cells) may express EpCAM and, to some extent, may contaminate the purified micrometastatic cell fraction. Thus, a universal marker for micrometastatic cells remains to be discovered., (Copyright 2004 American Cancer Society.)

Background: Breast carcinoma is one of the most common carcinomas in pregnant women. The incidence of breast carcinoma may increase in the future because of the trend toward delayed childbearing and increased screening. However, very few contemporary studies have attempted to identify the combined histopathologic and immunohistochemical features of breast carcinoma in these patients., Methods: The authors evaluated 39 patients with breast carcinoma occurring coincident with pregnancy. This was comprised of a critical histologic review and immunohistochemical evaluation to determine the status of prognostic and predictive markers including estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, Ki-67, and p53., Results: The mean age at presentation was 33 years (range, 24-44 years). Densities and/or masses were noted on mammograms in 14 of 16 patients with available radiographic information. The primary tumors were a mean of 4.5 cm in greatest dimension (range, 0.1-13.5 cm). Two of the 39 patients had clinical (American Joint Committee on Cancer) Stage I disease, 19 patients had Stage II disease, 16 had Stage III disease, and 2 patients had Stage IV disease at the time of presentation. Histologically, high-grade invasive ductal carcinomas were found in 32 of 38 patients. The primary tumor was not available for review in one patient. A predominantly solid pattern of growth was observed in nine patients. Lymphovascular invasion was identified in 61% of cases. Ductal carcinoma in situ was identified in 72% of tumors and was high grade in all cases. Of the 25 patients tested, ER positivity was found in 7 patients, PR positivity was found in 6 patients, HER-2/neu positivity was found in 7 patients, and p53 positivity was found in 12 patients. The proliferation rate as shown by Ki-67 staining was high in 60% of the cases. Follow-up information was available for 35 patients and the mean follow-up period was 43 months (range, 2-163 months). Distant metastasis occurred in seven patients. The mean time to disease recurrence was 20.4 months (range, 10-33 months). Of 35 patients, 4 have died, 22 were alive with no evidence of disease, and 9 were alive with disease at the last follow-up. The remaining four patients died of unknown causes., Conclusions: Pregnant women with breast carcinomas generally present with advanced-stage disease and the tumors have poor histologic and prognostic features. The findings from the follow-up indicated that these tumors do not follow a very aggressive clinical course as was proposed in earlier reports. Breast carcinomas occurring during pregnancy share many histologic and prognostic similarities with breast carcinoma occurring in other young women., (Copyright 2003 American Cancer Society.)

Background: Most commercial fecal occult blood tests (FOBT) used for colorectal carcinoma screening of Western populations are guaiac-based, manually developed, subjective, and sensitive to dietary components. Preliminary studies demonstrated the unsuitability of these tests for screening a Chinese population. The goal of the current study was to evaluate the performance characteristics of a human hemoglobin-specific automated immunochemical FOBT, the Magstream 1000/Hem SP (Fujirebio, Inc., Tokyo, Japan), in a Chinese population referred for colonoscopy., Methods: Two hundred fifty consecutive patients who were referred for colonoscopy and met the study inclusion criteria provided samples for the immunochemical FOBT (without dietary restrictions) from two successive stool specimens. Tests were developed with an automated instrument that had an adjustable sensitivity threshold. The sensitivity, specificity, and positive predictive value for detecting colorectal adenomas and carcinomas were calculated according to the manufacturer's instructions over a range of sensitivity levels., Results: At the optimal threshold level, the sensitivity, specificity, and positive predictive value for detection of significant colorectal neoplasia (adenomas >or= 1.0 cm and carcinomas) were 62%, 93%, and 44%, respectively. The test was easy to use, and results did not depend on operator experience., Conclusions: The automated immunochemical FOBT used in the current study was a robust, convenient, and useful tool for colorectal carcinoma screening in the study population., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11369)

Background: The authors recently reported that the SART2 and SART3 antigens encode tumor epitopes recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes (CTLs) established from esophageal carcinoma patients. The current study investigated these antigens to explore a potential molecule for specific immunotherapy for colorectal carcinoma patients., Methods: The SART2 and SART3 antigens were investigated by Western blotting in colorectal carcinoma cell lines and in cancer tissues. For induction of CTLs, peripheral blood mononuclear cells (PBMCs) of HLA A-24-positive cancer patients were stimulated in vitro with peptides., Results: The 140 kD SART3 antigen was expressed in both the cytosol and nuclear fractions of all six colon carcinoma cell lines, 27 of 41 (65.9%) cytosol fractions, 30 of 41 (73.2%) nuclear fractions of colorectal carcinoma tissue samples, and in 0 of 7 non-tumorous tissues. The 100 kD SART2 antigen was expressed in the cytosol fractions of 2 of 6 colon carcinoma cell lines, 5 of 20 (25%) cytosol fractions of colorectal carcinoma tissue samples, and in 0 of 7 non tumorous tissues. HLA-A24-restricted CTLs cytotoxic to colon carcinoma cells were induced from PBMCs of colon carcinoma patients by stimulation with the two immunogenic peptides of SART3., Conclusions: The SART3 antigen could be an appropriate target molecule for specific immunotherapy for colorectal carcinoma patients., (Copyright 2002 American Cancer Society.)

Background: The authors attempted to evaluate prospectively the usefulness of serum prostate specific antigen (PSA) complexed to alpha-1-antichymotrypsin (PSA-ACT) in the early detection of prostate carcinoma and its ability to discriminate between prostate carcinoma and benign prostatic hyperplasia (BPH), especially among patients with intermediate PSA levels., Methods: Between December 1999 and August 2000, systematic sextant biopsies were performed on 281 prospective patients with prostate carcinoma who had serum PSA levels between 4.1 ng/mL and 20.0 ng/mL. The serum samples were assayed by using kits that were designed specifically for measuring serum PSA, PSA-ACT, and free PSA levels. The clinical values of PSA, PSA-ACT, the free PSA to total PSA ratio (F/T ratio), the free PSA to PSA-ACT ratio, PSA density (PSAD), and PSA-ACT density (ACTD) were compared by using receiver operating characteristic (ROC) curve analysis., Results: Biopsy yielded no evidence of malignancy in 198 patients, and prostate carcinoma was confirmed in 83 patients. ROC analysis demonstrated that the area under the curve (AUC) for PSA-ACT was greater than that for total PSA and was equivalent to that for the F/T ratio in both groups of patients (PSA ranges of 4.1-20.0 ng/mL and 4.1-10.0 ng/mL, respectively). The AUC for the ACTD was greater than the AUC for the PSAD and had the highest value of all parameters., Conclusions: The measurement of PSA-ACT represents an alternative to the use of total and free PSA. The ACTD value is the most useful for discriminating between BPH and prostate carcinoma., (Copyright 2002 American Cancer Society.)

