BACKGROUND: This phase III study was designed to compare the combination paclitaxel (Taxol)-gemcitabine (PG) versus carboplatin-gemcitabine (CG) in patients with advanced inoperable non-small-cell lung cancer. METHODS: Chemotherapy-naive patients with performance status of zero or one were randomized to gemcitabine 1 gm/m(2) on days 1 and 8 plus either paclitaxel 200 mg/m(2) on day 1 (arm A) or carboplatin at an area under the concentration-time curve of 6 mg on day 1 (arm B) every 3 weeks. Primary end point was overall survival (OS). Secondary end points included objective response (OR), time to progression and toxicity. RESULTS: A total of 512 patients were enrolled and 452 eligible (arm A, 225; arm B, 227) were analyzed. All characteristics were well balanced with the exception of vena cava obstruction symptoms and lymph node involvement. Median survival was 9.97 months [95% confidence interval (CI) 8.74-12.0] for group A and 10.49 (95% CI 9.04-11.94) for group B. There was no difference in the OS, 1-year survival, OR and TtP. However, statistically significant differences were seen in toxicity. CONCLUSION: The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group.

INTRODUCTION Plasma cell dyscrasias include a wide variety of diseases characterized by the abnormal accumulation of plasma cells resulting in various systemic symptoms and signs. Plasma cells are usually widespread throughout the bone marrow; however, in a minority of patients malignant plasma cells may form a single lesion. These lesions are usually confined to the bone and, less frequently, in extramedullary sites. They are composed of monoclonal plasma cells that are otherwise identical to plasma cells found in myeloma. However, these patients do not have evidence of systemic multiple myeloma (MM), and an extensive work up shows no other foci of disease. When this solitary lesion is confined to bone it is characterized as a solitary bone plasmacytoma (SBP) while when this lesion is confined to extraosseous sites it is characterized as a solitary extramedullary plasmacytoma (SEP). DEFINITIONS According to criteria reported by the International Myeloma Working Group, diagnosis of solitary plasmacytoma of bone is based on histological evidence of a tumor consisting of monoclonal plasma cells identical to those seen in MM (Table 12.1). In addition, complete skeletal radiographs must show no other lesions of MM. Magnetic resonance imaging (MRI) has significantly increased sensitivity over conventional radiographs, especially in the imaging of the axial skeleton, and an MRI of the spine and pelvis may show unsuspected and asymptomatic skeletal lesions. Patients with multiple lesions in MRI should be considered as having myeloma and not SBP even if conventional radiographs show no other evidence of skeletal involvement. © Cambridge University Press 2009.

The majority of patients with indolent lymphomas relapse due to minimal residual disease (MRD). In the present study, we sought to determine whether by using rituximab consolidation, for eradication of MRD, following induction chemotherapy with fludarabine and mitoxantrone (FN) combination could improve the outcome of indolent lymphomas. Patients with indolent lymphoma received fludarabine 25mg/m2 Day 1-3 and mitoxantrone 10mg/m2 on Day 1 every 28 days. Patients who attained a response (complete response, CR or partial response, PR) received four weekly doses of Rituximab 375mg/m2 1 month and 3 months after completion of treatment. Forty-five patients were entered into this Phase II trial. The median follow-up time was 39 months. The median number of delivered cycles was 6. Fifty-three percent of patients attained a CR and 38% a PR for an overall response rate of 91%. One patient had stable disease, one had progression of the disease, whereas 2 were non-evaluable. After a median follow-up of 39 months, 32 of 46 patients (74%) are alive and disease-free. Grade III and IV toxicities included leucopenia (37%), neutropenia (28%), thrombocytopenia (7%), anemia (4%), and diarrhea (2%). Grade V toxicities included septic death in one patient and death due to hepatititis B reactivation 6 months after the last Rituximab dose in another patient. FN followed by R consolidation is a well-tolerated and active regimen in the treatment of patients with indolent lymphomas. Further follow-up is required to determine if these remissions are maintained.

Wegener's granulomatosis is a systemic necrotizing vasculitis that usually involves the kidneys, typically causing segmental necrotizing glomerulonephritis. An association between Wegener's granulomatosis and renal cell carcinoma was recently reported. We describe a case of Wegener's granulomatosis presenting as a renal mass in a 72-year-old woman. Histologic examination of the mass revealed granulomatous inflammation, an extremely rare manifestation of this disease. We also review the incidence of renal mass in Wegener's granulomatosis and highlight the importance of excluding the coexistence of renal cell carcinoma. © 2008 Elsevier Inc. All rights reserved.

The role of high-dose chemotherapy (HDCT) in epithelial ovarian cancer (EOC) remains controversial. This study was initiated to compare the efficacy and tolerability of HDCT as a consolidation approach in women with chemosensitive advanced EOC (FIGO stages IIC-IV). Patients who had achieved their first clinical complete remission after six cycles of conventional paclitaxel and carboplatin combination chemotherapy were randomly assigned to receive or not high-dose melphalan. The primary objective was to compare time to disease progression (TTP). A total of 80 patients were enrolled onto the trial. Patients who were randomized to receive HDCT were initially treated with cyclophosphamide 4g/m2 for PBPC mobilization. HDCT consisted of melphalan 200 mg/m2. Of the 37 patients who were allocated to HDCT, 11 (29.7%) did not receive melphalan either due to patient refusal (n = 5) or due to failure of PBPC mobilization (n = 6). In an intent-to-treat analysis, there were no significant differences between the two arms in TTP (P = 0.059) as well as in overall survival (OS) (P = 0.38).

