Vaccination against Fasciola hepatica infection using a Schistosoma mansoni defined recombinant antigen, Sm14

Fasciola hepatica is the causative agent of fasciolosis in many areas in America, Europe, Africa, Asia and Australia. There is an urgent need for improved methods to control the parasite's transmission. We describe the use of an experimental vaccine based on a recombinant antigen cloned from another parasite, Schistosoma mansoni (Sm14), that induces high levels of cross protection in mice against both S. mansoni and F. hepatica. Sheep and mice vaccinated with Sm14 were significantly protected against challenge infection with metacercariae of Fasciola hepatica and were completely free of the histopathological hepatic damage related to liver fluke infection. The vaccine will provide a valuable new tool to aid in transmission control of this economically important disease

Clinicopathologic features and human papillomavirus dna prevalence of warty and squamous cell carcinoma of the penis.

Squamous cell carcinoma (SCC) accounts for 95% of penile malignant neoplasms. A subtype of SCC, named warty carcinoma (WC), is a morphologically distinct verruciform tumor with features of human papillomavirus (HPV)-related lesions. Descriptions of the behavior and histologic features of this tumor are scarce in the literature. The aim of this report is to analyze the clinicopathologic features and HPV deoxyribonucleic acid status in 60 SCCs and 11 WCs. The mean patient age was 46.5 +/- 15.9 years for WC and 52.6 +/- 12.4 years for SCC. No significant differences in age (p = 0.154) and clinical staging (T, p = 0.649; N, p = 0.497) between the two groups of tumors were found. When compared with SCCs, WCs exhibited less lymphatic embolization (p = 0.001), nodal metastasis (p = 0.019), and corpora cavernosa and corpus spongiosum infiltration (p = 0.040). Lymph node metastases were found in 34 of 60 SCC patients (56.7%) and in two of 11 WC patients (18.2%). No patients with WC tumors died of the disease compared with 19 of 60 (5-year specific survival, 66.0%) in the SCC group (p = 0.032). HPV deoxyribonucleic acid was more likely to be associated with WC (five of 11, 45.5%) than SCC (16 of 60, 26.7%), although significance was not reached (p = 0.209). The results suggest that WC is less aggressive and confers a better prognosis than typical SCC of the penis.

LEA.135 expression: its comparison with other prognostic biomarkers for patients with primary breast carcinoma.

The purpose of this retrospective study was to examine the prognostic value of expression of luminal epithelial antigen (LEA.135) for recurrence and overall survival of patients with primary invasive breast carcinoma by both univariate and multivariate analyses. The possible prognostic value of LEA.135 was also compared with some widely utilized prognostic biomarkers such as c-erbB 2, topoisomerase II.alpha (TPII.alpha), MIB 1, estrogen receptor (ER) and progesterone receptor (PR), as well as age of the patients and clinicopathologic parameters. The study was carried out by immunohistochemical methods on formalin-fixed/paraffin-embedded tissue sections in a series of 225 patients with median follow-up of 8.5 years. Prognostic significance of the biomarkers was determined by two-sided p value. In this series of patients, among the age and clinicopathologic parameters, only age, was significantly associated with a decreased overall survival (logrank p = 0.027). Among the prognostic biomarkers, TPII a expression at high (> 50% positive cells) or moderate (6-50% positive cells) level was associated with an increased rate of recurrence (logrank p < 0.001). However, the association of TPII.alpha expression with a decreased overall survival failed to reach a statistically significance. Expression of c-erbB 2 showed a trend of being associated with an increased probability of recurrence, but the association did not reach statistical significance. The remaining biomarkers were not associated with either the probability of recurrence or overall survival. LEA.135 expression was observed in 163 (72.4%) of the 225 patients. The patients with high (> 50% positive cells) or moderate (6-50% positive cells) level of LEA.135-positive cancer cells showed a significantly decreased probability of recurrence (logrank p < 0.001) and an increased overall survival (logrank p < 0.001) compared with those with LEA.135-negative cancer cells. The association remained significant by multivariate analysis for recurrence (likelihood ratio test p < 0.001) and overall survival (likelihood ratio test p < 0.001) when assessed with other prognostic parameters. Furthermore, the combination of LEA.135 with other prognostic biomarkers stratified four subgroups of patients with distinct clinical outcome. The subgroup of patients who were LEA.135+/TPII.alpha- showed the lowest probability of recurrence and the longest overall survival compared with those who were LEA.135-/TPII.alpha+ (logrank p < 0.001). Interestingly, the patients whose cancer cells were LEA.135+/TPII.alpha+, LEA.135+ MIB.1+ or LEA.135+/c-erbB 2+ experienced a decreased probability of recurrence and an increased overall survival compared with those with LEA.135-/TPII.alpha+, LEA.135- MIB.1+ or LEA.135-/c-erbB 2+ (logrank p < 0.001). The results demonstrated that LEA.135 is an independent and favorable prognostic biomarker for patients with primary invasive breast carcinoma, that the loss of LEA.135 expression is associated with aggressive phenotype of cancer cells during the breast cancer progression, and that its continued expression seems to override the adverse effects of expression of an oncogene or cell proliferation-associated molecules.