Background: Based on the cross-reactivity of the human carcinoma antigen, HCA, with epiglycanin, a mouse mammary carcinoma cell surface glycoprotein, HCA has been detected in the tissue and blood of patients with every type of epithelium-derived cancer tested., Methods: Competitive binding assays utilized the following antiepiglycanin antibodies: a polyclonal rabbit antiserum (immunoglobulin [Ig] G and IgM) in a radioimmunoassay; mouse monoclonal antibodies (Ab-1, IgM) on immunoplates; anti-idiotypic (Ab-2) and anti-anti-idiotypic (Ab-3) monoclonal antibodies (both IgG) from spleen cells of C57BL mice immunized, respectively, with Ab-1 and Ab-2, and utilized on immunoplates. IgG and IgM antibodies were evaluated for their ability to detect HCA and to distinguish between the blood of patients with, or without, carcinomas., Results: Assays with the rabbit antiserum distinguished plasmas of metastatic breast carcinoma patients from those of patients with benign breast disease with a sensitivity of approximately 93% (specificity 90%). Antiepiglycanin IgM monoclonal antibodies (i.e., AE3) showed high specificity and sensitivity (> 90%) with sera from advanced carcinoma patients when compared with normal sera. The IgG anti-anti-idiotypic (Ab-3) monoclonal antibodies (i.e., AF2), which bind the same epitope as Ab-1, appear to possess less nonspecific binding capacity, however, than the Ab-1 (IgM) antibodies. Anti-Ab-1 (i.e., C8F2) anti-idiotypic monoclonal antibodies, which bear an idiotope equivalent to the epitope present in epiglycanin and the HCA, demonstrated greater consistency as a standard calibrator and for coating wells than epiglycanin., Conclusions: The concentration of the HCA in the body fluids of patients with carcinomas may be accurately determined by competitive binding assays. It is suggested that the use of anti-idiotypic antibodies (IgG), rather than epiglycanin/HCA, and Ab-3 anti-anti-idiotypic antibodies (IgG), rather than Ab-1 (IgM), will improve the consistency, as well as the sensitivity and specificity, of the assay., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10124)

Background: Cancer antigen 15-3 (CA 15-3), a circulating marker that determines secreted products of the polymorphic MUC1 gene, has been established as a convenient tool for monitoring breast carcinoma patients., Methods: The authors investigated alterations of soluble CA 15-3 in 57 postoperative breast carcinoma patients while they were receiving intensified adjuvant chemotherapy with granulocyte colony stimulating factor (G-CSF) support; 26 patients had American Joint Committee on Cancer (AJCC) Stage II, and 31 patients had AJCC Stage III breast carcinoma. Serial CA 15-3 values recorded thoughout the treatment were compared with baseline values, analyzed for correlation with hematologic and biochemical parameters, and compared with clinicopathologic characteristics and patient outcome. At a median follow-up time of 32 months, 47 of these patients remained relapse-free., Results: A twofold increase of CA 15-3 was detected at the end of the second week of treatment, remained significantly elevated in most patients at above the cutoff level of 30 U/mL throughout the treatment period (P < 0.0001), and subsided to pretreatment values 1-2 months after treatment cessation. CA 15-3 values were found to be associated strongly with absolute neutrophil count, serum lactate dehydrogenase, and alkaline phosphatase. The median values and the kinetics of tumor markers did not differ over time in regard to hormonal receptor status and disease recurrence., Conclusions: These data provide strong evidence that G-CSF administration can induce elevation of CA 15-3 and indicate that false-positive results should be considered when evaluating CA 15-3 in patients who are receiving G-CSF. It is speculated that this phenomenon occurs through the induction of MUC1 antigen of unknown origin by G-CSF. Experimental investigation of this clinical observation is warranted., (Copyright 2001 American Cancer Society.)

Background: The value of serum tissue polypeptide specific antigen (TPS) as a complement to CA 19-9 in the detection of pancreatic carcinoma was determined prospectively. TPS and CA 19-9 levels obtained at the time of diagnosis in patients suspected of having chronic pancreatitis or pancreatic carcinoma were evaluated in receiver operating characteristic (ROC) curve analysis., Methods: Serum TPS and CA 19-9 levels were measured by immunoassays in 122 subjects, 48 with pancreatic carcinoma and 74 with chronic pancreatitis., Results: Elevated levels of CA 19-9 were detected preoperatively in 70% of pancreatic carcinoma patients and in 19% of chronic pancreatitis patients. Elevated levels of TPS were detected in 100% of patients with pancreatic carcinoma and in 22% of patients with chronic pancreatitis. The median levels of TPS and CA 19-9 for pancreatic carcinoma were significantly higher than those for chronic pancreatitis (P < 0.0001). Increasing the upper reference value of TPS allowed for better discrimination between chronic pancreatitis and pancreatic carcinoma. ROC curve analysis showed that the introduction of 200 U/L as a decision criterion for TPS did not reduce its sensitivity but significantly improved its specificity. At a specificity of 98% for TPS, discrimination between pancreatic carcinoma and chronic pancreatitis was found to be 97%. Increasing the upper reference level for CA 19-9 to attain a specificity of 98% decreased its sensitivity from 70% to 33%., Conclusions: At an elevated cut-off level for TPS (200 U/L), almost complete discrimination between pancreatic carcinoma and chronic pancreatitis was obtained. TPS will be more useful than CA 19-9 in the differential diagnosis of pancreatic carcinoma and chronic pancreatitis., (Copyright 2000 American Cancer Society.)

Background: Up to now, the expression of the tumor-associated Thomsen-Friedenreich (TF) antigen in colorectal carcinoma has not been thoroughly investigated with particular emphasis on its correlation with established clinicopathologic characteristics and classifications as well as its prognostic relevance., Methods: Formalin fixed, paraffin embedded specimens from 264 patients with colorectal carcinoma were stained using an avidin-biotin complex-peroxidase assay. As primary monoclonal antibodies (MAbs), A78-G/A7, which binds to TFalpha and TFbeta antigen irrespective of its carrier, and BW835, which detects TFalpha on MUC1 repeat peptide, were applied., Results: MAbs A78-G/A7 and BW835 labeled 64.8% and 58. 0%, respectively, of carcinomas. None of the binding patterns correlated with gender, tumor localization, or growth type. Only BW835 reactivity exhibited a significant correlation with increasing pTNM staging and histologic grading. Staining of the MAb A78-G/A7 was significantly stronger in carcinomas that contained a mucinous component. In univariate survival analysis, in addition to pTNM staging and histologic grading, reactivity with A78-G/A7 as well as BW835 were significantly correlated with lower survival probability. Multivariate analysis according to the Cox proportional hazards model revealed only pTNM staging, histologic grading, and A78-G/A7 staining to be independent prognostic factors., Conclusions: According to these results, TF disaccharide represents a cancer-associated antigen in colorectal carcinoma that exhibits qualities of a prognostic marker. As demonstrated by BW835 staining, it is obviously coexpressed with MUC1 peptide core in a great number of cases. These results suggest that TF, in addition to MUC1, might also serve as a useful target antigen in the treatment of patients with colorectal carcinoma., (Copyright 2000 American Cancer Society.)

