Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin)

Abstract

Purpose

The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin).

Methods

We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8 %).

Results

Among 54 patients, the median age was 51.5 years (range 23–72 years). Male patients were 59.3 %. Seven patients (13.5 %) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among seven patients with tumors with FGFR2 expression, six achieved partial response (PR) with a 85.7 % response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5 %). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, P = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS.

Conclusions

FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx.

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Issue Information

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Volume-based growth tumor kinetics as a prognostic biomarker for patients with EGFR mutant lung adenocarcinoma undergoing EGFR tyrosine kinase inhibitor therapy: a case control study

Abstract

Background

We aim to determine whether volumetric assessment has the potential to serve as a prognostic biomarker, and to assess the relationship between longitudinal tumor data during treatment and prognosis in lung adenocarcinoma patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKI).

Methods

We retrospectively assessed patients with EGFR-mutant stage IV lung adenocarcinoma who were treated with EGFR TKIs until disease progression. CT studies of 106 patients were quantitatively analyzed in terms of tumor size and volume by comparing baseline and follow-up CT scans obtained at every two treatment cycles. Tumor response was quantified using longitudinal measurements, and tumor growth kinetics was determined. Correlation with early surrogate parameters for tumor response evaluation such as change in size, volume, and response rate was performed. The Cox-proportional hazard model and Log-rank test were used to predict overall survival (OS).

Results

Responders based on the percent change in volume after four cycles of TKI therapy had a higher OS than non-responders (P = 0.035). The percent of volume and size changes after four cycles of TKI therapy were significantly correlated with TTP (P < 0.001).

Conclusion

Volume measurements and corresponding rates of growth appear to be helpful adjuncts for predicting survival in patients undergoing EGFR-TKI therapy.

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The ENCCA-WP7/EuroSarc/EEC/PROVABES/EURAMOS 3rd European Bone Sarcoma Networking Meeting/Joint Workshop of EU Bone Sarcoma Translational Research Networks; Vienna, Austria, September 24–25, 2015. Workshop Report

Abstract

This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24–25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

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Delineation of Radiotherapy Target Volumes for Cutaneous Malignancies Involving the Ophthalmic Nerve (Cranial Nerve V-1) Pathway

Publication date: Available online 16 March 2016
Source:Practical Radiation Oncology
Author(s): Mekhail Anwar, Yao Yu, Christine M. Glastonbury, Ivan H. El-Sayed, Sue S. Yom
PurposeThe ophthalmic nerve (cranial nerve V-1) runs in close proximity to the globe, optic nerve, chiasm, and brain. The purpose of this study was to provide contouring guidance using computed tomography (CT)-identifiable landmarks, based on an analysis of skin cancer patients with V-1 invasion.Methods and MaterialsRadiation oncology planning CT scans were analyzed for landmarks to guide V-1 target delineation from the skin surface to the trigeminal ganglion. Axial and coronal MRI sequences were fused with the planning CT to confirm soft tissue findings and identify enhancement related to perineural spread. CT/MRI-based anatomic landmarks were catalogued and described on an atlas.ResultsSoft tissue and bony landmarks were confirmed as consistently identifiable on CT with assistance from fused MRI. A reference atlas was developed that shows the entirety of the V-1 pathway on consecutive CT slices.ConclusionsInitial delineation of the V-1 pathway can be accomplished using CT-visualized landmarks confirmed on fused MRI. This CT/MRI atlas will assist radiation oncologists in delineation of the V-1 pathway.



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Tumor-derived factors modulating dendritic cell function

Abstract

Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor-derived and stroma-derived factors, which may also impair DC maturation, differentiation and function, thus resulting in the deficient formation of antitumor immune response or development of DC-mediated tolerance and immune suppression. Identification of DC-stimulating and DC-suppressing/polarizing factors in the tumor environment and the mechanism of DC modulation are important for designing effective DC-based vaccines and for recovery of immunodeficient resident DC responsible for maintenance of clinically relevant antitumor immunity in patients with cancer. DC-targeting tumor-derived factors and their effects on resident and administered DC in the tumor milieu are described and discussed in this review.

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Malignancies after living-donor and cadaveric lung transplantations in Japanese patients

Abstract

Purpose

Lung transplant recipients are known to be at risk of a postoperative malignancy. In Western countries, skin cancer and post-transplant lymphoproliferative disorder (PTLD) are the most common malignancies in this cohort. We conducted this study to evaluate the characteristics of postoperative malignancies in Japanese patients following living-donor lobar lung transplantation (LDLLT) or cadaveric lung transplantation (CLT).

Methods

We reviewed the medical records of 120 Japanese patients who underwent either LDLLT (n = 62) or CLT (n = 58) between April 2002 and July 2015.

Results

Postoperative malignancy developed in 11 patients (9.2 %), as PTLD in 7, breast cancer in 1, gastric cancer in 1, glioblastoma in 1, and adenocarcinoma of unknown primary in 1. Twenty-six (21.7 %) of the 120 transplant patients had a history of malignancy pre-transplant; however, the postoperative malignancies were all de novo without any recurrence of the original disease. The malignancies developed after LDLLT in six patients (9.7 %) and after CLT in 5 patients (8.6 %). Three of the four patients with solid organ malignancies had distant metastasis at diagnosis. Three patients died of PTLD and one patient died of gastric cancer.

Conclusions

PTLD occurred after both LDLLT and CLT. There was no case of skin cancer in this series of Japanese patients, suggesting ethnic differences. Solid organ malignancies in lung transplant recipients tended to progress rapidly.

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The effects of roflumilast on the pancreas and remote organs in a cerulein-induced experimental acute pancreatitis model in rats

Abstract

Purpose

Systemic damage in acute pancreatitis (AP) can be characterized by oxidative stress and the release of pro-inflammatory cytokines. Roflumilast has been shown to be a potent anti-inflammatory and antioxidant agent. In the present study, we aimed to investigate the effect of roflumilast in cerulein-induced AP.

Methods

Thirty-two male rats were divided into four groups: group 1 (sham), group 2 (Roflumilast), group 3 (AP), and group 4 (AP + Roflumilast). AP was induced by injecting 4 × 75 μg/kg of body weight at an interval of 1 h. Rats were killed after 12 h following the last cerulein administration. AP was confirmed by measuring the serum amylase level and inflammatory features.

Results

Morphological changes were observed in the pancreas. Amylase levels were higher in the AP and AP + Roflumilast groups than the sham and Roflumilast groups. The serum levels of TNF-α, IL-1β, and IL-6 increased in the AP group, whereas they decreased in the Roflumilast group. The total oxidant activity (TOA) was higher and the total antioxidant capacity (TAC) was lower in the AP group. The administration of roflumilast decreased the TOA and increased the TAC in comparison with the AP group (p < 0.05 for both).

Conclusions

Roflumilast significantly decreases oxidative stress and inflammatory mediators in the plasma, pancreas, and lung in cerulein-induced AP rats.

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Efficacy of denosumab in joint preservation for patients with giant cell tumour of the bone

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Frank Traub, Janith Singh, Brendan C. Dickson, Stephanie Leung, Rakesh Mohankumar, Martin E. Blackstein, Albiruni R. Razak, Anthony M. Griffin, Peter C. Ferguson, Jay S. Wunder
BackgroundGiant cell tumour of the bone (GCTB) is an aggressive osteolytic primary tumour. GCTB is rich in osteoclast-like giant cells and contains mononuclear cells that express RANK ligand (RANKL), a key mediator of osteoclast activation. The potential therapeutic effect of denosumab was investigated with special reference to its role in joint preservation.MethodsIn this prospective non-randomised study patients with GCTB received denosumab for 6–11 months preoperatively. Serial radiographs and biopsy and resection tumour specimens were used to monitor response to denosumab.ResultsAll 20 patients experienced pain relief in the first month of treatment. All patients demonstrated a positive radiographic response with improved subchondral and cortical bone which allowed intralesional tumour resection and preservation of the joint and articular surface in 18 cases. Histological examination following denosumab revealed rarely detectable osteoclast-like giant cells. There was an obvious increase in osteoid matrix and woven bone which showed rare RANK staining amongst the mononuclear cells and only focal RANKL positivity. At median 30 months follow-up after resection, local tumour recurrence occurred in three patients.ConclusionDenosumab provides favourable and consistent clinical, radiographic and pathologic responses which facilitates less aggressive surgical treatment, especially joint preservation. However, the local recurrence rate for GCTB following resection does not seem to be affected by denosumab and remains a concern.



