Soft tissue lymphoma is a very rare clinical entity with varying presentation characteristics and atypical clinical and imaging features. The present report describes a patient who presented with a painless soft tissue mass on the posterolateral surface of the abdominal wall, simulating a neoplasm of mesenchymal origin. After complete surgical excision, the tumor was diagnosed as a diffuse large B-cell lymphoma. No B-symptoms were present and clinical staging did not reveal other sites of disease (stage I EA). The International Prognostic Index score was equal to 1 and classified the patient to the good risk group. Post-operatively the patient was treated with immuno-chemotherapy consisting of rituximab plus cyclophosphamide, epirubicin, vincristine and prednisolone and is currently free of disease for 10 months. The case is discussed with a brief review of the literature on the diagnosis, treatment and outcome of soft tissue lymphomas. © 2006 Taylor & Francis.

Fifty patients with multiple myeloma ≥75 years of age received primary treatment with melphalan (M) 8 mg/m2 on days 1-4, dexamethasone (D) 12 mg/m2 on days 1-4 and 17-20 and thalidomide (T) 300 mg at bedtime on days 1-4 and 17-20. This regimen was repeated every 5 weeks for three courses. Patients without evidence of disease progression received nine additional courses of MDT, but without DT on days 17-20, every 5 weeks. Sixty-two percent of patients achieved a partial response and 10% a complete response. The median time to response was 2 months. The median time to progression for all patients was 21.2 months. Deep venous thrombosis and peripheral neuropathy each occurred in 9% of patients. ©2006 Ferrata Storti Foundation.

BACKGROUND. The toxicity of platinum-based combinations represents a common problem for patients with advanced urothelial carcinoma. The authors previously reported encouraging efficacy for the combination of carboplatin and gemcitabine in patients considered to be unfit for cisplatin-based treatment. The objective of the current multicenter Phase II study was to evaluate the safety and efficacy of the combination of gemcitabine and carboplatin as first-line treatment in unselected patients with advanced urothelial carcinoma. METHODS. Patients with previously untreated, bidimensionally measurable, inoperable or metastatic urothelial carcinoma were treated with carboplatin, area under the concentration curve of 5 (Day 1) and gemcitabine at a dose of 1000 mg/m2 (Days 1 and 8), every 21 days for a total of 6 cycles. RESULTS. Sixty patients (49 men and 11 women, with a median age of 69 yrs) were enrolled in the current study. Intent-to-treat analysis demonstrated an objective response rate (ORR) of 38.4% (95% confidence interval [95% CI], 26-51.8%) (11.7% complete responses and 26.7% partial responses). The median time to disease progression was 7.6 months (95% CI, 4.5-10.7 mos) and the median overall survival was 16.3 months (95% CI, 12-20.6 mos). The median survival was comparable to that reported for the combination of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) according to the Memorial Sloan-Kettering Cancer Center prognostic model for patients with similar baseline prognostic features. Grade 3 or 4 toxicity (according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) included anemia (18%), thrombocytopenia (23%), and neutropenia (52%), with 7 episodes of febrile neutropenia (11%) reported. Nonhematologic toxicity was rare. One toxic death occurred during the study. CONCLUSIONS. The combination of gemcitabine and carboplatin appears to have considerable activity as the first-line treatment of unselected patients with advanced urothelial carcinoma with manageable toxicity, and deserves further evaluation in this setting. © 2005 American Cancer Society.

Background and Objectives. Pure infradiaphragmatic Hodgkin's lymphoma (HL) is a rare disease. The prognostic impact of a purely infradiaphragmatic localization of this lymphoma is controversial. We aimed to evaluate the baseline clinicopathologic features, prognostic factors and outcome of a large series of consecutive patients with pure infradiaphragmatic HL. Design and Methods. We analyzed 131 patients with clinical stage I/II infradiaphragmatic HL treated with ABVD or equivalent regimens with or without radiotherapy, and compared 54 of them with 444 patients with pure supradiaphragmatic disease, who were treated at the same center. Results. Older age, clinical stage II (borderline), involvement of ≥3 sites, lymphocyte predominant histology, elevated serum β2-microglobulin and higher International Prognostic Score were more frequent in patients with infradiaphragmatic disease than in those with supradiaphragmatic disease, while nodular sclerosis was less frequent. The complete remission rate was 100%, 97% and 82% for stages I, IIA and IB, respectively. Only B-symptoms independently predicted for inferior failure-free survival, while inferior overall survival was independently associated with the involvement of ≥3 sites. At 10 years failure-free survival was 82±6% (vs. 85±2% for patients with supradiaphragmatic disease, p=0.45), overall survival was 74±8% (vs. 91±2%, p=0.0006), and disease-specific survival 87±5% (vs. 94±1%, p=0.04). In multivariate analysis the differences between infradiaphragmatic and supradiaphragmatic disease were obscured by older age and B-symptoms. Interpretation and Conclusions. Pure infradiaphragmatic HL presents with distinct clinicopathologic characteristics. The previously reported poorer outcome may be explained by the unfavorable profile of the patients rather than the infradiaphragmatic presentation per se. Patients with stage IIB disease should probably be classified as having advanced HL because of the unacceptable rate of primary refractory disease. ©2006 Ferrata Storti Foundation.