Background: Accumulation of mutated p53 in malignant cells can lead to the generation of anti-p53 autoantibodies in the serum and other body fluids of cancer patients. This retrospective study was performed to evaluate the prognostic significance of preoperative serum and ascitic anti-p53 antibodies in advanced ovarian carcinoma., Methods: In 113 ovarian carcinoma patients who presented with significant amounts of ascites, anti-p53 autoantibodies were determined by a highly specific enzyme-linked immunosorbent assay of blood and ascites. Disease free and overall survival of study patients was estimated by the product limit method of Kaplan and Meier. Differences in survival were examined according to criteria of Mantel and Breslow. A multiple regression analysis based on the Cox proportional hazards model was used to determine the independence of prognostic variables., Results: Serum and ascitic anti-p53 antibodies were found in 28 (25%) and 21 (19%) of the study patients, respectively. In univariate analysis, detection of anti-p53 antibodies in ascites but not in serum was found to be a sign of unfavorable disease free survival (P<0.003) and overall survival (P < 0.01). Multivariate analysis revealed that anti-p53 positivity in ascites retained independent significance only in the prediction of adverse progression free survival (P<0.01)., Conclusions: The generation of a humoral immune response against p53 protein in the close tumor environment, as demonstrated by the occurrence of p53 autoantibodies in the ascitic fluid of ovarian carcinoma patients, is associated with poor disease free survival., (Copyright 2000 American Cancer Society.)

Background: Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes., Methods: One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed., Results: A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis., Conclusions: Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action.

Background: The expression of variant isoforms of CD44 is correlated with the ability of tumor cells to metastasize in some clinical carcinomas. In this study, the serum concentration of soluble splice isoforms of CD44 that shared exon variant 6 (sCD44v6) were measured and the histologic expression of CD44v6 in tumors from patients with gastric carcinoma examined., Methods: Serum samples were obtained from 102 patients with primary gastric carcinoma before surgery and serum levels of sCD44v6 were determined with an enzyme-linked immunoadsorbent assay. The expression of CD44v6 in tumors was examined by immunohistochemical staining., Results: Both the serum concentration of sCD44v6 and its expression in tumors were associated significantly with the depth of invasion of the tumor, lymph node metastasis, and clinical stage in patients with diffuse type gastric carcinoma. Among patients with gastric carcinoma, the serum level of sCD44v6 was higher in those with CD44v6 positive tumor cells than in those with CD44v6 negative tumor cells. The serum level of sCD44v6 was a prognostic indicator in patients with diffuse type gastric carcinoma, as was the histologic expression of CD44v6. However, neither CD44v6 nor sCD44v6 was a predictor of survival time in patients with intestinal type gastric carcinoma., Conclusions: It appears that CD44v6 and sCD44v6 are related to the progression of diffuse type gastric carcinoma. An elevated serum level of sCD44v6 may be useful as a prognostic indicator in patients with diffuse type gastric carcinoma.

Background: Controversial findings have been reported regarding the expression of the Thomsen-Friedenreich (TF) antigen in colorectal neoplasms when different monoclonal antibodies (MoAbs) have been used. Moreover, there is no information available regarding the carrier protein(s) of this antigen., Methods: Forty-five colorectal adenomas and 48 carcinomas were studied by avidin-biotin complex-peroxidase immunohistochemistry. The immunohistochemistry employed the MoAb BW835, which was reactive to a carrier specific and site specific TF antigen on MUC1 mucin, as well as reference antibodies directed to MUC1 (HMFG2) or MUC2 core peptides (4F1) and directed to TF antigen irrespective of its carrier (A78-G/A7, peanut agglutinin). To evaluate the coexpression of different epitopes by the same antigen, sandwich enzyme-linked immunoadsorbent assays were performed., Results: Although MUC1 peptide antigen and MUC1-bound TF antigen were not detectable in normal or transitional mucosa surrounding colorectal neoplasms, expression of these antigens in adenomas accompanied the development of high grade dysplasia. By contrast, MUC2 expression detected by the MoAb 4F1 was inversely correlated with the progression of the adenoma-carcinoma sequence. In well- and moderately differentiated colorectal carcinomas, the neo-expressed TF antigen is predominantly bound to MUC1. This feature could be demonstrated by antigen coexpression using peptide and the TF antigen specific MoAbs. However, in mucinous carcinomas exhibiting a weak MUC1 peptide expression in most specimens, the presence of TF antigen on the MUC2 peptide core cannot be ruled out., Conclusions: TF antigen is strongly coexpressed with MUC1 mucin peptide core in the colorectal adenoma-carcinoma sequence, resulting in well- and moderately differentiated carcinomas. Only in mucinous carcinomas may it be coexpressed with MUC2 antigen.

Background: Mechanisms whereby cells infected with human papillomavirus (HPV) escape immune surveillance, ultimately leading to invasive cervical carcinoma, may involve changes in local cytokine production, loss of responsiveness to cytokines, and alterations in the expression of immune-regulatory molecules such as histocompatibility-related leukocyte antigen (HLA) Class 1 and 2 and ICAM-I. This study examined the separate and combined effects of immune-activating cytokines, interferon (IFN)-gamma, IFN-beta, and tumor necrosis factor (TNF)-alpha, on the expression of these molecules., Methods: Membrane protein expression and cellular mRNA levels were analyzed in cervical carcinoma-derived cell lines, SiHa and CaSki (with low and high HPV16 copy number, respectively), after exposure to cytokines., Results: Both cell lines demonstrated constitutive expression of HLA Class 1 but not HLA Class 2 membrane antigens. IFN-gamma and -beta induced changes in Class 1 mRNA levels but not in membrane molecule expression. IFN-gamma induced dose-dependent expression of Class 2 membrane and mRNA molecules in both cell lines (more pronounced in SiHa than in CaSki cells), which was antagonized by IFN-beta. Constitutive ICAM-I membrane expression was observed only on CaSki cells, although ICAM-I mRNA was expressed in both cell lines. IFN-gamma up-regulated the membrane expression of this molecule, whereas IFN-beta led to its suppression. Differential modulation of ICAM-I mRNA was observed in both cell lines. A lack of response to TNF-alpha was observed throughout the experiments., Conclusions: The findings of this study point to possible mechanisms leading to suppression of local immune response in the pathogenesis of HPV-associated neoplasia. They also emphasize the complexity of developing an efficient cytokine therapy for patients with premalignant cervical disease.

Background: It has been reported that anticancer drugs induce apoptosis, thus it is considered that apoptosis may be important in cancer chemotherapy. The authors examined whether the administration of 5-fluorouracil (5-FU) enhanced apoptosis of gastric carcinoma cells, and investigated the relationship between apoptosis and the expression of Ki-67 and the Bax gene., Methods: Twenty patients with gastric carcinoma were divided into 2 groups. Ten patients received continuous intravenous 5-FU at 500 mg/body weight/day for 7 days preoperatively whereas the other 10 did not receive any chemotherapy or radiotherapy, and served as controls. For detection of apoptotic cells, apoptotic indices were examined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. The expression of Ki-67 and the Bax gene were examined by immunohistochemical staining., Results: Apoptosis of gastric carcinoma cells increased significantly to 6.1 +/- 3.6% in the 5-FU-treated group compared with the controls (3.2 +/- 1.8%; P < 0.05). The level of expression of Ki-67, a marker of cell proliferation, was inversely correlated with the extent of TUNEL staining that was specific for apoptosis. The percentage of cells that were immunopositive for Ki-67 fell to 50.8 +/- 7.3% of the apoptotic area in the 5-FU-treated group compared with 57.5 +/- 6.9% in the controls (P < 0.05). There was no significant correlation between frequency of apoptotic cells and the level of expression of the Bax gene., Conclusions: The authors demonstrated enhanced apoptosis in gastric tumors after continuous intravenous infusion of 5-FU for 7 days. This result suggests that it may be possible to evaluate the effects of chemotherapy by detecting apoptotic cells.

