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Aim: The purpose of this study is to evaluate the role of MET T1010I and MET rs40239 as potential risk factor and/or prognostic markers in patients with triple-negative breast cancer (TNBC). Methods: 114 samples of DNA from paraffin-embedded breast normal tissues of patients with TNBC and 124 samples of healthy controls were collected and analyzed for MET T1010I and MET rs40239 polymorphisms. Results: MET T1010I CT genotype was associated with increased risk of TNBC in both univariate and multivariate analysis. The status of rs40239 was not associated with a higher risk for TNBC at either the univariate or the multivariate analysis. None of the examined polymorphisms was associated with overall survival at the univariate or multivariate Cox regression analysis (adjusted HR=1.35, 95% CI: 0.31–5.97 for MET T1010I CT/TT vs CC; adjusted HR=1.78, 95% CI: 0.73–4.35 for rs40239 AG/GG vs AA). Conclusion: Our case–control study suggests that MET T1010I seems to be a risk factor for TNBC in the Caucasian Greek population, in contrast with MET rs40239, where no correlation was found.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS < 5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

End-of-treatment (EoT) PET/CT is used as a guide to omit radiotherapy (RT) patients with primary mediastinal large B-cell lymphoma (PMBCL). We present the mature and extended results of a retrospective study evaluating the prognostic significance of EoT-PET/CT after adequate response to R-CHOP. Among 231 consecutive PMLBCL patients, 182 underwent EoT-PET/CT and were evaluated according to the Deauville 5-point scale (D5PS) criteria. Freedom from progression (FFP) was measured from the time of PET/CT examination. Among 182 patients, 72 (40%) had D5PS score 1 (D5PSS-1), 33 (18%) had 2, 28 (15%) had 3, 29 (16%) had 4, and 20 (11%) had 5. The 5-year FFP was 97, 94, 92, 82, and 44% for D5PSS-1, D5PSS-2, D5PSS-3, D5PSS-4, and D5PSS-5, respectively. Among 105 patients with unequivocally negative PET/CT (D5PSS-1/D5PSS-2), 49 (47%) received RT (median dose 3420 cGy) and 56 (53%) did not with relapses in 0/49 vs. 4/56 patients (2 mediastinum and 2 isolated CNS relapses).The 5-year FFP for those who received RT or not was 100% versus 96%, when isolated CNS relapses were censored (p = 0.159). Among D5PSS-3 patients (27/28 irradiated-median dose 3600 cGy), the 5-year FFP was 92%. The 5-year FFP for D5PSS-4 and D5PSS-5 was 82 and 44%; 44/49 patients received RT (median dose 4000 and 4400 cGy for D5PSS-4 and D5PSS-5). Our study supports the omission of RT in a sizeable fraction of PET/CT-negative patients and definitely discourages salvage chemotherapy and ASCT in patients with PMLBCL who conventionally respond to R-CHOP, solely based on PET/CT positivity in the absence of documented progressive or multifocal disease. The persistence of positive PET/CT with D5PSS5 after consolidative RT should not trigger the initiation of further salvage chemotherapy in the absence of conventionally defined PD.

Supplemental material, DS_10.1177_2381468318814253 for Development of an Initial Conceptual Model of Multiple Myeloma to Support Clinical and Health Economics Decision Making by Sebastian Gonzalez-McQuire, Meletios-Athanassios Dimopoulos, Katja Weisel, Walter Bouwmeester, Roman Hájek, Marco Campioni, Craig Bennison, Weiwei Xu, Krystallia Pantiri, Marja Hensen, Evangelos Terpos and Stefan Knop in MDM Policy & Practice

Background. We aimed to develop and validate a conceptual model of multiple myeloma (MM) that characterizes the attributes affecting disease progression and patient outcomes, and the relationships between them. Methods. Systematic and targeted literature reviews identified disease- and patient-specific attributes of MM that affect disease progression and outcomes. These attributes were validated by a Delphi panel of four international MM experts, and a physician-validated model was constructed. Real-world clinical data from the Czech Registry of Monoclonal Gammopathies (RMG) was used to confirm the relationships between attributes using pairwise correlations and multiple Cox regression analysis. Results. The Delphi panel reached consensus that most cytogenetic abnormalities influenced disease activity, which results in symptoms and complications and affects overall survival (OS). Comorbidities and complications also affect OS. The entire panel agreed that quality of life was influenced by comorbidities, age, complications, and symptoms. Consensus was not reached in some cases, in particular, the influence of del(17p) on complications. The relationships between attributes were confirmed using pairwise analysis of real-world data from the Czech RMG; most of the correlations identified were statistically significant and the strength of the correlations changed with successive relapses. Czech RMG data were also used to confirm significant predictors of OS included in the model, such as age, Eastern Cooperative Oncology Group performance status, and extramedullary disease. Conclusions. This validated conceptual model can be used for economic modeling and clinical decision making. It could also inform the development of disease-based models to explore the impact of disease progression and treatment on outcomes in patients with MM.