This report by an international consensus panel updates current recommendations for defining clinical response in Waldenström's macroglobulinemia (WM). The previously published response criteria incorporated parameters for monoclonal protein reduction and/or improvement of marrow and nodal involvement, and included definitions of complete and partial remissions. The criteria have been updated to include minor response and stable disease categories. In addition, the criteria now recognize that delayed responses after treatment with nucleoside analogues and biologic agents and the time point for assessing response in patients with WM should be considered so as to not miss or miscategorize a response. The new criteria should therefore help in better delineating responses to therapy in patients with WM, particularly with the wide use of nucleoside analogues and biologically based agents for this disease.

Purpose: The cellular inhibitor of apoptosis protein (cIAP) is regarded as an important prognostic biomarker in cancer. Here, we sought to determine the prognostic value of cIAP protein levels in epithelial ovarian cancer using a novel method of compartmentalized in situ protein analysis. Methods: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking followed by platinum/paclitaxel-based combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis. Results: The mean follow-up time for the entire cohort was 34.4 months. Patients with tumors bearing high cIAP membranous expression had a 3-year survival rate of 31% compared with 73% for patients with low cIAP expressing tumors (P = 0.0020). In multivariable analysis, adjusting for well-characterized prognostic variables, low membranous cIAP expression level was the only significant prognostic factor for overall survival. Conclusions: Our results indicate that cIAP protein levels have prognostic value in ovarian cancer patients. Modulation of cIAP levels may improve clinical outcome in ovarian cancer. Copyright © 2006 American Association for Cancer Research.

The adverse prognostic role of cytogenetic abnormalities has recently been established in plasma cell dyscrasias. Modern techniques such as fluorescence in situ hybridization and comparative genomic hybridization have revealed a higher incidence of cytogenetic abnormalities in patients with multiple myeloma (MM) compared to conventional cytogenetics. Hypodiploidy and chromosome 13 abnormalities are found in more than 50% of myeloma patients, representing well known factors with adverse prognosis. Rearrangements involving the switch regions of immunoglobulin heavy chain (IgH) gene at 14q32 with various partner genes represent the most common structural abnormalities, having an incidence of 70% in MM. Structural abnormalities of chromosomes 17 and 8 involving the p53 and c-myc genes are considered to be less frequent events, but carry a poor prognosis. New therapeutic approaches such as non-myeloablative allotransplantation and modern therapeutic agents (thalidomide, lenalidomide, and bortezomib) and their combinations give promise for an improved therapeutic management of patients with MM. The detection of t(4;14), t(14;16), deletion of chromosome 13 on metaphase analysis, or deletion of p53 by FISH will define high-risk prognostic groups that are not generally controlled with high-dose melphalan and autologous stem cell transplantation (ASCT), and should therefore be treated with more investigational therapies. Alternatively, eligible patients who do not have these poor risk factors are more likely to benefit from a high-dose, melphalan-based, regimen followed by ASCT. © 2006 Taylor & Francis.

Monoclonal IgM-related neuropathies constitute a heterogeneous group of disorders, which are generally poorly responsive to treatment. Rituximab, a chimeric monoclonal antibody against the CD20 molecule, has been used with success in patients with neuropathy and monoclonal IgM with anti-MAG or anti-GM1 ganglioside activity. Based on this observation, four patients were treated with IgM-related neuropathy with rituximab. Between January 1999 - December 2000, four patients with IgM-related neuropathy (one with chronic inflammatory demyelinating polyneuropathy (CIDP) and three with sensorimotor demyelinating neuropathy) were treated with rituximab. Rituximab was administered at a standard dose of 375 mg m-2 iv weekly for a consecutive 4 weeks; 3 months later, four additional weekly courses were administered to patients who did not experience deterioration of their neuropathy symptoms. Neurological evaluation was performed before each rituximab infusion and at 1 week and 2 months after last infusion and every 6 months the following years; including motor (MRC in six muscle groups, 9-hole peg test, 10m walk, hand grip strength), sensory neuropathy (vibration threshold and sensory subjective score) assessment. Neurophysiological parameters were also assessed (MNCV, SNCV, CMAP, SNAP). Strength improved in three of four patients; including the patient with CIDP. This patient developed a significant worsening of her weakness 3 weeks after the initiation of rituximab. This phenomenon coincided with a serum monoclonal IgM flare and resolved spontaneously 1 week later. Her improvement is ongoing for more than 5 years. Considering neurophysiological parameters, two patients showed a slight improved regarding conduction velocities and CMAP (10%) and the patient with IgM flare had a transient worsening of conduction velocities followed by improvement. In conclusion, rituximab is a safe and well-tolerated treatment which may be effective in some patients with IgM-related neuropathy. © 2006 Taylor & Francis.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1α) and bone remodelling markers were evaluated in 38 patients with Waldenström macroglobulinaemia (WM) and correlated with clinical and laboratory variables. MIP-1α was elevated in WM; untreated patients had higher MIP-1α levels than patients in remission or with active disease after treatment. MIP-1α correlated with increased bone resorption, β2- microglobulin and splenomegaly. Receptor activator of nuclear factor-κB ligand serum levels were elevated in WM patients; the subsequent increased bone resorption was balanced by a comparable elevation of osteoprotegerin production and bone formation. These findings may explain the absence of lytic lesions in WM patients and suggest a potential role of MIP-1α in WM. © 2006 Blackwell Publishing Ltd.

