The identification of a monoclonal protein in serum protein electrophoresis (SPEP) is a common event requiring medical consultation. A monoclonal protein may be the hallmark of a malignant disease, such as multiple myeloma or Waldenstrom's Macroglobulinemia (and less often of other lymphoproliferative disorders), of diseases associated with a malignant plasma cell clone, such as AL amyloidosis or other plasma cell related disorders, or, quite commonly may have no direct impact and belong to monoclonal gammopathies of undetermined significance (MGUS). Jan Waldenstrom introduced the term “essential hyperglobulinemia” in order to describe patients who had a small serum protein electrophoretic spike but no evidence of overt multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), primary amyloidosis (AL), or related disorders. The seminal work by Kyle indicated that some patients with this monoclonal gammopathy develop MM, or WM or AL or other lymphoproliferative malignancies, and introduced the term “monoclonal gammopathy of undetermined significance” (MGUS)[1]. Kyle also described patients with histologic and biochemical features of myeloma (bone marrow clonal plasma cells (BMPC) involvement of 10% or higher, presence of a serum M-protein value higher than 3 g/dl) that did not have lytic bone lesions, anemia, renal impairment or other clinical manifestations of myeloma who remained stable, with no need for chemotherapy, for several years[2]. Alexanian also presented data on “indolent myeloma”[3], that included patients who had no clinical features of overt myeloma such as anemia and renal dysfunction and had fewer than three lytic bone lesions. Among these patients, median time to initiation of chemotherapy was two years, but some patients remained stable for several years. Thus, the term “smoldering” MM or “asymptomatic” or “indolent” MM, entered the clinical practice. The definitions, however, were not strict among different groups. In 2003 a consensus paper defined MGUS and asymptomatic or smoldering myeloma (Table 10.1). MGUS requires that M-protein in serum is <30 g/l and that bone marrow clonal plasma cells are <10% with no evidence of other B cell proliferative disorders and no end organ damage (anemia, renal impairment, hypercalcemia, lytic bone lesions). © Cambridge University Press 2014.

Encouraging progress has been made in the treatment of patients with relapsed/refractory multiple myeloma (MM). The rapidly evolving understanding of key pathways responsible for tumor growth and survival has led to the development of novel agents (including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and other targeted agents) with the potential to provide significant improvements in response and survival, and influence treatment guidelines. This review summarizes recent advances in understanding of the biology of relapsed/refractory MM and clinical trials with novel targeted agents that are currently under investigation for patients with this disease. © 2010 John Wiley & Sons A/S.

Objective: Endothelial progenitor cells (EPCs) contribute to the maintenance of endothelial integrity and function. We investigated the effects of rosuvastatin and allopurinol on the number of EPCs in patients with heart failure and aimed to provide insight into the molecular inflammatory and oxidative mechanisms that could be responsible for the alterations in EPC levels after treatment. Methods: Sixty patients with systolic heart failure were randomized to receive rosuvastatin 10mg/d, allopurinol 300mg/d or placebo and followed up for 1 month. The number of CD34 +/KDR + and CD34 +/CD133 +/KDR + EPCs in blood was evaluated by flow cytometry. Endothelial function was assessed by brachial artery flow-mediated dilation. Levels of markers of inflammation and oxidative stress were also determined. Results: Circulating EPCs were significantly increased after rosuvastatin treatment (from 230 (170-380) and 10 (8-24) to 390 (230-520) and 19 (8-33) cells/10 6 lymphomonocytes, respectively, p=0.004 and p=0.008), whereas they remained unchanged in the other groups. The increase in EPC levels was not associated with the changes in the levels of the measured inflammatory and oxidative markers. Conclusion: Short-term treatment with rosuvastatin, but not allopurinol, significantly increases the number of circulating EPCs in patients with heart failure providing further insights into its role in these individuals. The impact of rosuvastatin on EPCs is not mediated by changes in inflammatory and oxidative status. © 2010 Elsevier Ireland Ltd.

Background and aims. Primary malignant peritoneal mesothelioma is a rare malignancy with an unfavorable prognosis. Pemetrexed has proven effective in the treatment of malignant mesothelioma, alone or in combination with platinum agents. In the present study, chemo-naïve patients were evaluated for the efficacy and safety of the pemetrexed-cisplatin combination. Methods. Six patients with diffuse peritoneal mesothelioma were treated with 6 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Chemotherapy was administered on an outpatient basis every 3 weeks. Results. Complete response was observed in 2 patients (33%) and partial response was observed in 3 patients (50%). The estimated median overall survival was 24 months and the estimated median time to disease progression was 9.5 months. The regimen was well tolerated. Conclusions. Though our data reflect a small sample size, pemetrexed plus cisplatin accomplished a particularly high clinical benefit rate on chemo-naïve patients. Free full text available at www.tumorionline.it.

Objectives: This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high-dose therapy who received bortezomib plus melphalan-prednisone.Methods: Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/m2, days 1-4, cycles 1-9; and prednisone 60 mg/m2, days 1-4, cycles 1-9).Results: Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥3 (<1% grade 4). The PN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m2. Median time to PN onset was 2.3 months. Bortezomib-associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P = 0.0065], grade ≥2 PN (HR 2.205, P = 0.0032), and grade ≥3 PN (HR 2.438, P = 0.023); age, pre-existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN.Conclusions: Rates of bortezomib-induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases. (Clinicaltrials.gov identifier: NCT00111319). © 2010 John Wiley & Sons A/S.

Introduction: Waldenström's macroglobulinemia (WM) is a rare but distinct B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and IgM monoclonal paraproteinemia. Alkylators or nucleosides analogs, often in combination with rituximab, are the most commonly used drugs, but WM will relapse and even salvage treatments may fail. Areas covered: We present recent advances on the treatment of WM, focusing on drugs that are under clinical investigation and for which data indicate promising activity and positive future prospects. Bortezomib is a proteasome inhibitor that eventually becomes a major treatment option for WM. Everolimus and perifosine which target mTOR (mammalian target of rapamycin) and Akt, respectively, of the PI3K/AKT/mTOR pathway showed some activity. Bendamustine, a novel alkylating agent is active, especially in combination with rituximab. Immunomodulatory drugs can act synergistically with rituximab but are toxic. Targeting surface antigens of the lymphoplasmatic cells have shown promising results. Expert opinion: Combinations of novel drugs with established agents are feasible and increase response rates but whether there will be an increase in the survival of patients with WM needs further investigation. The toxicity profile is an important determinant for the feasibility of these drugs in patients with WM. © 2011 Informa UK, Ltd.

Sarcomas of the fallopian tube are exceedingly rare malignancies. They have been considered the most lethal of all gynaecological malignancies with high metastatic potential, frequent recurrences and cancer-related deaths. The reported pathological types of the fallopian tube sarcomas are malignant mixed mullerian (mesodermal) tumours or carcinosarcomas, leiomyosarcomas, rhabdomyosarcomas, liposarcomas, and synovial sarcomas. The rarity of these sarcomas and their often aggressive clinical course has resulted in a relatively limited amount of literature. Thus a single hospital or specialist cannot gain sufficient experience with these tumours. This review article tries to elucidate this uncommon malignancy, in a systematic way, focusing on the different pathological types, epidemiology, risk factors, diagnosis, survival, and different therapeutic modalities (surgery, chemotherapy, and radiotherapy). Copyright © 2011 S. Karger AG, Basel.