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values

Flora Zagouri,1 Theodoros N Sergentanis,2 Dimosthenis Chrysikos,2 Meletios-Athanassios Dimopoulos,1 Aristotle Bamias1 1Department of Clinical Therapeutics, Alexandra Hospital, 2First Propaedeutic Surgical Department, Hippokration Hospital, University of Athens, Athens, Greece Abstract: Ovarian cancer is the most lethal gynecologic malignancy; consequently, there is a need for effective therapies. Epothilones are microtubule-stabilizing agents that inhibit cell growth. Currently, patupilone and its four synthetic derivatives ixabepilone, BMS-310705, sagopilone, 20-desmethyl-20-methylsulfanyl epothilone B and epothilone D, as well as its derivative KOS-1584, are under clinical evaluation. This is the first systematic review conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines that synthesizes all available data emerging from trials and evaluates the efficacy and safety of epothilones in epithelial ovarian, primary fallopian tube, and primary peritoneal cancer. Despite the fact that epothilones have proven active in taxane-resistant settings in preclinical models, it is not yet clear from Phase II/III studies reviewed here that their clinical activity is superior to that of taxanes. Nevertheless, responses to epothilones have been observed in platinum-refractory/resistant ovarian cancer patients. Moreover, despite the shared mechanism of action of epothilones, their clinical profile seems clearly different, with diarrhea being the most common dose-limiting toxicity encountered with patupilone, whereas neutropenia and sensory neuropathy are the most common toxic effects observed with the other epothilones. In any case, randomized trials comparing epothilones with standard treatments seem warranted to define further the role of these agents, whereas biomarker analysis might further optimize patient selection. Keywords: ovarian cancer, epothilone, patupilone, ixabepilone, systematic review

Background Recognizing resistance or susceptibility to the current standard cisplatin and paclitaxel treatment could improve therapeutic outcomes of metastatic or recurrent cervical cancer. Methods Forty-five tissue samples from patients participating in a phase II trial of cisplatin and ifosfamide, with or without paclitaxel were collected for retrograde analysis. Immunohistochemistry and genotyping was performed to test ERCC1, III β-tubulin, COX-2, CD4, CD8 and ERCC1 (C8092A and N118 N) and MDR1 (C3435T and G2677 T) gene polymorphisms, as possible predictive and prognostic markers. Results were statistically analyzed and correlated with patient characteristics and outcomes. Results Patients with higher levels of ERCC1 expression had shorter PFS and OS than patients with low ERCC1 expression (mPFS:5.1 vs 10.2 months, p = 0.027; mOS:10.5 vs. 21.4 months, p = 0.006). Patients with TT in the site of ERCC1 N118 N and GT in the site of MDR1 G2677 T polymorphisms had significantly longer PFS (p = 0.006 and p = 0.027 respectively). ERCC1 expression and the ERCC1 N118 N polymorphism remained independent predictors of PFS. Interestingly, high III beta tubulin expression was associated with chemotherapy resistance and fewer responses [5/20 (25%)] compared to lower III β-tubulin expression [15/23 (65.2%)] (p = 0.008). Finally, ΙΙΙ β-tubulin levels and chemotherapy regimen were independent predictors of response to treatment. Conclusions ERCC1 expression proved to be a significant prognostic factor for survival in our metastatic or recurrent cervical cancer population treated with cisplatin based chemotherapy. ERCC1 N118 N and MDR1 G2677 T polymorphism also proved of prognostic significance for disease progression, while overexpression of III β-tubulin was positively correlated with chemotherapy resistance.

The establishment of high dependency units (HDUs) has been an undoubted advance in the management of patients undergoing major oncological procedures. The aim of this study was to examine the impact of various preoperative and perioperative patients’ characteristics on the prolonged HDU stay. We conducted a retrospective study including all gynecologic oncology patients who underwent surgical management and were admitted postoperatively to our hospitals’ HDU from 2006 to 2010. A total of 1,014 patients were transferred to the HDU and divided into two groups according to the length of HDU stay. Group A consisted of 840 (82.8 %) patients who stayed in the HDU for ≤24 h and Group B included 174 (17.2 %) patients who remained in the HDU under close observation for >24 h. Older age was the only preoperative characteristic that remained significantly associated with HDU prolonged stay. In addition, three intraoperative factors such as use of invasive hemodynamic monitoring, bowel resection and estimated blood loss were proved to be independently associated with prolonged HDU stay. Certain characteristics could identify those patients who are more likely to benefit most from HDU admission.

Purpose Pharmacological inhibition of Hsp90 shows great promise in breast cancer treatment. This is the first systematic review to synthesize all available data and to evaluate the efficacy and safety of Hsp90 inhibitors in breast cancer. Methods This study was performed in accordance with the PRISMA guidelines. Eligible articles were identified by a search of MEDLINE and ClinicalTrials.gov databases, using a predefined combination of the terms “breast”, “cancer”, “Hsp90”, “inhibitors”. Results Overall, 19 articles (190 patients) were eligible. The greatest clinical activity has been observed on the field of HER2-positive metastatic breast cancer. However, accumulating data suggest that Hsp90 inhibitors may play a significant role in the treatment of triple negative and aromatase inhibitor-resistant breast cancer. Conclusion In the last decade, the development of Hsp90 inhibitors has moved forward rapidly; however, no phase III trials have been conducted and none agent has been approved for use in the clinical practice.