Brain metastases in patients with epithelial ovarian cancer (EOC) have an estimated incidence of 0.3-1.9% and are isolated in up to 50% of these patients. The risk factors and the prognostic significance of isolated central nervous system (CNS) relapse in patients with EOC who received primary treatment with platinum and paclitaxel have not been identified. We conducted a retrospective study in patients with EOC who relapsed with isolated brain metastases and report our experience. Two hundred sixty-seven patients with stages III and IV EOC, in clinical complete remission after first-line treatment with platinum and paclitaxel, were included in our analysis. After a median follow-up of 65 months, 150 patients had relapsed. Eight patients (5%) had isolated brain metastases. Patient and disease characteristics did not differ among patients who relapsed with isolated brain metastases and those with relapse outside the CNS. Median time to first disease relapse, overall survival, and survival after relapse did not differ significantly between patients with brain metastases and those with relapse outside the CNS. Two patients have died 6 and 12 months after the diagnosis of brain metastases, and 5 patients are alive 4-35 months after the diagnosis of isolated brain metastases. Three patients remain free of disease 4-18 months after treatment with radiotherapy and systemic chemotherapy for their CNS metastatic disease. Patients with isolated brain metastases have comparable survival to patients with relapse outside the CNS, and long-term remission can be achieved in some cases, provided that systemic chemotherapy is added to local treatment. © 2006, Copyright the Authors.

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed. © 2006 by The American Society of Hematology.

Urothelial cancer is a common malignancy. The management of patients with recurrent disease after cystectomy or initially metastatic or unresectable disease represents a therapeutic challenge. Systemic chemotherapy prolongs survival but long-term survival remains infrequent. During recent years there has been improvement due to the use of novel chemotherapeutic agents, mainly gemcitabine and the taxanes. The long-considered-standard MVAC has been challenged by combinations showing more favourable toxicity profiles and equal (gemcitabine-cisplatin) or even improved (dose-dense, G-CSF-supported MVAC) efficacy. Specific interest has also been generated in specific groups of patients (elderly patients, patients with renal function impairment or comorbidities), who are not fit for the standard cisplatin-based chemotherapy but can derive significant benefit from carboplatin- or taxane-based treatment. Retrospective analyses have enabled the identification of groups of patients with different prognoses, who possibly require different therapeutic approaches. Modern chemotherapy offers a chance of long-term survival in patients without visceral metastases, possibly in combination with definitive local treatment. Finally, the progress of targeted therapies in other neoplasms seems to be reflected in advanced bladder cancer by recent studies indicating that biological agents can be combined with modern chemotherapy. The true role of such therapies is currently being evaluated. © 2006 Oxford University Press.

Purpose. To assess the prognostic and predictive significance of HER-2 overexpression and high expression of VEGF in high-risk patients with breast cancer treated with dose-dense sequential chemotherapy. Patients and methods. From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (T) 250 mg/m2 followed by three cycles of "intensified" CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. HER-2 was assessed by immunohistochemistry (IHC) in 394 patients, and by fluorescence in situ hybridization (FISH) in cases scored as 2+ by IHC. VEGF was evaluated in 323 patients by IHC. Results. HER-2 overexpression was detected in 123 patients (31%) and high expression of VEGF in 233 (72%). The rate of HER-2 overexpression was significantly higher in patients with positive VEGF staining (35% vs. 21%, p = 0.02). Overexpression of HER-2 was significantly associated with negative hormonal status, high histologic grade and larger tumors. HER-2 overexpression was a significant negative predictor of DFS (p = 0.002), but not of OS. Adjusting for HER-2 overexpression, DFS and OS did not significantly differ between treatment groups. Positive VEGF staining was not associated with receptor status, number of positive nodes, grade, tumor size, incidence of relapse or death. Conclusions. For both treatments, HER-2 overexpression was a significant negative prognostic factor for DFS but not for OS, while high expression of VEGF was not significantly associated to either DFS or OS. No predictive ability of HER-2 status or VEGF overexpression for T treatment was evident. © Springer 2006.