Objectives: Stage I testicular nonseminomatous germ-cell tumors (NSGCT) are highly curable. Following orchidectomy surveillance, adjuvant chemotherapy and retroperitoneal lymph node dissection can be applied. Certain factors are used to select patients in high-risk for relapse. We report the outcome and safety of a risk-adapted strategy by the Hellenic Cooperative Oncology Group. Methods: Between 1994 and 2004, 142 patients with stage I NSGCT and 1 of the following risk factors: lymphovascular invasion (LVI), invasion of tunica vaginalis, spermatic cord, rete testis or scrotal wall, embryonal component >50% of the total tumor, were prospectively included in a protocol of adjuvant chemotherapy consisting of two 3-week courses of bleomycin 15 IU, etoposide 120 mg/m2, and cisplatin 40 mg/m2 for 3 consecutive days with G-CSF support. Results: Median follow-up was 79 months and 138 patients have been followed for at least 2 years. Seventy-seven patients (54%) had LVI and 74 (52%) had >50% embryonal component. There was 1 relapse, which was cured with chemotherapy and surgery. Another patient died due to disease-unrelated causes and 1 patient developed a new primary of the remaining testicle, which was cured with surgery. Conclusion: Two cycles of bleomycin/etoposide/cisplatin is an effective and safe form of adjuvant therapy in high-risk stage I NSGCT. © 2011 Elsevier Inc.

Objectives To determine whether intermittent docetaxel might control disease while limiting the toxicity and improving the quality-of-life parameters in patients with advanced, castrate-resistant prostate cancer. Intermittent docetaxel represents an appealing therapeutic approach. Methods We reviewed the records of 35 patients with chemotherapy-naive castrate-resistant prostate cancer who had received docetaxel 45 mg/m2 every 2 weeks, with oral prednisone 5 mg twice daily. Treatment was held when the patients had reached a >50% prostate-specific antigen reduction from baseline that was confirmed by a second measurement 4 weeks later, in the absence of disease progression. Docetaxel was resumed at a >25% prostate-specific antigen increase from the nadir level, also confirmed by a second measurement 4 weeks later, or in cases of documented disease progression. Results Of the 35 patients, 18 (51.42%) had entered the first chemotherapy-free interval (CFI) after a median of 6 infusions (range 2-12), 6 patients had entered a second CFI after a median of 4 months (range 2-12), and 1 patient, a third CFI at the last follow-up point. The median interval "off chemotherapy" was 4.5 months (range 1-16) for the first CFI. Two patients discontinued docetaxel because of Grade 4 nonhematologic toxicity. The median interval to treatment failure was 8.1 months (95% confidence interval 5.1-12.2) for the entire cohort and 12.2 months (95% confidence interval 8.3-25+) for the patients who had entered the first CFI. Conclusions The results of our study have shown that intermittent docetaxel is a clinically active and likely more tolerable and less costly therapeutic strategy for patients with castrate-resistant prostate cancer than continuous administration. Additional validation of this approach is warranted. © 2011 Elsevier Inc.

Patients with advanced multiple myeloma (MM) often have increased osteolytic activity of osteoclasts and impaired osteogenesis by osteoblasts, resulting in osteolytic bone lesions that increase the risk of skeletal-related events (SREs) including pathologic fracture, the need for radiotherapy or surgery to bone, and spinal cord compression. Such SREs are potentially life-limiting, and can reduce patients' functional independence and quality of life. Bisphosphonates (e.g., oral clodronate and intravenous pamidronate and zoledronic acid) can inhibit osteoclast-mediated osteolysis, thereby reducing the risk of SREs, ameliorating bone pain, and potentially prolonging survival in patients with MM. Extensive clinical experience demonstrates that bisphosphonates are generally well tolerated, and common adverse events are typically mild and manageable. Studies are ongoing to optimize the timing and duration of bisphosphonate therapy in patients with bone lesions from MM. © 2011 Elsevier Ireland Ltd.

Background: The 90 kDa heat shock protein (HSP90), which facilitates proper folding and stability of numerous signaling molecules involved in growth control, cell survival, and development, has been implicated in malignant processes. Like its parent compound geldanamycin, tanespimycin binds to HSP90 and causes antineoplastic effects in vitro and in vivo. Materials and Methods: All relevant published papers identified through searches of PubMed and abstracts from major recent hematology and oncology meetings were reviewed as of October 2009. Results: Different formulations and schedules of tanespimycin monotherapy and combination therapy have been tested in several phase I studies in patients with solid tumors or multiple myeloma (MM). No responses have been reported in studies of tanespimycin monotherapy in patients with metastatic melanoma. Tanespimycin given in combination with trastuzumab in patients with metastatic breast cancer induced a partial response in 24% of patients. Single-agent tanespimycin showed activity in MM and in combination with bortezomib, 27% of patients achieved minor response or better (48% bortezomib-naive patients, 22% bortezomib-pretreated patients, 13% bortezomib-refractory patients). Conclusion: Tanespimycin represents a promising new agent for the treatment of relapsed/refractory MM. Results of ongoing and future trials will determine the role of tanespimycin both in MM and other malignancies, including breast cancer. © 2011 Elsevier Inc. All rights reserved.

C-C motif ligand 3 (CCL3) chemokine plays a crucial role in the inflammation process, cell migration and chemoattraction of monocytes/ macrophages, neutrophils and mast cells. CCL3 is overexpressed by malignant cells in B-cell disorders, including chronic lymphocytic leukemia and multiple myeloma. Elevated circulating CCL3 was previously described in Waldenström's macroglobulinemia (WM) but the source of its production was unknown. We performed an immunohistochemical study in bone marrow biopsies of 67 WM patients and found that the whole number of the neoplastic cells express CCL3 in all cases. This finding was constant in newly diagnosed patients with both symptomatic and asymptomatic WM and also in patients with active disease post previous therapies. Our results support, for the first time in the literature, the production of CCL3 by WM cells. They also suggest a possible role of CCL3 in WM biology and reveal CCL3 as a potential target for developing novel drugs against WM. © 2011 Elsevier Inc. All rights reserved.

