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Recent Critical Reviews in Oncology/Hematology Articles
The role of epigenetics in the regulation of apoptosis in myelodysplastic syndromes and acute myeloid leukemia
April 2014
Heidrun Karlic | Harald Herrmann | Franz Varga | Roman Thaler | Rene Reitermaier | Silvia Spitzer | Viviane Ghanim | Katharina Blatt | Wolfgang R. Sperr | Peter Valent | Michael Pfeilstöcker
Abstract: Disordered stem cell epigenetics and apoptosis-regulating mechanisms contribute essentially to the pathogenesis of myelodysplastic syndromes (MDS) and may trigger disease-progression to secondary acute myeloid leukemia (AML).Expression of apoptosis-mediators FAS (CD95) and DAPK1 the latter being also known for its association with autophagy are upregulated in neoplastic cells in patients with low-risk MDS and epigenetically silenced and downregulated in high-risk MDS and AML as confirmed by a study 50 MDS and 30 AMLs complementing this review. 5-Azacytidine (AZA) and 5-aza-2′deoxycytidine (DAC), promoted FAS and DAPK1 gene demethylation and their (re)expression as well as apoptosis in leukemic cell lines (HL-60, KG1) which can be reversed by siRNA against FAS. Thus, promoter-demethylation of FAS and DAPK1 represents a critical mechanism of drug-induced apoptosis in neoplastic cells in MDS and AML which underscores the clinical implication of epigenetically active therapies.
Tumor burden in Hodgkin's lymphoma: Much more than the best prognostic factor
April 2014
Paolo G. Gobbi
Abstract: The intense immunological crosstalk between the rare neoplastic cells and the prevalent reactive ones is responsible for the development of signs and symptoms of Hodgkin's lymphoma. It is likely the reason for the superior predictivity constantly demonstrated by the tumor burden, as the final expression of the whole cytological disorder.Moreover, the tumor burden is related to the probability of response and its 1-year stability, showing different relationships according to the treatment administered. The relative risk of early treatment failure can be predicted on the basis of the tumor burden at diagnosis and the therapy chosen.Tumor burden is measured from the diagnostic whole body computed tomography (CT) scan, but can also be indirectly calculated from some staging parameters when the CT-aided assessment cannot be performed.Preliminary promising results have been obtained with a semi-automatic positron emission tomography/CT scan measuring metabolically active volumes, instead of whole visible masses.
Salvage therapy of small volume prostate cancer nodal failures: A review of the literature
April 2014
Berardino De Bari | Filippo Alongi | Michela Buglione | Franco Campostrini | Alberto Briganti | Genoveffa Berardi | Giuseppe Petralia | Massimo Bellomi | Arturo Chiti | Andrei Fodor | Nazareno Suardi | Cesare Cozzarini | Di Muzio Nadia | Marta Scorsetti | Roberto Orecchia | Francesco Montorsi | Filippo Bertoni | Stefano Maria Magrini | Barbara Alicja Jereczek-Fossa
Abstract: New imaging modalities may be useful to identify prostate cancer patients with small volume, limited nodal relapse ("oligo-recurrent") potentially amenable to local treatments (radiotherapy, surgery) with the aim of long-term control of the disease, even in a condition traditionally considered prognostically unfavorable. This report reviews the new diagnostic tools and the main published data about the role of surgery and radiation therapy in this particular subgroup of patients.
Metastatic castration resistant prostate cancer: Current strategies of management in the Middle East
April 2014
Shouki Bazarbashi | Marwan Bachour | Muhammad Bulbul | Mohammed Alotaibi | Mohamed Jaloudi | Hassan Jaafar | Deborah Mukherji | Naim Farah | Tahseen Alrubai | Ali Shamseddine
Abstract: Although most patients with prostate cancer respond to initial androgen-deprivation therapy, progression to castration-resistant prostate cancer (CRPC) is almost inevitable. In 2004, the docetaxel/prednisone regimen was approved for the management of patients with metastatic CRPC, becoming the standard first-line therapy. Recent advances have also led to an unprecedented number of approved new drugs; thus, providing several treatment options for patients with metastatic CRPC. Five new drugs have received US Food and Drug Administration-approval between 2010 and 2012: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; enzalutamide, a novel androgen receptor inhibitor; and denosumab, a bone-targeting agent. Such drugs are either already marketed or about to be marketed in the Middle East. Data supporting the approval of each of these agents are described in this review, as are recent approaches to the treatment of metastatic CRPC.