Neoangiogenesis is involved in the pathophysiology of multiple myeloma and angiopoietins possibly contribute to myeloma-induced neovascularization. Bortezomib's antineoplastic potential includes an anti-angiogenic effect. We determined serum levels of angiopoietin-1 and angiopoietin-2 with ELISA pre- and post-bortezomib administration in 35 patients with relapsed/refractory multiple myeloma. Pre-bortezomib, serum angiopoietin-1 levels did not differ in patients and in healthy individuals, while serum angiopoietin-2 levels were elevated. Corresponding serum angiopoietin-1/angiopoietin-2 ratio was reduced in patients compared with controls. After treatment, serum angiopoietin-1 levels increased, while serum angiopoietin-2 levels decreased, therefore the angiopoietin-1/ angiopoietin-2 ratio increased and normalized. This increase was significant in patients who responded to treatment. In conclusion, angiopoietin-1/angiopoietin- 2 ratio normalization reflected response to bortezomib. ©2008 Ferrata Storti Foundation.

Objectives: To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy. Methods: This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m2 (day 2) and estramustine 140 mg three dimes daily (days 1-3). Results: Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9-19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6-7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p = 0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p = 0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p = 0.007). Conclusions: Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy. © 2007 European Association of Urology.

Background: Several cytokines have been associated with immune regulation and prognosis in ovarian cancer. CD4+CD25+ Tregs and CD3+CD56+ NK-like T cells are involved in the immune response against the tumor. We have investigated the association of cytokines in the ascites from patients with ovarian cancer with these populations, the platinum resistance and the prognosis of these patients. Patients and methods: Ascites from 64 patients with ovarian cancer was analysed. Forty-two patients were studied at diagnosis (FIGO stage III in 40 cases) and were treated with cytoreductive surgery and platinum-based chemotherapy. Ascites from 9 patients with cirrhosis was used as control. Vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNFα), interferon-gamma (IFNγ), inteleukin-10 (IL10) and interleukin-12 (IL12) in ascites and serum were measured by enzyme-linked immunosorbent assay (ELISA), while lymphocytic populations were studied with three-colour flow cytometry. Results: VEGF ascites levels were inversely correlated with CD3+CD56+ cells (rho = - 0.316, p = 0.012), while a similar correlation was observed between TNFα ascites levels and CD4+CD25+(hi) cells (rho = - 0.332, p = 0.041). Among patients receiving first-line chemotherapy, VEGF levels < 1900 pg/ml and TNFα levels > 35 pg/ml were associated with platinum sensitivity (p = 0.021 and p = 0.028, respectively) and improved progression-free survival (PFS) (p = 0.007 and p = 0.045, respectively). Low VEGF levels were also associated with improved overall survival (p = 0.026). Conclusion: VEGF and TNFα ascites levels are associated with prognosis in advanced ovarian cancer. Their prognostic significance may be due to their association with immunologically important populations, namely the NK T-like CD3+CD56+ cells and the Tregs CD4+CD25+(hi) cells. © 2007 Elsevier Inc. All rights reserved.

The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with ≤1 risk factor for VTE. LMWH (equivalent to enoxaparin 40mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

Although platinum-based chemotherapy remains the "standard" in advanced non small-cell lung cancer, not all patients-derive clinical benefit from such a treatment. Hence, the development of predictive biomarkers able to identify lung cancer patients who are most likely to benefit from cisplatin-based chemotherapy has become a scientific priority. Among the molecular pathways involved in DNA damage control after chemotherapy, the nucleotide excision repair (NER) is a critical process for the repair of DNA damage caused by cisplatin-induced DNA adducts. Many reports have explored the role of the excision repair cross-complementation group 1 enzyme (ERCC1) expression in the repair mechanism of cisplatin-induced DNA adducts in cancer cells. Using immunohistochemistry in resected tumors from patients included in the International Adjuvant Lung Cancer Trial, the study of important biomarkers showed that high ERCC1 protein expression was associated with improved survival in chemo-naïve patients. On the contrary, the benefit of adjuvant cisplatin-based chemotherapy was more profound in patients with low ERCC1 expression. In a prospective cohort studying mRNA expression in tumor biopsies from patients receiving customized therapy with cisplatin and gemcitabine depending on the molecular profile of the tumour, results showed that patients with low ERCC1 mRNA expression had a longer median survival compared to those with high expression. These data suggest the potent use of ERCC1 as a molecular predictor of clinical resistance to platinum-based chemotherapy in the adjuvant setting of NSCLC. Nevertheless, optimization of methodology, including standardization of technical procedures, as well as validation of ERCC1 protein expression in large prospective cohorts, seem necessary before any routine immunohistochemical validation of ERCC1 can be implemented in daily practice.

Background: Bortezomib is a novel, first-in-class proteasome inhibitor that has improved outcomes in multiple myeloma. with manageable toxicities. Objective: To summarise the chemistry, pharmacokinetics and metabolism of bortezomib, and review its clinical efficacy and toxicity, including use in elderly patients, use in patients with renal impairment and/or a poor prognosis, and effects on bone metabolism. Methods: Literature search of bortezomib studies (within 10 years) and recent congress abstracts. Results/conclusions: Bortezomib has improved response rates, overall survival, and time to progression in relapsed or refractory disease, both as a single agent and as part of combination regimens. Promising results have also been reported with bortezomib combinations in frontline induction therapy. Patient subgroups where conventional approaches are inappropriate may also benefit, thereby expanding the therapeutic armamentarium against this debilitating disease. © 2008 Informa UK Ltd.