Background: In two randomized phase III trials (MM-009 and MM-010), lenalidomide plus dexamethasone significantly prolonged time to progression and overall survival (OS) in patients with relapsed/refractory multiple myeloma compared with dexamethasone alone. In both trials the treatment was continued until disease progression or unacceptable toxicity. We conducted a subanalysis to determine if continuing therapy after achieving ≥ partial response (PR) improved survival. Patients and Methods: Data were collected on 212 patients who were treated with lenalidomide plus dexamethasone and achieved ≥ PR. Kaplan-Meier survival estimates were compared between patients on continued treatment versus patients discontinuing therapy because of adverse events, withdrawal of consent, or other reasons. Time-dependent multivariate regression analyses were used to determine the benefit of continuing treatment with lenalidomide. Results: A total of 174 patients received continued treatment until disease progression or death, and 38 patients discontinued therapy without progression. There was a trend toward longer median OS in patients who continued therapy (50.9 months vs. 35.0 months; P = .0594). When controlling for the number of previous antimyeloma therapies, β2-microglobulin levels, and Durie-Salmon stage (which adversely affected survival in these patients), continued lenalidomide treatment (HR, 0.137; 95% CI, 0.045-0.417; P = .0005) or each additional cycle of lenalidomide (HR, 0.921; 95% CI, 0.886-0.957; P < .0001) were both associated with longer survival. Conclusion: Continued lenalidomide treatment until disease progression after achievement of ≥ PR is associated with a significant survival advantage when controlling for patient characteristics. These findings should be confirmed in a prospectively designed trial. © 2011 Elsevier Inc. All rights reserved.

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these "poor-risk" patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies. © 2011 Elsevier Inc. All rights reserved.

Background: Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer.Methods: The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2intravenously (IV), LV 200 mg/m2and 5FU 450 mg/m2bolus (Arm A) versus LV 200 mg/m2and 5FU 500 mg/m2IV bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years.Results: The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms.Conclusions: Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity.Trial registration: Australian New Zealand Clinical Trials Registry: ACTRN12610000148077. © 2011 Papadimitriou et al; licensee BioMed Central Ltd.

We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of immunoglobulin A (IgA) and IgG paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. To determine the frequency of P-7 as a paraprotein target in IgM-MGUS and Waldenström macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant P-7 by enzyme-linked immunoabsorbent assay. The specificity of the paraprotein-mediated reaction was shown by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgM-MGUS) of 161 patients (11%) reacted with P-7. Isoelectric focusing and phosphatase treatment showed that P-7 was hyperphosphorylated (pP-7) in all patients with an anti - P-7-specific IgM paraprotein tested. Because only 4 of 200 healthy controls (2%) were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio = 6.2; P = .001) for developing IgM-MGUS/MW. Family analyses showed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgGMGUS and multiple myeloma, IgMMGUS/WM is the second neoplasia associated with pP-7 carrier state. The dominant inheritance of pP-7 explains cases of familial IgM-MGUS/WM and enables the identification of family members at increased risk. © 2011 by The American Society of Hematology.

The skeletal and immune systems have a complex relationship. Both systems are intimately coupled, with osteoclastogenesis and hematopoiesis occurring in the bone marrow. Bone and immune cells also share common hematopoietic precursors. Furthermore, the skeletal and immune systems share various cytokines, receptors, and transcription factors that regulate signal transduction pathways involved in osteoclastogenesis and immune system activation, including the receptor activator of nuclear factor-κΒ ligand/receptor activator of nuclear factor-κΒ/osteoprotegerin (RANKL-RANK-OPG) pathway. Cancer cells can disrupt both the skeletal and immune systems. Interaction between cancer and bone cells results in a vicious cycle of bone destruction and cancer growth. Bone remodeling generates a growth-factor-rich environment that attracts cancer cells and promotes their proliferation. In turn, cancer cells stimulate osteoclast formation and activity, resulting in additional bone resorption that further stimulates cancer cell growth. Currently available bone-targeted therapies may also modulate the immune system. Bisphosphonates such as zoledronic acid exert stimulating effects on the immune system, resulting in possible anticancer activity against malignant cells. Denosumab, an anti-RANKL monoclonal antibody with proven antiosteoclast activity, may suppress immune responses. This may result in the reported association with an increased risk of neoplasms, as well as serious skin and other infections as reported in some studies, mainly in the postmenopausal setting. When assessing bone-targeted therapies, it is important to consider the shared signaling pathways between bone and the immune system, as well as the clinical risk:benefit ratio. © 2011 Springer-Verlag.

Objectives: Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. Methods: Patients received nine 6-wk cycles of VMP (bortezomib 1.3mg/m 2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m 2 and prednisone 60mg/m 2, days 1-4, cycles 1-9; N=344) or MP alone (N=338). Results: Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. Conclusions: These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma. © 2011 John Wiley and Sons A/S.

Background: Paclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer. Patients and methods: Chemotherapy-naive patients, stage IIIbwet and IV with performance status (0-1), were randomized to receive paclitaxel 200 mg/m2 on day 1 plus gemcitabine 1 gm/m2 (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m2 plus vinorelbine 22.5 mg/m2 (group B) on days 1, 8 and 15 every 4 weeks. Results: A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3-5.6] and 4.4 months (95% CI 3.7-5.2) for groups A and B respectively (P = 0.365). Median survival was 11.1 months (95% CI 9.2-13.0) and 8.6 months (95% CI 7.0-10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P < 0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P < 0.001, P = 0.029 respectively) in group B. Conclusion: Although response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Background/Aim: Easily assessable clinical predictors of response to chemotherapy in advanced castration-resistant prostate cancer (CRPC) are few. The objective of this retrospective study was to search for and identify such candidate predictors of outcome. Patients and Methods: A retrospective analysis of clinical data of CRPC patients entered in the Clinical Therapeutics' departmental prostate cancer database from 1996-2009 was performed. Univariate and multivariate analyses for progression-free survival and overall survival included patients receiving both docetaxel- and non-docetaxel-containing regimens. Results: From 1996 until June 2009, 286 out of 313 patients in our database were treated with chemotherapy. Prostate-specific antigen (PSA) reduction >30% correlated with improved survival irrespective of treatment. Beyond previously reported predictors, i.e. baseline PSA>30 ng/dl, hemoglobin below 10 mg/dl, weight loss, poor performance status, elevated lactic dehydrogenase and alkaline phosphatase, and time to CRPC of less than or equal to two years was associated with a poor overall survival and shorter progression-free survival upon univariate analysis. Pain was associated with shorter survival. Multivariate analysis confirmed time to CRPC, lactate dehydrogenase and alkaline phosphatase as independent predictors of overall and progression-free survival. Conclusion: Time to castration resistance is an important predictor of outcome in CRPC. PSA reduction >30% predicts survival improvement following chemotherapy for CRPC regardless of chemotherapy applied.

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade ® as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n=344) versus MP (n=338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1·03 (95% confidence interval 0·76-1·39); P=0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P<0·0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival. © 2011 Blackwell Publishing Ltd.

Primary systemic immunoglobulin light chain amyloidosis (AL) results from the accumulation of amyloid fibrils that are composed of a monoclonal immunoglobulin light chain that is produced by a plasma cell clone. Almost every organ can be involved, resulting in multisystemic symptoms and signs. Diagnosis may be difficult and requires a certain degree of suspicion. Treatment is challenging and most patients may be quite frail. Careful assessment of the organ involvement and prognosis is needed before planning the treatment strategy. Supportive care is critical for AL patients. The goal of treatment is the reduction of light chain production. Conventional chemotherapy may be effective and recently introduced novel agents expand treatment options in patients who relapse or are not candidates for high-dose melphalan with autologous stem cell transplant (HDM-ASCT). In experienced centers, HDM-ASCT in patients deemed capable of tolerating the procedure is associated with high response rates with modest treatment-related mortality. © 2011 Blackwell Publishing Ltd.