Background: Genetic alterations of the p53 tumor suppressor protein are the most frequent molecular events in human carcinogenesis. For as yet unknown reasons, mutant p53 often acts as an immunogen for autoantibody generation. These autoantibodies can be detected in the serum of cancer patients. The presence of such antibodies has been identified in a subset of patients with ovarian carcinoma, but their clinical significance has not been investigated., Methods: Serum samples from patients with ovarian carcinoma were quantitatively analyzed for the presence of p53 autoantibodies with a time-resolved immunofluorometric procedure. Tumor p53 overexpression was assessed by immunohistochemical analysis of tissue sections. Kaplan-Meier survival curves were calculated for p53 antibody positive and negative patients, and the Cox model was used to evaluate the strength of the associations between the presence of serum p53 antibodies and cancer relapse or death, and also between the presence of such antibodies and other clinicopathologic features., Results: p53 antibodies were detected in the serum of 41 of 174 patients with ovarian carcinoma (24%). Antibody levels ranged from a few hundred to 9 x 10(6) arbitrary Units/L, and fluctuated during the course of the disease. p53 antibody positive patients tended to have tumors overexpressing p53, but the association between the two parameters was not statistically significant (P = 0.13). There was also no association between the presence of p53 antibodies and clinical stage, tumor histologic type, or overall patient survival. However, these antibodies were more frequently present in patients older than 50 years (P = 0.001), in patients with moderately or poorly differentiated tumors (P = 0.001), and in patients who received chemotherapy (P = 0.015), and who suffered relapse after surgery (P = 0.018). In univariate analysis, p53 antibody positive patients were at an increased risk for relapse but not death. In multivariate analysis, the differences in disease free and overall survival between patients who were p53 antibody positive or negative were not statistically significant., Conclusions: p53 autoantibodies are found frequently in the serum of patients with ovarian carcinoma. The presence of such autoantibodies was associated with older patient age, more aggressive tumors, and reduced patient disease free survival. In multivariate analysis the prognostic value of p53 autoantibodies was not statistically significant.

Background: The functional significance of cytokines expressed in situ by tumor cells and tumor infiltrating lymphocytes (TIL) in human colon carcinomas is largely unknown., Methods: We assessed TIL expression of interleukin-2 (IL-2), IL-4, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), granulocyte-macrophage colony stimulating factor (GM-CSF), IL-10, and transforming growth factor-beta (TGF-beta), and tumor cell expression of IL-10 and TGF-beta in situ in 49 primary colon carcinomas and 20 metastases using immunohistochemistry., Results: The percentage of primary colon carcinoma samples in which > 20% of TIL expressed each cytokine was as follows: IL-4: 47%; TNF-alpha: 22%; TGF-beta: 10%; IFN-gamma: 6%; IL-2:2%; IL-10: 0%; and GM-CSF: 0%. Lymphocytes more commonly infiltrated colon carcinoma primaries than metastases, and TIL expression of IL-4 and TNF-alpha was more common in primary than metastastatic carcinomas. Expression of TNF-alpha by even a small proportion (> or = 3%) of the TIL in a colon carcinoma specimen was associated with better overall survival (P = 0.01) when compared with patients with little or no TIL TNF-alpha expression (5-year survival 82% vs. 47%). Expression of IL-4 by > or = 20% of colon carcinoma TIL was also associated with improved survival (P = 0.01; 5-year survival 87% vs. 50%). The expression of IL-10 or TGF-beta by colon carcinoma TIL or colon tumor cells themselves was not associated with impaired survival. Benign epithelial cells stained positively for IL-10 and TGF-beta more frequently than tumor cells (P < 0.001)., Conclusions: There are differences between the immune microenvironment of primary tumors and metastases. Although IL-10 is expressed by colon carcinoma cells and TIL, it is unlikely that it plays an important immunosuppressive role. TNF-alpha and IL-4 are commonly expressed by colon carcinoma TIL and both are associated with improved survival.

Background: Immunosuppressive acidic protein (IAP) has been reported to have close correlation with the impairment of host immune response. To evaluate the significance of IAP in clinical studies, the prognostic value of preoperative IAP was investigated in clinical trials of patients with gastric carcinoma after curative resection., Methods: An appropriate IAP threshold value of 580 micrograms/mL was determined using Cox's proportional hazards model. Five-year survival rates were estimated for high and low IAP groups in three different clinical studies. Meta-analysis was performed based on individual patient data, and summarized hazard ratios were estimated using a stratified proportional hazards model., Results: Meta-analysis of the three clinical trials demonstrated that patients with preoperative IAP levels above the threshold had significantly poorer cancer related survival (P = 0.0039) and absolute survival (P = 0.0023), even after adjustment for the major prognostic factors., Conclusions: Gastric carcinoma patients with an IAP value above the threshold level of 580 micrograms/mL have a higher risk of cancer death and absolute death than patients with an IAP value below the threshold value.

Background: Thomsen-Freidenreich (T) antigen, the immediate precursor antigen of the human blood MN system, has been detected in malignant cells, but not in most normal cells in which it is cryptic but can be unmasked by desialylation. In this study, we determined the prognostic significance of T antigen in specimens with gastric carcinoma., Methods: Expression of T antigen was studied immunohistochemically in 157 gastric carcinoma tissue specimens obtained at surgery from the First Department of Surgery, Osaka City University Medical School between 1983 and 1987., Results: T antigen expression was detected in 72 of the tumors (45.9%). The staining pattern was inclined to change from a luminal surface type to a cytoplasmic type in accordance with decreasing degree of cell differentiation. The rate of expression of T antigen significantly increased (P < 0.05) with serosal invasion, and was significantly higher (P < 0.01) in patients with hepatic or lymph node metastasis or peritoneal dissemination than in those without such metastasis or dissemination. Furthermore, among patients with Stage III or IV disease, those with T antigen-positive tumors had a significantly poorer prognosis than those with T antigen-negative tumors., Conclusions: Our findings suggest that relationships exist between expression of T antigen and depth of invasion, hepatic metastasis, lymph node metastasis, or peritoneal dissemination, and that T antigen may be a good indicator of the prognosis of patients with gastric carcinoma.

