Bioprofiling over grid for eHealthcare.

A trend in modern medicine is towards individualization of healthcare and, potentially, grid computing can play an important role in this by allowing sharing of resources and expertise to improve the quality of care. In this paper, we present a new test bed, the BIOPATTERN Grid, which aims to fulfil this role in the long term. The main objectives in this paper are 1) to report the development of the BIOPATTERN Grid, for biopattern analysis and bioprofiling in support of individualization of healthcare. The BIOPATTERN Grid is designed to facilitate secure and seamless sharing of geographically distributed bioprofile databases and to support the analysis of bioprofiles to combat major diseases such as brain diseases and cancer within a major EU project, BIOPATTERN (www.biopattern.org); 2) to illustrate how the BIOPATTERN Grid could be used for biopattern analysis and bioprofiling for early detection of dementia and for brain injury assessment on an individual basis. We highlight important issues that would arise from the mobility of citizens in the EU, such as those associated with access to medical data, ethical and security; and 3) to describe two grid services which aim to integrate BIOPATTERN Grid with existing grid projects on crawling service and remote data acquisition which is necessary to underpin the use of the test bed for biopattern analysis and bioprofiling.

Regulation of progesterone receptor gene expression.

The levels of progesterone receptor (PR) mRNA, PR protein, and [3H]R5020 binding activity were measured in parallel experiments conducted on a T47D subline expressing the estrogen receptor. A significant increase of PR mRNA levels could be detected within 6 h of exposure of the cells to estradiol (10(-8) M). The changes in mRNA, however, did not lead to any variation of PR protein levels of [3H]R5020 binding activity. A parallel analysis of PR mRNA and [3H]R5020 binding was then performed in a series of tumor biopsies. In estrogen receptor-positive and PR-positive tissues a correlation among the two values was found. It is postulated that the above mentioned data could reflect the existence of a difference in the mechanisms controlling the numerous steps of the PR synthesis in the various hormone-responsive tissues. This variability could allow an organ-specific response to the cyclic changes of circulating hormone.

Conservative surgery in high-risk epithelial ovarian carcinoma.

BACKGROUND: In epithelial ovarian cancer, conservative surgery has mainly been adopted for stage Ia disease. The aim of this study is to report on a conservative surgical approach used in selected young patients with ovarian cancer who would usually undergo radical operations. STUDY DESIGN: From 1980 through 1994, 10 patients with invasive epithelial ovarian cancer and with high-grade or limited extraovarian disease were treated with conservative surgery. The mean age was 22.7 years. The stage was Ia grade 3 in 2 patients, Ic in 2 patients, IIIa in 2 patients, and IIIc in 4 patients. Eight patients were given adjuvant therapy (radiotherapy in 1 and chemotherapy in 7). RESULTS: All patients were alive and disease-free at a median followup time of 70 months (range 24-138 months). Nine patients were menstruating regularly and three had become pregnant. CONCLUSIONS: It seems that in selected patients, conservative operations can be used beyond the worldwide accepted criterion of stage Ia. This concept deserves additional investigation in larger series.

Cancer of the uterine cervix: clinical value of squamous cell carcinoma antigen (SCC) measurements.

The clinical value of SCC levels has been evaluated in four groups of women affected by cervical carcinoma. Among the 116 newly diagnosed patients, the SCC pretreatment level was elevated in 57% of cases and was strictly correlated with clinical stage (Ib to IV: p = < 0.01) and histotype (squamous cell carcinoma versus others: p = 0.0005). No significant difference was found in relation to nodal status. For the 28 patients submitted to neoadjuvant chemotherapy clinical response was correlated with the change in serum SCC level: stable or rising serum level indicated that the disease was unchanged or progressive, respectively. In the group of 48 patients affected by recurrent carcinoma, a raised SCC level was found in 71% of cases, with a lead time ranging from 0 to 12 months. No identification of the site of recurrence could be extrapolated from the value of SCC. As to the 108 regularly monitored patients, no significant difference in the risk to develop recurrence was shown for patients with a raised SCC level at the time of primary diagnosis (NED) versus relapsed: p = > 0.05).

A double determinant radioimmunoassay Mov2-MOv8 for monitoring ovarian carcinomas: definition of the methodology.