The introduction of the Immunomodulatory drugs (IMiDs) and proteasome inhibitors, used either as a single-agent or combined with classic anti-myeloma therapies, has improved the outcome for patients with relapsed myeloma. However, there is currently no generally accepted standard treatment for relapsed/refractory myeloma patients, partly because of the absence of trials comparing the efficacy of the novel agents in relapsed/refractory myeloma. Choice of a new treatment regimen depends on both patient and disease-specific characteristics. A lenalidomide-based regimen is the first choice in patients with neuropathy, while bortezomib has the highest efficacy in patients with renal insufficiency and is not associated with increased risk of thromboembolism. A second autologous stem cell transplantation (auto-SCT) can be applied in patients with a progression-free period of ≥18-24. months after the first auto-SCT. In high-risk relapse such as occurring early after auto-SCT consolidation with allogeneic SCT can be considered. In this review we provide an overview of the various salvage regimens and give recommendations for treatment of patients with relapsed/refractory myeloma in different clinical settings. © 2010 Elsevier Ltd.

The treatment of Waldenström's macroglobulinemia (WM) has changed over the last decades, mainly because of the introduction of nucleoside analogues and of rituximab while novel agents such as bortezomib have been recently introduced. We performed an analysis to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs became widely available, especially as part of the frontline treatment. We analyzed 345 symptomatic patients with WM: 130 who initiated treatment before and 215 who started treatment after January 1, 2000. Patients who started treatment in the latter group were older and had more often elevated beta2-microglobulin but the other characteristics were similar between the two groups. Most patients who started treatment before January 1, 2000 were treated upfront with alkylating agent-based regimens and most patients who started treatment after January 1, 2000 received rituximab-based regimens as initial treatment. Objective response (63 and 59%, respectively) and median overall survival, OS, (106.5 months for Group A and is estimated at 94 months for Group B, P = 0.327) were similar. There was also no difference regarding OS or cause specific survival (CSS) in each risk group according to IPSSWM. Our observation may be explained by the indolent course of WM in several patients and by the lack of profound cytoreduction in patients with high-risk disease. Possible differences in the 15- or 20-year survival rate between the two groups may be detected with further follow-up of these patients. © 2011 Wiley-Liss, Inc.

Osteolytic disease is a major complication of multiple myeloma that may lead to devastating skeletal-related events (SREs). Conventional radiography remains the gold standard for the evaluation of bone disease in patients with myeloma. However, whole-body magnetic resonance imaging (MRI) is recommended in patients with normal conventional radiography and should be performed as part of staging in all patients with a solitary plasmacytoma of bone. Urgent MRI is also the diagnostic procedure of choice to assess suspected cord compression, whereas computed tomography can guide tissue biopsy. Positron emission tomography with computed tomography can provide complementary information to MRI, but its use in multiple myeloma must be better defined by further studies. The incorporation of abnormal MRI findings into the definition of symptomatic myeloma also needs to be clarified. Bisphosphonates remain the cornerstone for the management of myeloma bone disease. Intravenous pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future. © 2011 by American Society of Clinical Oncology.

The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices. © AlphaMed Press.

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serumβ2-microglobulin level and International Staging System stages II and III, incorporating high β 2-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations. © 2011 by The American Society of Hematology.

It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript. © 2011 by The American Society of Hematology.

A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β2-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse. © 2011 by The American Society of Hematology.

During prostate carcinogenesis the cellular adhesion molecules, i.e.; integrins and cadherins mediate aberrant interactions between glandular epithelial cells and the extracellular matrix. Several integrin α subunits are downregulated, while β subunits are up-regulated. The expression of several cadherins and catenins has specific prognostic value. There is an association between the expression of the E-cadherin/catenin complex and high grade prostate cancer. Clinical trials evaluating the efficacy of integrin antagonists are ongoing with promising results. In this article we update the role of integrins and cadherins in prostate carcinogenesis and evaluate the therapeutic potential of their manipulation.

We report on a 63-year-old woman, previously in good health, who had undergone nephrectomy for clear cell renal cell carcinoma in 2002. Because of systemic relapse with multiple lung metastases in 2006, the patient was treated with sunitinib 50 mg daily on a 4-weeks on-/2-weeks off-schedule. After 3 years of treatment, she developed a purpuric rash on her feet and trunk. Biopsy revealed leukocytoclastic vasculitis. No other organ involvement was diagnosed. She was started on oral prednisone 30 mg daily with rapid resolution of the vasculitic skin lesions. Sunitinib was temporally discontinued and reintroduced at the same dose level. Reappearance of a less serious vasculitis after 2 cycles of re-treatment was resolved in the weeks off-treatment and by reducing the dose of sunitinib along with 5 mg of prednisone daily. One year after the diagnosis, the patient is still on this therapy. Oncology providers should be aware of this rare but potentially serious, possible adverse effect of sunitinib. Copyright © 2011 S. Karger AG, Basel.

An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma. © 2011 Macmillan Publishers Limited All rights reserved.

Dietary fat, both in terms of quantity and quality, has been implicated to cancer development, either positively or negatively. The aim of this work was to evaluate whether olive oil or monounsaturated fat intake was associated with the development of cancer. A systematic search of relevant studies, published in English, between 1990 and March 1, 2011, was performed through a computer-assisted literature tool (i.e., Pubmed). In total 38 studies were initially allocated; of them 19 case-control studies were finally studied (13800 cancer patients and 23340 controls were included). Random effects meta-analysis was applied in order to evaluate the research hypothesis. It was found that compared with the lowest, the highest category of olive oil consumption was associated with lower odds of having any type of cancer (log odds ratio = -0.41, 95%CI -0.53, -0.29, Cohran's Q = 47.52, p = 0.0002, I-sq = 62%); the latter was irrespective of the country of origin (Mediterranean or non-Mediterranean). Moreover, olive oil consumption was associated with lower odds of developing breast cancer (logOR = -0,45 95%CI -0.78 to -0.12), and a cancer of the digestive system (logOR = -0,36 95%CI -0.50 to -0.21), compared with the lowest intake. The strength and consistency of the findings states a hypothesis about the protective role of olive oil intake on cancer risk. However, it is still unclear whether olive oil's monounsaturated fatty acid content or its antioxidant components are responsible for its beneficial effects. © 2011 Psaltopoulou et al; licensee BioMed Central Ltd.

Reece et al report that single-agent bortezomib resulted in hematologic responses in two-thirds of patients with relapsed Light chain (AL) amyloidosis, including complete responses in one-third, while more than 75% of patients had response duration of more than or equal to 1 year.

