European Cancer Centers Research Articles

An international pooled analysis identifying predictive factors associated with toxicities in phase I trials (Delphi).

2517 Background: Phase I trials aim at identifying suitable dose levels and toxicity profiles of novel drugs or combinations for further evaluation in phase II trials. In most of these trials, the appearance of serious toxic events determines the maximum tolerated dose. Eligibility criteria are traditionally used in order to select those patients who could potentially benefit from trial participation with a minimal risk of developing toxicity. Nevertheless, better tools for identifying patients at high risk of toxicity are warranted. Methods: Patients treated in phase I trials from four major American and European Cancer Centers were included from December 2002 to December 2007. Grade 3 and 4 (G3-4) toxic events were recorded as well as clinical and biological characteristics at baseline. The prognostic value on toxicities of these factors was assessed using logistic models, stratified on center. Results: A total of 810 patients were included in 146 phase I trials. Of those patients, 357 presented at least one G3-4 toxic event. Median age was 58 years, with 56% male. Forty-nine percent of patients received a targeted therapy (TT) as single agent, while 42% and 9% received a combination of a cytotoxic drug + TT or a combination of TT, respectively. A multivariate analysis of 11 out of 19 clinical and biological factors selected after univariate analysis showed a higher risk of G3-4 toxicity in patients with lymphocytes count inferior to 700/mm3 (OR 1.84 [1.17-2.90]) and platelets count inferior to 400,000/mm3 (OR 1.66 [1.09-2.52]). Patients included in phase I trials combining cytotoxic drug and a TT or TT among them showed a higher risk of serious toxic events (OR 2.32 [1.67-3.247] and OR 3.57 [1.90-6.472], respectively). Conclusions: Our data showed that patients' clinical and biological values present at the time of inclusion could predict a higher risk of serious toxic events in phase I trials. Trials exploring combination treatments are at highest risk. The data of an additional 400 patients is expected at the time of the Meeting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Roche

Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in advanced rectal cancer.

3563 Background: Recent phase II trials in locally advanced rectal cancer patients have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without a significant improvement of clinical outcome. In order to identify a subgroup of patients with a marked benefit,we assessed gene expression of factors involved in tumor growth (EGFR), angiogenesis (VEGF, VEGFR1, VEGFR2d), DNA repair (ERCC1) and drug metabolism (TS) as well as KRAS gene mutation status to characterize molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation followed by surgery. Methods: 130 patients with locally advanced rectal cancer who were enrolled in phase II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Tumor tissue was obtained prior to neoadjuvant and after surgical therapy. Histomorphologic regression was defined using a modified Dworak regression system (grade 0/1: nonresponse; grade 4: complete response). After microdissection and extraction of the RNA/DNA, intratumoral gene expression levels and KRAS mutation status were analyzed. Results: Asignificantly decrease of TS, VEGFR1 and VEGFR2d expression was detected during neoadjuvant therapy (p < 0.02). High pre-therapeutic VEGF expression was significantly correlated with nonresponse (p = 0.033). KRAS mutations were found in 42 % of the patients. The mutation status (wild type [wt] vs. mutant [mt]) was significantly correlated with response: patients with a wt-status showed more frequently a complete response to neoadjuvant treatment (p = 0.025). In patients with a wt-status, high VEGF and EGFR mRNA expressions were significantly associated with complete response (p < 0.04). KRAS transversions (tv) vs. wt-status was also associated with tumor regression: nonresponse was more common in patients with KRAS tv (p = 0.007). Conclusions: This study suggests pretherapeutic intratumoral EGFR and VEGF mRNA expression as well as KRAS mutation status to be predictive markers for tumor response to neoadjuvant cetuximab-based chemoradiation of patients with locally advanced rectal cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Response Genetics Bristol-Myers Squibb, ImClone Systems, Merck KG Response Genetics Bristol-Myers Squibb, ImClone Systems, Merck KG, Merck Serono, Roche, sanofi-aventis Merck, Roche, sanofi-aventis

Use of EGF a+61G and TS-5'UTR 2R/3R polymorphisms to predict complete pathologic response in locally advanced rectal cancer patients undergoing preoperative cetuximab-based chemoradiation followed by surgery.