Background: Previous studies have established that soluble interleukin-2 receptor alpha (sIL-2R alpha) levels are elevated in ascites and sera from individuals with advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] Stage III/IV). This study was undertaken to evaluate sIL-2R alpha levels in individuals with benign ovarian neoplasms and early stage ovarian cancer (FIGO Stage I/II). Comparison with CA 125 levels was performed to assess screening potential., Methods: Sera from 92 healthy individuals, 61 with benign adnexal masses, 12 patients with FIGO Stage I/II ovarian cancers, and 27 patients with FIGO Stage III/IV ovarian cancers were assayed for sIL-2R alpha by enzyme-linked immunosorbent assay and CA 125 by radioimmunoassay., Results: The mean serum sIL-2R alpha levels for benign pelvic masses, and Stage I/II and Stage III/IV epithelial ovarian cancer were 1507 +/- 82, 1631 +/- 274, and 2596 +/- 384 U/ml, respectively. The difference between mean serum sIL-2R alpha levels in individuals with benign adnexal masses and Stage III/IV epithelial ovarian cancer was statistically significant (P < 0.05). In addition, of the four individuals with FIGO Stage I/II ovarian cancer who had CA125 levels below 35 U/ml, the accepted upper limit of normal, three patients had elevated serum sIL-2R alpha levels. Eleven of 12 patients (92%) with potentially curable Stage I/II disease had elevated serum levels of either sIL-2R alpha or CA125 and 8 of 12 (67%) had elevations of both sIL-2R alpha and CA125. Sensitivity and specificity of a combination of CA 125 and soluble IL-2R alpha were 88.5% and 27.1%, respectively., Conclusion: Soluble interleukin-2 receptor alpha levels do not appear to differentiate between benign adnexal lesions and early malignancy; however, measurement of sIL-2R alpha levels in combination with CA125 warrants further evaluation to determine if together they will identify individuals with Stages I and II ovarian cancer.

Background: The expression of a distinct alpha-3/4-monofucosylated polylactosaminoglycan epitope, which is detected by monoclonal antibody FW6, was investigated by comparative immunohistochemical analysis of colorectal tissue specimens exhibiting different grades of premalignant and malignant transformation. The presence of this peculiar epitope was compared with different lewis type 2 blood group antigens., Methods: Paraffin embedded specimens from 8 hyperplastic polyps, 46 adenomas, 27 colorectal carcinomas, and 10 corresponding liver metastases were studied. Staining reactions included monoclonal antibodies FW6, AM-3 (anti-sialosyl-Le(x)), LeuM1 (anti-Le(x)), and 12-4LE (anti-Le(y)) in a standard peroxidase-antiperoxidase method., Results: Hyperplastic polyps were not reactive with FW6 or LeuM1, but showed a slight binding of AM-3 and 12-4LE in some cases. Approximately two-thirds of the adenomatous polyps displayed a pronounced staining activity by AM-3, and approximately half of them revealed FW6, LeuM1, and 12-4LE binding. Only the expression of the FW6 (P < 0.005) epitope correlated with the presence of severe dysplasia. All antibodies were more or less reactive with colorectal carcinomas and their liver metastases, and some showed correlating binding patterns., Conclusions: FW6 revealed a high specificity for adenomas with areas of severe epithelial dysplasia. Because this monoclonal antibody also detects the great majority of carcinomas, it is reasonable to postulate that the alpha-3/4-monofucosylated polylactosaminoglycan epitope is an important marker for malignant transformation in the colorectal adenoma-carcinoma sequence.

Background: Although stomach carcinoma is estimated to be one of the most frequent cancers worldwide, still little is known about the immunity of patients with stomach cancer. Humoral tumor immunity has been studied by isolating B cells of patients with cancer to characterize the activity of such antibodies on tumor cells. Apoptosis, programmed cell death, explains the suicide of cells by fragmentation of DNA, cell shrinkage and dilation of endoplasmatic reticulum, followed by cell fragmentation and formation of membrane vesicles called apoptotic bodies. Apoptosis serves to remove unwanted, damaged, or dangerous, e.g., precancerous cells., Methods: The human monoclonal antibody SC-1 was isolated from a patient with a signet ring cell carcinoma of the stomach by fusion of spleen lymphocytes to the heteromyeloma SPM4-0. The antibody was tested for growth-inhibiting effects in vitro in soft agar assays, in 3-H thymidine uptake experiments, and in a mitochondrial enzymatic activity assay. In vivo intraperitoneal tumor growth was investigated in nu-nu mice., Results: The immunoglobulin M (lambda) antibody identifies a molecule with a molecular weight of approximately 49 kilodaltons in stomach carcinoma cells. No reactivity was observed with carcinomas of other origins, melanomas, lymphomas, or normal tissue. When tested in vitro, the antibody inhibited tumor cell growth in cell culture and soft agar. In vivo growth of stomach carcinoma cells in nu-nu mice was reduced when the antibody was injected after the tumor cells. Ultrastructural and functional studies revealed that the SC-1 antibody induced apoptosis of tumor cells., Conclusion: The human monoclonal antibody SC-1 described here inhibited growth of stomach carcinoma cells in vitro and in vivo by inducing apoptosis, and may, therefore, be valuable for treating patients with stomach carcinoma.

Background: The syndrome of multiple endocrine neoplasia type 1 frequently involves the adrenal cortex. The relationship between the diffuse neuroendocrine system and the adrenal cortex is not clear however, particularly as the adrenal cortex is not considered to be an intrinsic part of the diffuse neuroendocrine system., Methods: The possible relationship between the adrenal cortex and the diffuse neuroendocrine system was investigated in a study of the immunohistochemical characteristics of ten normal adrenal glands, four adrenal adenomas, and 18 adrenocortical carcinomas using the indirect peroxidase method of staining intermediate filaments and neuroendocrine proteins., Results: With synaptophysin, NSE, and vimentin there was focal staining in only few zona glomerulosa cells in the normal adrenal cortex, whereas adrenocortical carcinomas and adenomas were extensively positive for these proteins. Keratin immunoreactivity, present in 100% of the normal cortices, was demonstrable in only half of the carcinomas and absent in all adenomas., Conclusions: Adrenocortical tumors may originate from neuroendocrine foci. The findings illuminate the pathogenesis of adrenocortical carcinoma, and may carry significant implications about the choice of treatment of patients with this malignancy and other related tumors.

Background: The objective of this study was to identify factors that categorize patients with epithelial ovarian carcinoma into favorable and unfavorable prognostic groups at the time of initial treatment., Methods: Data were analyzed from 51 women who were treated at Yale University, had an evaluable CA 125 half-life (t1/2), and were followed for disease recurrence for at least 2 years., Results: Grade, maximum level of CA 125, and histology did not provide useful prognostic information. Stage, residual disease, minimum CA 125, and CA 125 t1/2 individually were predictive of persistent disease or recurrence within 3 years of diagnosis with sensitivities of 97, 70, 34, and 49%, respectively, and specificities of 33, 83, 100, and 83%, respectively. When these factors are combined, defining an unfavorable prognostic group as those patients having residual disease greater than 1 cm, CA 125 t1/2 greater than 12 days, or minimum CA 125 never falling below 35 U/ml, sensitivity and specificity were 96 and 65%, respectively, at 1 year of follow-up and 91 and 75%, respectively, at 3 years of follow-up. 75%, respectively, at 3 years of follow-up., Conclusions: In those patients in whom residual small volume disease after primary surgery indicates a good prognosis, minimum CA 125 and CA 125 t1/2 during chemotherapy can further categorize patients into favorable and unfavorable prognostic groups.