A double-determinant radioimmunoassay for the detection of circulating antigens associated with human ovarian carcinoma was developed using two monoclonal antibodies: MOv2 and MOv8 employed respectively as catcher and tracer. The development of the method through three different procedures enabled us to detect the presence of CaMOv2-CaMOv8 carrying molecules in 14 out of 15 ascitic fluids from ovarian carcinoma patients whose tumors were found to be positive with MOv2 and MOv8 monoclonal antibodies by immunofluorescence. Moreover, 13 out of 15 ovarian carcinoma patients presented high levels of antigen in their serum (60-170 Ua/ml). Low levels of antigen were observed in the normal population, the values ranging from 30-40 Ua/ml. However, in 13 out of 100 apparently healthy women high levels of antigen were found in the serum.

Detection of Lewis(a) antigen in sera of ovarian carcinoma patients by MOv2-MOv8 double-determinant radioimmunoassay.

The monoclonal antibodies MOv2 and MOv8, raised against ovarian carcinoma, were found to be directed against two non-crossreacting epitopes expressed on the same molecule. Immunochemical analysis of the MOv8 recognized epitope showed that the Le(a) oligosaccharide, or commercial anti-Le(a) MAb, but not the anti-Le(b) MAb, prevented Ov8 binding to the reference target cell line (SW626), indicating that it is carried by the Le(a) antigen. Since we previously reported that MOv2 also recognises the Le(a) antigen, these data suggest that Mov8 and Mov2 were directed against different epitopes on the same oligosaccharide chain. Bearing in mind the knowledge of the biochemical nature of the monoclonal antibody recognized epitopes (CaMOv2 and CaMOv8), the presence of the circulating molecules recognized by them was analyzed by double determinant immunoradiometric assay (DDIRMA) in 103 sera from ovarian carcinoma patients. Patients with clinical evidence of the disease (ED) with MOv2 and MOv8 reactive and negative tumors had sera reactivity in 67% and 19% respectively. Also, 26% of the patients with no clinical evidence of disease (NED) had positive sera. When we investigated the relationship between MOv2-MOv8 DDIRMA sera positivity and red blood cells (RBC) Lewis phenotype, a strong correlation was found between the Le(a)+ phenotype and DDIRMA sera reactivity in healthy donors (6/6) and in ovarian carcinoma patients (9/10) whatever their clinical condition. No Le(a)- healthy donors gave evidence of MOv2-MOv8 reactive sera. In contrast, 33% and 57% of the sera from ED carcinoma patients with respectively Lea-b+ and Lea-b- phenotype were positive.(ABSTRACT TRUNCATED AT 250 WORDS)

Radical surgery after induction chemotherapy in locally advanced cervical cancer. A feasibility study.

In locally advanced cervical cancer, neoadjuvant chemotherapy has been shown to be effective for treatment of both the primary lesion and of metastatic lymph nodes. However, tumor necrosis and regression are often associated with dense fibrosis, which may complicate the surgical management. Forty-five patients with stage IB bulky-IIIB squamous cell carcinoma of the cervix underwent radical hysterectomy plus para-aortic and pelvic lymphadenectomy after one to three courses of different neoadjuvant cisplatin-based chemotherapeutic regimens. Mean operating time was 240 min. One major hemorrage was the only complication related to the para-aortic and pelvic node dissection. The parametrial dissection could be carried out in all patients. Intraoperative complications related to this part of the operation included two rectal and three urinary injuries repaired with no postoperative sequelae. In the specimens, residual parametrial infiltration was present in three out of 15 stage IIB-IIIB cases. The intraoperative complication rate was 13.3% and the gross postoperative complication rate was 4.4%. Postoperatively, only one case of ureteral fistula was recorded, yielding a rate of 2% (1/45). These data are not significantly different from those reported in the literature for radical surgery without neoadjuvant chemotherapy. In locally advanced cervical cancer, radical surgery after neoadjuvant chemotherapy is feasible without any undue increase in morbidity and mortality.

Intestinal operations during surgical procedures for epithelial ovarian cancer.