3641 Background: Cetuximab has demonstrated significant clinical activity in metastatic colon cancer, however, cetuximab-containing neoajuvant chemoradiation has not been shown to improve local control or survival in locally advanced rectal cancer patients based upon recent phase II trials. In order to identify the subgroup of patients who may benefit from the cetuximab protocol, we evaluated functional germline polymorphisms of genes involved in critical pathways of cancer progression i.e., tumor growth (COX-2, EGF, EGFR, Kras), cell cycle regulation (CyclinD1), angiogenesis (VEGF, IL-8), ADCC (FCGR2A/3A), DNA repair (XRCC3, Rad51), and drug metabolism (TS, MTHFR), for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation followed by surgery. Methods: 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III and 15 with stage IV, 2 unknown) who were enrolled in phase II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was performed using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade 0-III vs grade IV: complete response). Results: Germline polymorphisms of EGF and TS were predictive for histopathologic response: 63 patients with EGF +61 G allele (AG + GG) had a 25% rate of pCR whereas the 50 patients with AA genotype had only a 2% rate of pCR (p < 0.001). In addition, the pCR rate of 69 patients with any 2R repeats in the TS 5'UTR (2R/2R + 2R/3R) was 20% while it was 0% in the 23 patients with the 3R/3R genotype (p = 0.006). Conclusions: This study suggests EGF A+61G and TS 5'UTR 2R/3R polymorphisms to be predictive markers for complete pathologic response to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems, Merck Bristol-Myers Squibb, ImClone Systems, Merck, Merck Serono, Roche, sanofi-aventis Merck, Roche, sanofi-aventis

The Organization of European Cancer Institute Pathobiology Working Group and its Support of European Biobanking Infrastructures for Translational Cancer Research

Today's translational cancer research increasingly depends on international multi-center studies. Biobanking infrastructure or comprehensive sample exchange platforms to enable networking of clinical cancer biobanks are instrumental to facilitate communication, uniform sample quality, and rules for exchange. The Organization of European Cancer Institutes (OECI) Pathobiology Working Group supports European biobanking infrastructure by maintaining the OECI-TuBaFrost exchange platform and organizing regular meetings. This platform originated from a European Commission project and is updated with knowledge from ongoing and new biobanking projects. This overview describes how European biobanking projects that have a large impact on clinical biobanking, including EuroBoNeT, SPIDIA, and BBMRI, contribute to the update of the OECI-TuBaFrost exchange platform. Combining the results of these European projects enabled the creation of an open (upon valid registration only) catalogue view of cancer biobanks and their available samples to initiate research projects. In addition, closed environments supporting active projects could be developed together with the latest views on quality, access rules, ethics, and law. With these contributions, the OECI Pathobiology Working Group contributes to and stimulates a professional attitude within biobanks at the European comprehensive cancer centers. Improving the fundamentals of cancer sample exchange in Europe stimulates the performance of large multi-center studies, resulting in experiments with the desired statistical significance outcome. With this approach, future innovation in cancer patient care can be realized faster and more reliably.

Intravaginal Brachytherapy in FIGO Stage I Low-Risk Endometrial Cancer

The purpose of the study was to compare postoperative vaginal irradiation with surgery alone in low-risk International Federation of Gynecology and Obstetrics (FIGO) stage IA-IB endometrial carcinoma. The study was a prospective, randomized trial of 645 evaluable low-risk endometrial carcinoma patients from 6 European gynecologic cancer centers. All tumors were in FIGO stage IA-IB, of endometrioid histological type, and FIGO grade 1-2. High-dose-rate afterloading equipments (iridium [Ir] 192 or cobalt [co] 60) were used at 5 centers, and low-dose-rate (LDR) afterloading equipment (cesium [Cs] 137) at 1 center. Perspex vaginal applicators or ovoids were normally used, and the dose was specified at 5 mm from the surface of the applicator. Three to 6 fractions (3.0-8.0 Gy) were given, and the overall treatment time was 4 to 15 days. A total of 319 patients were treated with surgery plus vaginal irradiation (treatment group), and 326 patients with surgery alone (control group).Twenty-six recurrences (4.0%) were recorded in the complete series. The locoregional recurrence rate was 2.6%, whereas distant metastases occurred in 1.4%. The rate of vaginal recurrences was 1.2% in the treatment group versus 3.1% in the control group. The difference was not statistically significant (P = 0.114). Side effects were few and mild (grade 1-2). Dysuria, frequency, and incontinence were slightly more common after vaginal irradiation (2.8% vs 0.6%, respectively). Late intestinal problems were few and similar in the 2 groups. The conclusions were that the impact of postoperative brachytherapy on even the locoregional recurrence rate seems to be limited in patients with low-risk endometrial carcinoma. The overall recurrence rate and survival were similar in the 2 groups.