A critical appraisal of systemic treatment options for metastatic non-clear cell renal cell carcinoma
April 2014
Salima Ismail | Malek Meskawi | Jens Hansen | Marco Bianchi | Zhe Tian | Mathieu Latour | Markus Graefen | Francesco Montorsi | Quoc-Dien Trinh | Paul Perrotte | Pierre I. Karakiewicz | Maxine Sun
Abstract: Current guidelines provide most support for the use of temsirolimus in first line therapy for metastatic non-clear cell renal cell carcinoma (nccRCC). However, this recommendation is based on scant level 2a evidence. The objective of this review is to examine the evidence supporting first line temsirolimus use in patients with metastatic nccRCC as well as alternative first line treatment options. Six studies, that assessed the efficacy of five agents qualified for inclusion. Among recognized treatment options for metastatic nccRCC, mean weighted progression free survival values of 7.9 months for temsirolimus vs. 7.3 for sunitinib vs. 8.5 months for sorafenib vs. ≈4.1 months for erlotinib were recorded based on data from 10, 74, 33 and 51 patients respectively. In conclusion, the data supporting first line temsirolimus for metastatic nccRCC are based on a small patient sample. Sunitinib's efficacy is similar to that of temsirolimus but is based on a bigger patient sample that originates from phase II studies.
Chemoradiation and brachytherapy in extrahepatic bile duct carcinoma
April 2014
Gian Carlo Mattiucci | Rosa Autorino | Giuseppe Roberto D'Agostino | Francesco Deodato | Gabriella Macchia | Vincenzo Perri | Andrea Tringali | Alessio Giuseppe Morganti | Massimiliano Mutignani | Vincenzo Valentini
Abstract: BackgroundTo explore the role of radiotherapy in the extrahepatic bile duct carcinoma, and to understand if and when radiotherapy could be effective for this group of patients.MethodsA systematic review of recently published literature was completed. Recent studies using radiotherapy with survival data, resection rates and quality of life data have been analyzed.ResultsThere are no randomized trials regarding the treatment of extrahepatic cholangiocarcinoma. The bulk of available studies suggest that in some cases radio-chemotherapy can be used as adjuvant therapy. Radiotherapy could also have a role in unresectable cholangiocarcinoma: external radiotherapy or intraluminal brachytherapy – alone or in combination – could improve the outcome in selected patients.Finally, radiotherapy, and in particular intraluminal brachytherapy, could be used as a palliative treatment to improve the quality of life and in controlling symptoms.ConclusionThe role of radiotherapy in extrahepatic cholangiocarcinoma remains undefined due to the lack of randomized trials or otherwise properly controlled studies.
Targeted therapy for advanced esophagogastric adenocarcinoma
April 2014
S. Kordes | A. Cats | S.L. Meijer | H.W.M. van Laarhoven
Abstract: BackgroundEsophagogastric adenocarcinoma (EGC) is a molecular heterogeneous disease, and therefore, strategies with targeted therapy may be effective.AimThis review will discuss phase III studies in advanced EGC concerning biologic agents targeting molecular pathways, such as EGFR, HER2, VEGFR, mTOR and c-MET.ResultsHER2 inhibition with trastuzumab in combination with first line chemotherapy results in a significant survival benefit for HER2 positive carcinoma patients. Chemotherapy in combination with bevacizumab does not prolong survival in an unselected EGC patient cohort. Preliminary results of trials with EGFR, VEGFR and mTOR inhibitors are, thus far, disappointing in unselected patient cohorts. Promising studies in biomarker selected cohorts with HER2, EGFR and c-MET inhibitors are ongoing.ConclusionTargeted therapy in EGC is emerging. Improved insight in the biologic background of EGC is needed to improve patient selection, combine agents and discover new targets and agents. This may improve outcome for metastasized EGC patients.