Aim: Hypertension (HT) complicates treatment with antiangiogenic agents, including the tyrosine kinase inhibitor (TKI) sunitinib. To prospectively evaluate the prevalence and management of HT in patients with advanced renal cell carcinoma (RCC) receiving sunitinib we used 24-h ABPM and we treated HT according to guidelines of the Joint National Committee on Prevention, Detection and Evaluation and the Treatment of High Blood Pressure (JNC7). Patients and methods: Normal 24-h ABPM at the baseline and at 2, 4 and 6 weeks of the first cycle was ensured with the successive use of hydrochlorothiazide + irbesartan, nebivolol and amlodipine. Office BP measurements were used in subsequent cycles to monitor HT. Sunitinib dose was modified only if BP was not controlled with four anti-hypertensive agents. Results: Forty patients were included in this analysis. Twenty-one patients (53%) had baseline HT, while 12 of 14 (84%) normotensive patients required anti-HT treatment during the 1st cycle of sunitinib. HT was infrequent in subsequent cycles and increase of anti-HT medication was required in only 2 cases. Two patients permanently discontinued sunitinib due to HT. The remaining 34 (94%) required no dose modifications for HT. One cardiac event (2.8%) was observed. There was no correlation of HT with sunitinib efficacy. Conclusion: Sunitinib-associated HT is more frequent than previously reported. The use of 24-h ABPM for diagnosis and tailoring of HT according to JNC7 guidelines may achieve uninterrupted, full dose therapy in most patients. The substitution of such protocols for currently used Toxicity Criteria may be warranted. © 2011 Elsevier Ltd. All rights reserved.

Objective: This study investigated whether changes in thyroid hormone (TH) in plasma are associated with the recovery of cardiac function in patients with acute myocardial infarction (AMI). Previous experimental studies have provided evidence of potential implication of TH signaling in post-ischemic recovery of cardiac function. Methods: A total of 47 patients with AMI and early reperfusion therapy were included in this study. Myocardial injurywas analyzed by peak creatinine kinase-MB(CKMB) and cardiac function was assessed by echocardiographic left ventricular ejection fraction (LVEF%). Recovery of function (ΔEF%) was estimated as the difference of LVEF% between 48 h and 6 months (6 mo) after AMI. Total triiodothyronine (T3), thyroxine (T4), and TSH were measured in plasma at different time points (24 h, 48 h, 5 d, and 6 mo). Results: A significant correlation between LVEF% and T3 (r=0.5, P=0.0004) was found early after AMI (48 h), whereas no correlation was observed between CKMB and T3 (r=-0.04, P=0.81). A strong correlation was found between ΔEF% and total T3 (r=0.64, P=10-6) at 6 mo after AMI. Furthermore, multivariate regression analysis revealed that T3 at 6 mo (r=0.64, r2=0.41, P=10-6) was an independent determinant of DEF%. Conclusion: Changes in T3 levels in plasma are closely correlated with the early and late recovery of cardiac function after AMI. T3 levels at 6 mo appear to be an independent predictor of late functional recovery. © 2011 European Society of Endocrinology.

Objectives: In some trials, particularly in oncology, patients whose disease progresses under the comparator treatment are crossed over into the experimental arm. This unplanned crossover can introduce bias in analyses because patients who crossover likely have a different prognosis than those who do not cross over; for instance, sicker patients not responding to standard therapy or those expected to benefit the most may be selectively chosen to receive the experimental treatment. Standard statistical methods cannot adequately correct for this bias. We describe an approach designed to minimize the impact of crossover, and illustrate this by using data from two randomized trials in multiple myeloma (MM). Methods: The MM-009/010 trials compared lenalidomide and high-dose dexamethasone (Len+Dex) with dexamethasone alone (Dex). Nearly half (47%) of the patients randomized to Dex crossed over to Len with or without Dex (Len+/-Dex) at disease progression or study unblinding. Data from these trials was used to predict survival in an economic model evaluating the cost-effectiveness of lenalidomide. To adjust for crossover, the prediction equations were calibrated to match survival with Dex or Dex-equivalent therapies in trials conducted by the Medical Research Council (MRC) in the United Kingdom. To adjust for differences between the MM and MRC trial populations, a prediction equation was developed from the MRC data and used to predict survival by setting predictors to mean values for patients in the MM-009/010 trials. The expected survival with Dex without crossover was then predicted from the calibrated MM-009/010 equation (i.e., adjusted to match survival predicted from the MRC equation). Results: The adjusted median overall survival predicted by the MRC equation was 19.5 months (95%CI, 16.622.9) for patients with one prior therapy, and 11.6 months (95% CI, 9.514.2) for patients with >1 prior therapy. These estimates are considerably shorter than was observed in the clinical trials: 33.6 months (27.1-NE) and 27.3 months (95% CI, 23.333.3) as of December 2005. Conclusion: The calibration method described here is simple to implement, provided that suitable data are available; it can be implemented with other types of endpoints in any therapeutic area. © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).

The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients. © 2011 by The American Society of Hematology.

The management of patients with AL requires meticulous risk assessment in order to plan treatment strategy and reduce the risk of treatment related complications. The most important prognostic feature and poor risk factor is amyloidotic involvement of the heart. Traditional techniques, such as ultrasonography provide significant information on the severity of cardiac amyloidosis, however cardiac biomarkers (cardiac Troponins and NTproBNP) are simpler to perform, are available in almost every lab or as a bedside test, are noninvasive, have reasonable cost, and are powerful predictors of outcome and assess the risk of treatment related complications (especially early death) in patients considered for autologous transplantation. Refinement of cardiac biomarker-based prognostic system with additional markers may help identify subgroups of patients at special risk. Additional markers could also help assess the risk of renal or liver damage or autonomic dysfunction and could help improve management. There are no formal guidelines for the management of AL patients based on risk stratification systems; however, recommendations have been published and current evidence supports the use of cardiac biomarkers as a helpful guide to treatment strategy.© 2011 Informa UK, Ltd.

Advanced transitional-cell carcinoma of the bladder is the most common cancer of the urinary tract, with a high mortality rate. Cisplatin-based chemotherapy has demonstrated prolonged survival of these patients and is considered the standard of care. Nevertheless, 40-50% of patients have impaired renal function that precludes the use of cisplatin. The non-nephrotoxic platinum analogue, carboplatin, has emerged as the most popular alternative in this setting, used mainly in doublets. However, it has not shown similar efficacy to cisplatin. In this article, platinum-based or platinum-free regimens, monotherapies or combination therapies are discussed as treatment options for this population. Their efficacy and toxicity are also being analyzed. The study of newer targeted therapies in the treatment of bladder cancer is also discussed, as are future perspectives and a five-year view in the treatment of the disease in patients with renal impairment. © 2011 Expert Reviews Ltd.