Background: The pulmonary side-effects induced by novel antineoplastic agents have not been well characterized. Methods: To further investigate this topic, relevant English and non-English language studies were identified through Medline. For our search we used the generic names of novel cytotoxic or non-cytotoxic antineoplastic agents and the key phrases pulmonary/lung toxicity, dyspnea, pneumonitis, acute lung injury, acute respiratory distress syndrome and alveolar damage. The references from the articles identified were reviewed for additional sources. Abstracts from International Meetings were also included. Furthermore, information was obtained from the Pneumotox® website, which provides updated knowledge on drug-induced respiratory disease as well as from pharmaceutical websites. Results: Most novel antineoplastic drugs may induce pulmonary toxicity, which involves mainly the parenchyma, and less frequently the airways, pleura or the pulmonary circulation. Furthermore, a subset of these agents impairs pulmonary function tests. The exact incidence of lung toxicity remains unclear. The most common patterns consist of dyspnea without further details and infiltrative lung disease (ILD), denoting changes in the interstitium or alveoli. The diagnosis is one of exclusion. ILD is usually benign and responds to appropriate treatment; however, fatalities have been reported. Conclusions: Clinicians should be aware of the potential of most novel antineoplastic agents to cause lung toxicity. A high index of suspicion is required if these are combined with other cytotoxic drugs or radiation. © 2005 European Society for Medical Oncology.

Primary lymphoma of the upper urinary tract is an extremely rare entity without specific clinical or laboratory findings. Thus, this particular diagnosis is rarely anticipated and might well be reached only after nephroureterectomy. We describe a patient with primary follicular and diffuse follicle center lymphoma arising in the renal pelvis that was treated with surgery and postoperative immunochemotherapy. Furthermore, we review the literature regarding the treatment and outcome of this rare disease.

99mTc-2-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy has been suggested in multiple myeloma (MM) patients. According to the International Staging System (ISS), serum b2-microglobulin (Sβ2M) and serum albumin (SA) are dominant predictive factors and different cut-off values of these factors can separate patients into various stages of the disease. The purpose of this study was to assess the relationship between ISS staging, by Sβ2M and SA, and the 99mTc-MIBI scan findings. Twenty-five MM patients have been studied. Eighteen patients were at stage I, three at stage II and four at stage III of MM. 99mTc-MIBI scans were obtained and scored according to intensity (I) and extent (E) of the radiotracer uptake. A summed score (S) for the 99mTc-MIBI scan was calculated for each patient. A statistically significant negative correlation between E, I and S uptake scores versus the SA levels (P=0.004, 0.049 and 0.018 respectively), as well as a statistically significant positive correlation between E and S scores and the Sβ2M levels (P=0.012 and 0.032) were detected. A statistically significant difference between the E and S uptake scores among the MM patients examined for every stage separately was also found (P=0.007 and 0.024 respectively). The gradual increase of the E and S scores across the three stages of MM was also significant (P=0.003 and 0.021 respectively), despite the relatively small number of patients in stages II and III. In seven patients who died at the end of the follow-up period all three scores were significantly increased as compared to the scores of the patients who remained alive at that time. In conclusion, this study provides additional evidence that 99mTc-MIBI scan not only reflects myeloma disease activity in bone marrow but it is also well correlated with the Sβ2M and SA levels according to ISS.

New uniform response criteria are required to adequately assess clinicaloutcomes in myeloma. The European Group for Blood and Bone MarrowTransplant/International Bone Marrow Transplant Registry criteria have beenexpanded, clarified and updated to provide a new comprehensive evaluationsystem. Categories for stringent complete response and very good partialresponse are added. The serum free light-chain assay is included to allowevaluation of patients with oligo-secretory disease. Inconsistencies in priorcriteria are clarified making confirmation of response and disease progressioneasier to perform. Emphasis is placed upon time to event and duration ofresponse as critical end points. The requirements necessary to use overallsurvival duration as the ultimate end point are discussed. It is anticipatedthat the International Response Criteria for multiple myeloma will be widelyused in future clinical trials of myeloma.

To investigate the molecular mechanisms of action of the nitrogen mustard melphalan in patients treated for multiple myeloma, the in vivo induction and repair of melphalan-induced DNA damage was measured in genes with different transcriptional activity (b-actin > p53 > N-ras > d-globin) from leukocytes of 20 multiple myeloma patients following chemotherapeutic administration of high-dose melphalan (200 mg/m2) and autologous blood stem cell transplantation. Heterogeneous repair was found among the studied genes. The extent of repair was always in the order: b-actin > p53 > N-ras > d-globin, correlating with the gene transcriptional state. Similar findings were obtained using peripheral blood mononuclear cells (PBMC) from healthy volunteers following in vitro treatment with melphalan, indicating that these results are not malignant disease-specific. Following in vitro treatment of PBMC from healthy volunteers with α-amanitin, an inhibitor of RNA polymerase II that can also induce condensation of chromatin structure, a significant inhibition of the removal of melphalan-induced damage in the three active genes but not in the silent d-globin gene was found, suggesting that transcription and/or chromatin structure may play important roles in the preferential DNA repair. When the in vivo DNA damage formation and repair in multiple myeloma patients following chemotherapeutic administration of melphalan was measured in the two strands of the active genes, no strand bias was found, indicating that the global genome repair subpathway of nucleotide excision repair may play a crucial role in the repair of these adducts. These results were also confirmed in PBMC from healthy volunteers following in vitro treatment with melphalan. Using micrococcal nuclease digestion of nuclei isolated from PBMC of multiple myeloma patients before the chemotherapeutic treatment, as well as from PBMC of healthy volunteers, we probed the chromatin structure in each gene and found that the "looseness" of the chromatin structure correlated with the levels of the gene-specific repair, being again in the order: b-actin > p53 > N-ras > d-globin. To conclude, the in vivo gene-specific repair of melphalan-induced damage in humans is greatly affected by the local chromatin structure. © 2006 Elsevier B.V. All rights reserved.

