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.

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.

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.

Ovarian cancer management. Practice guidelines for nuclear physicians.

Ovarian cancer is a frequent and severe malignancy. Over 75% of cases are diagnosed at an advanced stage with disease spread beyond the ovaries. Despite the high response rates of initial treatments (i.e.,70-80%), the median progression-free survival of advanced ovarian cancer is 16-22 months, and the 5-year overall survival, 20-30%. The majority of these patients relapse, with metastatic peritoneal spread, unresectable, or drug resistant disease. Our goal was to outline current knowledge about diagnosis, prognostic factors, and treatments, and to dwell on non-nuclear medicine and nuclear-medicine diagnostic procedures.

False-negative sentinel node in patients with vulvar cancer: a case study.

Evidence from recent studies indicates that the technique of sentinel node biopsy might be a useful solution for detecting lymph node status for primary vulvar cancer without having to perform radical inguinal lymphadenectomy. The patient in this report underwent sentinel node biopsy, then bilateral inguino-femoral node dissection, and, lastly, radical vulvectomy. The histologic analysis showed a well differentiated squamous cell carcinoma with metastases in one right inguinal node and one left inguinal node and a false-negative right sentinel node. Technically the biopsy of groin sentinel nodes should be quite easy to perform. The use of preoperative lymphoscintigraphy and the intraoperative use of the gamma probe combined with blue dye helps considerably in identifying lymphatic drainage and the sentinel node for vulvar cancer. Further results are needed to confirm the value of sentinel node dissection in the treatment of early stage vulvar cancer.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Childhood malignant ovarian germ cell tumors: a monoinstitutional experience.

OBJECTIVES: We reviewed our 23-year monoinstitutional exprience with childhood malignant ovarian germ cell tumors (MOGCT), with respect to survival and iatrogenic sequelae. METHODS: Twenty-nine patients (median age 12 years) with newly diagnosed MOGCT were treated: all girls but 2 underwent surgery as initial treatment. There were 9 pure dysgerminomas and 20 nondysgerminoma tumors (5 immature teratomas, 4 yolk sac tumors, and 11 mixed histology tumors). According to the FIGO classification, 9 girls were classified as stage I, 4 as II, 11 as III, and 3 as IV, and 2 were not evaluable because they were submitted to primary chemotherapy. Twenty-four received chemotherapy with VAC, PVB, or PEB regimens, according to the ongoing protocols through the years. Three stage I girls did not receive adjuvant chemotherapy because of their histology (2 dysgerminomas, 1 immature teratoma) and stage. In the early years, postoperative radiotherapy was given alone in advanced dysgerminoma stages. RESULTS: Five patients died of their disease: 2 dysgerminomas (stage IIIc and IV) and 3 nondysgerminomas (2 stage II and 1 stage IIIc). OS and EFS rates at a median of 112 months were 81.8%. Among 24 survivors, 4 experienced iatrogenic amenorrhea because of radiotherapy and/or bilateral oophorectomy. CONCLUSIONS: MOGCT are highly chemosensitive and curable, with preservation of reproductive function. The management of recurrent disease remains an open issue.

Prognostic indicators in melanoma of the vulva.

BACKGROUND: The aim of this study was to evaluate the prognostic significance of clinical-pathologic variables in melanoma of the vulva. METHODS: From 1979 through 1995, 40 women with a diagnosis of vulvar melanoma underwent radical surgery. Patient age, tumor size and site, histologic type, ulceration, tumor thickness, lymph node status, and number of positive lymph nodes were assessed for prognostic significance by multivariate analysis. RESULTS: Tumor thickness was a significant predictor of lymph node involvement, but not of survival. The most powerful predictors of survival by multivariate analysis were the lymph node status (P = .002) and the number of positive lymph nodes (P = .00003). CONCLUSIONS: The number of positive lymph nodes represents the strongest prognostic factor in melanoma of the vulva. Because of the lack of effective adjuvant therapies, such prognostic indicators might be used to define the timing and extent of the surgical approach.

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.

Systematic pelvic and paraaortic lymphadenectomy at second-look laparotomy for ovarian cancer.

A retrospective review of the medical records of all ovarian cancer patients admitted to our institution from January 1974 to December 1993 was performed. A total of 58 consecutive patients who underwent systematic pelvic and paraaortic lymphadenectomy during second-look surgery was found. Node metastases were found in 15 of 58 patients (25.8%). No significant correlation was found between the variables of disease (e.g., stage of the disease at diagnosis, histology, grade, residual tumor after the first cytoreductive surgery, and the type of chemotherapy administered) and node status at second-look. Node metastases were found in 8 of 45 (17.7%) patients with absence of intraperitoneal disease, compared with 7 of 11 (63.6%) patients with intraabdominal residual disease (P < 0.02). There was no difference in 5-year survival for patients with absence of residual tumor in the peritoneal cavity as well as in the retroperitoneum (5-year survival 80%) and for patients with retroperitoneal disease only (5-year survival 77%). On the contrary, a highly significant difference in survival (P < 0.001) was observed between these two groups of patients and those who had intraabdominal residual tumor. Twelve of 45 (26.6%) patients have recurred. FIGO stage, grade, and residual disease after primary surgery were determinant in predicting recurrence. Notably, no relation emerged between relapse rate and the node status at second-look.