Background: Endometrial carcinoma is generally diagnosed only after the onset of postmenopausal bleeding. Although most patients with Stage I disease can be cured, the prognosis worsens significantly when the tumor is no longer confined to the uterine corpus. Serum CA 125 is elevated in only 10-20% cases of Stage I and II endometrial carcinoma. A serum tumor marker that can detect early stage endometrial cancer might aid in management of the disease., Methods: An OVX1 double-determinant radioimmunoassay was used to detect an epitope on a high-molecular-weight mucinlike glycoprotein found in the sera of 45 patients with endometrial cancer., Results: Apparently healthy persons had serum OVX1 antigen levels of 2.23 plus or minus 2.48 U/ml (mean +/- standard deviation). Elevated levels of OVX1 antigen (> 7.2 U/ml) were found in 5% of 184 healthy persons and in 64% of 45 patients with endometrial cancer. OVX1 antigen was elevated in 64% of 36 patients with Stage I, 50% of 2 patients with Stage II, 60% of 5 patients with Stage III, and each of 2 patients with Stage IV endometrial cancer, but only 8.6% of 58 patients with endometriosis. Elevation of serum OVX1 was found more frequently in patients with deep myometrial invasion and with poorly differentiated tumors (P < 0.01)., Conclusions: The OVX1 antigen deserves further evaluation as a marker for early detection of endometrial cancers and as a prognostic factor for women with apparent early stage disease.

Background: The Cancer associated serum antigen (CASA) and CA125 assays used in the management of ovarian cancer measure distinct high molecular weight glycoproteins. The mechanisms of secretion of these molecules into the peripheral circulation are not clearly understood., Methods: Concentrations of CASA and CA125 were assessed in peripheral blood, blood from veins draining ovarian and omental tumors, and peritoneal fluid in 20 women with pelvic masses., Results: There was a near perfect correlation between peripheral vein and ovarian vein concentrations for both markers; concentrations in omental veins were higher than in peripheral veins in only a small proportion of cases, whereas the concentration in peritoneal fluid was universally much higher than in blood., Conclusions: These studies suggest a similar route of entry into the peripheral circulation and a similar half-life for these glycoproteins. These data provide no support for the hypothesis that a significant contribution to CA125 concentrations comes from peritoneal release by mesothelial cells rather than tumor cells, because the relative CA125 concentrations between compartments were similar to those of CASA within patients. The lack of a gradient between CASA levels in peripheral blood and tumor draining veins suggests that the CASA half-life is much longer than that predicted in animal studies. CA125 and CASA in peripheral blood are probably derived from markers secreted into peritoneal fluid and lymph, rather than directly into the bloodstream.

Background: The altered and anomalous expression of carbohydrate antigens (CA) occur in patients with lung carcinomas., Methods: To investigate the relationship between prognosis and immunohistochemical findings of CA in serum and pulmonary adenocarcinomas (PA), PA specimens surgically resected from 102 patients were studied with the use of A, B, H, Lewis(Le)a, Le(b), Le(x), Le(y), sialyl Le(a) (FH-7), sialyl Le(x-i) (SLX) (FH-6), sialosyl Tn (TKH-2), and CA 19-9. The Lewis blood group types were determined by the dot blotting method on patients' serum using monoclonal anti-Le(a), Le(b), Le(x), and Le(y). Formalin-fixed paraffin-embedded PA sections were stained using the avidin-biotin-peroxidase complex methods., Results: There was no correlation between the patients' postoperative survival and tissue expression of CA, although survival correlated with the clinical stages, histologic differentiation of PA, and serum SLX in Stage 4. The higher the positive rate of both Le(b) and Le(y), the better their differentiation in PA specimens. Regardless of blood group type, PA showed high positive reactions for FH-6 (88%) and Le(y) (87%). The serum concentration of CA 19-9 correlated with immunohistochemical reactions of tumors (Spearman correlation coefficient = 0.33, P = 0.02). The expression of Le(a) in Lewis (a-b+) phenotype patients and Type 2 CA, such as Le(y) and FH-6, is characteristic in PA., Conclusions: The findings suggest that CA tissue expression may not reflect postoperative survival length of patients with PA, but biological aberrant fucosylation or sialylation as well as morphologic alteration may occur in neoplastic cells.

Background: Neoplastic transformation is associated frequently with changes in the glycosylation process. Simple mucin-type glycosylation in cancer cells has been found to be characterized by incomplete synthesis with precursor accumulation, leading to the exposure of the structures Tn and sialosyl-Tn, which are normally cryptic in human cells and secretions, including saliva and salivary glands., Methods: Paraffin sections from 50 salivary gland carcinomas of different histologic types were investigated with immunohistologic studies and a panel of monoclonal antibodies with well-defined specificity for Tn and sialosyl-Tn., Results: Tn and sialosyl-Tn antigens were expressed in the cytoplasm of glandular differentiated cells; in the luminal membranes and mucinous content of the glandular differentiated areas in almost all mucoepidermoid carcinomas and adenocarcinomas; and in carcinoma in pleomorphic adenoma, when the malignant component was an adenocarcinoma. In contrast, acinic cell carcinomas and adenoid cystic carcinomas expressed only minimal amounts of Tn and sialosyl-Tn, and the staining was seen only in relation to the luminal membrane and mucin of a few glandular structures., Conclusions: Mucin-type Tn and sialosyl-Tn may be regarded as markers of a glandular differentiation pattern in salivary gland carcinomas. The cellular location of the antigen-antibody complex indicates that they are synthesized and secreted from the tumor cells into saliva or serum.

Background: Several lines of evidence indicate that a more favorable prognosis is correlated with the degree of lymphocyte infiltration within breast carcinomas. The characterization of these T-cell infiltrates appears necessary to explore the possible existence of an in situ immunologic response of the host against neoplastic cells. Previous studies have indeed suggested that the T-cell receptor (TCR) repertoire of tumor-infiltrating T-lymphocytes (TIL) should be restricted if they act specifically against tumor-related antigens., Methods: To address this question, the expression of variable (V) region genes of the TCR-alpha and beta chains in intratumoral lymphocytes from five breast carcinoma biopsy specimens and one normal mammary gland specimen was analyzed using the polymerase chain reaction (PCR). The neoplastic samples included one medullary carcinoma and four ductal infiltrating carcinomas selected on the basis of a rich lymphoid stromal component. Primers specific for 18 different V alpha and 21 V beta families were used for PCR., Results: In every case, TIL showed an unrestricted pattern of TCR V-region gene expression, similar to the repertoire observed in peripheral blood lymphocytes and in the normal breast tissue., Conclusions: According to these nonquantitative PCR experiments, the apparent lack of selection of a limited number of T-cell specificities in the affected tissues does not favor the existence of an in vivo lymphoid recruitment based on TCR recognition of neoplastic antigenic determinants. Further studies, however, leading to an accurate quantification of immunologically relevant T-cell clones and including larger series of cases still are necessary before it will be possible to draw a final conclusion.