Ovarian cancer is a leading cause of death from gynecological cancer. Although most patients will experience remission of their disease, following cytoreductive surgery and platinum (± paclitaxel) chemotherapy, relapse will occur in about 80% of cases with FIGO stages III and IV disease. Treatment of recurrent ovarian cancer represents a challenge. Cure is rare but long-term survival can be achieved in a significant proportion of patients. Treatment-free interval after first-line platinum-based chemotherapy determines sensitivity to platinum rechallenge. Nevertheless, other factors, such as symptoms, tumor bulk, ECOG PS and patients' preferences can also aid decision making in this setting. The recent ICON4/AGO and GCIC studies showed that combination of carboplatin with paclitaxel or gemcitabine are superior to carboplatin monotherapy in patients with platinum-sensitive disease, but at the expense of additional toxicity. Platinum refractory disease is associated with poor prognosis and monotherapy with a non-platinum agent, such as liposomal doxombicin, topotecan or a taxane is recommended. Biological agents targeting various components on cancer cells, such as vascular endothelial growth factor (VEGF), growth factors and stromal elements, are under investigation as adjuncts to chemotherapy. In addition, selected patients may benefit from surgery at recurrence, but they represent the minority of patients with relapsed ovarian cancer. © 2006 Bentham Science Publishers Ltd.

There are limited reports of young patients with multiple myeloma (MM) who presented with multiple lytic bone lesions but without intervening infiltration of bone marrow, a pattern consisting of macrofocal MM. In order to clearly define the clinical and laboratory features and outcome of such patients, a retrospective analysis was performed of symptomatic patients with MM ≤40 years of age at diagnosis who received primary treatment over a 20-year period. Ten of 51 patients fulfilled the criteria of macrofocal MM. When compared to patients with typical MM, patients with macrofocal pattern were less anemic, none had hypercalcemia, renal impairment, elevated serum LDH or stage 3 according to the International Staging System (ISS). Patients with macrofocal MM usually had preserved the uninvolved immunoglobulins. An objective response to primary treatment was noted in 55% of patients with macrofocal MM and in 50% of patients without this pattern. The median survival of patients with typical MM was 57 months and is projected to exceed 8 years in patients with macrofocal MM (p = 0.087). With macrofocal MM despite multiple lytic bone lesions, patients have features of low tumor burden and improved survival when compared with young patients with typical MM.

Purpose.: Ovarian clear-cell carcinomas (OCCC) are known to be possibly resistant to platinum-based chemotherapy and to have a poorer prognosis with respect to other subtypes of epithelial ovarian cancer (EOC). This study was undertaken to compare response and survival to platinum-based chemotherapy between patients with advanced stage III and IV OCCC and serous EOC (sEOC). Patients and methods.: A retrospective analysis was performed in patients with advanced stage of OCCC treated with first-line platinum-based chemotherapy in the context of several study protocols of the Hellenic Cooperative Oncology Group (HeCOG) between 1/2/1987 and 31/10/2003. The outcome was compared to that of patients with sEOC treated according to the same protocols during the same study period. Results.: One hundred and five patients (35 stage III and IV OCCC, 70 stage III and IV sEOC) treated with platinum-based chemotherapy were analyzed. The overall response rate for OCCC was 45% (complete response 25%) (95% CI, 23.1% to 68.5%) and 81% (complete response 46%) (95% CI, 67.4% to 91.1%) for sEOC. The overall response rate was significantly higher for sEOC (P = 0.008). In the subgroup of stage III patients, the rate of complete responders was higher among sEOC patients (P = 0.023). After a median follow-up of 61.1 months, median survival and time to tumor progression were not significantly different between the two groups (25.1 months [95% CI 11.7 to 38.5 months] versus 49.1 months [95% CI 36.5 to 61.6 months], P = 0.141, 12.0 months [95% CI 6.5 to 17.3 months] versus 18.0 months [95% CI 14.7 to 21.6 months], P = 0.384, respectively). Conclusion.: Patients with OCCC have significantly lower response to platinum-based first-line chemotherapy compared to patients with sEOC. This low response to platinum-based chemotherapy was not translated in significantly shorter survival. The current study outcomes are provocative and suggest that a new strategy for chemotherapy in OCCC should be adopted, possibly one that focuses on new agents without cross-resistance to platinum agents. © 2006 Elsevier Inc. All rights reserved.