Renal failure is a common feature of multiple myeloma and a major management problem. However there is limited data regarding the reversibility of renal failure, the kinetics of serum creatinine and the safety of novel agents such as bortezomib when administered to newly diagnosed or relapsed/refractory patients with renal failure. Patients and Methods. We evaluated 20 consecutive patients with newly diagnosed or relapsed/refractory multiple myeloma and renal failure, defined as a serum creatinine ≥ 2 mg/dl. All patients received bortezomib with dexamethasone or in combination with other agents (thalidomide, doxorubicin or melphalan). Results. Reversal of renal failure was documented in 40% of all patients and the median time to reversal was 17 days. Moreover 10 patients (50%) had 50% decrease in serum creatinine and the median time to decrease was 35 days. Some decrease of creatinine was documented in 85% of patients. The objective response rate was 65%. Toxicities were similar to those seen in myeloma patients without renal failure. Conclusions. Bortezomib based regimens can be administered to myeloma patients with renal impairment and their toxicity and efficacy are similar to those observed in patients without renal impairment. Moreover, bortezomib-based regimens induce improvement of serum creatinine in most patients and reversal of renal failure in approximately one-third.

Background: A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented. Patients and methods: From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m2 and paclitaxel (Taxol®, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m2 (group A), or concurrent epirubicin 83 mg/m2 and paclitaxel 187 mg/m2 (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments. Results: Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low. Conclusion: Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen. © The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P< .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy. © 2008 by The American Society of Hematology.

During the last decade several novel agents have been used in the management of patients with multiple myeloma. Immunomodulatory drugs and proteasome inhibitors exert their efficacy both directly by inducing apoptosis of myeloma cells and indirectly through the interruption of the interactions between myeloma and stromal cells in the bone marrow (BM) microenvironment. These interactions are crucial for myeloma cell growth and survival. The adherence of myeloma cells to BM stromal cells leads to the overproduction of several cytokines with angiogenic properties that enhance the survival and growth of myeloma cells through paracrine and autocrine loops. The correlation of these molecules with clinical features and survival of myeloma patients supports the importance of angiogenesis in the pathogenesis of the disease and reveals these cytokines as suitable targets for the development of novel anti-myeloma therapies. This review summarises all available preclinical and clinical data for the effect of novel agents that are used in myeloma therapy, such as thalidomide, lenalidomide, bortezomib and VEGF inhibitors, on angiogenesis, which is at least partially responsible for their remarkable anti-myeloma efficacy.

Aurora kinases represent a family of serine/threonine kinases highly conserved during evolution, whose main function is to promote mitotic spindle assembly by regulating centrosome duplication and separation. Inhibition of Aurora kinase activity may lead to defects in centrosome function, misaligned sister chromatides, mitotic spindle malformation, problematic cytokinesis and eventually mitotic arrest. Aurora kinases are overexpressed in a variety of tumor cell lines, suggesting their potential role in tumorigenesis and indicating that they could represent an appealing target for molecular therapies. Extensive pre-clinical information supports the development of Aurora kinase inhibitors in specific tumor types and a number of these novel agents are currently being extensively studied in phase I and II clinical trials exhibiting an acceptable toxicity profile and promising clinical efficacy. The current study aims to provide a comprehensive overview of the development of Aurora kinases as molecular targets for anticancer therapy by focusing on their physiological role in mitosis, their implication in oncogenesis and the potential ways of inhibiting their activity. The main pre-clinical and clinical studies concerning Aurora kinase inhibitors currently under investigation are reported and important considerations for their future development are discussed. © 2007 Elsevier Ltd. All rights reserved.

Multiple sclerosis (MS) is the most common cause of neurological disability. Therapeutic plasma exchange (TPE) has been used in the management of patients with MS with equivocal efficacy. With this work we would like to present our experience with 10 patients (seven male and three female, mean age 34 years [range 27-53 years]) with secondary progressive MS, who were treated with immunomodulating agents and who also underwent TPE. The patients' expanded disability status scale (EDSS) score of entry to the study varied from 5.0 to 6.5. One year before study entry all patients showed a marked deterioration (12 months before starting TPE they had been rated 4.5-5.5 on the EDSS). TPE was performed three times a week for two weeks and thereafter once a week, or once a month for the stable patients. The machine used was the Cobe Spectra and albumin 5% was the replacement fluid. Peripheral veins were used in nine patients and indwelling vascular access was required in one patient. Eighteen months later, patients stopped taking the immunomodulating agent therapy and continued only with TPE. No side-effects occurred during the TPE session. After 36 months of TPE therapy, five patients were stabilized in their disability, while two patients showed a minor progression of the disease (an additional 0.5 degree in disability as determined by the EDSS). No relapses occurred during TPE. Three patients stopped the therapy: one patient because of persistent nausea and two patients for reasons unrelated to TPE. Periodic TPE was associated with reduced accumulation of neurological deficits (as documented by EDSS) in patients with secondary progressive MS. © 2008 International Society for Apheresis.