The detection and role of lymphatic and blood vessel invasion in predicting survival in patients with node negative operable primary colorectal cancer
April 2014
Hester C. van Wyk | Campbell S. Roxburgh | Paul G. Horgan | Alan F. Foulis | Donald C. McMillan
Abstract: Although vascular invasion in colorectal cancer has been recognised since 1938, detection methods and results remain inconsistent. Vascular invasion is currently an independent prognostic factor in colorectal cancer influencing disease progression and survival. The vascular system consists of three components, arterial, venous and lymphatic vessels, all of which can be invaded but accurate distinction between the components remains difficult with routine staining techniques. Even though higher detection rates with elastica staining, for large vessel invasion, and recent techniques for immunohistochemistry for small vessel invasion, have been reported, a standardised method of detection has not been agreed upon which is reflected in the variability of published results. As a result of the Bowel Cancer Screening Programme in the UK it will be necessary to attempt to identify and stratify patients better, to be able to handle the stage migration to early node negative colorectal cancer. At present up to a third of patients, with node-negative colorectal cancer on conventional histopathological analysis, ultimately die of recurrent disease. It is therefore important to develop and standardised methods to identify lymphatic and blood vessel invasion which will influence ultimate survival. The present review summarises the current status of detection methods for these components of vascular invasion.
The research of nanoparticles as gene vector for tumor gene therapy
March 2014
Nian-feng Sun | Zhan-ao Liu | Wen-bai Huang | Ai-ling Tian | San-yuan Hu
Abstract: With the development of molecular biology, the application of the gene therapy becomes a tendency in the development of oncotherapy. The gene therapy has been acknowledged as the major progress of modern medicine, also a focus in the oncotherapy research. Commonly vectors of the gene therapy mainly include two categories, namely, viral vectors and nonviral vectors. Nanoparticles gene vector of various different kinds of materials, which belong to non-viral carriers. It presents excellent abilities of adsorption, concentration and protection of DNA, which can be attributed as a main reason of the adsorption and operation of nano-gene vector on exogenous genes. In this article, we mainly reviewed the recent studies of the characteristics of nanoparticles, characteristics and transport mechanism of nanoparticles as gene vector, the progress on nanoparticles as gene vector in tumor gene therapy. Nano-gene vectors, as new drug and gene carriers, present characteristics such as the controlled-release, targeting, and the improvement of bioavailability. Nanoparticles for cancer imaging and therapy have evolved rapidly during the last decade and it is expected that more and more will become clinical practise. In the near future, as a new nanometer gene delivery vector will be in medical research and treatment play a bigger role.
Targeting ALK in patients with advanced Non Small Cell Lung Cancer: Biology, diagnostic and therapeutic options
March 2014
Chiara Lazzari | Gianluca Spitaleri | Chiara Catania | Massimo Barberis | Cristina Noberasco | Mariacarmela Santarpia | Angelo Delmonte | Francesca Toffalorio | Fabio Conforti | Tommaso Martino De Pas
Abstract: The discovery of EML4-ALK fusion gene in a subgroup of patients with lung adenocarcinoma led to the development of a new class of agents, the ALK inhibitors, and dramatically improved the clinical outcome of these patients. The striking results from clinical trials with crizotinib, the first ALK inhibitor evaluated, allowed the accelerated approval of crizotinib from the USA Food and Drug Administration (FDA). Despite the high initial results, patients acquire resistance to crizotinib, and different next generation ALK kinase inhibitors have been developed. In the current review, we will analyze the biology of EML4-ALK gene, the acquired resistance mechanisms to crizotinib, the therapeutic strategies, currently under evaluation, designed to overcome crizotinib resistance, and the open issues that need to be addressed in order to improve outcome in ALK+ Non Small Cell Lung Cancer (NSCLC) patients.
Molecular biology of testicular germ cell tumors: Unique features awaiting clinical application
March 2014
Ludmila Boublikova | Tomas Buchler | Jan Stary | Jitka Abrahamova | Jan Trka
Abstract: Testicular germ cell tumors (TGCTs) are the most common solid tumors in young adult men characterized by distinct biologic features and clinical behavior. Both genetic predispositions and environmental factors probably play a substantial role in their etiology. TGTCs arise from a malignant transformation of primordial germ cells in a process that starts prenatally, is often associated with a certain degree of gonadal dysgenesis, and involves the acquirement of several specific aberrations, including activation of SCF–CKIT, amplification of 12p with up-regulation of stem cell genes, and subsequent genetic and epigenetic alterations. Their embryonic and germ origin determines the unique sensitivity of TGCTs to platinum-based chemotherapy. Contrary to the vast majority of other malignancies, no molecular prognostic/predictive factors nor targeted therapy is available for patients with these tumors. This review summarizes the principal molecular characteristics of TGCTs that could represent a potential basis for development of novel diagnostic and treatment approaches.