OBJECTIVE: To evaluate breast cancer characteristics in women aged 25 years and younger. METHODS: This was a retrospective, nested, within-cases matched study. The study design was based on a two-phase protocol. In the first phase, stage, grade, histologic subtype, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status were compared between 28 patients (aged 25 years and younger) and 685 older premenopausal women (aged older than 25 years) with breast cancer. The second phase aimed to determine whether young patients exhibited worse prognosis when compared with older premenopausal women. RESULTS: Young patients presented at a more advanced stage (P=.012) and exhibited a higher grade (P=.018). No significant differences were noted regarding histologic subtype, estrogen receptor, and progesterone receptor status. Genetic testing for BRCA1 and BRCA2 mutations was performed in 12 of 28 young patients and mutations were found in 25% of them. Moreover, young women presented poorer overall survival (hazard ratio [HR] 4.30, 95% confidence interval [CI] 1.09–17.03) than their older counterparts, matched by histologic subtype, stage, and grade; a similar pattern was noted regarding relapse-free survival (HR 8.28, 95% CI 2.24–30.60). CONCLUSION: Breast cancer diagnosis in women aged 25 years and younger is uncommon; however, these patients present at a more advanced stage, with a higher grade, and exhibit poorer survival. LEVEL OF EVIDENCE: II

Background Tumour-associated lymphocytes (TALs) present in effusions of ovarian cancer patients exhibit impaired activities, due to the immunosuppressive environment of the ascites. Means to enhance their cytotoxicity against autologous tumour cells are of clinical importance. The immunomodulator prothymosin alpha (proTα) increases the specific lysis of tumour cells by activated CD8 + T-lymphocytes and its immunoreactivity is exerted by the carboxy-terminal decapeptide, proTα(100-109). These two molecules were studied on TALs in vitro , and in SCID mice bearing human ovarian tumours. Methods TALs and tumour cells were isolated from 41 ovarian cancer patients and co-cultured in the presence of proTα or proTα(100-109). The cytotoxicity of peptide-stimulated TALs was tested against autologous tumour cells and K562. Ex vivo peptide-stimulated TALs from three patients were adoptively transferred intraperitoneally in SCID mice, previously inoculated with each patient's autologous tumour cells. Results ProTα and its immunoreactive peptide proTα(100-109), enhanced the cytotoxic activity of TALs against autologous tumour cells in vitro , but marginally affected the lysis of K562. The effect of proTα and proTα(100-109) was higher after 7–14days of stimulation, whereas TAL cytotoxicity was significantly decreased after 21days. Mice administered TALs, ex vivo activated with proTα or proTα(100-109) for 7days, showed a relatively lower tumour increase rate and a prolongation of their survial, compared to controls. Conclusion Our data demonstrate that, in the presence of tumour antigens, proTα and proTα(100-109) enhance the depressed cytotoxicity of TALs against autologous tumour cells in vitro and retard tumour growth in vivo .

Leptomeningeal carcinomatosis (MC) represents an uncommon, but devasting manifestation of metastatic breast cancer. This is the first systematic review/pooled analysis to synthesize all available data evaluating the efficacy and safety of intrathecal (IT) administration of trastuzumab for the treatment of MC in HER2-positive breast cancer patients. This study was performed in accordance with the PRISMA guidelines. A total of 13 articles (17 patients) were eligible. The mean age of patients at IT trastuzumab administration was 48.2 years (SD 8.4, range 38-66). The mean total dose was 399.8 mg (SD 325.4, range 35-1,110 mg). IT trastuzumab alone or as part of combination therapies seemed to be safe; no serious adverse events were reported in 88.2 % of cases. In 68.8 % of cases, a significant clinical improvement was observed, while stabilization or progression of the disease was noticed in 31.2 % of cases. Cerebrospinal fluid (CSF) response was noted in 66.7 % of cases. The median overall survival was 13.5 months, whereas the median central nervous system progression-free survival (CNS-PFS) was 7.5 months. In 23.5 % of cases, IT trastuzumab was administered beyond CNS progression with a response noticed in 75 % of cases and a CNS-PFS of 9.4 months. The cumulative dose of IT trastuzumab given was 1,040 mg (SD 697.9, median 1,215, range 55-1,675). The protective effect of prior radio- or neurosurgery upon CNS-PFS was sizeable but did not reach formal statistical significance (HR 0.28, 95 % CI 0.06-1.37). Clinical improvement (HR 0.14, 95 % CI 0.02-0.91) and CSF response (HR 0.09, 95 % CI 0.01-0.89) were associated with longer CNS-PFS. IT trastuzumab administration seems to represent a safe and in some cases effective option for the treatment of HER2-positive breast cancer patients with leptomeningeal involvement. However, clinical trials are urgently needed to establish the definite role of IT trastuzumab in HER2-positive metastatic breast cancer patients with MC.