Multiple myeloma, a plasma cell neoplasm, is the second most common hematologic malignancy after non-Hodgkins lymphoma and is responsible for 2% of cancer deaths. Melphalan and prednisone (MP) has been the standard treatment in elderly patients for many decades. The VISTA study evaluated the effect of this combination with or without the first-in-class proteasome inhibitor bortezomib in newly diagnosed myeloma patients who were not candidates for autologous stem cell transplantation. Altogether 682 patients were enrolled and prospectively randomized in this trial. All patients received nine 6-week cycles of oral melphalan (9 mg/m 2) and prednisone (60 mg/m 2) on days 1-4, either alone or with bortezomib administered intravenously (1.3 mg/m 2 on days 1, 4, 8, 11, 22, 25, 29 and 32 during the first four cycles and on days 1, 8, 22, 29 during remaining course of therapy). Median time to progression (the primary end point of the trial) was 24 months in the bortezomib-containing group compared with 16.6 months in the control group (p < 0.001). Response was evaluated in 337 patients receiving bortezomib compared with 331 patients in the control group who received MP alone; the percentages of partial response or better was 71 vs 35% (p < 0.001), with complete response seen in 30 vs 4%, respectively (p < 0.001). Median response duration in both groups was 19.9 versus 13.1 months, respectively. Median overall survival has not been reached in VMP group compared with 43 months in the MP group (p < 0.001), and this benefit is maintained after long term follow-up and subsequent antimyeloma therapies. Hematological adverse events (AEs) were similar in both groups, although patients in the bortezomib group experienced more frequent peripheral sensory neuropathy (including 13% grade 3, with less than 1% grade 4). Overall, the occurrence of grade 3 AEs was higher in patients receiving bortezomib (53 vs 44%, p = 0.02), but the risk of grade 4 AEs was identical (28 vs 27%). These results confirm the superiority of MP plus bortezomib combination over MP therapy in treatment-naive patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation. © 2011 Future Medicine Ltd.

To investigate the mechanisms of the therapeutic action and drug resistance to the nitrogen mustard melphalan, melphalan-induced DNA damage repair and chromatin structure were examined along the p53, N-ras and d-globin gene loci in cells carrying different repair activities. In nucleotide excision repair-deficient XP-A cells, similar levels of adducts were found in all fragments examined, indicating uniform distribution of DNA damage. In both, repair-proficient CS-B and XP-C cells, faster repair was observed in regions inside the transcribed N-ras and p53 genes, compared to regions on both sides outside of the genes, while no such difference was observed for the inactive d-globin gene. Moreover, very fast adduct repair on the transcribed strand of the active genes was seen immediately downstream of the transcription start site, together with a steeply decreasing gradient of repair efficiency along the gene towards the 3'-end. In all cells analyzed, the above variation in DNA repair efficiency was paralleled exactly by the variation in the degree of local chromatin condensation, more relaxed chromatin being associated with faster repair. Similar results were obtained using peripheral blood mononuclear cells from healthy volunteers, suggesting that the existence of a repair gradient along transcribed genes may be a universal phenomenon. In conclusion, these findings demonstrate that the repair of melphalan adducts in the transcribed strand of active genes is subject to a strong polarity effect arising from variations in the chromatin structure. © 2011 Elsevier B.V.

Systemic treatment represents the cornerstone of endometrial cancer management in advanced, relapsed and metastatic disease, which is still characterized by poor prognosis. Progestins remain an effective option for patients with low grade, estrogen and/or progesterone receptor positive disease, with some of them achieving prolonged survival. Platinum compounds, anthracyclines and more recently taxanes have been implemented in combination regimens achieving response rates more than 50% and resulting in overall survival above 1 year in randomized trials. Adjuvant chemotherapy with the same agents may be useful for patients with early stage disease and high-risk features, such as high grade or non-endometrioid histology. Combination of chemotherapeutic agents with radiotherapy remains investigational. Hematologic, cardiac toxicity and neurotoxicity represent the main concern of chemotherapy and increase the risk for treatment-related morbidity and death, especially in pretreated patients bearing substantial co-morbidities. The gradual elucidation of the molecular aspects of endometrial carcinogenesis has led to the development of novel, selective antineoplastic agents, targeting specific molecular pathways and mediators of signal transduction implemented in cell proliferation, survival and angiogenesis. In the current review, we report on the recent advances regarding systemic therapy of endometrial carcinoma with special emphasis on results of large, randomized phase III clinical trials. Biomarkers with potent prognostic significance or predictive value for response to treatment are presented and novel molecular agents showing promising results in early clinical trials are discussed. © 2010 Elsevier Ireland Ltd.

Background: Randomized studies have shown that bevacizumab combined with taxane-based regimens increases response rates and prolongs progression-free survival (PFS) of patients with metastatic breast cancer (MBC). However predictive or prognostic biological markers that identify the appropriate target population, thus improving the cost-effectiveness ratio of this treatment, are still needed. Patients and Methods: Retrospectively, 124 patients with MBC treated either with paclitaxel 90 mg/m2 weekly x12 plus bevacizumab 10 μg/kg every 2 weeks or 15 μg/kg every 3 weeks (85 patients) or paclitaxel 175 mg/m2 plus bevacizumab 15 μg/kg every 3 weeks for 6 cycles (36 patients) were identified. Additionally, the prognostic significance of a panel of key biological markers was evaluated centrally by immunohistochemistry (IHC) in 88 evaluable patients. Results: More than two thirds of the patients completed chemotherapy, as planned. The response rate was almost identical (55.3% vs. 55.6%) in the patients treated with weekly or 3-weekly paclitaxel, respectively. After a median follow-up time of 23 months, the median PFS of the study population was 13 months, while median survival had not yet been reached. Common severe adverse events were neutropenia (33%), neuropathy (18.6%) and metabolic disturbances (17.6%). The incidence of hypertension of all grades was 28.1%. High expression of vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3) was associated with clinical response, while high expression of VEGFR1 was associated with poor survival. Conclusion: The safety and activity of the combination of bevacizumab with paclitaxel given either weekly or 3-weekly in patients with MBC is confirmed.

In 203 consecutive unselected patients with symptomatic MM who received upfront treatment with novel agents, high levels of serum LDH were independently associated with poor survival and could identify subgroups of patients within ISS-2 and ISS-3 with even worse outcome. Evaluating serum LDH levels is a simple, inexpensive, and readily available procedure that could be considered among the variables that define very-high-risk MM. Background: In patients who have symptomatic multiple myeloma (MM), a high serum lactate dehydrogenase (LDH) level is associated with features of advanced disease, adds prognostic value to the international staging system (ISS) and predicts for inferior survival. However, it has not been clearly defined what the impact of this abnormality is for patients treated upfront with novel agent-based regimens. Patients and Methods: To address this issue we analyzed 203 consecutive unselected patients with symptomatic MM who received upfront treatment with novel agents in a single center. Results: The median overall survival for patients with normal LDH was 54 months but in patients with increased LDH levels it was 21 months (P =.003), whereas increased serum LDH was associated with a higher probability of early death. Multivariate analysis confirmed that an increased LDH level is independently associated with poor survival. Furthermore, increased LDH levels could identify subgroups of patients within ISS-2 and ISS-3 with even worse outcome. Conclusion: We conclude that serum LDH is a simple, inexpensive, and readily available blood test that may be included among the variables that define very-high-risk MM. © 2011 Elsevier Inc. All rights reserved.