Background: The aim was to examine characteristics and treatment results of patients with mucosa-associated lymphoid tissue (MALT) non-Hodgkin's lymphomas. Patients and methods: Epidemiological and clinical features of 97 patients with MALT lymphoma from the Hellenic Cooperative Oncology Group registry were analysed retrospectively for their prognostic significance in progression-free survival (PFS) and overall survival (OS). Comparisons were made between patients with gastric and nongastric sites of primary lymphoma and between different therapeutic modalities. Results: Sixty-five patients presented with gastric and 32 with nongastric lymphomas. The most frequent locations of nongastric lymphomas were the bowel, lung and parotid. Gastric lymphomas occurred more frequently in males and younger patients compared with nongastric lymphomas. Seventy-four per cent of patients had early (Ann Arbor stages I-II) and 26% had advanced (stages III-IV) disease. The median PFS for the entire population was 44 months. At 5 years, 47% of patients were progression free and the OS rate was 80%. The most reliable prognostic factor for PFS and OS was the Ann Arbor stage; 5-year PFS was 67% versus 13% and 5-year OS 91% versus 51% for patients with early versus advanced disease, respectively (P < 0.001). Of the patients treated with chemotherapy only, 87% achieved an objective response and 71% complete response. Surgery did not offer survival benefit compared with chemotherapy in localised gastric lymphoma. Conclusion: MALT lymphomas represent a distinct disease entity with widespread extranodal origin, indolent clinical course and high chemosensitivity. Ann Arbor stage was the most reliable prognostic and predictive factor. © The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.

Lenalidomide is an immunomodulatory drug, structurally related to thalidomide, with pleiotropic activity including antiangiogenic and antineoplastic properties. It is the product of advances in our understanding of the biology of myeloma cells, their interactions with the microenvironment and of the underlying molecular pathways. In preclinical and clinical studies, lenalidomide was more potent and less toxic than thalidomide. Subsequent phase II and III studies confirmed the activity of lenalidomide either as a single agent or in combination with dexamethasone in relapsed or refractory myeloma patients, whereas combinations with chemotherapy induce high response rates and durable remissions. Lenalidomide has been used successfully as an upfront treatment either with high or low dose dexamethasone or with melphalan and prednisone, resulting in high overall response and complete response rates and excellent 1-year survival. Lenalidomide causes less neuropathy than thalidomide; however, the risk of thromboembolism is high, especially in patients treated with lenalidomide and steroids. In this review, we summarize the mechanisms of action, toxicity and clinical activity, and the current role of lenalidomide in patients with multiple myeloma or other related plasma cell disorders.

Background: Kallikreins, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. Here, we sought to determine the prognostic value of kallikrein 7 (hk7) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. Patients and methods: A tissue array composed of 150 advanced-stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel (Taxol) combination chemotherapy, was constructed. For evaluation of kallikrein 7 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Results: Mean follow-up time ofthe cohort was 34.35 months. One hundred and twenty eight of 150 cases had sufficient tissue for AQUA. In univariate survival analysis, low tumor hk7 expression was associated with better outcome for overall survival (OS) and disease-free survival in 3 years (P values 0.032 and 0.037, respectively). In multivariate survival analysis, adjusting for well-characterized prognostic variables, low tumor hk7 expression level was the most significant predictor variable for OS (95% confidence interval 0.125-0.729, P = 0.007). Conclusions: High tumor hk7 protein expression is associated with inferior patient outcome in ovarian cancer. hk7 may represent a promising prognostic factor in ovarian cancer. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Purpose: There are major differences affecting genes in adenocarcinomas in ever and never smokers. However, data on whether mitogen-activated protein kinase (MAPK) activation state differs according to smoking status are limited. Experimental Design: Expression of activated extracellular signal - regulated kinases, c-Jun NH2-terminal kinases, and P38 enzymes (pP38) were evaluated by means of immunohistochemistry in 188 chemonaïve patients with surgically resected lung adenocarcinoma. Cell viability of the lung adenocarcinoma cell line HCC827 was studied after treatment with cisplatin or the P38 MAPK inhibitor SB 203580. Results: Thirty-seven of 44 never smokers [84%; 95% confidence intervals (95% CI), 70-92%] expressed high pP38 levels compared with 45 of 104 ever smokers (43%; 95% CI, 34-53%; P < 0.0001). The proportion of never smokers expressing high c-Jun NH2-terminal kinase levels (72%; 95% CI, 57-83%) was greater than that of ever smokers (53%; 95% CI, 44-62%; P = 0.03). The proportion of ever smokers expressing high extracellular signal - regulated kinase levels (51%; 95% CI, 42-59%) was similar to that of never smokers (57%; 95% CI, 42-71%; P = 0.47). Never smokers were 10.5 times (95% CI, 3.5-31.5) more likely to express high pP38 levels after adjustment for variables linked to smoking status, including age, sex, and histologic subtype. None of the activated MAPKs predicted for overall survival. Cell viability of HCC827 was significantly reduced after exposure to SB203580 alone or when combined with cisplatin. Conclusions: Life-long nonsmoking is associated with high activated P38 levels in patients with lung adenocarcinoma. Activated P38 can contribute to the viability of adenocarcinoma cells in never smokers, but is not predictive for overall survival. © 2008 American Association for Cancer Research.