Validation of a global self-assessment and peer-review quality programme dedicated to comprehensive cancer centres: A method to assess, improve and promote quality of integrated care, research, and education in cancer centers

e17565 Background: Oncology is a specialty requiring a combination of multidisciplinary expertises, novel technology, integration of innovation into care and research efforts in order to improve the quality of life and survival of patients. Provision of high-quality care and improvement of disease outcome should be promoted in cancer centers. Methods: The Organization of European Cancer Institutes developed an Accreditation Programme combining: 1-a quantitative questionnaire assessing the human, technical and financial resources and activities in care, research and education dedicated to oncology; 2- a set of standards and criteria for high-quality cancer management integrated in an electronic tool with a scoring system of compliance; 3- a peer-review process for review of the self-assessment outcome and on-site visits; 4- a report and improvement plan allowing to designate comprehensive cancer centers complying with required criteria for high-quality comprehensive cancer patient management. All components of the Accreditation Programme were tested in 8 different voluntary cancer centers in Europe. The objectives were to assess the feasibility, reproducibility and acceptance of the Accreditation Programme; to improve the standards and criteria in terms of understanding and consensus; to validate the peer review methodology and establish a method for reporting and implementing an improvement plan; to provide with a preliminary system of designation of comprehensive cancer centers based on criteria of high-quality integrated research, care and education. Results: The 2 consecutive pilot tests allowed to validate 1- relevant items for the quantitative questionnaire; 2-criteria and standards for high-quality integrated multidisciplinary cancer patient's management. 3-The impact of the Accreditation Programme on improvement of patients management and professionals involvement. Conclusions: The OECI Accreditation Programme is ready for dissemination. Participation to the Programme allows development of improvement plans for innovative and integrated comprehensive cancer patients management in cancer centers. No significant financial relationships to disclose.

Nilotinib in the treatment of advanced gastrointestinal stromal tumours resistant to both imatinib and sunitinib

Patients diagnosed with advanced gastrointestinal stromal tumours (GISTs) who are resistant or intolerant to both imatinib and second-line sunitinib have a poor prognosis and few therapeutic options. We evaluated the efficacy of nilotinib, a novel tyrosine kinase inhibitor (TKI) in patients pretreated with imatinib and sunitinib. Fifty-two consecutive patients treated with oral nilotinib, 400 mg twice daily, within the nilotinib compassionate use programme in 12 European cancer centres, were included in this retrospective analysis. Median age was 59 years (range 24–80), and all patients had WHO performance score better than 3. All patients had failed both imatinib and sunitinib pretreatment, either due to progressing GIST (96%) or intolerance (4%). Five patients (10%; 95% confidence interval (CI) 2–18) responded to nilotinib and 19 patients (37%; 95% CI 24–50) achieved a disease stabilisation. Nilotinib was generally well tolerated, but six patients (12%) discontinued treatment due to intolerance. Median progression-free survival of nilotinib treatment was 12 weeks (95% CI 9–15; range 0–104) and median overall survival was 34 weeks (95% CI 3–65; range 2–135). Nilotinib is active in GIST resistant to both imatinib and sunitinib. These results warrant further investigation of nilotinib in GIST.