Osteonecrosis of the jaw is an uncommon but potentially serious complication of bisphosphonate therapy in multiple myeloma. Previous studies showed that the presence of one or two minor alleles of the cytochrome P450, subfamily 2C polypeptide 8 gene (CYP2C8) polymorphism rs1934951 was an independent prognostic marker associated with development of osteonecrosis of the jaw in multiple myeloma patients treated with bisphosphonates. The aim of this study was to validate the frequency of SNP rs193451 in 79 patients with multiple myeloma. In 9 (22%) patients developing osteonecrosis of the jaw, a heterozygous genotype was found, in contrast with those who did not develop osteonecrosis of the jaw (n=4, 11%) or healthy individuals (n=6, 13%). We found no differences in the cumulative risk of developing osteonecrosis of the jaw between patients homozygous and heterozygous for the major allele. We were unable to confirm a significant association between this polymorphism and the risk of developing osteonecrosis of the jaw. © 2011 Ferrata Storti Foundation.

To assess the importance of the quality of response and of early relapse in unselected elderly patients with myeloma treated upfront with novel agents. Methods: We analyzed 135 unselected transplant-ineligible patients older than 65yr who were treated upfront with novel agent-based regimens in a single center. Results: On intent to treat, 81% of patients achieved a response (28% sCR/CR, 23% VGPR, and 30% PR). Median progression-free survival (PFS) for patients who achieved sCR/CR was 31 vs. 20months for VGPR and 23months for PR (P=0.048). Median overall survival (OS) for patients with sCR/CR was 62months, 53months for VGPR and 38months for patients with PR (P=0.028). Early relapse (PFS<12months) was more common in patients with PR (39% vs. 21% for VGPR vs. 3% for sCR/CR). Patients who relapsed or progressed <12months from initiation of treatment had a median OS of 15.4months compared with 53months (P<0.001) for patients who had a PFS>12months despite the fact that after relapse or progression most patients were treated again with novel agents. In multivariate analysis, short PFS was the most significant adverse prognostic factor affecting OS, associated with a 7.25-fold (P<0.0001) increase in the risk of death. Conclusion: In newly diagnosed patients over 65yr, treated upfront with novel agents achievement of CR and a PFS ≥12months is associated with improved outcome. Patients who fail to respond or experience early relapse after primary therapy with novel agent-based regimens should be encouraged to participate in clinical trials of novel agents and combinations. © 2011 John Wiley & Sons A/S.

Triple-negative breast cancers are an aggressive subtype of breast cancer with poor survival, but there remains little known about the etiologic factors that promote its initiation and development. Commonly inherited breast cancer risk factors identified through genome-wide association studies display heterogeneity of effect among breast cancer subtypes as defined by the status of estrogen and progesterone receptors. In the Triple Negative Breast Cancer Consortium (TNBCC), 22 common breast cancer susceptibility variants were investigated in 2,980 Caucasian women with triple-negative breast cancer and 4,978 healthy controls. We identified six singlenucleotide polymorphisms, including rs2046210 (ESR1), rs12662670 (ESR1), rs3803662 (TOX3), rs999737 (RAD51L1), rs8170 (19p13.1), and rs8100241 (19p13.1), significantly associated with the risk of triple-negative breast cancer. Together, our results provide convincing evidence of genetic susceptibility for triple-negative breast cancer. ©2011 AACR.

Gastric cancer is the second leading cause of cancer related-death. Most patients present with an advanced stage of disease that has a dismal outcome. Evidently, there is a clear need for the development of new agents with novel mechanisms of action in the treatment of this disease. A number of biological agents modulating different signal transduction pathways are currently in clinical development, such as angiogenesis inhibitors and agents targeting epidermal growth factor receptor, cell cycle, matrix metalloproteinases, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) or proteasome. This is the first systematic review of the literature to synthesize all available data coming from trials and evaluate the efficacy and safety of molecular targeted drugs in unresectable and metastatic gastric cancer. As knowledge accumulates on the molecular mechanisms underlying carcinogenesis in the stomach, the anticipated development and assessment of molecularly targeted agents may offer a promising perspective for a disease which, to date, remains incurable. © 2011 Elsevier Ltd.

The Mediterranean dietary pattern has a well-established beneficial role in health promotion. Epidemiologic studies reveal the protective role of adherence to this pattern on overall cancer incidence and mortality. This review examines results from prospective cohort, cross-sectional, and case-control studies assessing the role of the Mediterranean diet in cancer prevention. Original research studies that were published in English between 1985 and April 6, 2010, were selected through a computer-assisted literature search (i.e., PubMed and Scopus). From the initial search, 273 papers were selected. After the titles and the abstracts of these papers were read for relevance to this review, 17 studies were selected and are discussed here; 8 had a prospective design, 7 were case-control, 1 was a randomized screening study, and 1 was an interventional study. Although there is a lack of definitive evidence for the association of Mediterranean diet with various types of cancer, a dietary pattern emphasizing the consumption of fruits and vegetables, whole grains, legumes, nuts, seeds, and low-fat dairy products could be highly recommended for all people, and especially those at risk for cancer. © 2011 Mary Ann Liebert, Inc.

Abstract Renal impairment (RI) is a common presenting complication of multiple myeloma associated with significant morbidity and early mortality, while it has been associated with inferior survival in patients treated with conventional regimens. We assessed the impact of RI in 203 unselected consecutive patients treated upfront with novel agents (thalidomide, lenalidomide, bortezomib). RI was assessed by the estimated glomerular filtration rate (eGFR). RI (eGFR <60 mL/min) was present in 93 (45.8%) of patients at diagnosis and was associated with advanced age, advanced International Staging System (ISS) stage, poorer performance status, hypercalcemia, urine Bence-Jones proteinuria, anemia and thrombocytopenia. Myeloma response rates were similar for patients with or without RI. In univariate analysis RI was associated with shorter survival and a higher rate of early death (7% vs. 3.5%); however, when adjusted for other prognostic factors, RI was not independently associated with survival. In conclusion, in unselected newly diagnosed patients treated with novel agent-based therapies, RI is not independently associated with inferior survival, probably due to the significant activity of novel agents even in the context of RI.

Biochemical markers of bone turnover provide insight into ongoing rates of skeletal metabolism and tumor-bone interactions in patients with malignant bone disease. This article reviews the available recent evidence assessing the potential of bone markers for detecting and monitoring malignant bone lesions in patients with advanced cancers, and for assessing overall skeletal health and response to antiresorptive therapies in patients at all stages of cancer progression. Most data thus far are for urinary N-terminal cross-linked telopeptide of type I collagen (NTX) in predicting risks of skeletal morbidity and death and monitoring response to zoledronic acid in patients with bone metastases. Ongoing studies are evaluating such correlations for other markers and therapies. Emerging evidence suggests that bone markers may help identify patients at high risk for bone metastasis or bone lesion progression, thereby allowing improved follow-up. Results from ongoing clinical trials evaluating such potential applications of bone markers are awaited. © 2011 Elsevier Ireland Ltd.