Objective: Taxanes, anthracyclines, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, epirubicin and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. Methods: Sixty-three consecutive patients were treated on an outpatient basis with epirubicin 50 mg/m2, followed by paclitaxel 150 mg/m2, administered intravenously over a 3-h period. Subsequently, the patients received carboplatin at AUC of 5. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. Results: Response was assessed among 56 eligible patients. Thirty-six (63.2%) patients achieved objective clinical response (95% CI, 50.6-75.7%) including 14 (24.6%) complete and 22 (38.6%) partial responses. The median duration of response was 7.9 months, and the median times to progression and survival for all patients were 7.8 and 13.8 months, respectively. Grade 3 or 4 neutropenia occurred in 9 (15.5%) patients but only 3 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 19% of patients. Two patients died of sudden cardiac death 10 and 14 days after the administration of the first chemotherapy cycle, respectively, but these deaths were not clearly treatment related. Conclusions: The combination of paclitaxel, epirubicin and carboplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium. © 2008 Elsevier Inc. All rights reserved.

Background: Cancer of unknown primary (CUP) lacks established therapy although it affects 3% of cancer patients. We evaluated the irinotecan- oxaliplatin combination (IROX regimen) in previously untreated patients with non-favorable subsets of unknown primary carcinomas. Methods: This was a multicenter phase-II trial. Protocol treatment consisted of oxaliplatin 80 mg/m2 followed by irinotecan 160 mg/m2 administered every 3 weeks. The primary end points were response rate and toxicity, and secondary end points were time to progression and survival. Results: Forty-seven patients with liver, bone or multiple visceral metastases entered into the trial and received a median 6 chemotherapy cycles (1-11). The regimen was very well tolerated with one febrile neutropenia case and six cases with diarrhea grade 3 (16%). In intent-to-treat analysis the tumor response rate was 13% (95% CI = 4.8-25.7%) and 12 patients (27%, 95%CI 13.9-40.4%) had at least 4 months' duration of disease stabilization. The median time to progression was 2.7 months and the median survival was 9.5 months, with 40% of patients alive at 1 year. Conclusions: The IROX regimen demonstrated similar efficacy and a favorable toxicity profile compared to other more toxic chemotherapy combinations in patients with poor-prognosis CUP. © 2007 Springer-Verlag.

Background: Cycloxygenase (COX)-2 has been associated with proliferation, apoptosis and angiogenesis in urothelial cancer. The prognostic significance of COX-2 in patients who received adjuvant chemotherapy for urothelial cancer was examined. Patients and Methods: Expression of COX-2, p53, ki67, β-catenin, vascular endothelial growth factor (VEGF) and microvessel density (MVD) were studied retrospectively in 59 patients with urothelial cancer (pT3, pT4, N+) who had undergone surgery. The patients had subsequently received adjuvant chemotherapy. Results: Thirty-eight out of 59 cases (64% ) were positive for COX-2. COX-2 was not associated either with progression-free survival (PFS) or overall survival (OS). MVD levels ≥47 were associated with longer median PFS compared with lower levels (not reached vs. 13 months [95% CI: 8-18], p=0.048). The median PFS for patients with β-catenin nuclear accumulation and COX-2 expression was 6 months (95% CI: 4-7) compared with 19 months (95% CI: 14-23) for neither or only one of these factors (p=0.018). Conclusion: MVD may be a useful indicator of relapse in high-risk urothelial cancer treated with adjuvant chemotherapy.

Objectives: Docetaxel is an effective first-line treatment for hormone-refractory prostate cancer. Nevertheless, the prognosis subsequent to progression after first-line therapy is poor and no second-line treatment has been established. Methods: A total of 34 patients with androgen-independent prostate cancer received doxorubicin, 30 mg/m2, every 2 weeks and ketoconazole daily, 400 mg orally every 8 hours. All patients had been treated with docetaxel and had disease progression within 6 months after completion of first-line treatment. Results: Of the 32 evaluable patients, 13 (43.7%, 95% confidence interval [CI] 26.3% to 62.3%) had a prostate-specific antigen (PSA) response, and 4 (28%, 95% CI 8.4% to 58.1%) of 14 patients with measurable disease had a response to therapy. The median time to progression (TTP) was 3.9 months (95% CI 2.0 to 5.9), and the median overall survival (OS) was 13 months (95% CI 8.7 to 17.3). Toxicity was mild, with only 4 cases of nonhematologic grade 3 or 4 toxicity. The most frequent toxicity was nail changes (33 of 34 patients), which was mainly grade 1 (30 cases). Conclusions: The combination of biweekly doxorubicin and ketoconazole is an effective, well-tolerated, second-line therapy for hormone-refractory prostate cancer. © 2008 Elsevier Inc. All rights reserved.

Primary objective: Granulocyte-colony stimulating factor (G-CSF) is used for the mobilization of bone marrow and endothelial progenitor cells, though G-CSF-induced inflammation may cause endothelial dysfunction. We examined the effects of G-CSF on endothelium, C-reactive protein (CRP), tumour necrosis factor-α (TNF-α) and anti-inflammatory cytokines namely interleukin 10 (IL-10). Research design: We studied 60 women with breast cancer, who were randomized to either subcutaneous G-CSF (5 μg/kg), o.d. for 5 days after adjuvant chemotherapy (n = 40) or placebo (n = 20). Experimental interventions: We measured flow-mediated dilatation (FMD%) of the brachial artery by ultrasonography, CRP, TNF-α, IL-10 and the ratio TNF-α/IL-10 blood levels before, 2-h and 5-days after the G-CSF or placebo treatment. Main outcomes and results: There was a greater increase of FMD, IL-10 and reduction of TNF-α/IL-10, 2 h and 5 days after the G-CSF treatment compared to placebo. Although, CRP and TNF-α were higher, TNF-α/IL-10 was lower at the end of G-CSF treatment compared to placebo. Improvement of FMD was related to changes of IL-10 and TNF-α/IL-10. Conclusions: Treatment with G-CSF improves endothelial function in vivo, possibly by shifting the balance between the pro- and anti-inflammatory cytokines.