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Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma

Publication date: May 2016
Source:European Journal of Cancer, Volume 58
Author(s): Michael A. Fridrik, Ulrich Jaeger, Andreas Petzer, Wolfgang Willenbacher, Felix Keil, Alois Lang, Johannes Andel, Sonja Burgstaller, Otto Krieger, Willi Oberaigner, Kurt Sihorsch, Richard Greil
BackgroundChemoimmunotherapy containing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) is the standard treatment for diffuse large B-cell lymphoma (DLBCL). Doxorubicin may induce early and late cardiotoxicity. Non-pegylated liposomal (NPL) doxorubicin may reduce cardiotoxicity.Patients and methodsPatients with untreated CD20+ DLBCL were randomised to conventional R-CHOP chemoimmunotherapy or rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone (R-COMP) with doxorubicin substituted by NPL-doxorubicin. Left ventricular ejection fraction (LVEF) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels were measured before each treatment cycle and after the end of treatment.ResultsThe mean LVEF of 178 and 158 measurements in the R-COMP and R-CHOP arms was 63.31% and 62.25%, respectively (P = 0.167). During treatment the LVEF measurements were below 50% in 10/218 (4.6%) in the R-COMP arm and 31/196 (15.8%) in the R-CHOP arm (P<0.001). Thirty-six of 40 (90%) patients in the R-COMP arm, but only 24/36 (66.7%) in the R-CHOP arm had all NT-proBNP levels below 400 pg/ml during and at the end of treatment (P = 0.013). There were more serious adverse events in the R-CHOP arm (26 versus 40, P = 0.029). Infections were more common (15 versus 28) in the R-CHOP arm.InterpretationIn patients with normal cardiac function, six cycles of R-CHOP resulted in a low rate of early cardiotoxicity. NPL-doxorubicin did not reduce cardiotoxicity, although cardiac safety signals were elevated in R-CHOP compared to R-COMP.FundingCephalon provided the Arbeitsgemeinschaft Medikamentöse Tumortherapie with NPL-doxorubicin and an unrestricted grant, but was not involved in the study protocol, data acquisition, data analysis or the writing of the paper.



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Management of liver metastases in colorectal cancer patients: A retrospective case-control study of systemic therapy versus liver resection

Publication date: May 2016
Source:European Journal of Cancer, Volume 59
Author(s): Jannemarie A.M. de Ridder, Eric P. van der Stok, Leonie J. Mekenkamp, Bastiaan Wiering, Miriam Koopman, Cornelis J.A. Punt, Cornelis Verhoef, Johannes H. de Wilt
ObjectiveTo evaluate and compare the overall survival (OS) in case-matched patient groups treated either with systemic therapy or surgery for colorectal liver metastases (CRLM).MethodsPatients with CRLM, without extra-hepatic disease, treated with chemotherapy with or without targeted therapy in two phase III studies (n = 480) were selected and case-matched to patients who underwent liver resection (n = 632). Matching criteria were sex, age, established prognostic factors for survival (clinical risk score). Available computed tomography (CT)-scans of patients treated with systemic therapies were reviewed by three independent liver surgeons for resectability. Survival was compared between patients with resectable CRLM (based on CT-scan review) who were treated with systemic therapy versus patients who underwent liver resection.ResultsA total of 96 patients treated with systemic therapy were included. Pre-treatment CT-scans of the liver were available for review in 56 of the systemically treated patients, and metastases were unanimously considered resectable in 36 patients (64.3%) (complex resectable: n = 25; 69%). These 36 patients were case-matched with 36 patients who underwent liver resection (wedge resection or segmentectomy: n = 26; 72%). Median OS in the patient group treated with systemic therapy was 26.5 months (range 0–81 months), which was significantly lower than that in case-matched patients who underwent liver resection (median OS 56 months; range 6–116) (p = 0.027).ConclusionsIn this case-matched control study, surgery provided superior OS rates compared to systemic therapy for CRLM. Resection of CRLM should always be considered, preferably in a dedicated liver centre, since not all patients that qualify for resection are identified as such.



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Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

Abstract

Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome-wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180, MST1R, OCIAD2 and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event-free survival. These findings demonstrate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.

This article is protected by copyright. All rights reserved.

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Tumor-derived factors modulating dendritic cell function

Abstract

Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor-derived and stroma-derived factors, which may also impair DC maturation, differentiation and function, thus resulting in the deficient formation of antitumor immune response or development of DC-mediated tolerance and immune suppression. Identification of DC-stimulating and DC-suppressing/polarizing factors in the tumor environment and the mechanism of DC modulation are important for designing effective DC-based vaccines and for recovery of immunodeficient resident DC responsible for maintenance of clinically relevant antitumor immunity in patients with cancer. DC-targeting tumor-derived factors and their effects on resident and administered DC in the tumor milieu are described and discussed in this review.

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Results of a phase II study of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphoma: an interim analysis

Abstract

Purpose

Mantle cell lymphoma (MCL) is a disease that frequently relapses and primarily affects elderly people. We performed an open-label, multi-center, phase II study to investigate the effect and quality of life (QoL) of treatment with vorinostat in combination with fludarabine, mitoxantrone and dexamethasone (V-FND) for relapsed or refractory MCL.

Methods

The treatment schedule was composed of four cycles of induction treatment with V-FND and subsequent consolidation therapy involving autologous hematopoietic stem cell transplantation or six cycles of vorinostat maintenance. QoL was assessed using EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) every 2 cycles.

Results

Data from a total of 20 patients were collected for an interim analysis. The median age was 67 years (range 49–75), and 14 or the patients (70 %) were male. The full course of V-FND induction treatment was completed in 11 patients, but only three completed all six cycles of maintenance therapy. Response to V-FND was not available in two patients. Among the other 18 patients, the objective response rate was 77.8 % (complete response in five patients + partial response in nine patients). Median progression-free survival was 9.3 months [95 % confidence interval (CI) 4.0–12.3]. Fifteen patients (75 %) experienced grade 3/4 toxicities. Analysis of QoL demonstrated significant deterioration of social functioning (p = 0.01), and significant aggravation of fatigue and nausea/vomiting (p = 0.04 and 0.01, respectively) after two cycles of V-FND induction.

Conclusions

V-FND is effective in patients with relapsed or refractory MCL. However, significant toxicities were hurdles to sustained V-FND therapy.

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Subtype-specific incidence rates of lymphoid malignancies in Hong Kong compared to the United States, 2001–2010

Publication date: June 2016
Source:Cancer Epidemiology, Volume 42
Author(s): Bryan A. Bassig, Wing-Yan Au, Oscar Mang, Roger Ngan, Lindsay M. Morton, Dennis K.M. Ip, Wei Hu, Tongzhang Zheng, Wei Jie Seow, Jun Xu, Qing Lan, Nathaniel Rothman
Clinical studies of lymphoid malignancies (LMs) have suggested that the descriptive patterns of LMs differ in East Asia compared to Western populations. However, there are very limited available data on population-based, subtype-specific incidence rates of LMs in the East Asian population, particularly in Chinese. Using data from the Hong Kong (HK) Cancer Registry and United States (U.S.) SEER Program, we calculated and compared age-adjusted incidence rates of LM subtypes in HK to those in Whites and Asians living in the U.S. Overall and sex-specific rates were calculated for the period 2001–2010. The incidence of most subtypes was low in the HK population, with rates <1 case per 100,000 for all subtypes except for diffuse large B-cell lymphoma (3.26/100,000) and plasma cell neoplasms (1.99/100,000). Age-adjusted incidence rates of all evaluated B-cell subtypes were significantly higher in U.S. Whites compared to HK, with standardized rate ratios (SRRs) ranging from 1.6 (Burkitt lymphoma) to 9.1 (chronic lymphocytic leukemia/small lymphocytic lymphoma). Rates in U.S. Asians were generally intermediate to those in U.S. Whites and HK. Conversely, rates of extranodal NK/T-cell lymphoma were significantly lower in both U.S. Whites (SRR=0.2) and U.S. Asians (SRR=0.5) compared to HK. Our data provide new insight into the subtype-specific patterns of LMs in the Chinese population, and suggest the need for etiological studies of LMs in the East Asian population to elucidate the factors responsible for these differences in the geographic incidence patterns.



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Title page / Editorial Board

Publication date: April 2016
Source:Cancer Epidemiology, Volume 41





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Table of contents

Publication date: April 2016
Source:Cancer Epidemiology, Volume 41





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Pathology and Surgical Treatment of High-Grade Pancreatic Neuroendocrine Carcinoma: an Evolving Landscape

Abstract

Pancreatic neuroendocrine neoplasms (PNENs) are rare, accounting for less than 5 % of all pancreatic tumors. High-grade pancreatic neuroendocrine carcinomas (hgPNECs) represent about 5 % of all PNENs. They show highly aggressive behavior with dismal prognosis. Throughout the last two decades, there has been a notable progress in basic and clinical research of PNENs and a therapeutic trend towards both more aggressive and minimally invasive surgery. Despite these advances, hgPNECs as a distinct clinical entity remains largely unexplored among surgeons. This review of current development in pathology reporting and surgical treatment of hgPNECs aims at increasing the awareness of an evolving field in pancreatic surgery.