Biological Samples Bank and Cancer Research Database: Experience from pilot project at Aga Khan University Hospital, Karachi, Pakistan

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

Managing cancer in the EU: The Organisation of European Cancer Institutes (OECI)

Organization of European Cancer Institutes (OECI) has the mission to facilitate the development of European comprehensive cancer centres by integrating care and prevention with research and education. Core issues are to deliver a complete multidisciplinary care of high quality and stimulate translational cancer research. The goal is to innovate the cancer care. The increasing problem of critical mass will be solved by networking comprehensive cancer centres containing quality assured harmonized infrastructures. This will give Europe a new potential to extend the cancer research to areas not possible to cover by single centres.

Towards Quality, Comprehensiveness and Excellence. The Accreditation Project of the Organisation of European Cancer Institutes (OECI)

There are important gaps in the health status of citizens across Europe, as measured by life expectancy, mortality or morbidity data (Report for the European Commission on the health status of the European Union, 2003). Among the main determinants of the major causes of mortality and morbidity, stated in this report, stands recurrently access to quality healthcare. There is a fundamental need to define quality indicators and set minimal levels of performance quality criteria for healthcare. There is a need to integrate research into healthcare and to provide patients with equity of access to such high quality care. Oncology is a specialty particularly suited to experimenting a first application of accreditation at European level. The Organisation of European Cancer Institutes is a growing network of cancer Centres in Europe. The focus of the OECI is to work with professionals and organisations with regard to prevention, care, research, development, patient's role and education. In order to fulfil its mission, the OECI initiated in 2002 an accreditation project with three objectives: * to develop a comprehensive accreditation system for oncology care, taking into account prevention, care, research, education and networking. * to set an updated database of cancer centres in Europe, with exhaustive information on their resources and activities (in care, research, education and management) * to develop a global labelling tool dedicated to comprehensive cancer centres in Europe, designating the various types of cancer structures, and the comprehensive cancer centres of reference and Excellence. An accreditation tool has been established, defining standards and criteria for prevention, care, research, education and follow-up activities. A quantitative database of cancer centres is integrated in the tool, with a questionnaire, that provides an overall view of the oncological landscape in OECI cancer centres in Europe. Data on infrastructures, resources and activities have been collected. This OECI accreditation tool will be launched in autumn 2008 for all cancer centres in Europe. It serves as a basis for the development of the labelling tool for cancer structures in Europe, with a focus on Comprehensiveness and Excellence labels. Quality assessment and improvement is a critical need in Europe and is addressed by the OECI for cancer care in Europe. Accreditation is a well accepted process and is feasible. Standards and criteria as well as an accreditation tool have been developed. The OECI questionnaire gives an accurate vision of cancer institutions throughout Europe, helping assessing the needs and providing standards. The accreditation project is a long-term complete and voluntary process with external and internal added value, an active process of sharing information and experience that should help the whole cancer community reach comprehensiveness and excellence.

Risk factors for breakthrough invasive fungal infection during secondary prophylaxis

Intensive chemotherapy with severe neutropenia is associated with invasive fungal infections (IFIs) leading to high mortality rates. During leukaemia induction chemotherapy, IFI often prohibited further curative treatment, thus predisposing for leukaemia relapse. Continuing myelosuppressive chemotherapy after diagnosis of IFI has become feasible with the now expanding arsenal of safe and effective antifungals. Secondary prophylaxis of IFI is widely administered, but reliable data on outcome and risk factors for recurrent IFI during subsequent chemotherapy are not available. This study determines risk factors for recurrent IFI in leukaemia patients. From 25 European cancer centres, 166 consecutive patients with acute myelogenous leukaemia (AML) and a recent history of proven or probable pulmonary IFI were included. Patients were followed for recurrence or breakthrough IFI during the subsequent chemotherapy cycle. Of the 166 patients included, 69 (41.6%) were female, the median age was 53 years (range 2-81) the and 3 (1.8%) were <16 years. Recurrent IFI occurred in 26 patients (15.7%). Multiple logistic regressions yielded predisposing factors: duration of neutropenia [per additional day; odds ratio (OR) 1.043, confidence interval (CI) 1.008-1.078], high-dose cytarabine (OR 3.920, CI 1.120-12.706), number of antibiotics (per antibiotic; OR 1.504, CI 1.089-2.086), partial response as outcome of prior IFI (OR 4.037, CI 1.301-12.524) and newly diagnosed AML (OR 3.823, CI 0.953-15.340). Usage of high efficiency particulate air filter appeared protective (OR 0.198, CI 0.036-1.089). Duration of neutropenia, high-dose cytarabine, prior antibiotic therapy and a partial response to the first IFI therapy were risk factors for recurrent IFI and should be considered in AML patients with prior pulmonary IFI undergoing further chemotherapy.