Thalidomide with dexamethasone (thal-dex) is an active therapy for patients with relapsed or refractory multiple myeloma (MM). In this Practice Point, we discuss the findings of a trial by Rajkumar et al. that aimed to compare the response rate, time to progression and progression-free survival among previously untreated patients with MM who received either thal-dex or placebo plus dexamethasone. The thal-dex regimen was associated with a significantly higher response rate at the expense of more-frequent adverse effects, in particular deep-vein thrombosis, which occurred in almost 20% of patients. Median time to progression was three times longer with thal-dex than with placebo plus dexamethasone, but was shorter, however, than the time to progression observed in studies in which thalidomide or bortezomib was added to melphalan and prednisone. Nevertheless, thal-dex is a convenient oral and relatively inexpensive non-myelosuppressive regimen, which can be used in patients with previously untreated MM.

Background: Primary fallopian tube carcinoma (PFTC) is a rare gynecologic malignancy with very few data existing on the activity of the combination of paclitaxel with a platinum analogue as adjuvant chemotherapy. Methods: We retrospectively analyzed 41 consecutive patients with PFTC who were treated postoperatively with paclitaxel- and platinum-containing chemotherapy regimens. Results: We observed 12 (63.2%) complete and 6 (31.6%) partial responses among 19 patients with measurable disease. The median time to disease progression (TTP) for all patients was 68 months. The median overall survival (OS) for all patients has not been reached yet. The median TTP was 84 months for patients with stage I/II disease and 34 months for patients with advanced disease (p = 0.017). Median OS has not been reached yet for patients with stage I/II PFTC, while it was 63.8 months for patients with stage III/IV disease (p = 0.002). Furthermore, OS has not been reached yet for patients with optimally debulked tumors, while it was 34.1 months for patients with residual disease >2 cm (p < 0.0001). Conclusion: Adjuvant platinum- and paclitaxel-based chemotherapy should be regarded as the standard treatment in patients with PFTC. Early stage disease and optimal debulking are associated with improved TTP and OS. Copyright © 2008 S. Karger AG.

Background: A number of studies have shown that absence of myelotoxicity during chemotherapy is associated with worse outcome for various types of cancer, including carcinoma of the breast. The aim of this study was to determine whether myelosuppression in patients being treated with chemotherapy for advanced breast cancer has an impact on their prognosis. Patients and Methods: A retrospective review was conducted of a series of 475 patients with advanced breast cancer enrolled in two randomised trials, who received first-line chemotherapy. The impact of severe (grade 3 or 4) hematological toxicity on survival and time to disease progression was assessed. Results: When severe myelotoxicity was evaluated as a whole, a significant negative association for time to disease progression and a trend for a worse survival were demonstrated. In multivariate analysis, hematological toxicity retained its significance as an independent negative prognostic factor for time to disease progression. Conclusion: Our findings do not confirm the results of previous studies which have demonstrated a better outcome for patients experiencing hematological toxicity during treatment.

Background: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. Methods: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. Results: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.). Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Objective: Taxanes, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, topotecan and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. Methods: Thirty-nine consecutive patients were treated on an outpatient basis with paclitaxel 150 mg/m2, administered intravenously over a 3-h period and followed by carboplatin at AUC of 5 on day 3, with both agents proceding topotecan that was given at 0.75 mg/m2/day on days 1 through 3. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. Results: Twenty-one (60%) patients achieved objective clinical response (95% CI, 42.2-75.7%) including 4 (11.4%) complete and 17 (48.6%) partial responses. The median times to progression and survival for all patients were 8.9 and 17.7 months, respectively. Grade 3 or 4 thombocytopenia and neutropenia occurred in 5 (13%) and 4 (10%) patients, respectively, but only 2 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 23% of patients. Conclusions: The combination of paclitaxel, topotecan and carboplatin with G-CSF support appears active with acceptable toxicity in patients with metastatic or recurrent carcinoma of the endometrium. © 2008 Elsevier Inc.

Introduction: The combination of Carboplatin and Paclitaxel is considered the standard of care as initial chemotherapy for Advanced Ovarian Cancer (AOC). We compared this regimen with the combination of Cisplatin, Paclitaxel and Doxorubicin. Patients and methods: Patients with AOC were randomised to either six courses of Paclitaxel 175 mg/m2 plus Carboplatin 7AUC or Paclitaxel at the same dose plus Cisplatin 75 mg/m2 plus Doxorubicin 40 mg/m2. Results: Analysis was performed on 451 patients. The treatment groups were well balanced with regard to patient and disease characteristics. Performance status (PS) was better in the anthracycline arm. In terms of severe toxicity, the only significant difference between the two groups was the development of febrile neutropaenia in the anthracycline arm. Overall response rate was similar in both groups. With a median follow-up of 57.5 months, a marginal significance towards improved Progression-Free Survival (PFS) was noted in favour of the anthracycline arm, whilst there was no difference in overall survival. In multivariate analysis the hazard of disease progression at any time was significantly decreased by 25.5% for patients of the anthracycline arm. Conclusion: The combination of Cisplatin, Paclitaxel and Doxorubicin demonstrates a marginal PFS improvement, but no additional survival benefit when compared with the standard Carboplatin/Paclitaxel regimen. © 2008 Elsevier Ltd. All rights reserved.