GOAL: An inverse toxicity-related algorithm for daily clinical practice decision making in advanced kidney cancer
March 2014
Sergio Bracarda | Michele Sisani | Francesca Marrocolo | Alketa Hamzaj | Sabrina del Buono | Valeria De Simone
Abstract: Metastatic renal cell carcinoma (mRCC), considered almost an orphan disease only six years ago, appears today a very dynamic pathology. The recently switch to the actual overcrowded scenario defined by seven active drugs has driven physicians to an incertitude status, due to difficulties in defining the best possible treatment strategy. This situation is mainly related to the absence of predictive biomarkers for any available or new therapy. Such issue, associated with the nearly absence of published face-to-face studies, draws a complex picture frame. In order to solve this dilemma, decisional algorithms tailored on drug efficacy data and patient profile are recognized as very useful tools. These approaches try to select the best therapy suitable for every patient profile. On the contrary, the present review has the "goal" to suggest a reverse approach: basing on the pivotal studies, post-marketing surveillance reports and our experience, we defined the polarizing toxicity (the most frequent toxicity in the light of clinical experience) for every single therapy, creating a new algorithm able to identify the patient profile, mainly comorbidities, unquestionably unsuitable for each single agent presently available for either the first- or the second-line therapy. The GOAL inverse decision-making algorithm, proposed at the end of this review, allows to select the best therapy for mRCC by reducing the risk of limiting toxicities.
Risk of gastrointestinal perforation in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A systematic review and meta-analysis
March 2014
Wei-Xiang Qi | Yuan-Jue Sun | Li-Na Tang | Zan Shen | Yang Yao
Abstract: sBackgroundThe use of vascular-endothelial growth factor (VEGF) antibody bevacizumab is associated with an increased risk of gastrointestinal (GI) perforation, but the incidence and risk of GI perforation associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has not been well described. We conduct a systematic review and meta-analysis of published trials to evaluate the overall incidence and risk of GI perforation associated with VEGFR-TKIs.MethodsDatabases from PubMed, Web of Science and abstracts presented at ASCO meeting up to March 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating VEGFR-TKIs in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.ResultsA total of 5352 patients with a variety of solid tumors from 20 clinical trials were included in our analysis. The incidence of GI perforation was 1.3% (95%CI: 0.8–2.0%) among patients receiving VEGFR-TKIs, with a mortality of 28.6% (15.0–47.6%). Patients treated with VEGFR-TKIs did not significantly increase the risk of GI perforation compared with patients treated with control medication, with an OR of 2.99 (95%CI: 0.85–10.53, p=0.089). Sub-group analysis showed that the incidence of GI perforation did not significantly vary with tumor types, VEGFR-TKIs and treatments regimens. No evidence of publication bias was observed.ConclusionsThe use of VEGFR-TKIs dose not significantly increase the risk of GI perforation in comparison with the controls. Further studies are recommended to investigate this association and the risk differences among different tumor types, VEGFR-TKIs or treatment regimens.
Circulating tumor cells in Hodgkin's lymphoma—A review of the spread of HL tumor cells or their putative precursors by lymphatic and hematogenous means, and their prognostic significance
March 2014
Rajendra Gharbaran | Jongwhan Park | Chris Kim | A. Goy | K. Stephen Suh
Abstract: About 15% of patients diagnosed with classical Hodgkin's lymphoma (cHL) are considered high risk with unfavorable prognosis. The biology of the disease bears a direct relationship to its clinical course. However, some aspects of the disease are still being debated. Related topics include origin of neoplastic cells as circulating precursor versus germinal center B cell, and disease metastasis via hematogenous routes and the effect of HL circulation on relapse potential and further spread of the disease. The terminally differentiated giant neoplastic Hodgkin Reed–Sternberg (HRS) cells (HRSC) have limited proliferation and lack mobility. Therefore, they are unable to penetrate epithelium. Thus, the clinical aggressiveness of HRSCs that disseminate via both lymphatic and hematogenous may be determined by their molecular composition. This review discusses in detail the historical perspectives on scientific and clinical evidences of precursors of circulating HL cells and the prognostic importance of these circulating cells for predicting outcome.