The cause of the polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes (POEMS) syndrome is currently unknown, but increased levels of vascular endothelial growth factor (VEGF) appear to play a pathogenetic role. Osteosclerotic bone lesions are a characteristic finding in POEMS, but there are no data about the specific role of various molecules that control bone remodeling in patients with POEMS. Serum levels of angiogenic cytokines (VEGF, angiogenin, angiopoietin-2, and basic fibroblast growth factor) along with a series of bone remodeling indices (C-telopeptide of type I collagen, bone-alkaline phosphatase [bALP], osteocalcin [OC], soluble receptor activator of nuclear factor-κB ligand [RANKL], osteoprotegerin [OPG], and macrophage inflammatory protein-1α) were measured in 2 patients with POEMS before and after high-dose therapy (HDT) with autologous stem cell transplantation and in age- and sex-matched controls. Increased VEGF levels before HDT were reduced significantly after treatment, although levels of the other angiogenetic factors did not differ from that of controls and were less influenced by HDT. Serum RANKL levels were increased before HDT, whereas OPG levels were within the levels of healthy controls, resulting in an abnormal soluble RANKL to OPG ratio. Levels of bone resorption markers (C-telopeptide of type I collagen) were very low or undetectable before HDT, although bALP and OC levels were similar to that of controls. After HDT, soluble RANKL levels decreased, OPG remained rather stable, bone resorption markers increased to levels of normal individuals, bALP levels were rather unchanged, and OC levels increased. Decreasing VEGF levels parallel clinical improvement, and the restoration of normal bone metabolism follows HDT.

Background.: Neoplastic meningitis in patients with carcinoma of the uterine cervix is unusual in the course of their diseases. Even more unusual are intramedullary spinal metastases. Case.: We report the case of a 64-year-old woman who presented with leptomeningeal and intramedullary spinal cord metastases from a grade 2 squamous cell cancer of the uterine cervix. This is just the second case of intramedullary metastases from cervical carcinoma. Conclusion.: Neoplastic meningitis or intramedullary metastases are extremely rare in the course of uterine cervix carcinoma. Nevertheless, when indicated by symptoms, patients should undergo MRI of the brain and/or spine and have a lumbar puncture performed, for the diagnosis of this devastating complication. Treatment is mainly palliative but may offer symptom relief. © 2006.

Osteonecrosis of the jaw (ONJ) has been associated with the use of pamidronate and zoledronic acid. ONJ was assessed prospectively since July 2003 in 202 patients with multiple myeloma (MM) who received bisphosphonates since April 1995. Fifteen patients (7.4%) developed ONJ. The median time of exposure to bisphosphonates was 39 months for patients with ONJ compared to 28 months (p=0.048) for patients with no ONJ. The cumulative hazard of developing ONJ was significantly higher in patients treated with zoledronic acid alone than in those treated with pamidronate alone/pamidronate+zoledronic acid/zoledronic acid+ibandronate sequentially (1% at 1 year and 15% at 4 years vs. 0% and 5%, p=0.003). In conclusion, the risk of ONJ is increased with time of exposure and probably with the use of zoledronic acid. ©2006 Ferrata Storti Foundation.

Purpose: Waldenström's macroglobulinemia (WM) is a lymphoplasmacytoid lymphoma characterized by a relatively indolent course with median survival ranging from 5 years to 10 years in different series. Several clinical and laboratory variables have been associated with inferior survival, such as advanced age, hyperviscosity, presence of cytopenia, and hypoalbuminemia. Recent data indicate that serum β2-microglobulin (β2M) might also be significant. The purpose of our study was to assess possible correlations of β2M with clinical and laboratory variables and to further evaluate its association with cause-specific and overall survival (OS) of patients with WM requiring treatment. Patients and Methods: We analyzed 124 patients with WM with an available pretreatment value of β2M. Median age was 70 years (range, 28-89 years), and median survival was 105 months. Multiple clinical and laboratory parameters were evaluated for their possible correlation with OS. Results: Patients with older age, anemia, thrombocytopenia, hypoalbuminemia, and higher creatinine levels had significantly greater serum β2M levels. This variable was associated with impaired cause-specific survival and OS in the whole group of patients and in patients aged ≤ 70 years. More specifically, OS for all patients according to serum β2M > 4 mg/dL versus ≤ 4 mg/dL was 79 months versus 115 months (P = 0.01). Conclusion: Our data provide further evidence that high β2M levels are an important parameter associated with inferior OS and cause-specific survival of patients with WM requiring treatment. This parameter may be used to stratify patients involved in prospective clinical trials.

Introduction: Glycodelin and survivin are key polypeptide regulators of cellular proliferation, apoptosis and angiogenesis. In view of contradictory reports on their functional role in tumors, we studied their transcriptional levels in localized breast cancer. Patients and methods: Glycodelin and survivin messenger ribonucleic acid (mRNA) was isolated and amplified by quantitative reverse-trancription PCR from paraffin-embedded breast carcinomas of 275 women. A normalized score was calculated by the use of GAPDH, RPL37A reference genes and was correlated with clinicopathologic/molecular parameters and patient outcome. Results: A total of 272 patients were eligible, most harbored stage III node-positive breast carcinomas larger than 2 cm. Glycodelin mRNA was expressed in 68 patients (25%), more frequently in premenopausal women (P = 0.01) and those with HER2 mRNA-positive tumors (P = 0.02). Survivin mRNA was present in 263 tumors (97%) and its levels correlated significantly with high nuclear grade, VEGF mRNA and p53 mRNA presence (P < 0.05). At a median follow-up of 64 months, neither glycodelin nor survivin mRNA expression demonstrated prognostic utility for overall or disease-free survival at univariate and multivariate analysis. Conclusions: Glycodelin and survivin transcriptional activity are associated with adverse clinicopathologic and molecular characteristics of node-positive primary breast cancer but do not predict patient outcome. Further study is needed for illumination of their functional roles in tumorigenesis. © 2006 Springer Science+Business Media, LLC.