Landmark studies have established taxanes in the treatment of patients with breast cancer; however, recommendations regarding their administration during pregnancy are controversial. The present systematic review aims to synthesize all available data that stem exclusively from breast cancer case series to evaluate the efficacy and safety of taxanes during pregnancy. Overall, 16 studies (50 pregnancies) were eligible for the systematic review according to prisma guidelines. The mean age of patients with breast cancer at pregnancy was 34.6 years. The gestational age (GA) at chemotherapy administration varied from 12 to 36 weeks. The mean GA at delivery was 35.9 weeks. The mean weight of babies at delivery was 2380 g. In 76.7% of cases, a completely healthy neonate was born; in the remaining cases, a neonate who was dystrophic and premature, one with mild hydrocephalus, one with signs of bacterial sepsis, one with hyperbilirubinemia, one with apnea of prematurity, respiratory distress syndrome and gastroesophageal reflux, one with meconium-stained fluid, and another neonate with neutropenia and pyloric stenosis were reported. Ninety percent of children were completely healthy, with a median follow-up of 16 months; in the remaining cases, one child with recurrent otitis media, one with immunoglobulin A deficiency and mild constipation, and another child with delayed speech were reported. In conclusion, available data suggest that taxanes may potentially play a promising role in the optimal therapeutic strategy of patients with breast cancer diagnosed during pregnancy.

Landmark studies have established trastuzumab in the treatment of HER2-positive breast cancer. The present systematic review and meta-analysis aims to synthesize all available data, so as to evaluate the safety of trastuzumab during pregnancy. This study was performed in accordance with the PRISMA guidelines. All studies that examined the safety of trastuzumab administered during pregnancy, regardless of sample size, were considered eligible. Overall, 17 studies (18 pregnancies; 19 newborns) were included. In 55.6 % of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration was 14.8 weeks. Occurrence of oligohydramnios/anhydramnios (O/A) was the most common (61.1 %) adverse event. 73.3 % of pregnancies exposed to trastuzumab during the second/third trimester were complicated with O/A; the respective rate of pregnancies exposed to trastuzumab exclusively during the first trimester was 0 % (P = 0.043). The mean GA at delivery was 33.8 weeks, and the mean weight of babies at delivery was 2,261 gr. In 52.6 % of cases, a healthy neonate was born. At the long-term evaluation, all children without problems at birth were healthy with a median follow-up of 9 months, while four out of nine children facing troubles at birth were dead within an interval ranging between birth and 5.25 months. All children exposed to trastuzumab in utero exclusively in the first trimester were completely healthy at birth. Trastuzumab should not be administered during pregnancy. However, for women who become accidentally pregnant during trastuzumab administration and wish to continue pregnancy, trastuzumab should be stopped and pregnancy could be allowed to continue.

Clinical utility of serum free light chains (sFLC) and heavy chain (HLC) IgM were assessed, using Freelite and Hevylite assays in 70 WM patients. The result showed that median involved (i) sFLC -kappa and -lambda were 45.6 and 78.3mg/ L respectively; median sFLC (kappa+lambda) was 67.4 mg/ L. While, median FLCR (involved/uninvolved FLC ratios) were 2.7 and 6.9 in ikappa- and ilambda -restricted patients respectively. Moreover, increased isFLC, sFLC (kappa+lambda) and FLCR were correlated significantly with shorter time to first treatment (TFT) and adverse survival (OVS). Median iIgM-kappa and iIgM -lambda were 25.4 and 34.8g/L respectively; median HLCR (involved/uninvolved HLC ratios) were 185.5 and 101.9 in kappa- and lambda- restricted patients respectively. In addition, the increased iHLC and HLCR correlated significantly with shorter TFT. Hence, sFLC and HLC measurements appeared to be both prognostic in WM.

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of

There is a controversy in the literature regarding the role and the prognostic significance of serum markers in uterine carcinosarcomas (CSs). We attempted to determine the utility of serum CA 125, CA 15-3, CA 19-9, and CEA as prognostic factors and disease follow-up in patients with CS of the uterus. Thirty-seven patients with CS of the uterus were included in this study. Information regarding demographic, clinical, pathologic, tumor marker data (CA 125, CA 19-9, CA 15-3, and CEA both pre- and postoperatively) treatment and outcome information was obtained, followed by Statistical analysis. The mean follow-up period was 3.5 years. None of the study serum markers showed significant association with the outcome. Greater hazard was found for cases that staged from IIIA to IV compared to those staged from IA to IIB (HR = 4.75, 95 % CI: 1.99–11.3). Also, greater hazard was found for adenosquamous histological type compared to the other histological types. When multiple Cox regression analysis with stepwise approach was implied, it indicated stage as the only significant factor for the outcome. Elevated CA19-9 was more frequent in cases with heterologous sarcoma (p = 0.036). In this retrospective study, none of the preoperative serum tumor markers, neither epithelial component, histological type, nor grade showed a significant association with prognosis. This null finding may have significant implications in the common clinical practice; given that there is a controversy in the literature regarding the role and the significance of the prognostic significance of serum CEA, CA 125, CA 19-9, and CA 15-3.