Prognostic factors in supraglottic carcinoma patients treated by surgery or radiotherapy.

The decision regarding treatment of supraglottic carcinoma remains controversial, despite recent advances in radiotherapy and surgical procedures. The need to evaluate the prognostic importance of demographic, clinical, pathologic, and treatment-related variables prompted this study. The patient population was of 164 consecutive cases of supraglottic carcinoma. Clinical charts were reviewed and cases were restaged according to the 1987 version of the UICC-AJC classification based on the initial clinical description: 18 T1, 30 T2, 58 T3, 58 T4, 61 NO, 24 N1, and 79 N2a-N3. Management policy for these patients varied during the study, reflecting different opinions of the responsible physicians and technical advances. Seventy-seven patients (47%) underwent surgery, patients who underwent surgery and radiotherapy, respectively, remained alive with no evidence of disease. The 5-year actuarial survival rates were 58.5% for patients initially treated by surgery, and 16.3% for patients in the radiotherapy group. Although several demographic, clinical, and pathologic variables were studied, only initial treatment (p <.0001), N stage (p = .0003), and T stage (p = .0017) were deemed to have independent prognostic value by multivariate regression techniques based on Cox's proportional hazards model. This study has shown that survival of supraglottic carcinoma patients depends on the treatment modality, T stage, and N stage. Our results are disappointing with regard to radiotherapy as a treatment for supraglottic carcinoma in patients with tumors at clinical stages III and IV.

P53 overexpression in epidermoid carcinoma of the head and neck.

UNLABELLED: The theory of field cancerization in tumors of the head and neck reflects the complex oncogenesis that occurs in this region. The mechanisms that control cell proliferation at the molecular level in epidermoid carcinomas (ECs) of the upper aerodigestive tract are still unclear. Mutations in p53 are the genetic alterations most often detected in ECs of the head and neck and seem to contribute actively to the carcinogenic process triggered by p53 as a tumor-suppressor gene and to its association with tobacco. The objective of the present study was to investigate the expression of p53 protein in epidermoid head and neck carcinomas by immunohistochemistry and its immunohistochemical correlation with other prognostic factors. The study was conducted on 63 consecutive ECs cases not submitted to previous treatment. Specimens of the tumor and of the normal adjacent mucosa were collected during surgery and submitted to immunohistochemical reaction for the determination of the expression of anti-protein p53 antibody (M7001 DAKO A/S, Denmark). Anatomo-clinical and demographic data were not significantly correlated with the presence of lymph node metastases or p53 expression in the tumor or in the adjacent normal mucosa. Tumor localization in the larynx was significantly correlated with p53 expression. Histological grading as grades I, II, III and IV was correlated with significant p53 expression (p = 0.025). CONCLUSIONS: 1) in the studied material obtained from 63 cases of head and neck ECs, we detected a 48 percent rate of immunohistochemically detectable p53 overexpression; 2) we did not detect a relationship between demographic patient data and p53 expression in the tumor or in the normal adjacent mucosa; 3) p53 overexpression was significantly more frequent in ECs material from the larynx: and 4) The presence of 12 cases with p53 overexpression in the normal adjacent mucosa and with a p53-negative tumor is in agreement with the theory of field cancerization. Follow-up of this patient series for a longer period of time will permit a better analysis of these values.

Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy.

PURPOSE: The major issue in penile cancer is deciding who should or should not undergo lymph node dissection. Clinical and invasive methods are not reliable for staging. Clinical and pathological factors involved in lymph node metastases and prognosis were evaluated in 145 patients with penile carcinoma staged according to the 1978 TNM system, and treated with amputation and lymphadenectomy. MATERIALS AND METHODS: Clinical factors studied were patient age, race, disease evolution time, symptoms, and clinical T and N stages. Pathological factors of the primary tumor considered were tumor thickness, histological grade, lymphatic and venous embolization, infiltration of the corpora cavernosa, corpus spongiosum and urethra, mononuclear and eosinophilic infiltrates, and cell alterations suggestive of human papillomavirus. All slides were reviewed by 1 pathologist. The Cox regression hazards method for multifactorial analysis was used. RESULTS: Followup ranged from 0.7 to 453.2 months (mean 85.8, median 32.7). The 5-year disease-free and overall survival rates were 45.3 and 54.3%, respectively. Venous and lymphatic embolizations were the main factors affecting significantly the incidence of lymph node metastasis, which were the main risks factors for recurrence and death. Pathologically proved infiltration of the corpora cavernosa, urethra and adjacent structures, which corresponded to stages T2, T3 and T4 disease, respectively, of the current TNM classification, were not significant predictors for incidence of lymph node metastasis, disease-free and overall survival or risk factors for recurrence and death. CONCLUSIONS: Because venous and lymphatic embolizations were related to greatest risk of lymph node metastasis, we propose their evaluation in staging and therapeutic planning of patients with infiltrative tumors of the penis.

A sialoglycoprotein (LEA.135) associated with favourable prognosis of patients with lymph node-negative primary breast carcinoma.

A cell-surface sialoglycoprotein (LEA.135) was identified using a monoclonal antibody that was generated by immunization of Balb/c mice with extracts of normal breast tissue following prior immune-tolerization with mammary carcinoma cell lines. LEA.135 is distinct from other known epithelial cell-associated antigens, including the family of mucins or keratins and epidermal growth factor receptor. Using immunohistochemical staining methods, LEA.135 expression was detected predominantly on the apical plasma membrane of normal and neoplastic mammary and extramammary epithelial cells in freshly frozen or formalin-fixed paraffin-embedded tissue sections. A retrospective study of 111 cases of lymph node-negative patients (TanyN0M0) with primary infiltrating ductal breast carcinoma, with a median follow-up of 7.9 years, was conducted. A comparison of overall survival (O.S.) was made of patients whose tumor cells exhibited reactivity with anti-LEA.135 antibody (O.S. 92.9 +/- 3.3% at 8 years), compared with those whose specimens showed the absence of LEA.135 expression (O.S. 68.3 +/- 10.8% at 8 years). A statistically significant univariant association between LEA.135 expression and O.S. was observed (logrank p < 0.001). In addition, in a subgroup of patients with histologically moderately differentiated tumors (N = 71), LEA.135-positive cases showed an improved O.S. (90.8 +/- 4.6% at 8 years; p < 0.001) compared with those who were LEA.135-negative (O.S. 55.6 +/- 13.6% at 8 years). The association remained statistically significant in a multivariable analysis after adjusting for histological grade, tumor size and age (p < 0.02). Thus, in this series of patients with lymph node-negative primary breast carcinoma, LEA.135 expression was associated with a significant decrease in the rate of recurrence and with an increase in overall survival, independent of tumor size, histologic grade, and patient's age. In contrast to the majority of other prognostic markers which predicts a worse biology, LEA.135 is a unique class of antigen whose expression indicates a lower aggressiveness of the tumor cells.

Ultrasonography evaluation of bone lesions of the jaw.