Dickkopf-1 (DKK-1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK-1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK-1 levels were increased in MM at diagnosis compared with MGUS (mean ± SD: 67 ± 54 ng/mL vs. 38 ± 13 ng/mL; p = 0.006) and controls (31 ± 11 ng/mL; p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK-1 values than stage 1 patients (79 ± 63 vs. 40 ± 13; p = 0.005), no significant correlation between serum DKK-1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK-1 (63 ± 77 ng/mL; p = 0.03) compared with controls, supporting the notion that DKK-1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK-1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK-1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK-1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma. © 2006 Wiley-Liss, Inc.

The aim of this retrospective study was to illustrate the clinicopathologic data and the treatment results in patients with primary gastrointestinal tract non-Hodgkin's lymphoma (GI NHL). Among 810 patients with NHL, 128 cases (15.8%) were diagnosed as primary GI tract NHL. There were 79 males and 49 females with median age of 62 years. The most common primary site was the stomach (68%). Overall, 67.2% of the patients were in stages I-II, and 32.8% in stages III-IV. Simultaneous involvement of the GI tract and other extranodal sites was observed in 26 patients (20%). Extranodal marginal zone B-cell lymphoma (MZBL) (i.e., low-grade lymphoma of mucosa-associated lymphoid tissue type) accounted for 48.4% of lymphomas. Aggressive lymphomas (diffuse large B-cell lymphoma [DLBL]) accounted for 44.5%. Eighty-three patients (67.5%) achieved complete response (CR), either by surgery (43/ 43 patients, 17 with DLBL and 25 with MZBL) or by primary chemotherapy (40/64 patients, 22 with DLBL and 17 with MZBL). Sixty-two patients remain in CR; 33/43 after surgical resection (13/17 with DLBL and 20/25 patients with MZBL), and 29/40 after only chemotherapy (18/22 with DLBL and 10/17 with MZBL). The major prognostic factor for outcome in the present study was the stage of the disease. Patients with localized lymphoma (stage I and II) had significantly longer DFS and OS (DFS and OS at 3-year: 83% and 87%, respectively) than patients with extended disease (stage III and IV) (DFS and OS at 3-year: 46% and 60%, respectively) (P < 0.0001). The International Prognostic Index (IPI) for patients with aggressive lymphomas was prognostic only for DFS (79% for low-risk patients [IPI score 0-1] vs 49% for higher risk groups [IPI score 0-1] at 3-year, P = 0.0131).

Background: Young age has been reported to be a favorable prognostic factor in ovarian cancer. The aim of the present study was to investigate the characteristics of ovarian cancer presenting in patients aged ≤40 and assess the prognostic significance of young age. Methods: Data from 591 consecutive ovarian cancer patients, including 37 subjects (6.3%) aged ≤40, who were treated postoperatively with platinum-based chemotherapy in our institution were retrospectively reviewed. Results: In our series, age ≤40 did not show an independent association with overall (p = 0.542) or progression-free survival (p = 0.334). Nonetheless, it was correlated with low tumor grade (p = 0.009) and small volume of residual disease after primary surgery (p = 0.020), while there was a nonsignificant trend for correlation with performance status 0 (p = 0.052). Stratified analysis showed that age ≤40 was associated with improved overall survival in the subgroups of serous histology and stage IIC-IV disease; however, multivariate analyses failed to identify age as an independent predictor of survival within either subgroup (p = 0.079 and p = 0.585, respectively). Conclusions: Age ≤40 was not an independent prognostic factor in our analysis.The survival advantage of young patients may be attributed to the association with low tumor grade, more complete surgical debulking and better performance status. Copyright © 2006 S. Karger AG.