Fifty-two intestinal operations were performed during 45 laparatomies in 43 non-obstructed ovarian cancer patients. The histology of the tumor was serous in 29/43 cases (67.5%). The gross postoperative morbidity rate was 15.5% and postoperative mortality rate 6.9%. The 5-year survival was 28.3%, and was not affected by the time of intestinal surgery (during the first or following laparotomies). As a result, intestinal surgery in advanced ovarian cancer patients is feasible without an undue increase in morbidity. However, it must be carefully tailored because, though contributing to the quality of life of these patients, it does not seem to affect their survival, at least in this retrospective series.

Surgical staging for epithelial ovarian tumors of low malignant potential.

From January 1975 to December 1991, 34 patients with a diagnosis of epithelial ovarian tumors of low malignant potential (LMP) were admitted to the Istituto Nazionale Tumori of Milan. Eighteen of them (group 1) underwent complete staging laparotomy and retroperitoneal para-aortic and pelvic lymphadenectomy, as for ovarian cancer. In the remaining 16 cases (group 2), the surgical treatment ranged from unilateral oophorectomy to incomplete staging procedure. In group 1, nine patients (50%) were found to have retroperitoneal nodal involvement. In group 2, all patients had stage I disease. Patients were followed up for 20-222 months (mean 108, median 86). There were two recurrences in group 2 (after 5 years) and none in group 1 (NS). Currently all patients are alive and disease free. Nine of 18 group 1 patients were upstaged to stage III on the basis of lymph node involvement only. However, at least in this retrospective series, lymph node metastases did not affect prognosis or survival.

Cisplatin and cyclophosphamide in advanced ovarian carcinoma: activity and toxicity of an ambulatory regimen.

Chemotherapy with cisplatin (CDDP, 90 mg/m2) and cyclophosphamide (CTX, 600 mg/m2) was administered to 54 consecutive patients with advanced epithelial ovarian cancer (37 stage III and 17 stage IV). In 51 patients, surgery was performed prior to chemotherapy. Of the 37 stage III patients, 13 had only minimal residual disease after surgical debulking. The overall response rate was 69%, with 44% patients achieving clinical (cCR; n = 2) or pathological (pCR; n = 20) complete response. Median follow-up and overall survival time was 26 months, and median CR duration was 30 months. CR was achieved in 6 of 14 patients (43%) who were partial responders after five cycles of chemotherapy and had continued treatment for three to five more cycles. Severe bone marrow toxicity or renal function impairment was never observed, but eight patients presented peripheral signs of dose-related neurotoxicity. These findings indicate that CDDP and CTX in combination are an effective treatment for patients with advanced ovarian carcinoma, and can be administered with tolerable toxicity. In selected cases, prolonged chemotherapy administration can result in durable complete remissions.

Second surgical treatment of retroperitoneal persistent disease in epithelial ovarian cancer.

AIMS AND BACKGROUND: This report retrospectively analyzes 9 cases of epithelial ovarian cancer with persistent retroperitoneal metastasis after intraperitoneal surgery (without systematic lymphadenectomy) and chemotherapy. METHODS: All 9 patients were diagnosed as FIGO stage I to IV at the time of primary surgery. They received combined postoperative chemotherapy (8 cases with a cisplatin-based regimen and 1 with adriamycin and endoxan). They were submitted to pelvic and paraaortic lymphadenectomy at the National Cancer Institute of Milan during the period 1990-1994. RESULTS: All patients presented no evidence of disease in the abdominal cavity but retroperitoneal metastasis, which was the unique metastatic site. Chemotherapy was administered as adjuvant therapy after lymphadenectomy. Six patients were free of disease for 14 to 61 months. One patient with vaginal recurrence at the 18th month was treated with radiotherapy and chemotherapy, but died of widespread disease 25 months after lymphadenectomy. Two patients with massive positive lymph nodes dies of brain and lung metastasis 20 and 6 months later, respectively. CONCLUSIONS: We conclude that retroperitoneal metastasis may be the only site of persistent disease and that systematic lymphadenectomy technically feasible in this situation to increase the opportunity for local disease control and to obtain a good result.

State of the art of sentinel node biopsy in oncology.