This phase 2 study aimed to determine the efficacy and safety of the combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) and its effect on bone remodeling and angiogenesis in relapsed/refractory myeloma. Bortezomib (1.0 mg/m2) was given on days 1, 4, 8, 11, oral melphalan (0.15 mg/kg) on days 1-4, whereas thalidomide (100mg per day) and dexamethasone (12 mg/m2) were administered on days 1-4 and 17-20 of a 28-day cycle, for four cycles. Patients without disease progression continued for up to eight cycles. VMDT effect on bone remodeling was evaluated by measuring osteoclast regulators (soluble receptor activator of nuclear factor-κ B ligand/osteoprotegerin ratio, osteopontin, macrophage inflammatory protein-1α), dickkopf-1 protein, bone resorption and formation markers, whereas its effect on angiogenesis was assessed by measuring serum vascular endothelial growth factor, angiogenin, angiopoietin-2 and basic fibroblast growth factor, after four cycles and at the study end. A total of 62 patients were enrolled. The overall response rate was 66%: CR 13%, vgPR 27% and PR 26%. Median time to response was 35 days and median time to progression was 9.3 months. Common adverse events included cytopenias, peripheral neuropathy and infections. No patient experienced deep-vein thrombosis. VMDT reduced angiogenic cytokines, osteoclast regulators, dickkopf-1 and bone resorption. We conclude that VMDT with intermittent thalidomide is an active and well-tolerated regimen for relapsed/refractory myeloma, affecting abnormal bone remodeling and angiogenesis.

Purpose: To evaluate the natural history of bisphosphonate-related osteonecrosis of the jaw (ONJ) in patients with multiple myeloma. Patients and Methods: Ninety-seven patients with myeloma from the United States (n = 37) and Greece (n = 60) were observed prospectively for a minimum 3.2 years after ONJ. Patients characteristics were similar with regard to age, bisphosphonate use, and myeloma therapy, except more autologous transplantations were performed on patients in the United States than in Greece (73% v 28%; P < .0001). Results: ONJ resolved in 60 patients (62%), resolved and recurred in 12 patients (12%), and did not heal in 25 patients (26%). Dental procedures preceded ONJ in 46 patients (47%) and were more common in those with single episodes (35 of 60, 58%) than recurrent or nonhealing (11 of 37, 30%; P = .007). Recurrent ONJ followed reinitiation of bisphosphonates in six of 12 patients. Greek patients had more bone pain than United States patients (60% v 30%, P = .001) and were less likely to restart bisphosphonates (5% v 35%, P < .0002). Myeloma relapses were more common in patients with recurrent/nonhealing than single-episode ONJ (84% v 62%; P = .02). Median overall survival from myeloma diagnosis was 10.8 years (95% CI; 9.3 years to not reached) and did not differ between patients with single, recurrent, and nonhealing ONJ (P = .2). Conclusion: ONJ healed in 75% of patients. Patients with spontaneous ONJ have a higher risk of nonhealing and recurrence. Reinitiating bisphosphonates after healing of ONJ is a reasonable option in patients experiencing relapse who are at risk of skeletal complications. Further studies of the pathogenesis and healing of ONJ are needed. © 2008 by American Society of Clinical Oncology.

The aim of the study was to evaluate the prognostic ability of the transcriptional profiling of the HER family genes in early breast cancer, as well as to investigate the predictive value of HER2 mRNA expression for adjuvant treatment with paclitaxel. RNA was extracted from 268 formalin-fixed paraffin-embedded (FFPE) tumour tissue samples of high-risk breast cancer patients enrolled in the randomised HE10/97 trial, evaluating the effect of dose-dense anthracycline-based sequential adjuvant chemotherapy with or without paclitaxel. The mRNA expression of all four HER family members was assessed by kinetic reverse transcription-polymerase chain reaction (kRT-PCR). The overall concordance between kRT-PCR and IHC/FISH for HER2 status determination was 74%. At a median follow-up of 8 years, multivariate analysis showed that EGFR and HER2 mRNA expression was associated with reduced overall survival (OS). HER3 and HER4 mRNA level had a favourable prognostic value in terms of OS and disease-free survival (DFS), respectively. Adjusting for HER2 mRNA expression, OS and DFS did not differ between treatment groups. These data indicate that EGFR as well as HER2 are prognostic factors of worse clinical outcomes, whereas HER3 and HER4 gene transcription is associated with better prognosis in high-risk early breast cancer. However, HER2 mRNA expression did not predict clinical benefit from paclitaxel. Kinetic RT-PCR represents an alternative method for evaluating the expression of HER family members in FFPE breast carcinomas. © 2008 Cancer Research.