Background: Surgery can cure a significant percentage of ovarian carcinoma confined to the pelvis. Nevertheless, there is still a 10-50% recurrence rate. We administered paclitaxel/carboplatin as adjuvant treatment in early-stage ovarian carcinoma. Methods: Patients with stages Ia or Ib, Grade 2 or 3 and Ic to IIb (any grade) were included. Patients were treated with 4 cycles of Paclitaxel 175 mg/m2 and Carboplatin [area under the curve (AUC) 6 (Calvert Formula)] every 3 weeks. Results: Sixty-nine patients with no residual disease following cytoreductive surgery and minimal or modified surgical staging were included in this analysis. Grade 3 or 4 neutropenia occured in 29.9% of patients, while neutropenic fever was reported in 4.5%. Neurotoxicity (all Grade 1 or 2) was reported in 50% of cases. Median follow-up was 62 months. 5-year overall survival (OS) and relapse-free survival (RFS) were: 87% (95% confidence intervals [CI]: 78-96) and 79% (95% CI: 69-89), respectively. Significantly fewer patients with stages Ic-IIb and tumor grade 2 or 3 achieved a 5-year RFS than patients with only one of these two factors (73% vs 92%, p = 0.03). Conclusion: Paclitaxel/Carboplatin chemotherapy is a safe and effective adjuvant treatment in early-stage ovarian carcinoma Patients with stages Ic-IIb and tumor grade 2 or 3 may benefit from more extensive treatment. © 2006 Bamias et al; licensee BioMed Central Ltd.

Background: There is limited information about the benefit from systemic chemotherapy in non-pure Transitional Cell Carcinomas (TCCs) of the urothelial tract. In this study the efficacy of platinum-based chemotherapy in patients with pure squamous or mixed carcinomas was retrospectively analysed and compared with that in pure TCCs. Patients and Methods: Analysis included 446 consecutive patients treated with platinum-based chemotherapy for advanced or metastatic urothelial cancer. There were 389 (87%) patients with pure TCC, 15 (3.5%) with pure Squamous Cell Carcinomas (SCC) and 42 (9.5%) patients had mixed histology (TCC+SCC) tumors. Results: There were no statistically significant differences in baseline characteristics (gender, PS, haemoglobin, sites of metastases) although disease in the pelvis was more frequent in mixed tumors than in pure TCCs (46% vs. 30%, p=0.034). Median survival for patients with TCC histology was 11.3 months, for SCC patients 13.6 months and 10.4 months for patients with mixed histology (p=0.720). Response rates were 44% for patients with TCC, 27% for patients with SCC and 34% for mixed histology patients (p=0.210). Multivariate analysis showed that presence of visceral metastases and poor performance status, were associated with worse prognosis in mixed histology tumors. Conclusion: Non-transitional histology does not predict for an inferior survival after platinum-based chemotherapy for advanced urothelial carcinoma. Well-known prognostic factors in transitional cell carcinomas were also associated with prognosis in mixed carcinomas.

Background: The deleted in colorectal cancer (DCC) protein, the product of DCC tumor suppressor gene, is frequently altered in cancer. Preclinical data demonstrate that DCC regulates β-catenin levels. Here, we sought to determine the association of DCC with β-catenin protein levels, clinicopathological parameters and patient outcome in ovarian cancer using a method of in situ compartmentalized protein analysis. Methods: A tissue array composed of 150 advanced-stage ovarian cancers, treated with surgical debulking and platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: One hundred and twelve patients (74%) had sufficient tissue for AQUA. The median follow-up time for the entire cohort was 33 months. Patients with low nuclear DCC expression had a 3-year progression-free survival (PFS) rate of 0% compared with 33% of those with high DCC expression (P = 0.0067). In multivariate analysis, low nuclear DCC expression level retained its prognostic significance for PFS. Between DCC and β-catenin, a significant relationship was found, where tumors with low DCC had low β-catenin and vice versa (P = 0.003). Conclusions: Low nuclear DCC levels predict for poor patient outcome inepithelial ovarian cancer. DCC may exert its antitumor function, in part, through regulation of β-catenin levels. © 2006 Oxford University Press.

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-κB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma. © 2006 The Authors.

Background: Synchronous presentation of more than one germ cell tumours of different histology in the same patient is considered to be very rare. In these cases of multiple germ cell tumours, strong theoretical and clinical data suggest an underlying common pathogenetic mechanism concerning genetic instability or abnormalities during the pluripotent embryonic differentiation and maturation of the germ cell. Case presentation: A 25 year-old young man presented with an enlarging, slightly painful left cervical mass. Despite the initial disorientation of the diagnosis to a possible thyroid disorder, the patient underwent complete surgical resection of the mass revealing mediastinal choriocarcinoma. Subsequent ultrasound of the scrotum indicated the presence of a small lobular node in the upper pole of the left testicle and the patient underwent radical left inguinal orchiectomy disclosing a typical seminoma. Based on these results, the patient received 4 cycles of Bleomycin, Etoposide and Platinum chemotherapy experiencing only mild toxicity and resulting in complete ongoing clinical and biochemical remission. Conclusion: The pathogenesis of concurrent germ cell tumours in the same patient remains an area of controversy. Although the genetic instability of the pluripotent germ cell offers an adequate explanation, the possibility of metastasis from the primary, less differentiated tumour to a distant location as a more mature subtype cannot be excluded. Possible development of a metastatic site of different histology and thus biological behaviour (e.g choriocarcinoma) should be anticipated. Furthermore, urologists, pathologists and medical oncologists should be meticulous in the original pathological diagnosis in these patients, since there is a significant frequency of germ cell tumours with mixed or overlapping histological elements with diverse potential of evolution and differentiation. © 2006 Mountzios et al; licensee BioMed Central Ltd.