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.

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.

Generation and phenotypic characterization of new human ovarian cancer cell lines with the identification of antigens potentially recognizable by HLA-restricted cytotoxic T cells.

This study describes a simple method for long-term establishment of human ovarian tumor lines and prediction of T-cell epitopes that could be potentially useful in the generation of tumor-specific cytotoxic T lymphocytes (CTLs). Nine ovarian tumor lines (INT.Ov) were generated from solid primary or metastatic tumors as well as from ascitic fluid. Notably all lines expressed HLA class I, intercellular adhesion molecule-1 (ICAM-1), polymorphic epithelial mucin (PEM) and cytokeratin (CK), but not HLA class II, B7.1 (CD80) or BAGE. While of the 9 lines tested 4 (INT.Ov1, 2, 5 and 6) expressed the folate receptor (FR-alpha) and 6 (INT.Ov1, 2, 5, 6, 7 and 9) expressed the epidermal growth factor receptor (EGFR); MAGE-1 and p185HER-2/neu were only found in 2 lines (INT.Ov1 and 2) and GAGE-1 expression in 1 line (INT.Ov2). The identification of class I MHC ligands and T-cell epitopes within protein antigens was achieved by applying several theoretical methods including: 1) similarity or homology searches to MHCPEP; 2) BIMAS and 3) artificial neural network-based predictions of proteins MAGE, GAGE, EGFR, p185HER-2/neu and FR-alpha expressed in INT.Ov lines. Because of the high frequency of expression of some of these proteins in ovarian cancer and the ability to determine HLA binding peptides efficiently, it is expected that after appropriate screening, a large cohort of ovarian cancer patients may become candidates to receive peptide-based vaccines.

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).

Systematic pelvic and paraaortic lymphadenectomy for advanced ovarian cancer: prognostic significance of node metastases.

A retrospective study of 488 patients with untreated advanced ovarian cancer is presented. Systematic pelvic and paraaortic lymphadenectomy was performed in 248 cases (50.8%). Selective sampling and node biopsy was performed in 33 (6.7%) and 47 (9.6%) patients, respectively. Node metastases were found in 194 of 328 patients (59.1%). The incidence of metastatic nodes significantly increased with more advanced stages, with serous histology, and with a greater amount of residual tumor. Node status appeared to be related to pathology findings at second-look. A complete pathologic response was documented in 26 of 31 (83.8%) patients with negative nodes and in 38 of 59 (64.6%) with positive nodes at first surgery. Patients with negative nodes survived significantly longer (5-year survival, 46%; median, 60 months) than those who had node metastases (5-year survival, 25%; median, 36 months). Using multivariate analysis, lymph node status, together with the stage of disease and residual tumor, still had a significant impact on 5-year survival. Moreover, among patients with optimal cytoreduction, 5-year survival was 46% (median, 56 months) and 30% (median, 41 months) for patients who did and did not undergo lymphadenectomy, respectively (P = 0.05). Likewise, when suboptimal cytoreduction was considered, a median 5-year survival of 24 months was obtained in patients who underwent lymphadenectomy compared with 14 months in patients who did not (P < 0.005).

Combined preoperative chemoradiotherapy followed by radical surgery in locally advanced vulvar carcinoma. A pilot study.

BACKGROUND: Although for decades exenterative surgery has represented the standard treatment for patients with locally advanced vulvar cancer, combined approaches, including preoperative radiation with or without chemotherapy, are now considered the treatment of choice. We report the results of a pilot study on concurrent chemoradiotheraphy followed by radical surgery for patients with locally advanced squamous cell carcinomas of the vulva. METHODS: Thirty-one patients with squamous cell carcinoma of the vulva were treated with two courses of combination chemotherapy mitomycin C, 15 mg/m2 intravenously (i.v.) on Day 1, and 5-fluorouracil, 750 mg/m2 i.v., in continuous 24-hour infusion on Days 1 to 5. Inguinal and pelvic lymph node chains and the vulva were irradiated (starting on the same day as the chemotherapy) up to a total dose of 36 Gy. After a 2-week interval, a second course of chemoradiotherapy was given (18 Gy on the vulvar region only). After 2 weeks, patients underwent radical surgery. RESULTS: An objective response was observed in 22 of 24 primary cases (91.6%) and in 7 of 7 recurrent cases. All but two unresponsive patients underwent radical surgery. The postoperative morbidity rate was 65% (19 of 29 patients), and the mortality rate was 13.8% (4 of 29 patients). Five of nine patients (55%) with biopsy-proven inguinal lymph node metastases showed no residual lymph node disease in the surgical specimen. The recurrence rate was 31.8% and the medial follow-up time was 34 months. CONCLUSIONS: Chemoradiotherapy seems to be effective for squamous cell carcinoma of the vulva. If treatment-related morbidity could be decreased, such a combined approach might offer a new perspectives for a conservative treatment of locally advanced vulvar cancer.

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.

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.