Background: Small cell carcinomas (SCC) originate mainly from bronchial tissue. Several extrapulmonary sites of origin have been described, including the genitourinary and gastrointestinal tracts, the ear, nose and throat and lymph nodes. SCC of the lung may be associated with paraneoplastic neurologic syndromes. Case Report: We report an oat cell histological variant of SCC found in the thymus gland of a 53-year-old woman who presented with subacute cerebellar dysfunction. Conclusions: SCC of the thymus gland, which is a rare extrapulmonary site of origin of SCC, accompanied by cerebellar dysfunction, is rarely reported.

Background: Giant cell arteritis (GCA) of the breast is one of the less recognized variants of this vasculitis and may represent an isolated finding or a manifestation of a more widespread disease. Case Report: We present the case of a 74-year-old woman with malaise and a 14-day persistent fever, reaching 38°C. There was a bilateral, painless and mobile axillary lymphadenopathy and a slight tenderness over the medial and lateral upper quadrants of her left breast, as well as an independent palpable tender mass in the upper outer quadrant of the same breast measuring 2 cm in its greatest diameter. Constitutional symptoms, anemia and an elevated erythrocyte sedimentation rate suggestive of polymyalgia rheumatica were also present. An invasive ductal carcinoma of the breast with coincidental pathologic findings of GCA in the same biopsy specimen was revealed. In this case, arteritis was limited to the breast and presented with diffuse breast tenderness. No other artery was involved by GCA. All arteritis-related symptoms disappeared after the removal of the tumor. Conclusions: There is a relationship between cancer, particularly breast cancer, and GCA of the same organ, but the real nature of this association still remains unknown. Copyright © 2008 S. Karger AG.

This analysis assessed the efficacy and safety of lenalidomide + dexamethasone in patients with relapsed or refractory multiple myeloma (MM) previously treated with thalidomide. Of 704 patients, 39% were thalidomide exposed. Thalidomide-exposed patients had more prior lines of therapy and longer duration of myeloma than thalidomide-naive patients. Lenalidomide + dexamethasone led to higher overall response rate (ORR), longer time to progression (TTP), and progression-free survival (PFS) versus placebo + dexamethasone despite prior thalidomide exposure. Among lenalidomide + dexamethasone-treated patients, ORR was higher in thalidomide-naive versus thalidomide-exposed patients (P = .04), with longer median TTP (P = .04) and PFS (P = .02). Likewise for dexamethasone alone-treated patients (P = .03 for ORR, P = .03 for TTP, P = .06 for PFS). Prior thalidomide did not affect survival in lenalidomide + dexamethasone-treated patients (36.1 vs 33.3 months, P > .05). Thalidomide-naive and thalidomide-exposed patients had similar toxicities. Lenalidomide + dexamethasone resulted in higher rates of venous thromboembolism, myelosuppression, and infections versus placebo + dexamethasone, independent of prior thalidomide exposure. Lenalidomide + dexamethasone was superior to placebo + dexamethasone, independent of prior thalidomide exposure. Although prior thalidomide may have contributed to inferior TTP and PFS compared with thalidomide-naive patients, these parameters remained superior compared with placebo + dexamethasone; similar benefits compared with placebo + dexamethasone were not evident for thalidomide-exposed patients in terms of overall survival. Studies were registered at http://www.clinicaltrials. gov under NCT00056160 and NCT00424047. © 2008 by The American Society of Hematology.

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0·1% to 1·8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed. © 2008 Elsevier Ltd. All rights reserved.

Kallikrein-related peptidases, a subgroup of the serine protease enzyme family, are considered important prognostic biomarkers in cancer. In the present study, we sought to determine the prognostic value of kallikrein-related peptidase 6 (KLK6) in ovarian cancer using a novel method of compartmentalized in situ protein analysis. A tissue array composed of 150 advanced stage ovarian cancers, uniformly treated with surgical debulking followed by platinum-paclitaxel combination chemotherapy, was constructed. For evaluation of KLK6 protein expression, we used an immunofluorescence-based method of automated in situ quantitative measurement of protein analysis (AQUA). Mean follow-up time of the cohort was 34.35 months. One hundred and thirty-five of 150 cases had sufficient tissue for AQUA analysis. In univariate survival analysis, low tumor KLK6 expression was associated with better outcome for overall survival over 3.years (P = 0.019). There was no association between tumor KLK6 expression and progression-free survival (P = 0.128). In multivariate survival analysis, adjusting for well-characterized prognostic variables, low tumor KLK6 expression level was one of the most significant predictor variable for overall survival (95% confidence interval, 1.19-3.50; P = 0.009). High tumor KLK6 protein expression is associated with inferior patient outcome in ovarian cancer. KLK6 may represent a promising disease biomarker and therapeutic target in ovarian cancer. © 2008 Japanese Cancer Association.

Patent WO02095012A1 claims for the development of antibodies against receptor activator of nuclear factor-κ B ligand (RANKL) and immunologically functional fragments that neutralize RANKL. These molecules can be used to detect RANKL in biological samples, allowing the identification of pathological conditions in which RANKL alteration contributes to their pathophysiology. The use of anti-RANKL antibodies is of high importance in the treatment of bone disorders characterized by the stimulation of osteoclast function and subsequent bone loss. Postmenopausal and steroid-induced osteoporosis, myeloma bone disease, cancer bone metastases with lytic lesions and bone loss due to rheumatoid disorders (including rheumatoid arthritis) are candidates for anti-RANKL therapy, as RANKL is implicated in their pathogenesis. © 2008 Informa UK Ltd.