TuBaFrost 1: Uniting local Frozen Tumour Banks into a European Network: an overview

TuBaFrost is the consortium responsible for the creation of a virtual European human frozen tumour tissue bank: a collection of high quality frozen residual, accurately classified tumour tissue samples, which are stored in European cancer centres and universities. This virtual tissue bank, searchable on the internet, has rules for access and use, and a code of conduct to comply with the various legal and ethical regulations in European countries. The easy accessibility and the European scale of the bank will result in the availability of a large number of samples even of rarer tumour types. Standardisation of collection, storage and quality control throughout the network is achieved minimising inter-institutional variability. A website providing access to upload, search and request samples is a key tool of the tissue bank. The search engine makes use of virtual microscopy. An overview of the development of the European virtual frozen tissue bank infrastructure is described in this paper. The various key aspects are described in more detail in a series of articles to appear in this Journal.

The Use of Cell Line Standards to Reduce HER-2/neu Assay Variation in Multiple European Cancer Centers and the Potential of Automated Image Analysis to Provide for More Accurate Cut Points for Predicting Clinical Response to Trastuzumab

The Use of Cell Line Standards to Reduce HER-2/neu Assay Variation in Multiple European Cancer Centers and the Potential of Automated Image Analysis to Provide for More Accurate Cut Points for Predicting Clinical Response to Trastuzumab

The Use of Cell Line Standards to Reduce HER-2/neu Assay Variation in Multiple European Cancer Centers and the Potential of Automated Image Analysis to Provide for More Accurate Cut Points for Predicting Clinical Response to Trastuzumab

Immunohistochemical analysis, the most efficient way of assaying for HER-2/neu overexpression in patients with invasive breast cancer, is subject to variation in sensitivity and evaluation when used in multiple laboratories. Cell lines with differing but constant levels of HER-2/neu expression have been advocated as standard material against which assay sensitivity can be gauged. Automated image analysis could provide more precise linear measurements of HER-2/neu expression than the subjective and categorical scoring system originally designed for the HER-2/neu clinical trials. Multiple European laboratories (range, 92-126) stained 7 cell line standards on 6 successive occasions using a variety of immunohistochemical assays for HER-2/neu. During the 2-year study period, a trend toward a standard sensitivity level was observed, with significant improvement in numbers of laboratories achieving appropriate results. Image analysis gave reproducible and significantly different linear values for a total of 621 HER-2/neu results on cell lines previously categorized manually as 3+, 2+, 1+, or 0. The use of cell line standards and image analysis have the potential to assist in standardizing immunohistochemical results for predictive markers and provide more accurate and quantifiable cut points for predicting clinical response to therapy, respectively.

Tumor necrosis factor-based isolated limb perfusion for soft tissue sarcoma and melanoma: ten years of successful antivascular therapy.

TNF-based ILP is very successful as a treatment to achieve limb salvage in the management of advanced, multiple, or drug-resistant extremity tumors. TNF-based ILP is now performed in 30 cancer centers in Europe. TNF-based antivascular therapy for cancer is here to stay, and its potential needs to be studied further [7].