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What Is the Place of PARP Inhibitors in Ovarian Cancer Treatment?

Abstract

Poly-ADP-ribose polymerase (PARP) inhibitors have been one of the most exciting developments in the treatment of ovarian cancer in recent years. Demonstration of anti-cancer activity has led to the European Medicines Agency (EMA) approval of the PARP inhibitor (PARPi) olaparib as maintenance therapy in women with BRCA-mutated (BRCAm) ovarian cancer with platinum-sensitive recurrence following response to platinum therapy and the US Food and Drug Administration (US FDA) approval of olaparib in relapsed germline BRCA-mutated (gBRCAm) ovarian cancer in women who have received at least three prior chemotherapy treatments, both occurring in 2014. Additional trials are underway or awaiting final analysis with olaparib, other PARPis, and PARPi combinations to further elucidate the activity of these drugs in various clinical settings. This review will focus on the current clinical experience and ongoing trials with PARPis in ovarian cancer.

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Improving Systemic Chemotherapy for Bladder Cancer

Abstract

Systemic chemotherapy is integral to the management of muscle-invasive and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy has been increasingly utilized for muscle-invasive BCa over the past several years, and several options for cisplatin-based regimens have emerged. Adjuvant chemotherapy may be considered for select patients who did not receive neoadjuvant therapy. Systemic chemotherapy added to radiotherapy is a critical component of a bladder-preserving approach and superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa for more than three decades. Novel targeted agents are in development fueled by the recent molecular characterization of BCa. Recent trials of immunotherapy have demonstrated the possibility of a less toxic and potentially more effective treatment for metastatic disease. It is an extremely exciting time for BCa research, and much needed improvements in systemic treatment are most certainly on the horizon.

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Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma

Abstract

Observational studies indicate a similar or higher probability of disease control, higher risk of non-relapse mortality (NRM), and similar overall survival (OS) with allogeneic stem cell transplantation (alloSCT), compared to autologous SCT, in relapsed or refractory non-Hodgkin lymphoma. Careful patient selection and utilization of reduced intensity conditioning (RIC) alloSCT may allow reduction in NRM. The optimal conditioning regimen and the roles of radioimmunotherapy, T cell depletion, and tandem SCT continue to be explored. Recent studies highlight comparable results with haploidentical SCT and cord blood SCT, thus providing alternate donor sources. Disease relapse and late effects continue to be major problems. Optimization of SCT techniques (e.g., improved graft-versus-host disease prophylaxis), post-transplant monitoring of minimal residual disease, and post-transplant maintenance, or pre-emptive therapy (e.g., with novel therapies) are emerging strategies to reduce the risk of relapse. Survivorship management using a multidisciplinary care approach, adoption of healthy lifestyle, and socioeconomic counseling are integral parts of a high-quality transplant program.

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Management of Patients with MYC-Altered Lymphomas

Abstract

Patients diagnosed with non-Burkitt high-grade B cell non-Hodgkin lymphomas demonstrating rearrangement in MYC, an oncogene promoting cellular proliferation, frequently do not achieve long-term disease-free survival due to a suboptimal response to standard front-line and salvage therapies. Double-hit lymphomas, harboring rearrangements in MYC as well as BCL2 and/or BCL6, appear to carry a particularly poor prognosis, although patients with this disease appear to achieve better survival outcomes when treated with intensified chemotherapy. Increased expression of MYC protein by immunohistochemistry as well as increased copy number or amplification of MYC may also be adverse pathologic features of non-Burkitt high-grade B cell non-Hodgkin lymphomas, although the benefit of treating these patients with intensified as opposed to standard dose chemotherapy remains unclear. Recognition and proper management of patients with MYC-altered lymphomas is crucial to improving patient outcomes.

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Correlation between EGFR gene mutation, cytologic tumor markers, 18F-FDG uptake in non-small cell lung cancer

Abstract

Background

EGFR mutation-induced cell proliferation causes changes in tumor biology and tumor metabolism, which may reflect tumor marker concentration and 18F-FDG uptake on PET/CT. Direct aspirates of primary lung tumors contain different concentrations of tumor markers than serum tumor markers, and may correlate better with EGFR mutation than serum tumor markers.

The purpose of this study is to investigate an association between cytologic tumor markers and FDG uptake with EGFR mutation status in non-small cell lung cancer (NSCLC).

Methods

We prospectively collected tumor aspirates of 61 patients who underwent EGFR mutation analysis. Serum and cytologic CYFRA 21-1, CEA, and SCCA levels were measured and correlated with EGFR gene mutations. FDG PET/CT was performed on 58 patients for NSCLC staging, and SUV was correlated with EGFR mutation status.

Results

Thirty (50 %) patients had EGFR mutation and 57 patients had adenocarcinoma subtype. Univariate analysis showed that female gender, never smoker, high levels of cytologic CYFRA 21-1 (c-CYFRA) and lower maximum standard uptake value (SUVmax) were correlated with EGFR mutations. ROC generated cut-off values of 20.8 ng/ml for c-CYFRA and SUVmax of 9.6 showed highest sensitivity for EGFR mutation detection. Multivariate analysis revealed that female gender [hazard ratio (HR): 18.15, p = 0.025], higher levels of c-CYFRA (HR: 7.58, and lower SUVmax (HR: 0.08, p = 0.005) were predictive of harboring EGFR mutation.

Conclusions

The cytologic tumor marker c-CYFRA was positively associated with EGFR mutations in NSCLC. EGFR mutation-positive NSCLCs have relatively lower glycolysis compared with NSCLCs without EGFR mutation.

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Nephrotoxicity of cisplatin combination chemotherapy in thoracic malignancy patients with CKD risk factors

Abstract

Background

Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI.

Methods

We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25 % from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level.

Results

Eighty of the 84 patients (95.2 %) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4 %). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95 % confidence intervals [CI] 1.21–29.87 and 1.11–11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95 % CI 1.11–326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI.

Conclusions

We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.

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Elevated ratio of MMP2/MMP9 activity is associated with poor response to chemotherapy in osteosarcoma

Abstract

Background

Matrix metalloproteinases (MMPs) are crucially involved in the regulation of multiple stages of cancer progression. Elevated MMP levels have been associated with the development of metastases and poor prognosis in several types of cancer. However, the role of MMPs in osteosarcoma and their prognostic value is still unclear. Available data are conflicting, most likely due to different technical approaches. We hypothesized that in contrast to total mRNA or protein levels frequently analyzed in previous studies the enzymatic activities of MMPs and their inhibitors the tissue inhibitors of matrix metalloproteinases (TIMPs) are closer related to their biological functions. We therefore aimed to evaluate the reliability of different zymography techniques for the quantification of MMP and TIMP activities in osteosarcoma biopsies in order to investigate their distribution, possible regulation and prognostic value.

Methods

All analyses were done using cryo-conserved osteosarcoma pretreatment biopsies (n = 18). Gene and protein expression of MMPs and TIMPs were analyzed by RT-qPCR and western blot analysis, respectively. Overall MMP activity was analyzed by in situ zymography, individual MMP activities were analyzed by gelatin zymography. Reverse zymography was used to detect and quantify TIMP activities.

Results

Strong overall MMP activities could be detected in osteosarcoma pretreatment biopsies with MMP2 and MMP9 as predominant active MMPs. In contrast to total RNA or protein expression MMP2 and MMP9 activities showed significant quantitative differences between good and poor responders. While MMP9 activity was high in the good responder group and significantly decreased in the poor responder group, MMP2 activity showed a reverse distribution. Likewise, significant differences were detected concerning the activity of TIMPs resulting in a negative correlation of TIMP1 activity with MMP2 activity (p = 0.044) and negative correlations of TIMP2 and TIMP3 with MMP9 activity (p = 0.007 and p = 0.006).

Conclusion

In contrast to mRNA or protein levels MMP and TIMP activities showed significant differences between the analyzed good and poor responder groups. A shift from MMP9 to predominant MMP2 activity is associated with poor response to chemotherapy suggesting that the ratio of MMP2/MMP9 activity might be a valuable and easily accessible marker to predict the response to chemotherapy in osteosarcoma.