Central nervous system (CNS) involvement in patients with primary mediastinal large B-cell (PMLBCL) lymphoma is a rare event, occurring in approximately 6% of patients, on the basis of the review of the literature prior to induction of Rituximab. The aim of this retrospective study was to describe the incidence of CNS relapse among 100 consecutive patients with PMLBCL who were treated with R-CHOP ± RT in comparison to patients treated with CHOP ± RT (n = 45) in 11 hospitals in Greece. Two patients experienced a CNS relapse, representing an overall frequency of 2.0% in R-CHOP treated patients and a 2-year actuarial incidence of 2.3%. Both patients had isolated CNS relapses. The incidence of CNS relapse after CHOP without Rituximab was 2/45 (4.4%) for a 2-year actuarial incidence of 7.5% (p = 0.29). Again, both patients had isolated CNS relapses. Parenchymal-only localizations accounted for 3/4 cases. Risk factors for CNS involvement could include leukocytosis, poor performance status and higher age-adjusted International Prognostic Index, although their impact was weakened by competing risk survival analysis. Both patients relapsing after R-CHOP required CNS radiotherapy to achieve a complete remission and be forwarded to high-dose therapy and autologous stem cell transplantation: They are both alive and disease-free 18 and 23 months after CNS relapse. Both cases relapsing after CHOP without Rituximab were salvaged by CNS radiotherapy (one also received intrathecal chemotherapy) entering long-term remissions. In conclusion, CNS relapses are rare in PMLBCL tending to be isolated in the CNS, probably reflecting the persistence of latent CNS disease than dissemination of resistant disease. The impact of Rituximab in reducing CNS relapses remains unknown. Established risk factors for CNS involvement in aggressive lymphomas may not be helpful in assessing the risk of CNS recurrence in this disease. Routine CNS prophylaxis is not probably required in PMLBCL. Copyright © 2012 John Wiley & Sons, Ltd.

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.

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.

Lenalidomide is a novel immunomodulatory agent with a unique dual mechanism of action: its tumoricidal effect leads to direct tumor cell death, and its immunomodulatory effect keeps the tumor in remission. Phase III clinical trials have demonstrated that in patients with relapsed/refractory multiple myeloma (MM), lenalidomide in combination with dexamethasone offers high clinical response rates and improved time to disease progression, progression-free survival (PFS), and overall survival (OS) compared with dexamethasone alone. In patients with newly diagnosed MM, the combination of lenalidomide and low-dose dexamethasone prolonged survival compared with lenalidomide and standard high-dose dexamethasone. The benefits of lenalidomide-based treatment regimens can be optimized by initiating treatment early in the disease course, either as a frontline treatment or at first relapse. Lenalidomide is generally well tolerated; the primary adverse events are myelosuppression and venous thromboembolic complications. These adverse events emerge early in the course of treatment and can be managed using standard interventions such as granulocyte colony-stimulating factor, dose reduction, and thromboprophylaxis. The combination of lenalidomide and dexamethasone is effective and generally well tolerated in patients with renal impairment provided that creatinine clearance level and adverse events are carefully monitored and the starting dose of lenalidomide is adjusted appropriately. Early results from phase III trials indicate that in patients with newly diagnosed MM, continuous lenalidomide therapy is well tolerated and associated with significant improvements in PFS, offering a new treatment option for patients with MM – although no OS benefit has yet been seen in this setting. Lenalidomide-based treatment is effective across the spectrum of MM disease phases, allowing for the long-term management of myeloma.

Paraneoplastic syndromes represent a group of clinical manifestations widely separated from the primary site of malignancy, which are not caused by local infiltration of the tumor or its metastases. Alterations of hemostasis and vascular abnormalities commonly accompany the progression of malignant disease. Hypercoagulability, changes in coagulation factors, anticoagulant proteins, circulating anticoagulants or platelets, and vascular responses have been noted during the disease process. The purpose of this review is to illustrate and present the current state of knowledge surrounding vascular paraneoplastic manifestations in gynecologic oncology. Since they may constitute the presenting feature of an undiagnosed gynecologic cancer, it is important to seek to identify such malignancies in women presenting with clinical thrombotic or bleeding syndromes.

The introduction of mAbs has changed the clinical approach to patients with lymphoma and leukemia.To summarize the most significant applications of mAb-based regimens in the treatment of hematological malignancies and explore their possible role in the future management of these patients.Rituximab (anti-CD20) was the first mAb developed for the treatment of B-cell lymphomas. Several randomized studies have demonstrated its efficacy in lymphomas and low toxicity profile; rituximab also has significant activity in chronic lymphocytic leukemia (CLL). Alemtuzumab (anti-CD52) has shown efficacy in previously untreated or refractory CLL patients, while gemtuzumab ozogamicin (anti-CD33) appears to have significant activity in acute myeloid leukemias and myelodysplastic syndromes.In the next few years, investigations will be concentrated on the improvement of the older mAbs, and the development of new mAbs, targeting molecules important for malignant cell cycle and survival in an attempt to further improve patient survival.