A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer

With the availability of chemotherapy agents for first- and second-line treatment of advanced non-small-cell lung cancer (NSCLC), the patient population that requires subsequent chemotherapy is increasing. This retrospective analysis was performed to describe the clinical course after two standard or approved chemotherapy agents in patients with good overall performance status. Data were selected from patients with advanced NSCLC who had received third- or fourth-line chemotherapy after two prior chemotherapy regimens that included platinum and docetaxel given concurrently or sequentially. Prior regiments had failed due to discase progression within 90 days of chemotherapy, or unacceptable toxicity. Examination of over 700 patient records between January 1993 and January 2000 at one US and one European cancer centre revealed 43 patients that fulfilled the inclusion criteria. Response rates decreased with each line of treatment: first line, 20.9%; second line, 16.3%; third line, 2.3%; and fourth line, 0%. The disease control rate (response plus stable disease) also decreased dramatically from first- to fourth-line treatment, although it was higher for second-line treatment (74.4%) than for first-line treatment (62.8%). The median overall survival time from diagnosis was 16.4 months. The median overall survival time from the start of the last treatment (either third or fourth line) was 4 months. Patients with stage III disease at diagnosis had a longer overall survival from diagnosis than patients with stage IV disease ( P=0.02). This review highlights the need for novel therapy approaches for patients with recurrent NSCLC who have failed second-line therapy and provides a baseline for the statistical design of such studies.

Cancer mortality and incidence in Hungary in relation to international data

In Hungary mortality caused by malignant tumour diseases is very high. It is the second cause of death showing approximately 25% frequency. Statistics on disability has revealed that during the past 25 years the number of patients become invalid because of cancer has nearly doubled.In comparative international statistics cancer mortality and incidence of the Hungarian male population take the first and that of the female population the second place. The alarming public health problems caused by cancer in Hungary have prompted the authors to identify the causes and search for points of outbreak to stop and reverse these unfavourable tendencies. When analysing the current state of this country authors primarily rely on the studies of the European Cancer Centre, Lyon and those of the Hungarian Central Statistical Office (KSH) and National Cancer Registry. By years 2000-2001 the National Cancer Registry has become a reliable well functioning system. Its activities include the registration of all new cancer patients announced in the previous calendar year. Data processing requires information such as: year of diagnosis, tumour localisation and extension, morphological code and therapeutic interventions. It is a promising sign that the first time over the past 25 years cancer mortality decreased in year 2000. The unfavourable cancer mortality and incidence status in Hungary might be improved by the consistent accomplishment of the project "For a Healthy Nation, A Public Health Project for years 2001-2010".

Incidence of metachronous testicular cancer in patients with extragonadal germ cell tumors.

The frequency of subsequent testicular cancer (referred to as metachronous testicular cancer) in men who have had previous testicular cancer is relatively high. The rate of metachronous testicular cancer in men with extragonadal germ cell tumors (EGCTs), however, is largely unknown. We conducted a retrospective study of EGCT patients to determine the incidence, cumulative risk, and specific risk factors for metachronous testicular cancers. A standardized questionnaire about patient characteristics, the extent of EGCT disease, any second malignancies, and treatments received was completed for 635 patients with EGCTs identified from the medical records of 11 cancer centers in Europe and the United States from 1975 through 1996. Comparisons with age group-specific data from the Saarland, Germany, population-based cancer registry were used to calculate the standardized incidence ratio (SIR). The Kaplan-Meier method was used to analyze survival data and cumulative risk. All statistical tests were two-sided. Sixteen EGCT patients (4.1%) developed metachronous testicular cancers, with a median time between diagnoses of 60 months (range, 14-102 months). The risk of developing metachronous testicular cancers was statistically significantly increased in patients with EGCTs (observed = 16; expected = 0.26; SIR = 62; 95% confidence interval [CI] = 36 to 99) and in subsets of EGCT patients with mediastinal location (SIR = 31; 95% CI = 8 to 59), retroperitoneal location (SIR = 100; 95% CI = 54 to 172), and nonseminomatous histology (SIR = 75; 95% CI = 43 to 123). The cumulative risk of developing a metachronous testicular cancer 10 years after a diagnosis of EGCT was 10.3% (95% CI = 4.9% to 15.6%) and was higher among patients with nonseminomatous EGCTs (14.3%; 95% CI = 6.7% to 21.9%) and retroperitoneal EGCTs (14.2%; 95% CI = 5.6% to 22.8%) than among patients with seminomatous EGCTs (1.4%; 95% CI = 0.0% to 4.2%) and mediastinal EGCTs (6.2%; 95% CI = 0.1% to 12.2%). Patients with EGCTs, particularly those with retroperitoneal or nonseminomatous tumors, but also those with primary mediastinal EGCTs, are at an increased risk of metachronous testicular cancer.

Current trends in the management of adamantinoma of long bones. An international study.