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Tumor-derived factors modulating dendritic cell function

Abstract

Dendritic cells (DC) play unique and diverse roles in the tumor occurrence, development, progression and response to therapy. First of all, DC can actively uptake tumor-associated antigens, process them and present antigenic peptides to T cells inducing and maintaining tumor-specific T cell responses. DC interaction with different immune effector cells may also support innate antitumor immunity, as well as humoral responses also known to inhibit tumor development in certain cases. On the other hand, DC are recruited to the tumor site by specific tumor-derived and stroma-derived factors, which may also impair DC maturation, differentiation and function, thus resulting in the deficient formation of antitumor immune response or development of DC-mediated tolerance and immune suppression. Identification of DC-stimulating and DC-suppressing/polarizing factors in the tumor environment and the mechanism of DC modulation are important for designing effective DC-based vaccines and for recovery of immunodeficient resident DC responsible for maintenance of clinically relevant antitumor immunity in patients with cancer. DC-targeting tumor-derived factors and their effects on resident and administered DC in the tumor milieu are described and discussed in this review.

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Autophagy and Apoptosis Play Opposing Roles in Overall Survival of Esophageal Squamous Cell Carcinoma

Abstract

Esophageal cancer is among the most aggressive gastrointestinal tract malignancies, and squamous cell carcinoma is the most common subtype. Although both autophagy and apoptosis involve programmed cell death, autophagy also maintains cell survival by recycling cellular waste. The relationship between autophagy and apoptosis in esophageal squamous cell carcinoma (ESCC) is unclear. Autophagic and apoptotic markers of ESCC were detected by immunohistochemical staining (IHC) in 43 ESCC patients treated during 2007–2011. Chi-square test and Kaplan-Meier method were used to determine how clinicopathological parameters were related to IHC results for LC3B, Beclin-1 and caspase-3 (CASP-3). Correlations among Beclin-1, LC3B, and CASP-3 were analyzed by Spearman rho. The statistical analyses revealed no clinicopathological parameters that significantly correlated with expressions of Beclin-1, LC3B, and CASP-3. However, low CASP-3 expression and high LC3B expression revealed by IHC were predictors of a poor prognosis. Additionally, LC3B expression had a significant negative correlation with CASP-3 expression. Autophagy is antagonistic to apoptosis and predicts poor overall survival in ESCC.

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A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers

Abstract

Purpose

This study compared the pharmacokinetics of PF-06439535, a potential bevacizumab biosimilar, to bevacizumab sourced from the European Union (bevacizumab-EU) and USA (bevacizumab-US), and of bevacizumab-EU to bevacizumab-US.

Methods

In this double-blind study, 102 healthy males, aged 21–55 years, were randomized 1:1:1 to receive a single 5 mg/kg intravenous dose of PF-06439535, bevacizumab-EU, or bevacizumab-US. Pharmacokinetic assessments were conducted for 71 days, with additional safety and immunogenicity assessments until day 100. Pharmacokinetic similarity was achieved if 90 % confidence intervals (CIs) for the test-to-reference ratios of the maximum serum concentration (C _max), area under the serum concentration–time curve from zero to infinity (AUC_0–∞), and from zero to time of last quantifiable concentration (AUC_0–t ) were within the 80.00–125.00 % bioequivalence acceptance window.

Results

The three study drugs exhibited similar pharmacokinetic properties. For the comparisons of PF-06439535 to bevacizumab-EU or bevacizumab-US, and of bevacizumab-EU to bevacizumab-US, the 90 % CIs for the ratios of C _max, AUC_0–t , and AUC_0–∞ were all within 80.00–125.00 %. Two, one, and two subjects treated with PF-06439535, bevacizumab-EU, and bevacizumab-US, respectively, tested positive for antidrug antibodies, none of whom tested positive for neutralizing antibodies. Treatment-related adverse events were reported in 15.2, 25.7, and 18.2 % of subjects in the PF-06439535, bevacizumab-EU, and bevacizumab-US treatment arms, respectively.

Conclusions

This study demonstrated the pharmacokinetic similarity of PF-06439535 to both bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. The safety profile (including immunogenicity) was similar in the three treatment groups, with no significant safety findings reported.

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A phase I pharmacokinetics study comparing PF-06439535 (a potential biosimilar) with bevacizumab in healthy male volunteers

Abstract

Purpose

This study compared the pharmacokinetics of PF-06439535, a potential bevacizumab biosimilar, to bevacizumab sourced from the European Union (bevacizumab-EU) and USA (bevacizumab-US), and of bevacizumab-EU to bevacizumab-US.

Methods

In this double-blind study, 102 healthy males, aged 21–55 years, were randomized 1:1:1 to receive a single 5 mg/kg intravenous dose of PF-06439535, bevacizumab-EU, or bevacizumab-US. Pharmacokinetic assessments were conducted for 71 days, with additional safety and immunogenicity assessments until day 100. Pharmacokinetic similarity was achieved if 90 % confidence intervals (CIs) for the test-to-reference ratios of the maximum serum concentration (C _max), area under the serum concentration–time curve from zero to infinity (AUC_0–∞), and from zero to time of last quantifiable concentration (AUC_0–t ) were within the 80.00–125.00 % bioequivalence acceptance window.

Results

The three study drugs exhibited similar pharmacokinetic properties. For the comparisons of PF-06439535 to bevacizumab-EU or bevacizumab-US, and of bevacizumab-EU to bevacizumab-US, the 90 % CIs for the ratios of C _max, AUC_0–t , and AUC_0–∞ were all within 80.00–125.00 %. Two, one, and two subjects treated with PF-06439535, bevacizumab-EU, and bevacizumab-US, respectively, tested positive for antidrug antibodies, none of whom tested positive for neutralizing antibodies. Treatment-related adverse events were reported in 15.2, 25.7, and 18.2 % of subjects in the PF-06439535, bevacizumab-EU, and bevacizumab-US treatment arms, respectively.

Conclusions

This study demonstrated the pharmacokinetic similarity of PF-06439535 to both bevacizumab-EU and bevacizumab-US, and of bevacizumab-EU to bevacizumab-US. The safety profile (including immunogenicity) was similar in the three treatment groups, with no significant safety findings reported.

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Results of a phase II study of vorinostat in combination with intravenous fludarabine, mitoxantrone, and dexamethasone in patients with relapsed or refractory mantle cell lymphoma: an interim analysis

Abstract

Purpose

Mantle cell lymphoma (MCL) is a disease that frequently relapses and primarily affects elderly people. We performed an open-label, multi-center, phase II study to investigate the effect and quality of life (QoL) of treatment with vorinostat in combination with fludarabine, mitoxantrone and dexamethasone (V-FND) for relapsed or refractory MCL.

Methods

The treatment schedule was composed of four cycles of induction treatment with V-FND and subsequent consolidation therapy involving autologous hematopoietic stem cell transplantation or six cycles of vorinostat maintenance. QoL was assessed using EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) every 2 cycles.

Results

Data from a total of 20 patients were collected for an interim analysis. The median age was 67 years (range 49–75), and 14 or the patients (70 %) were male. The full course of V-FND induction treatment was completed in 11 patients, but only three completed all six cycles of maintenance therapy. Response to V-FND was not available in two patients. Among the other 18 patients, the objective response rate was 77.8 % (complete response in five patients + partial response in nine patients). Median progression-free survival was 9.3 months [95 % confidence interval (CI) 4.0–12.3]. Fifteen patients (75 %) experienced grade 3/4 toxicities. Analysis of QoL demonstrated significant deterioration of social functioning (p = 0.01), and significant aggravation of fatigue and nausea/vomiting (p = 0.04 and 0.01, respectively) after two cycles of V-FND induction.

Conclusions

V-FND is effective in patients with relapsed or refractory MCL. However, significant toxicities were hurdles to sustained V-FND therapy.

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Food of animal origin and risk of non-Hodgkin lymphoma and multiple myeloma: A review of the literature and meta-analysis

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Saverio Caini, Giovanna Masala, Patrizia Gnagnarella, Ilaria Ermini, William Russell-Edu, Domenico Palli, Sara Gandini
BackgroundSeveral studies investigated whether the consumption of foods of animal origin affects the risk of haematological malignancies, with conflicting results. To help clarify this issue, we performed a meta-analysis of observational studies published until November 2014 that investigated the association between the consumption of foods of animal origin (red, processed and white meat, fish and seafood, dairy products and eggs) and the risk of non-Hodgkin lymphoma and its major subtypes and multiple myeloma among adults.MethodsWe calculated summary relative risks (SRR) and 95% confidence intervals (95% CI) by using random effect models with maximum likelihood estimation.ResultsOverall, 16,525 non-Hodgkin lymphoma and 3665 multiple myeloma cases from thirty-three independent studies were included. We found an association between consumption of red meat and the risk of non-Hodgkin lymphoma (SRR 1.22, 95% CI 1.03–1.44, I²=35%). The consumption of fish and seafood was inversely associated with the risk of multiple myeloma (SRR 0.71, 95% CI 0.51–1.00, I²=82%), although the between-studies heterogeneity was high. Finally, the consumption of dairy products was positively associated, with borderline significance, with the risk of non-Hodgkin lymphoma (SRR 1.26, 95% CI 0.99–1.60, I²=49%).ConclusionsFoods of animal origin likely play a role in the aetiology of non-Hodgkin lymphoma and multiple myeloma, with red meat and dairy tending to increase the risk, and fish that tends to decrease it. Our findings reinforce the recommendations to reduce the consumption of red meat by replacing it with vegetables, legumes and fish.