Anti-angiogenic therapy in pediatric brain tumors: An effective strategy?
March 2014
Mariska Sie | Wilfred F.A. den Dunnen | Eelco W. Hoving | Eveline S.J.M. de Bont
Abstract: Brain tumors are still the leading cause of cancer morbidity and mortality among children, despite different therapeutic options including neurosurgery, chemotherapy and radiation. As angiogenesis is highly crucial in brain tumor growth and progression, numerous clinical trials evaluating diverse anti-angiogenic agents have been described. In the present review, we aimed to answer the question if anti-angiogenic therapy is an effective strategy in the treatment of children with brain tumors. Although some encouraging results have been published of anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF)/VEGF receptor signaling or epidermal growth factor receptor (EGFR), still more insight is warranted to be highly conclusive about the efficacy of anti-angiogenic therapy with currently potential upcoming anti-angiogenic agents in pediatric brain tumors. However, given the need for new therapeutic strategies, multi targeted therapy with anti-angiogenic agents anticipating on possible tumor escape mechanisms could be effective in the future treatment of pediatric brain tumors.
Translational evidence on the role of Src kinase and activated Src kinase in invasive breast cancer
March 2014
Beatrix Elsberger
Abstract: Src kinase is a member of a non-receptor tyrosine kinase family. It has been implicated as a regulator of cell proliferation and survival and plays a complex role in cell adhesion and motility. In vitro evidence for a role for Src in breast cancer is compelling. However, only a few translational clinical studies have been undertaken in this field. This review summarises translational evidence on expression and activation of Src kinase in breast cancer patient cohorts exploring clinical significance and the possibility of identifying key biomarkers. There is strengthened translational proof for a definitive role of Src in breast cancer. Nevertheless, there remains a need to find a robust biomarker to identify patients responsive to Src inhibitors for clinical trials.
Role of BAFF/BAFF-R axis in B-cell non-Hodgkin lymphoma
Available online 23 February 2014
Shu Yang | Jian-Yong Li | Wei Xu
Abstract: B-cell activating factor (BAFF), as a member of the tumor necrosis factor (TNF) ligand family, plays important roles in B-cell homeostasis, tolerance, and malignancy. BAFF binds to three receptors of TNF, TACI, BCMA and BAFF-receptor (BAFF-R). In particular, the BAFF/BAFF-R pathway is crucial to the survival and growth of mature normal and malignant B-cells. BAFF is displayed on the cell surface or is released in a soluble form after cleavage from the plasma membrane. BAFF-R as the main BAFF receptor is expressed mainly on B-cells. Aberrant BAFF expression was found in malignant B-cells from B-cell non-Hodgkin lymphoma (B-NHL) patients, which protects these cells from spontaneous or drug-induced apoptosis and stimulated NF-κB activation via autocrine and/or paracrine pathways. However, the mechanisms involved in the gene expression and regulation of BAFF or BAFF-R has not been elucidated. More importantly, the design of reagents able to counteract BAFF/BAFF-R pathways may be of therapeutic value for B-NHL. Results of ongoing clinical trials with BAFF or BAFF-R antagonists are eagerly awaited.