Background: To develop useful markers for the gastrointestinal neoplasms, the authors have established a new monoclonal antibody (MoAb), FU-MK-1, directed to gastric adenocarcinoma., Methods: The MoAb was produced by a mouse hybridoma technique by immunizing a BALB/c mouse with cancerous ascites derived from a poorly differentiated adenocarcinoma of the stomach., Results: FU-MK-1 did not react with the normal adult gastric mucosa, but did react with most carcinomas of the gastrointestinal tract. In addition, the MoAb recognized cholangiocarcinomas (CC), but it did not react with hepatocellular carcinomas (HCC). Furthermore, in the combined type tumor consisting of a mixture of HCC and CC, the MoAb react only with CC element, but not with pseudoglandular structures in the HCC areas. These results indicate that FU-MK-1 is a useful antigenic marker for distinguishing HCC from CC in the liver. Furthermore, because this MoAb retains its reactivity with formalin-fixed paraffin-embedded material, it may become a useful reagent for routine or retrospective immunohistologic studies. The molecular weight of the FU-MK-1 antigen was estimated to be ca. 41,000 dalton by the Western blot analysis. Periodic acid and trypsin treatment on the antigen suggested that the antigenic determinant is a glycoprotein., Conclusions: This MoAb may contribute to the histopathologic and immunologic studies of the digestive system.

Thymic carcinomas arising within a thymoma have been reported, but the relationship between thymoma and thymic carcinoma is poorly understood. Epithelial membrane antigen (EMA) is known to be an effective marker for establishing the epithelial nature of neoplastic cells, and it is reported that staining of tumors is clearly related to the degree of tumor differentiation. Eighty-one thymomas (59 noninvasive, 22 invasive) and 14 thymic carcinomas were studied immunohistologically using antiepithelial membrane antigen (anti-EMA) monoclonal antibody. Thymic carcinomas tended to express much larger quantities of EMA than thymomas, and instances of EMA-positive thymoma were seen significantly more often in invasive thymomas than in noninvasive ones (P < 0.05). However, EMA positivity was also associated with gland-like structures, which were not necessarily associated with malignant disease. Nevertheless, in view of the concept that thymoma and thymic carcinoma show a similar cellular differentiation, EMA-positive epithelial cells in thymoma with no relation to gland-like configurations might represent a pool of cells having a latent potential for malignant disease and might be transformed into thymic carcinoma cells under certain conditions. Immunolabeling for EMA appears to be a useful tool for determining the degree of malignant disease among thymic epithelial neoplasms.

In this presentation the authors review the pathology of prostatic carcinoma (PCa), and discuss criteria for pathologic diagnosis, premalignant lesions, lesions that simulate PCa, immunopathology, special types of PCa, effects of therapy on the prostate, and recent efforts to improve diagnostic and prognostic capabilities. The possible role of study of nucleolar organizing regions is reported. A new method for demonstration of chromosome in formalin-fixed, paraffin-embedded tissue is presented. The need for research in all aspects of pathology is emphasized.

The intrathecal immune response in neoplastic meningitis (NM) was studied by quantitation of immune parameters such as immunoglobulin G (IgG); IgM; interleukins (IL) 1, 2, 4, and 6; soluble IL-2 receptors (sIL-2R); interferon gamma (IFNy); tumor necrosis factor-alpha (TNF alpha); and three tumor markers, carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and fibronectin (FN), in 47 paired cerebrospinal fluid (CSF) and serum samples from patients with NM from different carcinomas, malignant melanoma, and lymphoma. Elevated IgG and IgM indices, CSF oligoclonal Ig bands, and CSF IL-6 indicated an intrathecal immune activation in most patients with NM. Results for IL-1, IL-2, and IL-4 were always negative. sIL-2R and IFNy were detected occasionally but not associated with specific malignant neoplasms. CSF TNF alpha was detected only in NM from cases of malignant melanoma. None of the immune parameters proved useful for the differentiation of NM from autoimmune or inflammatory conditions. Immune parameters were not correlated with tumor markers CEA, AFP, or FN. Results for AFP were positive only in a case of glioblastoma. CEA was a useful and specific diagnostic parameter in carcinomatous NM. CSF FN levels frequently were elevated but are not specific for NM.

Patients with lung cancer (LC) have a reduced T-cell proliferative response to phytohemagglutinin (PHA) compared with that of healthy individuals. This decreased response is a result of an inhibitory effect exerted by the monocytes as evidenced by: (1) a restoration to normal levels of the response to PHA when the peripheral blood mononuclear cells were depleted of adherent cells (AD) and (2) a dose-dependent inhibition of the response to PHA when the nonadherent cell population was co-cultured with increasing numbers of autologous AD cells. The addition of indomethacin to the cultures resulted in only a partial restoration of the response to PHA. Monocyte production of interleukin-1 from patients with LC in response to lipopolysaccharide was normal. These findings support the hypothesis that the AD cell population plays a major role in the low T-cell proliferative response to PHA in patients with LC. This suppressor effect is partially mediated by the prostaglandins released by the monocytes.

Surgical thyroid sections from 30 papillary carcinomas (PC), six medullary carcinomas (MC), three anaplastic carcinomas (AC), two follicular carcinomas (FC), and 16 adenomas (AD) were examined with an indirect immunofluorescence technique employing different monoclonal antibodies to evaluate the expression of human leukocyte antigen (HLA)-A, B, C (Class I) and DR, DP, DQ (Class II) by thyrocytes, together with the phenotype and distribution of inflammatory cells. Ten PC and four FC were also investigated for the presence of intercellular adhesion molecule-1 (ICAM-1). In situ deposits of immunocomplexes and circulating thyroid autoantibodies were also evaluated. An increased expression of Class I antigens was found in all PC and FC, in 33% of MC and AC, and in 31% of AD. An anomalous expression of Class II antigens was observed in 70% of PC, in 50% of FC, in 33% of AC, in 19% of AD, and in none of the MC. Expression of DP or DQ was revealed only in a portion of the DR-positive glands. A reduction of microsomal autoantigen expression was found. No ICAM-1-positive thyrocytes were detected. A moderate T-lymphocytic infiltrate was noticed only in PC, where it was correlated with DR and DP and/or DQ coexpression. B-cells and natural killer cells were virtually absent. The authors speculate that the weak Class II antigens expression, together with the partial or complete loss in microsomal autoantigen and the absence of ICAM-1 by thyrocytes, may account for the limited engagement of immunocompetent cells observed in thyroid tumors.