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Is the cardiovascular toxicity of NSAIDS and COX-2 selective inhibitors underestimated in patients with haemophilia?

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Ana Boban, Catherine Lambert, Cedric Hermans
Joint pain secondary to chronic arthropathy represents one of the most common and debilitating complications of haemophilia, often requiring analgesic care. When compared with nonselective non-steroidal anti-inflammatory drugs (ns-NSAIDs), selective COX-2 inhibitors (coxibs) offer the major advantage of not increasing the bleeding risk, thus being a better choice of analgesics for haemophilia patients. However, several studies have highlighted the cardiovascular risks posed by coxibs and NSAIDs. Given the assumed protection against thrombosis conferred by the deficiency in coagulation factors VIII or IX, these precautions regarding the use of coxibs and NSAIDs have never really been taken into account in haemophilia management. However, contrary to what has long been suspected, haemophilia patients are indeed affected by the same cardiovascular risk factors as nonhaemophiliac patients. Further studies should be conducted to evaluate the impact of NSAIDs on cardiovascular risks and the prevalence of hypertension in haemophilia patients.



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The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Samaher Besbes, Marc Pocard, Massoud Mirshahi, Christian Billard
Small-molecule BH3 mimetics are designed to mimic the BH3 domain of BH3-only BCL-2 family members which are antagonists of the prosurvival members (such as BCL-2, BCL-XL and MCL-1). The BH3 mimetics are intended to bind with high affinity to prosurvival proteins, in order to inhibit their functional activity and hence to induce apoptosis in cancer cells. Both navitoclax (BCL-2/BCL-XL antagonist) and ABT-199/venetoclax (BCL-2-selective inhibitor) have demonstrated therapeutic efficacy especially in chronic lymphocytic leukemia (CLL). However, these BH3 mimetics cannot antagonize the prosurvival protein MCL-1 that is overexpressed and involved in therapeutic resistance in CLL. Furthermore, until now, none of the reported small-molecule MCL-1 inhibitors bound to their target with high affinity. The first MCL-1-selective BH3 mimetics capable of high-affinity binding and inducing apoptosis in cancer cells through an on-target mechanism have just been identified. This discovery should advance the translational research to implement novel drugs in treating CLL.



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Editorial Board

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100





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Endocrine therapy in post-menopausal women with metastatic breast cancer: From literature and guidelines to clinical practice

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Valentina Sini, Saverio Cinieri, Pierfranco Conte, Michelino De Laurentiis, Angelo Di Leo, Carlo Tondini, Paolo Marchetti
Current international guidelines recommend endocrine therapy as the initial treatment of choice in hormone receptor positive advanced breast cancer. Endocrine therapy has been a mainstay of hormone responsive breast cancer treatment for more than a century. To date it is based on different approaches,such as blocking the estrogen receptor through selective receptor estrogen modulators, depleting extragonadal peripheral estrogen synthesis by aromatase inhibitors or inducing estrogen receptor degradation using selective down-regulators.Despite estrogen and/or progesterone receptor positive status, up to a quarter of patients could be either primarily resistant to hormone therapies or will develop hormone resistance during the course of their disease. Different mechanisms, either intrinsic or acquired, could be implicated in endocrine resistance.In the present work available endocrine therapies and their appropriate sequences have been reviewed, and the most promising strategies to overcome endocrine resistance have been highlighted.



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PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Sara Gandini, Daniela Massi, Mario Mandalà
BackgroundDespite the success of immunotherapy directed at inhibiting of programmed death-1 (PD-1)/PD-ligand (L)1 signaling, it is not established whether PD-L1 expression correlates with the clinical response and outcome in different tumors. The present meta-analysis investigates whether the PD-L1 status, detected by immunohistochemistry, is associated with clinical response and mortality in patients treated with anti-PD-1/PD-L1 therapy.MethodsA systematic literature search and quantitative analysis were planned, conducted and reported following CONSORT and QUORUM checklists, up to December 2015, to identify clinical trials with information on cancer outcome by PD-L1 immunohistochemical expression in tumor tissues. We used random effects models to estimate Summary Objective Response Rates (SORRs) and Summary Odd Ratio (SOR) for the comparison of PD-L1 positive and negative patients.ResultsWe summarized 20 trials carried out in metastatic melanoma (MM), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) patients receiving anti-PD-1/PD-L1 antibodies (4230 MM, 1417 NSCLC and 312 RCC patients). Positive PD-L1 MM patients showed a significant decrease (53%) in the risk of mortality vs. negative cases with no heterogeneity. Furthermore, SORRs were 45% and 27% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference in term of responses: 2.14 (95% CI: 1.65, 2.77), with low between-study heterogeneity (I²=35%). Furthermore, results from randomized clinical trials on MM showed that PD-L1 expression is significantly associated with greater clinical response rates to anti-PD1 treatments (SOR 1.89; 95%CI: 1.35, 2.64) but not to other treatments (SOR 0.96; 95%CI: 0.5, 1.87).In non-squamous NSCLC SORRs were 29% and 11% in PD-L1 positive and negative patients, respectively, and SOR indicates a significant difference between responses: 3.78 (1.54, 9.24), with no between-study heterogeneity. Squamous NSCLC and RCC did not show any significant difference in response according to the PD-L1 status.ConclusionPD-L1 expression is significantly associated with mortality and clinical response to anti-PD-1/PD-L1 antibodies in MM patients and with clinical response in patients with non-squamous NSCLC.



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Second-line angiogenesis inhibition in metastatic colorectal cancer patients: Straightforward or overcrowded?

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Riccardo Giampieri, Marta Caporale, Filippo Pietrantonio, Filippo De Braud, Francesca V. Negri, Francesco Giuliani, Valeria Pusceddu, Laura Demurtas, Angelo Restivo, Caterina Fontanella, Giuseppe Aprile, Stefano Cascinu, Mario Scartozzi
Although the number of therapeutic options targeting tumour angiogenesis is becoming increasingly relevant, the question of the optimal choice for second-line anti-angiogenic inhibition in combination with chemotherapy for metastatic colorectal cancer patients remains largely unanswered.In fact the lack of head to head comparison between consolidated options such as bevacizumab and new treatment alternatives such as aflibercept and ramucirumab makes the selection in the clinical practice challenging, particularly when the patient has already received an anti-angiogenic-based combination up-front.In the following pages we described the biological scenario validating second-line angiogenesis inhibition in colorectal cancer along with potential mechanism of resistance. We also critically described the available evidence recommending the use of the bevacizumab, aflibercept and ramucirumab in this setting with the final aim to guide the choice in the clinical practice.



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The role and mechanism of autophagy in sorafenib targeted cancer therapy

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Yi Heqing, Long Bin, Ye Xuemei, Li Linfa
Targeting kinase inhibitors (TKIs) are effective tools for treating advanced cancer. However, acquired resistance represents a roadblock in the use of TKIs, such as sorafenib, for cancer therapy. Understanding the acquisition of resistance to sorafenib will help doctors to cope with acquired resistance to TKIs in general and to develop personalized medicine strategies for cancer patients. Autophagy is a biological process that occurs in normal organisms. However, it is also a component of multiple disease processes, including cancer development and progression. However, the roles of autophagy in cancer and in response to cancer therapy are controversial. In this review, we summarize the progress in autophagy and sorafenib resistance research, which is representative of acquired resistance to targeted cancer therapy.



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Translating gastric cancer genomics into targeted therapies

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Yvonne L.E. Ang, Wei Peng Yong, Patrick Tan
Gastric cancer is a common disease with limited treatment options and a poor prognosis. Many gastric cancers harbour potentially actionable targets, including over-expression and mutations in tyrosine kinase pathways. Agents have been developed against these targets with varying success- in particular, the use of trastuzumab in HER2-overexpressing gastric cancers has resulted in overall survival benefits. Gastric cancers also have high levels of somatic mutations, making them candidates for immunotherapy; early work in this field has been promising. Recent advances in whole genome and multi-platform sequencing have driven the development of molecular classification systems, which may in turn guide the selection of patients for targeted treatment. Moving forward, challenges will include the development of appropriate biomarkers to predict responses to targeted therapy, and the application of new molecular classifications into trial development and clinical practice.