Sentinel node biopsy has become a standard diagnostic procedure to assess lymph node status of various tumors. The combination of blue dye and a radioactive tracer offers the best chances of identifying the sentinel lymph node. Most progress in the technique of the sentinel node procedure has been made in melanoma and breast cancer. In melanoma, sentinel node biopsy has been introduced as a fundamental procedure for staging. Information on the lymphatic drainage from a melanoma can have a direct impact on the surgery. More recently, the technique has been successfully introduced in the management of breast cancer, in which a large number of unnecessary axillary dissections could be avoided. However, there are many other potential fields of application of the sentinel node biopsy (e.g. endometrial, vulvar, head and neck cancers) that are worthy of investigation. In any case, multicenter trials are required to standardize the procedures, taking into account several variables such as particle size and mode of delivery of the radiotracer, amount of radioactivity administered, number and location of injections, and choice of the hand-held probe. We briefly describe the technical and historical aspects of the sentinel node biopsy and summarize the main clinical trials proposed and/or performed in the field.

Adult granulosa cell tumor of the ovary: a clinico pathologic study of 35 cases.

AIMS AND BACKGROUND: Adult granulosa cell tumor has a low malignant potential but requires an extensive follow-up of more than 5 years to accurately assess tumor activity. The aim of the present study was to evaluate the clinical characteristics, the treatment and the outcome of this rare ovarian tumor. STUDY DESIGN: A retrospective review of 35 cases treated at primary onset of disease during a 23-year period from 1971 to 1993. RESULTS: The disease-free survival rate for stages IA-B-C at 5 and 10 years was 90% and 84%, respectively; for stages III-IV the 5-year freedom from progression rate was 16%. CONCLUSIONS: The most important prognostic factor appears to be the extent of tumor involvement outside of the ovary.

[Sequelae of radiosurgical treatment in patients having undergone Wertheim radical hysterectomy]. / Sulle sequele del trattamento radiochirurgico nelle pazienti operate di isterectomia radicale alla Wertheim.

The sequelae from therapeutic treatment in a series of 361 patients subjected to Wertheim's hysterectomy, 125 of whom had a lumbo-aortic lymphadenectomy, have been studied. All these patients underwent postoperative external beam irradiation and intracavitary radium or caesium. Twenty-six cases of functional vesical disturbance, 12 of iliac lymphocele, 24 of parametritis, 4 of bladder vaginal fistula, 35 of ureteral fistula, 16 of ureteral fibrosis, 6 of lymphedema of the lower limbs and 1 of rectal ulcer were found. In some types of sequelae, the most important cause was surgery, with greater evidence if the operation was more extensive. For other types of sequelae the most important cause was radiotherapy for dystrophy and fibrosis of the irradiated tissues, leading to occlusion of lymphatic vessels, and intestinal and ureteral fibrosis. Recovery was easier with better results if the causes of sequelae were prevalently from surgery. The clinical findings were later and recovery more difficult if the causes were prevalently from radiotherapy.

The role of secondary surgery in recurrent ovarian cancer.

Despite optimal treatment (complete cytoreduction and adjuvant chemotherapy), 5-year survival for advanced ovarian cancer is approximately 30% and most patients succumb to their disease. Cytoreductive surgery is accepted as a major treatment of primary ovarian cancer but its role in recurrent disease is controversial and remains a field of discussion mainly owing to missing data from prospective randomized trials. A critical review of literature evidence on secondary surgery in recurrent ovarian cancer will be described.

Photodynamic therapy using a methyl ester of 5-aminolevulinic acid in recurrent Paget's disease of the vulva: a pilot study.

OBJECTIVE: In the past, treating vulvar Paget's disease through surgery has resulted in a high recurrence rate of the disease. Photodynamic therapy (PDT) using 5-aminolevulinic acid (5 ALA) is an effective treatment for some conditions such as Bowen's disease, subsets of basal cell carcinomas and vulvar carcinoma. Methyl 5-aminolevulinate (MAL) is an ester of 5 ALA that seems to be more effective and produces fewer side effects than 5 ALA. This paper outlines a pilot study designed to test the feasibility of using MAL-PDT in the treatment of recurrent vulvar Paget's disease. METHODS: 5 MAL-PDT was applied for 3 h and than irradiated with red-light (620 nm) using a total light dose of 37 J/cm2 for a period of 10 min. Patients taking part in the study were treated once every 3 weeks, for a total of three treatments. Vulvar biopsies were obtained before and 1 month after the PDT-treatment. RESULTS: Seven patients were enrolled in the study. Four cases had a complete clinical response, and this was pathologically confirmed in two of the cases. The cosmetic outcome was acceptable and the treatment was well tolerated. All the patients developed local edema and mild local pain, controlled with non-steroidal antiinflammatory drugs (NSAIDS). One patient experienced severe pain and a mild local phototoxicity reaction. CONCLUSIONS: MAL-PDT is a feasible treatment and seems to offer a reliable strategy in the control of vulvar Paget's disease and of its symptoms.