The ultrasonographic aspects of 72 intraosseous lesions of the jaws were evaluated to identify the usefulness of this type of examination. The principal aim of ultrasonography was to recognize the lesion's content before surgical treatment. Four groups of lesions were classified after the definitive histopathologic examination: lesions with solid, liquid, dense liquid, and mixed contents. The initial ultrasonography examination was in agreement with the histopathologic findings in 24 (92.3%) cases with solid content, 17 (73.9%) cases with liquid content, 7 (7.7%) cases with dense liquid content, and 13 (92.8%) cases with mixed content. On the basis of the results of this study, we propose the use of ultrasonography as a complementary examination for intraosseous lesions of the jaws. If a liquid component is identified in ultrasonography, a surgical procedure should be performed immediately. Otherwise, if a lesion with solid component is identified, it should be biopsied for histopathologic examination and final diagnosis before definitive surgery.

Prognostic factors in T3,N0-1 glottic and transglottic carcinoma. A multifactorial study of 221 cases treated by surgery or radiotherapy.

OBJECTIVE: To evaluate prognostic factors in patients with T3,N0-1 glottic and transglottic carcinoma treated in a single institution. DESIGN: Retrospective, nonrandomized case series. SETTING: Tertiary case referral centers, ambulatory or hospitalized care. PATIENTS: Two hundred twenty-one consecutive cases of stage III glottic or transglottic squamous cell carcinoma. Tumor stage was T3,N0,M0 in 167 cases and T3,N1,M0 in 54 cases. INTERVENTIONS: Surgery in 176 cases and radiotherapy in 45 cases. MAIN OUTCOME MEASURES: Recurrences and survival (multivariate). RESULTS: Almost 7% of the patients who underwent surgery and 39.6% who had radiotherapy had local recurrences. Recurrences in the neck were seen in 16.4% of the patients who underwent surgery and in 10.5% of those who had radiotherapy. Distant metastases were diagnosed only in patients who underwent surgery (4.6%). The 5-year actuarial overall survival rates were 56.3% in the surgical group and 35.2% in the radiotherapy group (P = .007). Age involvement of pyriform sinus, N stage, and history of tracheostomy were independent prognostic factors for risk of death. CONCLUSIONS: The presence of metastatic lymph nodes, age, and involvement of the pyriform sinus were the important prognostic factors in patients who underwent surgery. A small group of patients with T3,N0,M0 tumors could benefit from radiotherapy, with surgery reserved for recurrence.

Lateness of diagnosis of oral and oropharyngeal carcinoma: factors related to the tumour, the patient and health professionals.

The risk of presenting with advanced stage vs. early stage disease was evaluated in a prospective study of 336 consecutive patients with oral and oropharyngeal carcinomas referred to three head and neck surgery services in Sao Paulo, Curitiba and Goiania during the period from February 1986 to December 1988. Income and educational levels were not associated with stage distribution. The risk of having advanced disease was dependent upon male gender. Another important determinant of advanced stage was tumour location on the less visible surfaces of the oral cavity and oropharynx. Although there was a clear increase in delay of referral among cases who were seen by more than one health professional, duration of symptoms and patient and professional delays were not associated with the risk of advanced disease in unifactorial analysis. The following factors were independently associated with the risk of advanced disease for lip carcinoma: a painful ulcer, alcoholism and delay caused by a non-specialist medical doctor. The risk factors associated to advanced oral carcinoma were: type of lesion, odynophagia/dysphagia, delay caused by a dentist and delay caused by a non-specialist medical doctor. Two of the most important immediate consequences of advanced stage were a conspicuous increase in treatment costs and a longer hospital stay.

Genetic alterations in c-erbB-2 protooncogene as prognostic markers in human primary breast tumors.

c-erbB-2 DNA amplification and mRNA expression were analyzed by dot and Southern blots in 65 human primary breast tumors. Gene amplification was observed in 21 of 65 (32.3%) and elevated levels of c-erbB-2 transcript in 14 of 60 (23.3%) of the tumors analyzed. Only 55% of the tumors with c-erbB-2 gene amplification presented gene overexpression, showing an incomplete correlation between gene amplification and overexpression. No statistically significant correlation was observed between c-erbB-2 genetic alterations and other prognostic factors in breast cancer. However, patients with tumors presenting c-erbB-2 gene amplification and/or overexpression appeared to have a shorter disease-free interval than patients without c-erbB-2 genetic alterations. High levels of c-erbB-2 gene amplification were more powerful predictors of risk of recurrence than was overexpression of the gene. Cox univariate-bivariate analyses suggested that gene amplification was independent of nodal status to predict recurrence in breast cancer.