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.

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.

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.

Bone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors, including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators (receptor activator of nuclear factor-κB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction, as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) and bone remodelling markers were evaluated in 38 patients with Waldenström macroglobulinaemia (WM) and correlated with clinical and laboratory variables. MIP-1alpha was elevated in WM; untreated patients had higher MIP-1alpha levels than patients in remission or with active disease after treatment. MIP-1alpha correlated with increased bone resorption, beta2-microglobulin and splenomegaly. Receptor activator of nuclear factor-kappaB ligand serum levels were elevated in WM patients; the subsequent increased bone resorption was balanced by a comparable elevation of osteoprotegerin production and bone formation. These findings may explain the absence of lytic lesions in WM patients and suggest a potential role of MIP-1alpha in WM.

In most cases multiple myeloma is an incurable plasma cell malignancy. Despite the use of conventional therapy or high-dose chemotherapy with autologous stem cell transplantation (ASCT), patients continue to relapse at a constant rate. A small minority of patients are cured by allogeneic transplantation. Novel drugs targeting not only the myeloma cell but also its interactions with the malignant microenvironment have recently been used in patients with relapsed/refractory disease. So far, ASCT has been the treatment of choice for eligible myeloma patients. However, many questions regarding the management of myeloma patients remain unanswered. How safe is ASCT in elderly patients? Is there a role for non-myeloablative allogeneic transplantation in multiple myeloma? What is the role of novel agents, such as thalidomide, its analogues and bortezomib, in the treatment of newly diagnosed patients or as maintenance post-ASCT? This review summarises all available data for the current treatment options for myeloma providing a useful algorithm for its management.

This is a retrospective analysis of 150 patients with advanced non-small cell lung cancer who had failed prior treatment or were unfit for chemotherapy and were treated with oral gefitinib ('Iressa', ZD1839; AstraZeneca) 250 mg/day. Thirty-two patients who received gefitinib for 3 weeks or less were not included in the analysis. For the remaining 118 evaluable patients, the mean age was 63.1 years; most patients had received prior chemotherapy (97.5%), Eastern Cooperative Oncology Group performance status scores 0-2 (97.4%) and stage IV disease (64.4%). The majority were symptomatic (84.6%). Disease control was observed in 30 patients (25.4%), of whom five had a partial response and 25 had stable disease; 18 (15.3%) were not evaluable. Median duration of treatment was 29.9 weeks in responding patients and 11.5 in patients with progressive disease (p

Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib. Cardiac toxicity was observed with thalidomide and may occur with proteasome inhibition. Thromboembolic complications occur with thalidomide and its derivatives, but are less common with bortezomib. Peripheral neuropathy (PN), an important complication of MM, may be exacerbated by bortezomib and thalidomide, and was also observed with lenalidomide. In contrast, PN is rarely observed with carfilzomib and pomalidomide. Renal impairment reduces the clearance of lenalidomide but does not seem to affect substantially the pharmacokinetics of pomalidomide, carfilzomib, or bortezomib. Several therapies have recently been approved, such as the oral proteasome inhibitor ixazomib, the HDAC inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab. Others are still in clinical development, including the HDAC inhibitors romidepsin and vorinostat, with safety data continuing to emerge. Therapy decisions should consider safety profiles in association with pre-existing comorbidities and toxicities from previous therapeutic regimens. Optimal treatment selection and the management of toxicities will result in fewer patients requiring dose reductions and treatment discontinuations, ultimately leading to improved outcomes.

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.

Elderly patients with advanced non-small cell lung cancer (NSCLC) are thought to receive suboptimal treatment mainly due to concerns for poor compliance and/or excessive toxicity.Using the age of 70 years as the pre-defined cut-off, we compared elderly patients with advanced NSCLC suitable for first line chemotherapy with their younger counterparts in terms of: i) diagnosis and disease characteristics ii) adherence to treatment schedule, including dose intensity (DI), and relative dose intensity (RDI), iii) toxicity, tolerance, and efficacy outcomes.Among 292 eligible patients, data were available for 245, of whom 107 (43.7%) belonged to the elderly group. This group was more likely to present with co-morbidities, non-smoking current status and diagnosis based on cytology alone. As compared to the non-elderly, elderly patients were more likely to receive single-agent therapy (8.0% vs. 29.2% respectively, p0.001) and less likely to receive platinum-based chemotherapy (80.3% vs. 57.9%, p0.001). Elderly patients also received docetaxel (24.3% vs. 40.4%), and bevacizumab (7.5% vs. 21.3%) significantly less often and received oral vinorelbine (24.3% vs. 11.8%) more frequently. Non-elderly patients were more likely to receive any of the cytotoxic drugs with RDI0.8 (49.6% vs. 33.0%, p = 0.012) and RDI0.9 (29.6% vs. 16%, p = 0.015). Substantial toxicity, as well as median overall survival did not differ significantly between the two groups.Only one third of the elderly patients received at least 80% of the scheduled treatment intensity. Nearly half received diagnosis based on cytology alone, which may deprive them from new, histology-driven, therapeutic approaches.

The mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that plays a key role in cell survival, growth, angiogenesis and metastasis. Because its expression is frequently altered in tumors, MET is currently under investigation as a potential target for anticancer therapy. The purpose of the present study was to determine the prognostic value of tumor MET expression levels in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, in order to strengthen the rationale for targeted therapy using MET inhibitors in this breast cancer subpopulation.We determined the expression of MET in formalin-fixed paraffin-embedded surgical specimens of ER- and HER2-positive breast cancer by immunohistochemistry.Comparisons of MET expression with clinical parameters, including survival of the patients, were performed with MET expression as a dichotomized variable classified as high or low. Out of 78 tumors, 3 (3.8%) showed high MET expression. The analysis examining the association between MET and survival did not yield any statistically significant result regarding overall survival or disease-free survival.ER- and HER2-positive breast carcinomas do not exhibit high MET expression. This null finding, the first to be reported in the literature, is of great importance, since it indicates that this sub-group population is not proper candidate for clinical trials with MET inhibitors.

OBJECTIVES The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan prednisone, plus interferon in both arms. METHODS Eighty-nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon-alpha (rIFN-alpha) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN-alpha. The two treatment groups were comparable in terms of pretreatment characteristics. RESULTS The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN-alpha group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN-alpha group (p=0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN-alpha group and was not reached in the VBMCP/IFN-alpha group (p = 0.6). Overall survival was long in both treatment groups. The estimated 5-yr survival was 66% and 62% in the MP/IFN-alpha and VBMCP/IFN-alpha group, respectively (p=0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN-alpha group. CONCLUSIONS The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon-alpha has no advantage over conventional MP plus interferon-alpha, in regard to response rate, response duration, and overall survival of patients.

we are investigating the epigenetic regulation of the pro-apoptotic gene Bim. In contrast to CD9, pyrosequencing analysis showed no DNA methylation of the Bim promoter. Both Western blot and ChIP demonstrated that induced upregulation of Bim upon treatment with LBH589 and/or 5-aza-2`deoxycitidine was due to the acetylation and methylation of histones in the promoter region. These results are thus more or less in line with the results obtained for CD9. Therefore, we can conclude that epigenetic phenomena represent an interesting target for treatment in MM and MM stem cells and that further studies on targeted genes and biological sequelae are warranted. Additional studies on new and less known epigenetic mechanisms (eg, acetylation of proteins, miRNA) could furthermore provide new and improved insights into the development and progression of MM.

This case control study aims to investigate the role of MMP-2 −1306C > T polymorphism as a potential risk factor and possible prognostic marker for breast cancer in a South European population. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy controls were recruited. MMP-2 −1306C > T polymorphism was genotyped; multivariate logistic regression as well as Cox regression analysis were performed. MMP-2 −1306C > T status was not associated with breast cancer risk either at the total sample or at the subanalyses on premenopausal and postmenopausal women. At the survival analysis, a trend towards a favorable association between MMP-2 −1306C > T allele and disease-free survival as well as overall survival was observed. Regarding subanalyses on ER-negative and ER-positive cases, the favorable association implicating MMP-2 −1306C > T allele was particularly evident among ER-positive cases; no significant associations emerged among ER-negative cases. MMP-2 −1306C > T polymorphism does not seem to be a risk factor for breast cancer in South European population; however, a trend towards a favorable association with survival has been observed.

Intensive chemotherapy confers benefit to patients with high-risk early breast cancer (BC). We characterized the feasibility and toxicity profile of anthracycline-containing adjuvant chemotherapy (ACAC) in older women with early BC.Available data from women who received ACAC for BC in 3 randomized trials were retrieved. We identified women aged65 years and we examined differences in tolerability and delivery of chemotherapy, toxicity, and treatment outcome.From a total of 2640 patients, we identified 453 patients (17%) as being65 years old, 89% of whom had tumors that were node-positive, with 77% who were hormone receptor-positive. At least 90% of the planned doses were delivered in 37% of the elderly, compared with 49% in the younger patients (P .0001). Grade 3 and 4 hematological toxicity was observed in 32% of elderly patients, compared with 21% of the younger (P .0001). Febrile neutropenia occurred in 4.5% of the elderly patients, as opposed to 2.0% in the younger patients (P .002). Elderly patients experienced more frequent Grade 3 and 4 fatigue, mucositis, and sensory neuropathy. Relative dose intensities were significantly lower in elderly patients. Treatment discontinuation was not different in the 2 groups. At a median follow-up of 120 months, competing risks analysis showed a significant benefit in disease-free survival for elderly patients.Elderly BC patients treated with ACAC derive clinical benefit comparable to that in younger patients, mainly at the cost of increased risk of hematological toxicity. This should be taken into account in decision-making and treatment individualization in high-risk BC patients.

Pertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermal growth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breast cancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neoadjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease (1023 patients). Six studies were conducted in HER2 + breast cancer population (1354 patients), whereas 5 studies (86 patients) were conducted in HER2 – (or unknown HER2 status) disease. Pertuzumab is the most recent agent approved by the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patients with HER2 + metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval has been based on data from a phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflected upon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenue for achieving additional benefit for patients with HER2 + . Moreover, pertuzumab seems to have a putative role in the management of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neoadjuvant and adjuvant settings remains to be further investigated and established in the future.

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.

Central nervous system (CNS) involvement in patients with primary mediastinal large B-cell (PMLBCL) lymphoma is a rare event, occurring in approximately 6% of patients, on the basis of the review of the literature prior to induction of Rituximab. The aim of this retrospective study was to describe the incidence of CNS relapse among 100 consecutive patients with PMLBCL who were treated with R-CHOP ± RT in comparison to patients treated with CHOP ± RT (n = 45) in 11 hospitals in Greece. Two patients experienced a CNS relapse, representing an overall frequency of 2.0% in R-CHOP treated patients and a 2-year actuarial incidence of 2.3%. Both patients had isolated CNS relapses. The incidence of CNS relapse after CHOP without Rituximab was 2/45 (4.4%) for a 2-year actuarial incidence of 7.5% (p = 0.29). Again, both patients had isolated CNS relapses. Parenchymal-only localizations accounted for 3/4 cases. Risk factors for CNS involvement could include leukocytosis, poor performance status and higher age-adjusted International Prognostic Index, although their impact was weakened by competing risk survival analysis. Both patients relapsing after R-CHOP required CNS radiotherapy to achieve a complete remission and be forwarded to high-dose therapy and autologous stem cell transplantation: They are both alive and disease-free 18 and 23 months after CNS relapse. Both cases relapsing after CHOP without Rituximab were salvaged by CNS radiotherapy (one also received intrathecal chemotherapy) entering long-term remissions. In conclusion, CNS relapses are rare in PMLBCL tending to be isolated in the CNS, probably reflecting the persistence of latent CNS disease than dissemination of resistant disease. The impact of Rituximab in reducing CNS relapses remains unknown. Established risk factors for CNS involvement in aggressive lymphomas may not be helpful in assessing the risk of CNS recurrence in this disease. Routine CNS prophylaxis is not probably required in PMLBCL.

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).

In cancer biology angiogenesis plays a vital role in tumour growth and its subsequent metastatic potential. By targeting the angiogenic process, a new treatment strategy was added in the clinician's therapeutic armamentarium. On the other hand, numerous classic cytotoxic agents are currently considered as potential angiogenesis inhibitors, although they were not originally developed as such, representing the so-called "accidental" anti-angiogenic drugs. The discovery of these new properties of classic cytotoxic agents led to the re-evaluation of their effect on vascular cells, rendering thus the endothelium an appealing target for therapeutic intervention, either with chemotherapy alone or with combination of cytotoxics with molecular angiogenesis inhibitors. Moreover, current evidence supports that chemotherapy-induced endothelial dysfunction constitutes an integrating predictive marker of future cardiovascular events and correlates well with traditional cardiovascular risk factors. It has therefore been suggested that evaluation of endothelial function may be useful in identifying asymptomatic subjects at high risk for cardiovascular events as well as for risk stratification of patients with established cardiovascular disease. Integration of the assessment of endothelial function in the clinical setting will thus enable effective intervention strategies to prevent or minimize the impact of these late adverse effects and design accurate follow-up protocols focused on cardiovascular complications. In the current review we provide a comprehensive overview of the effects of cytotoxic chemotherapeutic agents on endothelial function and the clinical implications of chemotherapy-associated endothelial toxicity in patients with cancer.

The molecular triad, which includes the receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL decoy receptor osteoprotegerin (OPG), has emerged as an important determinant of bone metabolism. We aimed to evaluate the effect of treatment with the biphosphonate zoledronic acid (ZA) on biochemical markers of bone remodeling and to detect possible correlations of markerlevel changes with skeletal morbidity and clinical outcomes in patients with solid tumors and osseous metastases. The following serum markers were measured at the onset of skeletal metastases and after 6 months of treatment with ZA (4 mg intravenously monthly) in 70 patients with breast (n = 30), lung (n = 18), or prostate (n = 22) cancer: RANKL, OPG, C-terminal cross-linking telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), bone-specific alkaline phosphatase (bALP), and osteopontin (OPN). Logistic regression models were applied to assess the correlation between marker-level changes and skeletal related events (SRE, primary endpoint), recurrence or progression, and death. Within a median follow-up of 32 months, 34 patients (48.6%) presented with at least 1 SRE and 48 patients (68.6%) relapsed. The RANKL/OPG ratio was upregulated in patients with breast and lung cancer, and it tended to decline after treatment with ZA, whereas prostate cancer patients presented with profound elevation of OPG only that persisted after treatment. CTX levels were significantly reduced after treatment in the whole study population (P = 0.003). None of the markers was able to predict skeletal morbidity or clinical outcomes independently of well-established prognostic clinical parameters. Transl Res