Prognostic factors in microinvasive cervical squamous cell cancer: long-term results.

We examined tumor-related pathologic factors and cone-related characteristics to identify parameters related to recurrence in microinvasive squamous cell carcinoma of the cervix treated with conization. This is a retrospective study on 67 consecutive cases of microinvasive carcinoma of the cervix [depth of invasion (DI) < 3 mm] treated with conization. The mean follow-up was 121 months (range 72-276 months). Four (6%) invasive recurrences were observed. Presence of lymphvascular space involvement (LVSI) was significantly related with recurrences (P < 0.05). The mean distance between tumor margin and apex of the cone (apical clearance) was 10.6 mm (range 5-22 mm), and the mean distance between lateral border of the cone and tumor margin (lateral clearance) was 6.5 mm (range 1.7-15 mm). We adopted cut-off values of 10 and 8 mm for apical and lateral clearances, respectively. We found a statistically significant difference between apical clearance and recurrence rate (P < 0.02). The LVSI was, other than DI, an important prognostic factor. Apical clearance was significantly correlated with recurrence. The cone-related characteristics, other than tumor-related pathologic factors, could help the decision concerning the definitive therapy for microinvasive carcinoma of the cervix.

The role of appendectomy in surgical procedures for ovarian cancer.

To assess the role of appendectomy in the surgical procedures for ovarian cancer, we evaluated retrospectively the clinical charts of 435 patients who underwent surgery after diagnosis of ovarian cancer. The appendix was removed in 160 cases and pathological examination revealed 37 with metastatic implants (23%). All the patients with appendiceal metastases showed advanced disease (stages III-IV) with an incidence of 43%. Ninety-one percent (31/34) of the tumors with appendiceal involvement at the staging operation were of the serous cell type and grade II or III. No case with early stage, right ovary carcinoma showed appendiceal metastatic foci, denying the existence of a preferential lymphatic pathway. Microscopic involvement was found only in 4 patients with advanced disease (11.7%). No intra- or postoperative complication directly related to the appendectomy was recorded. We conclude, with these results, that appendectomy should be part of the cytoreductive operation for ovarian cancer.

Histologic evidence for an association of cervical intraepithelial neoplasia with human papilloma virus infection.

All the cytologic and histologic material pertaining to 100 patients who underwent cervical conization for advanced cervical intraepithelial neoplasia (CIN) was reviewed. The revision of the histology of the biopsies and cones showed in 56 cases the association of CIN with viral cytopathic effects (VCE) attributable to human pappiloma virus (HPV) and in 52 the coexistence of a predominantly flat condyloma. The comparison of the two groups of CIN, with and without VCE, showed that in the first the association had favored in 20% of the cases the histologic overestimation of the severity of the lesion. Of the patients with CIN III, 46% showed additional changes due to VCE. The mean age of the patients with CIN and VCE was 39.8 years and that of the patients with CIN was 48.6 (p less than 0.0001). The exocervix was significantly more often involved by CIN + VCE than by CIN alone (p less than 0.00001). Follow-up studies revealed in both groups the same percentage of residual disease and, preliminarily, a trend to a better control of CIN with VCE. New disease developed more often in the group of patients with CIN without VCE. Cytologic sensitivity for VCE in cervical smears was high (95%) in the cases of CIN II and somewhat lower (81%) in those with CIN III. Cytologic follow-up showed the persistence of VCE in 17% of the patients treated surgically for CIN and VCE. The morphologic and clinical features displayed by CIN associated with VCE warrant its recognition as a distinct variant of CIN.