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Mucositis in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus statements.

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Vitaliana De Sanctis, Paolo Bossi, Giuseppe Sanguineti, Fabio Trippa, Daris Ferrari, Almalina Bacigalupo, Carla Ida Ripamonti, Michela Buglione, Stefano Pergolizzi, Johannes A. Langendjik, Barbara Murphy, Judith Raber-Durlacher, Elvio G. Russi, Rajesh V. Lalla
BackgroundOral mucositis (OM) due to radiotherapy and systemic therapies in head and neck cancer treatment represents a major problem causing a wide spectrum of clinical signs and symptoms. This adverse event may reduce quality of life, resulting from debilitating oral pain, bleeding, dysphagia, infections, impairment of food intake, high rate of hospitalization and may interfere with the delivery of programmed treatment plans, ultimately jeopardizing patient outcome. Globally, there is a lack of evidence on effective measures for the prevention and treatment of OM, and only scant uniform conclusions and recommendations can be derived from the existing literature and guidelines. A multidisciplinary team of Italian head and neck cancer experts met in Milan 17–18 February 2013 with the aim of reaching consensus on prophylaxis and management of mucositis. The results of the literature review and the statements that achieved consensus are reported and discussed in this paper.Material and methodsThe Delphi Appropriateness Method was used as a structured communication method for achieving consensus. Subsequently, external expert reviewers evaluated the conclusions carefully according to their area of expertise.ResultsThis paper presents 13 clusters of statements on prophylaxis and treatment of mucositis that achieved consensus.ConclusionsOM represents a very stressfull situation for head and neck cancer patients submitted to chemo-radiation or exclusive radiation treatment. A multidisciplinary approach is mandatory, but there is still no gold-standard protocol that is prominently better than others.



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Diagnosis and management of typical and atypical lung carcinoids

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Sara Pusceddu, Giuseppe Lo Russo, Marianna Macerelli, Claudia Proto, Milena Vitali, Diego Signorelli, Monica Ganzinelli, Paolo Scanagatta, Leonardo Duranti, Annalisa Trama, Roberto Buzzoni, Giuseppe Pelosi, Ugo Pastorino, Filippo de Braud, Marina Chiara Garassino
An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1–5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids.



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Significance and therapeutic implications of endothelial progenitor cells in angiogenic-mediated tumour metastasis

Publication date: April 2016
Source:Critical Reviews in Oncology/Hematology, Volume 100
Author(s): Valentina Flamini, Wen G. Jiang, Jane Lane, Yu-Xin Cui
Cancer conveys profound social and economic consequences throughout the world. Metastasis is responsible for approximately 90% of cancer-associated mortality and, when it occurs, cancer becomes almost incurable. During metastatic dissemination, cancer cells pass through a series of complex steps including the establishment of tumour-associated angiogenesis. The human endothelial progenitor cells (hEPCs) are a cell population derived from the bone marrow which are required for endothelial tubulogenesis and neovascularization. They also express abundant inflammatory cytokines and paracrine angiogenic factors. Clinically hEPCs are highly correlated with relapse, disease progression, metastasis and treatment response in malignancies such as breast cancer, ovarian cancer and non-small-cell lung carcinoma. It has become evident that the hEPCs are involved in the angiogenesis-required progression and metastasis of tumours. However, it is not clear in what way the signalling pathways, controlling the normal cellular function of human BM-derived EPCs, are hijacked by aggressive tumour cells to facilitate tumour metastasis. In addition, the actual roles of hEPCs in tumour angiogenesis-mediated metastasis are not well characterised. In this paper we reviewed the clinical relevance of the hEPCs with cancer diagnosis, progression and prognosis. We further summarised the effects of tumour microenvironment on the hEPCs and underlying mechanisms. We also hypothesized the roles of altered hEPCs in tumour angiogenesis and metastasis. We hope this review may enhance our understanding of the interaction between hEPCs and tumour cells thus aiding the development of cellular-targeted anti-tumour therapies.



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A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of hepatocellular carcinoma

Abstract

Purposes

Microvascular invasion (mVI) is known to be a risk factor of hepatocellular carcinoma (HCC) recurrence. Several factors such as the tumor grade, tumor size, tumor margin status on imaging studies, fluorine-18 fluorodeoxyglucose-positron emission tomography (¹⁸F-FDG-PET) results, and tumor markers have been proposed to predict mVI of HCC. However, the values of these factors have not yet been validated.

Methods

Among the patients evaluated using enhanced CT/MRI, ¹⁸F-FDG-PET, and tumor markers prior to hepatectomy from 2007 to 2012, 79 HCC patients without apparent macrovascular invasion in preoperative imaging were enrolled in this study. The image tumor margin status (smooth/non-smooth), ¹⁸F-FDG-PET, and tumor markers, which were previously described as predictors for mVI, were evaluated.

Results

Fifteen patients had mVI (mVI+ group) and 64 patients had no evidence of mVI (mVI− group) on pathological examinations. A univariate analysis showed that the mVI+ group had a higher SUV and TNR (5.2 vs 3.8, p = 0.02 and 1.8 vs 1.3, p = 0.02, respectively) and a higher portion of non-smooth tumor margin (87 vs 27 %, p = 0.0001). There was no significant difference in the tumor markers. A multivariate analysis showed that non-smooth tumor margin alone could independently predict mVI (odds ratio 18.3, 95 % CI 3.27–102.6, p = 0.0009).

Conclusion

A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of HCC.

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Role of Histological Criteria and Immunohistochemical Markers in Predicting Risk of Malignancy in Parathyroid Neoplasms

Abstract

Parathyroid carcinoma (PC) is a rare neoplasm accounting for 0.5–6 % of primary hyperparathyroidism. Histological criteria are currently considered as established means to diagnose malignancy in parathyroid neoplasms; however, it does not accurately predict the risk of aggressive behaviour of PC. Immunohistochemical (IHC) markers have been used in the literature with variable results. This work was planned to study whether IHC markers would have any added advantage over histology in predicting outcome in parathyroid neoplasms. Two hundred twenty-seven parathyroid neoplasms were reviewed according to older and revised histological criteria. IHC was performed for parafibromin, APC, galectin-3, PGP9.5 and Ki67. Diagnostic categories were correlated with clinical, biochemical, histological features and IHC markers. Chi-square test was used to analyse categorical variables. Review of histology by earlier and revised criteria showed a change in diagnosis of five cases of atypical adenoma (15.1 %), all of which were diagnosed as carcinoma according to earlier criteria. Change in diagnosis did not affect behaviour of disease as none of the cases showed recurrence or metastasis on follow-up. Combination of PF, Gal-3 and PGP9.5 showed 50 % sensitivity, 97.9 % specificity and 95.4 % predictive accuracy for PC. Histological criteria still remains the most established method for predicting risk of malignancy in parathyroid neoplasms irrespective of whether old or revised criteria are used. Combination of positive (Gal-3, PGP9.5) and negative (PF) IHC markers may be used as an adjunct to histology in histological, atypical and malignant parathyroid neoplasms to obviate the need for repeated follow-up.

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Incidence and risk factors for morbidity and mortality in elderly head and neck cancer patients undergoing major oncological surgery

Abstract

Purpose

Cancer incidence in the elderly population has been continuously rising, and their treatment is an increasing concern among oncologists. This study aimed to evaluate the incidence and risk factors for morbidity and mortality after major oncological surgery in elderly patients with head and neck squamous cell carcinoma (HNSCC).

Methods

The 196 HNSCC patients aged 55 and older who underwent major curative surgery. Patients were categorized into three groups: far-old (≥75 years; n = 41); old (65–74 years; n = 72); or middle-aged (55–64 years; n = 83). The rates of early and late postoperative complications, hospital stays, and mortality were compared among groups. Univariate and multivariate analyses were performed to identify the factors associated with early postoperative complications.

Results

No study patients had mortality during surgery or within 3-month postoperation. Karnofsky performance status, frail functional status, comorbidity, and index cancer and noncancer mortality were the poorest in the far-old group. The far-old group demonstrated significantly higher rates of early overall complications, readmission within 1 month, and recurrence rates (P < 0.05 each). Multivariate analysis showed that age, postoperative hemoglobin, and C-reactive protein are independent predictors of early postoperative complications (P < 0.05 each).