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10 -10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10 -9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10 -9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. © 2011 Nature America, Inc. All rights reserved.

This review attempts to outline the alternative measures and interventions used in bloodless surgery in the field of gynecologic oncology and demonstrate their effectiveness. Nowadays, as increasingly more patients are expressing their fears concerning the potential risks accompanying allogenic transfusion of blood products, putting the theory of bloodless surgery into practice seems to gaining greater acceptance. An increasing number of institutions appear to be successfully adopting approaches that minimize blood usage for all patients treated for gynecologic malignancies. Preoperative, intraoperative and postoperative measures are required, such as optimization of red blood cell mass, adequate preoperative plan and invasive hemostatic procedures, assisting anesthetic techniques, individualization of anemia tolerance, autologous blood donation, normovolemic hemodilution, intraoperative cell salvage and pharmacologic agents for controlling blood loss. An individualised management plan of experienced personnel adopting a multidisciplinary team approach should be available to establish non-blood management strategies, and not only on demand of the patient, in the field of gynecologic oncology with the use of drugs, devices and surgical-medical techniques. © 2011 Simou et al; licensee BioMed Central Ltd.

Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients withMM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes. © 2011 by The American Society of Hematology.

This analysis assessed the effect of lenalidomide on progression-free survival (PFS). Patients with relapsed or refractory multiple myeloma (RRMM) who received lenalidomide plus dexamethasone in the MM-009 and MM-010 trials were pooled and those who had not progressed and were still receiving lenalidomide at 12 months were included. The median follow-up of surviving patients was 48 months. Of 353 patients who received lenalidomide plus dexamethasone, 116 (33%) had not progressed. Overall, 52 patients (45%) had no dose reductions, 25 (22%) had dose reductions ≥12 months and 39 (34%) had dose reductions before 12 months. Patients who had dose reductions ≥12 months had a significantly longer median PFS than those who had reductions before 12 months (P=0.007) or no dose reductions (P=0.039) (not reached vs 28.0 vs 36.8 months, respectively). In a multivariate Cox regression model, dose reduction ≥12 months was an independent predictor of improved PFS (hazard ratio, 0.47; 95% confidence interval, 0.23-0.98) after adjusting for patient characteristics. The data suggest that to achieve maximum PFS benefit, patients with RRMM should be treated for ≥12 months with full-dose lenalidomide plus dexamethasone. Thereafter, patients may benefit from lower-dose continued therapy; prospective studies are needed to confirm these findings. © 2011 Macmillan Publishers Limited All rights reserved.

Objective: Early-stage epithelial ovarian cancer represents a prognostically heterogenous group. We studied prognostic factors in patients treated with adjuvant paclitaxel/carboplatin chemotherapy. Methods: Data was extracted from 147 patients with FIGO stage IA/IB, grade 2/3 or stage IC/IIA (any grade) who underwent primary surgery followed by paclitaxel/carboplatin chemotherapy. Results: Median follow-up was 88 months. Ten-year relapse-free (RFS) and disease-specific survival (DSS) were: 81% (95% confidence interval [CI]: 73-89) and 81% (95% CI: 73-89). On multivariate analysis, non serous histology was associated with reduced risk for RFS (0.294, 95% CI: 0.112-0.577, p = 0.001) and DSS (0.194, 95% CI: 0.075-0.504, p = 0.001), while high-risk category (stage IC/IIA and grade 2/3) with increased risk for RFS (3.989, 95% CI: 1.189-13.389, p = 0.009) and DSS (3.989, 95% CI: 1.064-16.386, p = 0.038). The combination of histology and grade identified 3 groups with distinctly different 10-year RFS and DSS rates (p < 0.001): grade 1 (100% and 100%), non-serous grade 2/3 (83% and 86%) and serous grade 2/3 (60% and 60%). Conclusions: Serous histology is an adverse prognostic factor in early-stage ovarian cancer treated with adjuvant paclitaxel/carboplatin. Risk stratification according to histology and grade is a useful discriminator of prognosis and can be used in the design of future studies. © 2011 Elsevier Inc. All rights reserved.

Objective: We investigated the efficacy of risk-adapted adjuvant paclitaxel/carboplatin chemotherapy in early-stage ovarian carcinoma. Methods: Fifty-three patients were treated according to the risk of relapse: patients with stages IA or IB or with grade 1 (low risk) received 4 cycles of paclitaxel and carboplatin; patients with IC/IIA and grade 2 or 3 (high risk) received 6 cycles of chemotherapy. The outcome was compared with that of 95 patients who were all treated with 4 cycles. Results: Median follow-up was 88, 113 and 42 months for the whole cohort, non-risk-adapted and risk-adapted treatment, respectively. Five-year relapse-free and diseasespecific survival was 86 and 93% for the whole population, 96 and 97% for low-risk and 81 and 91% for high-risk patients. Risk classification was the only significant prognostic factor for relapse-free (p = 0.011) and disease-specific survival (p = 0.039). Among high-risk patients, the administration of 6 cycles was associated with a significantly lower relapse rate after censoring events, which occurred beyond 2 years (3 vs. 18%; p = 0.013), but this difference was diminished at 5 years (23 vs. 25%; p = 0.797). Conclusions: Six cycles of chemotherapy reduced the risk of relapse within 2 years, but the benefit from two additional cycles beyond this time is questionable. Copyright © 2012 S. Karger AG, Basel.

BACKGROUND: Urothelial carcinoma of the upper urinary tract (UUT-UC) was a rare, aggressive urologic cancer with a propensity for multifocality, local recurrence, and metastasis. High-risk patients had poor outcomes. Because of the rarity of these tumors, randomized clinical trials and data regarding adjuvant chemotherapy in locally advanced tumors are currently unavailable. Our objective was to assess the effect of adjuvant chemotherapy and the impact of potential prognostic factors on survival in high-risk, postsurgical UUT-UC patients. METHODS: Using a multi-institutional, international retrospective database, identified were 627 patients with high risk UUT-UCs (pT3N0, pT4N0 and/or N+ and/or M+) who underwent surgical removal. Only patients who received adjuvant chemotherapy were included. RESULTS: Overall, 140 patients (22.6%) with a median age of 67 years were included. The median follow-up was 22.5 months. The 5-year, overall survival for the entire cohort was 43%, the 5-year recurrence-free survival was 54%, and metastasis-free survival was 53% at 5 years. Positive surgical margins were an independent prognostic factor for recurrence (P =.06), cancer-specific mortality (P =.05), and overall mortality (P =.02) of any cause. Adjuvant chemotherapy was not linked with overall or cancer-specific survival in patients with high risk disease (adjuvant chemotherapy [n = 140] vs no treatment [n = 487]) (P >.5). CONCLUSIONS: Adjuvant postoperative chemotherapy did not offer any significant benefit to overall survival in our population. Additional data were necessary, and studies enrolling patients at high risk in clinical trials investigating neoadjuvant chemotherapy in conjunction with chemotherapy should have been highly encouraged. Copyright © 2011 American Cancer Society.