The authors studied data of combination assays of tumor markers, because simultaneous elevation of different types of tumor markers in the serum was puzzling. They interpreted such phenomena regarding cancer antigen 125, carcinoembryonic antigen, and carbohydrate determinant 19-9 in ovarian tumors. The tissue expression of the antigens was compared with preoperative serum levels. Several different factors were found to cause the simultaneous elevation of two or three of these markers in the serum. Furthermore, even when the levels of some of the tumor markers were raised in the serum, the ovarian tumor did not always produce the marker by itself. This study indicates that immunohistochemical identification of a marker in tumor tissue is prerequisite to the use of that marker in the serum to monitor disease status.

Immunocompetence, as determined by skin reactivity to five microbial antigens, dinitrochlorobenzene (DNCB), and percent and absolute number of total T and B rosette-forming cells (RFC), was assessed before and up to 180 days after radiotherapy in 29 patients with carcinoma of the lung. Pretherapy evaluation showed a depressed response to microbial antigens (only 38% positive), to DNCB (50% positive), and lower level of T-RFC. Postradiotherapy determinations were further depressed. Patients with positive pretherapy responses to microbial antigens and DNCB and higher than median absolute numbers at total T-RFC had significantly longer survival. These data suggest that pretherapy immune evaluation is a good prognostic indicator. No prognostic significance was found in B-RFC evaluation. No correlation was seen between the stage of disease (locally advanced or with distant metastases) and the pretherapy immune response.

Fourteen patients with nasopharyngeal carcinoma were evaluated immunologically prior to standard radiotion therapy. All had elevations of serum IgA, ranging from 300 mg/100 ml to 1000 mg/100 ml, with a mean value of 549 mg/100 ml. Seven patients demonstrated depression of cell-mediated immunity as measured by delayed hypersensitivity skin tests, total lymphocyte count, in vitro stimulation with PHA, and T-cell rosette formation. Elevation of serum IgA associated with depression of cell mediated immunity may be characteristic of patients with nasopharyngeal carcinoma.

Fifty cases of nasopharyngeal carcinoma (NPC) and its metastasis in ten lymph nodes were studied for specific red cell adherence (SRCA) to determine if any loss of blood group isoantigens was present to explain some of the differences such as their preponderance in local Chinese population and variable clinicopathologic behavior. While a patchy positive SRCA was noted on the surface of tumor cells in all cases of NPCs, it was not so in any of their metastasis. The findings suggest that in NPCs a few tumor cells may be capable of partially retaining isoantigens, and that this is neither influenced by their histologic type nor in any way seems to account for the variable prognosis. While the exact mechanism for negative SRCA in metastatic deposits in lymph nodes is unknown, it is possible that metastatic tumor cells may have lost isoantigens on reaching lymph nodes. The remote possibility of a 'preferential discharge' of isoantigen-free tumor cells from the primary tumor seemed unlikely in view of a mildly positive SRCA in all the NPCs.

Indomethacin (prostaglandin synthetase inhibitor) was found to be capable of enhancing the mitogen-induced lymphocyte proliferative responses of healthy subjects and patients with lung cancer. A whole-blood culture technique was used. Indomethacin had no mitogenic activity. We observed a greater enhancement of lymphocyte response by indomethacin in weak responders as compared with strong responders in healthy subjects and lung cancer patients. A greater enhancement was also noted in lung cancer patients with active disease as compared with lung cancer patients in remission. In a separated cell culture system, the indomethacin exerted no effect on purified T cells in the absence of monocytes, while this agent exerted its enhancement effect on T lymphocyte response in the presence of autologous monocytes of lung cancer patients. This suggests that monocytes (suppressor cells) may secrete prostaglandins, which are responsible for the impairment of T lymphocyte response in lung cancer patients.

Fifty-two patients with thyroid epithelial cell cancer were studied for evidence of association with human leukocyte antigens (HLA). Twenty-eight patients (53.8%) and 19.4% of 160 controls were HLA-DR1-positive, conferring a relative risk of 4.85 (chi 2 = 21.3, P less than 0.0001). HLA-DR1 was increased in all histologic types of thyroid cancer. Interestingly 10 of 12 patients with metastatic disease were DR1-positive compared to 18 of 41 patients without metastases (relative risk = 6.1, chi 2 = 4.7, P less than 0.05). This study suggests that major histocompatibility complex-linked gene(s) determine susceptibility to and the biologic behavior of thyroid cancer.

Forty-one patients with small cell carcinoma of the uterine cervix were evaluated and treated at the University of Kentucky Medical Center from 1962 to 1974. Eighteen patients (44%) developed widespread metastases and died of recurrent cancer within 2 years of therapy. Common sites of metastases included the lung, liver, and bone. There was a significantly lower incidence of lymphoplasmacytic infiltration in small cell cancers than the keratinizing or nonkeratinizing squanmous cell carcinomas of the cervix. In addition, there was a significant increase in the number of unstimulated regional lymph nodes in patients with small cell cancer when compared with the lymph nodes of patients with the other cell types of cervical cancer. These data suggest that small cell cancer of the cervix is a highly aggressive tumor similar to small cell carcinoma of the lung and behaves quite differently from other types of squamous cell carcinoma of the cervix. Radiation therapy was superior to radical surgery in eradicating pelvic disease, but prospective studies need to be undertaken to determine the effect of adjunctive chemotherapy in patients with this rare tumor.

The poor postsurgical prognosis in patients with colorectal cancer of the Dukes' C classification has prompted a clinical trial of adjuvant immunotherapy versus chemoimmunotherapy intended to prolong either the disease-free interval or the overall survival or both. One hundred and twenty-one patients have been entered on this study. Fifty-two patients received BCG alone and 69 patients received the combination of 5-FU and BCG. The disease-free interval and the overall survival were compared with similar parameters in a group of historical controls with similar prognostic characteristics who were operated on in our institution prior to the initiation of the current study. There was no difference as yet between BCG alone and the combination of 5-FU + BCG in terms of both the disease-free interval and the survival. Both treatments, however, had significantly better results than the surgical controls. Adjuvant therapy, especially with BCG is advocated for patients with colorectal carcinoma, Dukes' C class, following potentially curative surgery.

The study was performed to evaluate the influence of thyroxine substitution therapy and the presence of thyroglobulin antibodies (TgAb) on the usefulness of serum thyroglobulin (Tg) measurements in the follow-up of patients treated for well differentiated thyroid carcinoma. Seventy-two consecutive patients with differentiated thyroid cancer and eight with medullary carcinoma as well as controls were studied on one or more occasions and blood was drawn for measurement of serum Tg, TgAb, TSH and thyroid hormones. In 23 patients the hormonal substitution was withdrawn and 3-4 weeks later new blood samples and a 131I scintigraphy was performed. Eighteen patients were shown to have recurrence or metastases. Four of these had TgAb, two had normal Tg values, and the remaining 12 had extremely elevated levels. Those with TgAb and normal Tg values all had high Tg levels off thyroxine substitution. The 54 patients without evidence of recurrence had low levels of serum Tg except for one with highly elevated values. Based on the results from this and other studies is concluded that serum Tg is an important adjunct in the follow-up of patients with well differentiated thyroid carcinoma, but certain limiting factors have to be taken into account, i.e., the radicality of surgery, the sufficiency of the substitution, the presence of TgAb and the method for measurement of Tg.