A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? on behalf of the REFCOR (French rare head and neck cancer network)
Available online 16 February 2014
Thomas Cerda | Xu Shan Sun | Vignot Stéphane | Pierre-Yves Marcy | Bertrand Baujat | Anne-Catherine Baglin | Ali Mohamed Ali | Sylvie Testelin | Emile Reyt | Francois Janot | Juliette Thariat
Abstract: BackgroundSalivary gland carcinomas constitute a heterogeneous group of tumors, with over 20 histological subtypes of various prognoses. The mainstay of treatment is surgery, with radiotherapy advocated for unresectable disease or postoperatively in case of poor prognostic factors such as high grade, locally advanced and/or incompletely resected tumors. Concurrent chemotherapy is sometimes advocated in routine practice based on criteria extrapolated from squamous cell carcinomas of the head and neck, on radioresistance of salivary gland tumors and on results obtained in the metastatic setting. The aim of this review was to identify situations where chemotherapy is advocated.Material and methodsA search of literature was performed with the following key words: parotid, salivary gland, neoplasm, cancer, malignant tumor, chemoradiation, chemotherapy, radiotherapy, treatment. Case report and studies published before 2000 were not included.Resultsplatinum-based regimens were the most frequent. Other regimens were reported and seemed dependent on histology. The level of evidence for the concurrent delivery of chemotherapy with radiation therapy is supported by a low level of evidence. Prescribing chemotherapy mostly relies on por prognostic factors similar to those used to indicate high dose radiotherapy. Protocols vary with histology.ConclusionThe rationale for adding chemotherapy to radiotherapy remains to be demonstrated prospectively. Although the type of systemic treatments used may be adapted on histology, the strongest rationale remains in favor of cisplatin.
Taxanes in the management of metastatic castration-resistant prostate cancer: Efficacy and management of toxicity
Available online 15 February 2014
Fabio A. Schutz | Antonio C. Buzaid | Oliver Sartor
Abstract: Androgen deprivation is the therapy of choice in the majority of patients with metastatic prostate cancer. However, a state of castration resistance ultimately occurs after hormone therapy, thus defining metastatic castration-resistant prostate cancer (mCRPC). mCRPC has historically been considered a relatively chemoresistant tumor. However, due to its ability to improve survival and the quality of life in comparison with mitoxantrone, docetaxel has been established as the standard chemotherapeutic agent for first-line therapy since 2004. Moreover, recent results have shown that the novel taxane cabazitaxel is able to prolong the overall survival of patients with mCRPC previously treated with docetaxel. Even though these taxanes display a favorable toxicity profile, their routine use in clinical practice requires knowledge about the most frequent and distinct adverse events that may result from their administration.
Anti-angiogenic therapy, a new player in the field of sarcoma treatment
Available online 15 February 2014
Yvonne M.H. Versleijen-Jonkers | Myrella Vlenterie | Addy C.M. van de Luijtgaarden | Winette T.A. van der Graaf
Abstract: Sarcomas encompass a heterogeneous family of mesenchymal malignancies. In metastatic disease improvement in outcome has been limited and there is a clear need for the development of new therapies. One potential target is angiogenesis, already an accepted target for treatment of more prevalent cancers. Multiple (pre)clinical studies focused on the role of angiogenesis and anti-angiogenic treatment in sarcomas. However, getting significant results is complicated due to the relatively small number of patients and the broad range of sarcoma subtypes. Recently, pazopanib has been approved for the treatment of advanced soft tissue sarcoma patients, which is an important step forward and paves the way for the introduction of anti-angiogenic treatment in sarcomas. However, more studies are needed to understand the biological mechanisms by which patients respond to angiogenic inhibitors and to detect markers of response. This review covers the knowledge that has been gained on the role of angiogenesis and anti-angiogenic therapy in sarcomas.
Impact of prednisone on toxicities and survival in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis of randomized clinical trials
Available online 2 February 2014
Charity J. Morgan | William K. Oh | Gurudatta Naik | Matthew D. Galsky | Guru Sonpavde
Abstract: We conducted a meta-analysis of randomized trials comparing regimens that included daily oral prednisone (P) in only one arm to investigate its impact on toxicities and outcomes in metastatic castration-resistant prostate cancer (mCRPC). Five trials were identified totaling 2939 patients, of whom 1471 were randomized to an arm not containing P and 1468 received therapy containing P. There was no difference between the non-P and P groups for severe toxicities (incidence rate ratio [IRR]=0.82, p=0.712, I2=97.9%). When examining toxicities as a reason for discontinuing therapy, the non-P groups were not different from the P groups (relative risk [RR]=1.24, p=0.413, I2=86.8%). The non-P groups demonstrated no difference in OS compared to the P groups (HR=1.09, p=0.531, I2=79.7%). The meta-analysis is limited by the trial level design and small number of trials.