Supraomohyoid neck dissection in the treatment of head and neck tumors. Survival results in 212 cases.

Elective supraomohyoid neck dissection is considered part of standard treatment of oral and oropharyngeal cancer in most institutions, but its role in the treatment of clinically positive neck cancer remains a subject of controversy. The main object of this study is to report the results of 212 consecutive patients who underwent supraomohyoid neck dissections from 1954 to 1990. Most patients had squamous cell carcinoma of the oral cavity. Eighty-six patients (40.6%) had histologically positive lymph nodes in the surgical specimen (sensitivity, 0.55; specificity, 0.53). At the study closing date there were 58.8% actuarial 10-year overall survival rates. Forty-five patients (21.2%) had 50 tumor recurrences (32 local, 13 regional, five distant), and in 40 patients (18.8%) a second primary tumor was diagnosed. A multivariate regression technique based on Cox's proportional hazards model was used, and age (65 years or younger vs older than 65 years) represented the variable with the highest predictive strength with respect to overall survival (relative risk, 2.3). Tumor site, sex, and histologically proved metastasis were also associated with overall survival rates. The same variables were also related to the risk of recurrence. In conclusion, the death rate is mainly related to the control of the primary site tumor and the occurrence of a second primary tumor rather than to neck recurrences. It confirms that supraomohyoid neck dissection is an adequate elective procedure and possibly sufficient in the treatment of a selected group of patients with lip cancer with positive nodes at level 1.

Carcinoma of the vulva. Clinicopathologic factors involved in inguinal and pelvic lymph node metastasis.

Eighty-five women with vulvar squamous cell carcinoma were subjected to radical vulvectomy with bilateral inguinal and femoral node dissection or to radical vulvectomy with bilateral inguinofemoral and deep pelvic node dissection. The association between lymph node status (metastatic or not) and several parameters was analyzed: tumor location, size and clinical stage; tumor thickness, histologic grade and mitotic index; blood vessel, lymphatic and perineural infiltration; and lymphocytic and plasma cell infiltrates. There were no metastases to the pelvic lymph nodes without previous inguinal lymph node involvement. Unilateral vulvar carcinomas did not have contralateral metastatic nodes when there was no ipsilateral nodal involvement. Lymphatic vessel infiltration showed a statistically significant correlation with inguinal node metastases (P less than .05). No correlation was found between lymph node metastasis and tumor size, clitoral invasion, tumor thickness, histologic grade, blood vessel and perineural infiltration, lymphocytic and plasma cell infiltrates, and mitotic index.

Independent prognostic value of laminin receptor expression in breast cancer survival.

We studied the possible prognostic role of laminin, estrogen (ER), and progesterone (PR) receptors and other pathological factors in relation to the disease-free interval and overall survival of female breast carcinoma patients. Multivariate analyses of clinical and pathological data with respect to the above survival time variables were performed by Cox regression. The statistical dependence of prognosis on ER, PR, and tumor size was based on the discriminant cutoff value that could best distinguish between survival curves. Axillary nodal status was the most significant independent factor in the prediction of both disease-free interval and overall survival of these patients. Use of the information on laminin receptor expression, PR concentration, tumor size, lymphocytic infiltrate, and tumor necrosis improved significantly the prediction of the risk of recurrence. Patients with tumors expressing laminin receptors had 40% less risk of recurrence (P = 0.0209) than those with no expression. On the other hand, four covariates were independently predictive of the risk of death: axillary nodal status, lymphocytic infiltrate, PR and ER concentration. There was a marginally significant (10% level) interaction between tumor size and lymphocytic infiltrate with respect to the prediction of the risk of recurrence. The above sets of variables were used to classify patients into risk groups for the prediction of recurrence and death.

Human papillomavirus DNA in respiratory papillomatosis detected by in situ hybridization and the polymerase chain reaction.