Conclusions

In elderly patients, chronological age affects the increased risk of early postoperative morbidity and later mortality following major HNSCC surgery. In combination with these risk factors, older patients who are diagnosed with HNSCC should be carefully monitored in order to determine the potential occurrence of postsurgical complications.

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[History of immunotherapy. Paradigm change?]

[History of immunotherapy. Paradigm change?]

Bull Cancer. 2016 Mar 11;

Authors: Fridman WH

Abstract
Born at the dawn of the 20th century with W.B. Coley's intratumoral injections of bacteria, cancer immunotherapy was built on the corpus of the immune surveillance theory in 1957, modified by R.D. Schreiber in 2004. Scientific knowledge and technological advances have allowed it to become efficacious and to expand in the 21st century as the 4th and most important pillar of cancer treatment.

PMID: 26976507 [PubMed - as supplied by publisher]

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Association de radiothérapie et d’hormonothérapie dans la prise en charge des cancers localisés de la prostate : où en est-on ?

Publication date: Available online 15 March 2016
Source:Cancer/Radiothérapie
Author(s): S. Bellefqih, K. Hadadi, I. Mezouri, A. Maghous, E. Marnouche, K. Andaloussi, M. Elmarjany, H. Sifat, H. Mansouri, N. Benjaafar




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Comparison of passive-beam proton therapy, helical tomotherapy and 3D conformal radiation therapy in Hodgkin's lymphoma female patients receiving involved-field or involved site radiation therapy

Publication date: Available online 15 March 2016
Source:Cancer/Radiothérapie
Author(s): S. Horn, N. Fournier-Bidoz, V. Pernin, D. Peurien, M. Vaillant, R. Dendale, A. Fourquet, Y.M. Kirova
PurposeSecond cancers and cardiovascular toxicities are long term radiation toxicity in locally advanced Hodgkin's lymphomas. In this study, we evaluate the potential reduction of dose to normal tissue with helical tomotherapy and proton therapy for Hodgkin's lymphoma involved-field or involved-site irradiation compared to standard 3D conformal radiation therapy.Patients and methodsFourteen female patients with supradiaphragmatic Hodgkin's lymphoma were treated at our institution with 3D conformal radiation therapy or helical tomotherapy to a dose of 30Gy in 15 fractions. A planning comparison was achieved including proton therapy with anterior/posterior passive scattered beams weighted 20Gy/10Gy.ResultsMean doses to breasts, lung tissue and heart with proton therapy were significantly lower compared to helical tomotherapy and to 3D conformal radiation therapy. Helical tomotherapy assured the best protection of lungs from doses above 15Gy with the V20Gy equal to 16.4%, compared to 19.7% for proton therapy (P=0.01) or 22.4% with 3D conformal radiation therapy (P<0.01). Volumes of lung receiving doses below 15Gy were significantly larger for helical tomotherapy than for proton therapy or 3D conformal radiation therapy, with respective lung doses V10Gy=37.2%, 24.6% and 27.4%. Also, in the domain of low doses, the volumes of breast that received more than 10Gy or more than 4Gy with helical tomotherapy were double the corresponding volumes for proton therapy, with V4Gy representing more than a third of one breast volume with helical tomotherapy.ConclusionsHelical tomotherapy achieved a better protection to the lungs for doses above 15Gy than passive proton therapy or 3D conformal radiation therapy. However, dose distributions could generally be improved by using protons even with our current passive-beam technology, especially allowing less low dose spreading and better breast tissue sparing, which is an important factor to consider when treating Hodgkin's lymphomas in female patients. Prospective clinical study is needed to evaluate the tolerance and confirm these findings.



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Feasibility of a 12-month-exercise intervention during and after radiation and chemotherapy in cancer patients: impact on quality of life, peak oxygen consumption, and body composition

Abstract

Background

Accumulating evidence suggests that exercise is effective in treating many of the acute and chronic side effects of anti-cancer therapy. A recent meta-analysis supported the use of exercise to prevent or treat fatigue and lymphoedema and to improve functional status in breast cancer patients.

Patients and methods

This trial was intended as a controlled, prospective feasibility study evaluating the impact of physical exercise (PE) in cancer patients during and after treatment with radio- and chemotherapy. Inclusion criteria were previous or ongoing treatment for cancer, motivation for PE of 0.5-1hour duration at least twice weekly for at least 3 months. Continuation of PE was encouraged thereafter. Every three months the following endpoints were assessed: Peak oxygen consumption as measured by supervised cardiopulmonary exercise test, body composition and quality of life.

Results

A total of 45 patients were included with a median age of 49 years. Forty were female and five male. Cancer types were: Breast cancer (n = 30/67 %), gastrointestinal cancer (n = 5/12 %), other types (n = 10/22 %). Thirty-eight (84 %) of the patients were included during curative treatment of their disease. Seven (16 %) were considered palliative. Adherence to the PE-programme longer than 6 months was noted for 41/45 (91 %) of the patients. Intensity of PE was thrice weekly in 32/45 (71 %), twice weekly in 11/45 (24 %). Two of 45 patients (5 %) had no PE. Mean peak oxygen consumption increased from 18.8 ± 5.6 ml/min/kg to 20.5 ± 3 ml/min/kg and 19.9 ± 4.7 ml/min/kg at 3 months (p = 0.005) and 12 months (p = 0.003), respectively.

Median fat mass decreased from 30.7 ± 15 kg to 28.9 ± 15 kg and 29.5 ± 13 kg at 3 months (p = 0.001) and 12 months (p = 0.017), respectively. Global health status scores increased from a median baseline value of 54.9 ± 16.3 to 66.4 ± 14 % and 68.0 ± 20.3 % at 3 months (p = 0.001) and 12 months (p = 0.002), respectively.

Conclusion

This exercise programme in cancer patients with 2–3 weekly supervised sessions over three months was well feasible and demonstrated measurable improvement of oxygen consumption, body composition and quality of life. In addition, a 90 %-adherence rate to the PE-programme beyond 6 months was encouraging. Further randomized prospective data in a larger patient population will be collected comparing the impact of two versus four months supervision.

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[ 18 F]FDG-PET/CT metabolic parameters as useful prognostic factors in cervical cancer patients treated with chemo-radiotherapy

Abstract

Background

To compare the prognostic value of different anatomical and functional metabolic parameters determined using [¹⁸F]FDG-PET/CT with other clinical and pathological prognostic parameters in cervical cancer (CC).

Methods

Thirty-eight patients treated with standard curative doses of chemo-radiotherapy (CRT) underwent pre- and post-therapy [¹⁸F]FDG-PET/CT. [¹⁸F]FDG-PET/CT parameters including mean tumor standardized uptake values (SUV), metabolic tumor volume (MTV) and tumor glycolytic volume (TGV) were measured before the start of CRT. The post-treatment tumor metabolic response was evaluated. These parameters were compared to other clinical prognostic factors. Survival curves were estimated by using the Kaplan-Meier method. Cox regression analysis was performed to determine the independent contribution of each prognostic factor.

Results

After 37 months of median follow-up (range, 12–106), overall survival (OS) was 71 % [95 % confidence interval (CI), 54–88], disease-free survival (DFS) 61 % [95 % CI, 44–78] and loco-regional control (LRC) 76 % [95 % CI, 62–90]. In univariate analyses the [¹⁸F]FDG-PET/CT parameters unfavorably influencing OS, DFS and LRC were pre-treatment TGV-cutoff ≥562 (37 vs. 76 %, p = 0.01; 33 vs. 70 %, p = 0.002; and 55 vs. 83 %, p = 0.005, respectively), mean pre-treatment tumor SUV cutoff ≥5 (57 vs. 86 %, p = 0.03; 36 vs. 88 %, p = 0.004; 65 vs. 88 %, p = 0.04, respectively) and a partial tumor metabolic response after treatment (9 vs. 29 %, p = 0.0008; 0 vs. 83 %, p < 0.0001; 22 vs. 96 %, p < 0.0001, respectively). After multivariate analyses a partial tumor metabolic response after treatment remained as an independent prognostic factor unfavorably influencing DFS and LRC (RR 1:7.7, p < 0.0001, and RR 1:22.6, p = 0.0003, respectively) while the pre-treatment TGV-cutoff ≥562 negatively influenced OS and DFS (RR 1:2, p = 0.03, and RR 1:2.75, p = 0.05).

Conclusions

Parameters capturing the pre-treatment glycolytic volume and metabolic activity of [¹⁸F]FDG–positive disease provide important prognostic information in patients with CC treated with CRT. The post-therapy [¹⁸F]FDG-PET/CT uptake (partial tumor metabolic response) is predictive of disease outcome.