Clinical management of older persons with haemophilia
February 2014
C. Hermans | P. de Moerloose | G. Dolan
Abstract: Life expectancy for people with haemophilia (PWH) has improved and is now approaching that of the general population. The growing population of elderly PWH will therefore increasingly face the age-related morbidities such as cardiovascular diseases, malignant disease, liver disease, and bone and joint related diseases, as well as the lifestyle and psychosocial factors that accompany many of these conditions. For many PWH, frequent contact with haemophilia specialists within the comprehensive care centres supplants the relationship that individuals in the general population have with their general practitioners. As a result, there is a risk that elderly PWH may miss the chronic disease screening opportunities offered to the general population. This review focuses on the screening tests and examinations recommended for age-related comorbidities in the general population that may be applicable to the growing population of older people with haemophilia.
Sensitivity and resistance to treatment in the primary management of epithelial ovarian cancer
February 2014
Pierre-Emmanuel Colombo | Michel Fabbro | Charles Theillet | Frédéric Bibeau | Philippe Rouanet | Isabelle Ray-Coquard
Abstract: Ovarian carcinoma is the most lethal gynaecologic malignancy. Despite wide initial sensibility to chemotherapy especially to platinum-based regimens, the vast majority of patients with advanced stages of the disease develop recurrences and subsequent resistance to treatments. Ovarian cancer is actually considered as a heterogeneous disease at the clinical, histological and molecular level. In this review, the mechanisms of intrinsic sensitivity or resistance to treatment, especially to platinum-based chemotherapy are considered with particular reference to the significance of tumour heterogeneity. The molecular features involved in acquired resistance are reviewed and the current hypotheses are discussed. In particular, potential disruptions of the DNA reparation pathways are highlighted.
Methods of overcoming treatment resistance in colorectal cancer
February 2014
Sally Temraz | Deborah Mukherji | Raafat Alameddine | Ali Shamseddine
Abstract: Metastatic colorectal cancer remains a lethal disease with a poor prognosis in the majority of patients. Multiple drug combinations have been developed in recent years that have significantly improved response rates and overall survival however resistance to these drugs is inevitable. Novel agents are currently being developed and participation in clinical trials should be encouraged. In the absence of other treatment options in a patient with good performance status, there is compelling evidence for re-challenging with previously administered agents in different combinations. The aim of this review is to discuss mechanisms of resistance and methods to overcome treatment resistance in patients with metastatic colorectal cancer who are refractory to 5-FU, irinotecan, oxaliplatin, cetuximab and bevacizumab therapy.
The role of lymphatic and blood vessel invasion in predicting survival and methods of detection in patients with primary operable breast cancer
February 2014
Fadia J.A. Gujam | James J. Going | Joanne Edwards | Zahra M.A. Mohammed | Donald C. McMillan
Abstract: Lymphovascular invasion (LBVI) has long been recognized as an essential step of metastases in patients with cancer. However, the process of invasion into lymphatic and blood vessels is still not well defined in breast cancer. To examine the evidence for LBVI, lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) in predicting survival in patients with primary operable breast cancer, and to evaluate the detection methods of vessel invasion. A systematic review of data published from 1964 to 2012 was undertaken according to a pre-defined protocol. There is robust evidence that general LBVI and LVI are independent prognostic factors of poorer survival. The prognostic role of BVI remains unclear. Most studies detected LBVI using H&E stained sections. The overall weighted average of the LBVI rate using immunostaining was higher (35%) than H&E (24%). The LBVI rate using H&E was variable (9–50%) and less variable using immunostaining (32–41%). The overall weighted average of the LVI rate was similar using H&E and immunostaining (33% vs. 25%). The LVI rate using H&E was variable (10–49%) and less variable using immunostaining (21–42%). The overall weighted average of the BVI rate was similar using H&E and/or classical staining and immunostaining (16% vs. 10%). The BVI rates using H&E and/or classical staining approach (4–46%) and immunostaining (1–29%) were both variable. The LBVI and LVI are powerful prognostic factors in primary operable breast cancer. However, BVI was rarely specifically examined and its role in predicting survival is not clear. Further work is required using reliable specific staining to establish the routine use of LVI and BVI in the prediction of outcome in patients with primary operable breast cancer.
Dasatinib, large granular lymphocytosis, and pleural effusion: Useful or adverse effect?