Adamantinoma of long bones is a rare tumor. Published reviews of the orthopaedic management of adamantinoma have involved limited follow-up of small numbers of patients. The oncological aggressiveness of this tumor is unknown. Limb salvage is currently the treatment of choice for most adamantinomas. The purpose of this study was to evaluate the characteristics of adamantinoma of long bones as well as the oncological outcome and the complications of limb salvage operations. A retrospective study was designed to evaluate the clinical outcomes of limb salvage operations for the treatment of adamantinoma. Data on seventy biopsy-proven cases of adamantinoma treated between 1982 and 1992 at twenty-three different cancer centers in Europe and North America were obtained. The median duration of follow-up was 7.0 years. The male:female ratio was 3:2, and the mean age was thirty-one years. Limb salvage was attempted in 91 percent (sixty-four) of the seventy patients, and the final rate of limb preservation was 84 percent (fifty-nine of seventy). Wide operative margins were obtained in 92 percent (fifty-eight) of sixty-three patients. An intercalary allograft was used to reconstruct the segmental bone defect in 51 percent (thirty-six) of the seventy patients. Reconstruction-related complications occurred in 48 percent (thirty) of sixty-two patients. Nonunion and fracture were the most common complications, occurring in 24 percent (fifteen) and 23 percent (fourteen) of sixty-two patients, respectively. Kaplan-Meier analysis demonstrated a rate of local recurrence of 18.6 percent at ten years. Wide operative margins were associated with a lower rate of local recurrence than marginal or intralesional margins were (p < 0.00005). Kaplan-Meier analysis showed a survival rate of 87.2 percent at ten years. There were no significant relationships between survival and the stage of the tumor (p = 0.058), duration of symptoms (p = 0.90), gender (p = 0.79), or wide operative margins (p = 0.14). Current treatment of adamantinoma, including en bloc tumor resection with wide operative margins and limb salvage, provides lower rates of local recurrence than has been previously reported. In the present study, the limb preservation rate was 84 percent (fifty-nine of seventy), and the survival rate was 87.2 percent at ten years. The rate of complications related to the limb reconstruction was high.

High-Dose Chemotherapy With Autologous Bone Marrow Rescue in Children With Poor-Risk Burkitt's Lymphoma: A Report From the European Lymphoma Bone Marrow Transplantation Registry

AbstractTo evaluate the role of high-dose chemotherapy (HDC) followed by autologous bone marrow transplantation (ABMT) in children with poor-prognosis Burkitt's lymphoma, the European Lymphoma BMT registry was critically reviewed. Between February 1979 and July 1991, a selected group of 89 children (78 boys and 11 girls) were considered as ABMT candidates in 12 European cancer centers for the following reasons: poor initial response (PIR) to first-line chemotherapy in 28 patients, primary refractory disease (PRD) in nine patients, sensitive relapse (SR) in 38 patients, and resistant relapse (RR) in 14 patients. The median age at ABMT was 8.2 years (range, 2.8 to 16.2 years). Thus, this report reflects data for patients surviving the salvage attempt deemed appropriate for HDC/ABMT and who then actually underwent the transplant procedure. The median follow-up period after HDC/ABMT was 4.3 years (range, 2 to 12 years). The prognosis was dismal for PRD patients and those with RR, ie, all patients died within 1 year. The 5-year event-free survival (EFS) was 56.6% (P < .0001) for patients in partial remission (PR) and 48.7% (P = .002) for patients with SR. The toxic death rate was 11.1%. Continuous complete remissions (CRs) in 39.4% of these otherwise incurable children highlight the fact that HDC/ABMT was an effective complementary procedure after conventional-dose chemotherapy protocols used during the given period. In addition, these data show that patients with PRD or RR clearly had no advantage from this aggressive and cost-intensive procedure. It has to be considered that the need for HDC/ABMT has greatly diminished in parallel with the improvement in survival using the modern intensive pulsed CCT of current protocols. To further rescue patients failing to respond to modern protocols, new approaches appear necessary, ie, combinations of HDC with antibody-targeted therapy plus allogeneic BMT for the additional benefits of the potential graft-versus-lymphoma effect.