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Cancers, Vol. 8, Pages 37: Proteomics Analysis Reveals Novel RASSF2 Interaction Partners

RASSF2 is a tumor suppressor that shares homology with other Ras-association domain (RASSF) family members. It is a powerful pro-apoptotic K-Ras effector that is frequently inactivated in many human tumors. The exact mechanism by which RASSF2 functions is not clearly defined, but it likely acts as a scaffolding protein, modulating the activity of other pro-apoptotic effectors, thereby regulating and integrating tumor suppressor pathways. However, only a limited number of RASSF2 interacting partners have been identified to date. We used a proteomics based approach to identify additional RASSF2 interactions, and thereby gain a better insight into the mechanism of action of RASSF2. We identified several proteins, including C1QBP, Vimentin, Protein phosphatase 1G and Ribonuclease inhibitor that function in diverse biological processes, including protein post-translational modifications, epithelial-mesenchymal transition, cell migration and redox homeostasis, which have not previously been reported to interact with RASSF2. We independently validated two of these novel interactions, C1QBP and Vimentin and found that the interaction with C1QBP was enhanced by K-Ras whereas, interestingly, the Vimentin interaction was reduced by K-Ras. Additionally, RASSF2/K-Ras regulated the acetylation of Vimentin. Our data thus reveal novel mechanisms by which RASSF2 may exert its functions, several of which may be Ras-regulated.

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Lysine residues K66, K109, and K110 in the bovine foamy virus transactivator protein are required for transactivation and viral replication

Abstract

Bovine foamy virus (BFV) is a complex retrovirus that infects cattle. Like all retroviruses, BFV encodes a transactivator Tas protein (BTas) that increases gene transcription from viral promoters. BFV encodes two promoters that can interact with BTas, a conserved promoter in the 5' long terminal repeat (LTR) and a unique internal promoter (IP). Our previous study showed that BTas is acetylated by p300 at residues K66, K109, and K110, which markedly enhanced the ability of BTas to bind to DNA. However, whether these residues are important for BFV replication was not determined. Therefore, in this study we provide direct evidence that BTas is required for BFV replication and demonstrate that residues K66, K109, and K110 are critical for BTas function and BFV replication. Full-length infectious clones were generated, which were BTas deficient or contained lysine to arginine (K→R) mutations at position 66, 109, and/or 110. In vivo data indicated that K→R mutations at positions 66, 109, and 110 in BTas impaired transactivation of both the LTR and IP promoters. In addition, the K→R mutations in full-length infectious clones reduced expression of viral proteins, and the triple mutant and BTas deletion completely abrogated viral replication. Taken together, these results indicate that lysine residues at positions 66, 109, and 110 in the BTas protein are crucial for BFV replication and suggest a potential role for BTas acetylation in regulating the viral life cycle.

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Recombinant Newcastle disease virus expressing African swine fever virus protein 72 is safe and immunogenic in mice

Abstract

African swine fever (ASF) is a lethal hemorrhagic disease that affects wild and domestic swine. The etiological agent of ASF is African swine fever virus (ASFV). Since the first case was described in Kenya in 1921, the disease has spread to many other countries. No commercial vaccines are available to prevent ASF. In this study, we generated a recombinant Newcastle disease virus (rNDV) expressing ASFV protein 72 (p72) by reverse genetics and evaluated its humoral and cellular immunogenicity in a mouse model. The recombinant virus, rNDV/p72, replicated well in embryonated chicken eggs and was safe to use in chicks and mice. The p72 gene in rNDV/p72 was stably maintained through ten passages. Mice immunized with rNDV/p72 developed high titers of ASFV p72 specific IgG antibody, and had higher levels of IgG1 than IgG2a. Immunization also elicited T-cell proliferation and secretion of IFN-γ and IL-4. Taken together, these results indicate that rNDV expressing ASFV p72 might be a potential vaccine candidate for preventing ASF.

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Self-sampling in cervical cancer screening: comparison of a brush-based and a lavage-based cervicovaginal self-sampling device

Abstract

Background

High coverage and attendance is essential for cervical cancer screening success. We investigated whether the previous positive experiences on increasing screening attendance by self-sampling in Finland are sampler device dependent.

Methods

All women identified to cervical cancer screening in 2013 in 28 Finnish municipalities were randomised to receive a lavage- (n = 6030) or a brush type of self-sampling device (n = 6045) in case of non-attendance after two invitation letters. Seven hundred seventy non-attending women in the lavage device group and 734 in the brush group received the self-sampling offer. Women's experiences were enquired with an enclosed questionnaire.

Results

Total attendance in the lavage group increased from 71.0 to 77.7 % by reminder letters and further to 80.5 % by self-sampling. Respective increase in the brush group was from 72.2 to 78.6 % and then to 81.5 %. The participation by self-sampling was 21.7 % (95 % CI 18.8–24.6) in the lavage group and 23.8 % (95 % CI 20.8–26.9) in the brush group. Women's self-sampling experiences were mainly positive and the sampler devices were equally well accepted by the women.

Conclusion

Our study shows that the lavage device and brush device perform similarly in terms of uptake by non-attending women and user comfort. If self-sampling is integrated to the routine screening program in Finland, either of the devices can be chosen without the fear of losing participants due to a less acceptable device.

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Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

Abstract

Background

Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin.

Methods

Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects.

Results

We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model.

Conclusion

Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy.

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Is Wilms’ tumor gene 1 a useful biomarker for detecting minimal residual disease in chronic myeloid leukemia (BCR-ABL1-p210-positive) patients?

Abstract

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the presence of Philadelphia (Ph) chromosome. Wilms' tumor gene 1 (WT1) plays an important role in leukemogenesis and can be useful as a molecular marker to detect minimal residual disease (MRD). The goal of this study was to evaluate WT1 expression and compare it with BCR-ABL1 expression in peripheral blood (PB) of CML patients, in order to explore the utility of WT1 as an alternative marker for MRD detection. Eighteen newly diagnosed CML patients (BCR-ABL1-p210-positive), 16 chronic CML patients with a history of imatinib therapy, and 18 normal individuals (BCR-ABL1-p210-negative) as controls were enrolled in this study. WT1 and BCR-ABL1 expression was evaluated by quantitative real-time polymerase chain reaction (Q-RT-PCR). Analysis of RT-PCR data was performed using REST Software (2009, QIAGEN, Valencia, USA). Data were analyzed by SPSS software (v.16.0) using Spearman's rho and Kruskal-Wallis methods. WT1 expression in all PB samples of newly diagnosed CML patients was significantly higher than that of the normal individuals (P = 0.003). WT1 expression was not different in patients on imatinib therapy compared to normal individuals (P = 0.6), but it was significantly lower than that of the newly diagnosed CML patients (P = 0.001). There was no significant correlation between expression of WT1 and BCR-ABL1 and hematological findings in newly diagnosed CML patients. We confirm the oncogenic role of WT1 by WT1 upregulation in CML. Due to lack of significant correlation between BCR-ABL1 and WT1 expression, using WT1 as an additional marker for CML monitoring could not be applicable.

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Open-Mouth Bone Scintigraphy Is Better than Closed-Mouth Bone Scintigraphy in the Diagnosis of Temporomandibular Osteoarthritis

Abstract

Purpose

Closed-mouth bone scintigraphy (CM scan) and closed-mouth single-photon emission computed tomography (CM SPECT) are used for conventional evaluation of osteoarthritis of the temporomandibular joint (TMJ). However, the adequacy of open-mouth bone scintigraphy (OM scan) has not yet been evaluated. Therefore, the purpose of this study was to compare the diagnostic performance of CM scan, CM SPECT, and OM scan.

Methods

Thirty-six patients with suspicion of an abnormality of the TMJ and who underwent a ^99mTc-HDP CM scan, CM SPECT, and an OM scan were enrolled. The scans were assessed visually for the presence of positive focal uptake in the TMJ. Osteoarthritis was defined as arthralgia plus crepitus or radiologic signs of arthrosis.

Results

Of 72 TMJs, 21 (29.2 %) were diagnosed with osteoarthritis. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 90.5 %, 49.0 %, 42.2 %, 92.6 % and 61.1 % for the CM scan, 81.0 %, 58.8 %, 44.7 %, 88.2 % and 65.3 % for CM SPECT, and 81.0 %, 82.4 %, 65.4 %, 91.3 % and 81.9 % for the OM scan, respectively. The accuracy of the OM scan was higher than that of CM SPECT and the CM scans (p = 0.004 and p < 0.001, respectively).

Conclusions

The OM scan was more accurate than the conventional CM scan and even CM SPECT for diagnosing TMJ osteoarthritis.

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