The authors have demonstrated the presence of human papillomavirus (HPV) types 6 and 11 in 10 of 13 (77%) juvenile laryngeal papillomatosis by in situ DNA hybridization using as probes the radiolabeled DNAs of HPVs 6, 11, 16, and 18. Of six specimens from adult laryngeal papillomatosis assayed by the same technique, only 33% were positive. Immunohistochemistry to detect HPV capsid antigens performed on serial sections gave positive signals in 44% (8 of 18) of the specimens, all from juvenile lesions. These results were in agreement with in situ hybridization, except in two cases. When both series (juvenile and adult) were analysed by amplification of a 450-bp fragment corresponding to the L1 ORF of the HPV genomes directed by the polymerase chain reaction, the frequency of positive specimens rose to 100%. Our data agree with the concept that HPV is implicated in the etiology of laryngeal papillomatosis.

Tumor and serum beta-2-microglobulin expression in women with breast cancer.

To investigate whether the tumor expression of beta-2-microglobulin (beta 2-M) could serve as a marker of tumor biologic behavior, the authors studied specimens of breast carcinomas from 60 consecutive female patients. Presence of beta 2-M was analyzed by immunohistochemistry. No significant correlations were found between tumor beta 2-M expression and several histologic attributes such as type, histologic and nuclear grades, mitotic index, necrosis, vascular invasion, and lymphocytic infiltration. Likewise, beta 2-M was not associated with markers of disease extension such as TNM, (UICC, classification of malignant tumors) staging and axillary lymph node involvement or with estrogen, progesterone, and glucocorticoid receptor levels. However, there was a significantly positive association between tumor beta 2-M expression and the degree of lymphocytic infiltration in the tumor tissue. Beta 2-M serum levels were determined by an enzyme-linked immunosorbent assay in samples from 22 of the above women. Although some of the highest values had been obtained in women with larger (T4) primary tumors, the authors failed to detect any statistical relationship between beta 2-M expression in the tumor with serum levels or between serum beta 2-M and the above histologic, laboratory, and clinical factors.

Risk factors for oral cancer in Brazil: a case-control study.

A case-control study of risk factors for carcinomas of the tongue, gum, floor, and other specified parts of the mouth was conducted in 3 metropolitan areas in Brazil: São Paulo (southeast), Curitiba (south), and Goiânia (central-west). We analyzed information on demographics, occupational history, environmental exposures, tobacco smoking and alcohol drinking habits, as well as diet, oral and other health characteristics obtained from interviews with 232 cases and 464 hospital non-cancer controls matched for 5-year age-group, sex, hospital catchment area and trimester of admission. Tobacco and alcohol consumption were the strongest risk factors irrespective of the anatomical site. The adjusted relative risks (RR) for ever vs. never smokers were: 6.3, 13.9, and 7.0, for industrial-brand cigarettes, pipe, and hand-rolled cigarettes, respectively. A strong correlation was seen between number of pack-years and risk. The RR for the heaviest vs. the lowest consumption categories (greater than 100 vs. less than 1 pack-years) was 14.8. Risk levels generally decreased to those of never smokers after 10 years had elapsed since stopping smoking. The risk associated with alcohol was mostly evident for wine (cancer of the tongue) and "cachaça" (all sites), a hard liquor distilled from sugar cane. Other important risk factors were drinking "chimarrão" (a type of maté), use of a wood stove for cooking, and frequent consumption of charcoal-grilled meat and manioc. Oral hygiene characteristics represented correlates of disease risk. A significant protective effect was observed for consumption of carotene-rich vegetables and citric fruits, but not for green vegetables in general.

Multiple steroid receptors in nasopharyngeal angiofibromas.

Cytosols from 12 nasopharyngeal angiofibroma tissues were analyzed for the presence of estrogen (ER), progesterone (PR), androgen (AR), and glucocorticoid (GR) receptors, by using a dextran charcoal assay. Progesterone receptors (58%) clearly predominate over ER and AR (25%). Thus, nasoangiofibromas can be classified as ER-PR+ tumors. Glucocorticoid receptors were found in 84% of the tumors. Steroid receptor levels, although slightly higher than those determined in three specimens of normal turbinate, were quantitatively low. Positive PR and AR tumors appeared to correlate with high density of fibroblasts and endothelial cells.