February 2014
Semra Paydas
Abstract: Dasatinib is a second generation tyrosine kinase inhibitor approved for clinical use in first line and imatinib-resistant chronic myeloid leukemia and Philadelphia positive (Ph+) acute lymphoblastic leukemia. In addition to BCR-ABL1, dasatinib inhibits TEC kinases and SRC family kinases and is more potent than imatinib in the treatment of Ph+ leukemias. In the last 3 years, increases in cytotoxic T and natural-killer cells in peripheral blood samples have been reported in cases treated by dasatinib. The awareness of the clonal expansion of large granular lymphocytes and beneficial effect of these clonal cells increased the interest to dasatinib in cases receiving this drug. Clonal expansion of large granular lymphocytes is an important effect of dasatinib therapy, shown to be an off-target phenomenon associated with pleural effusion and better clinical response. The benefit of dasatinib-induced lymphocytosis and its underlying mechanism of this are important points for clinicians working in hematology and oncology.
Peripheral T-cell lymphoma: The role of hematopoietic stem cell transplantation
February 2014
Maria Gkotzamanidou | Christos A. Papadimitriou
Abstract: Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs). Whereas the incidence of the disease appears to increase during last decades and the prognosis remains dramatically poor, so far no standard treatment has been established. High-dose chemotherapy and autologous stem cell transplantation (HDT–ASCT) has been proven effective in relapsed PTCL, while retrospective studies have shown a survival benefit as first-line treatment in some subsets of PTCL patients.However, given disease rarity, there is a paucity of randomized trials in both upfront and relapse setting. Here, we critically evaluated eligible prospective and retrospective studies that address the role of ASCT in treatment of PTCL, with respect to quality of design and performance. Additionally, the role of allogeneic transplantation has been reviewed.The comparison of ASCT with novel agents that emerge or the combination of both, are to be ascertained via prospective randomized trials in this field.
Toll-like receptors in lymphoid malignancies: Double-edged sword
February 2014
Sara Harsini | Maani Beigy | Mahsa Akhavan-Sabbagh | Nima Rezaei
Abstract: Toll-like receptors (TLRs) are the best characterized pattern recognition receptors (PRRs), which play an essential role in the recognition of invading pathogens via specific microbial molecular motifs, comprising a bridge between the innate and adaptive immune responses. Toll-like receptors expression is determined in both normal immune cells and malignant cells, with a distinctive pattern compared to each other, rendering them plausible targets for cancer therapy. Improved molecular profiling of lymphoid malignancies may give new insights into pathogenesis of these cancers and pave the way for novel therapeutic agents, including TLR agonists. In the current review, we summarize the immunopathogenic roles of TLRs in B cell and T cell lymphomas, acute lymphoblastic leukemia, multiple myeloma, and chronic lymphocytic leukemia, as well as the results of studies on TLR ligands and their future implications to manage these hematologic malignancies.
Are erlotinib and gefitinib interchangeable, opposite or complementary for non-small cell lung cancer treatment? Biological, pharmacological and clinical aspects
February 2014
Giuseppe Bronte | Christian Rolfo | Elisa Giovannetti | Giuseppe Cicero | Patrick Pauwels | Francesco Passiglia | Marta Castiglia | Sergio Rizzo | Francesca Lo Vullo | Eugenio Fiorentino | Jan Van Meerbeeck | Antonio Russo
Abstract: Gefitinib and erlotinib are the two anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) approved for treatment of advanced NSCLC patients. These drugs target one of the most important pathways in lung carcinogenesis and are able to exploit the phenomenon of 'oncogene addiction', with different efficacy according to EGFR gene mutational status in tumor samples. Gefitinib has been approved only for EGFR mutation bearing patients regardless the line of treatment, while erlotinib is also indicated in patients without EGFR mutation who undergo second- or third-line treatment. Some studies evaluated the main differences between these drugs both for direct comparison and to improve their sequential use. In particular, toxicity profile resulted partially different, and these observations may be explained by several molecular and pharmacokinetic features. Therefore, this review integrates preclinical data with clinical evidences of TKIs to guide the optimization of currently available treatments in advanced NSCLC patients.
A review of the profile of endothelin axis in cancer and its management
February 2014
Soussan Irani | Ali Salajegheh | Robert Anthony Smith | Alfred King-Yin Lam
Abstract: The endothelins and their associated receptors are important controllers of vascular growth, inflammation and vascular tone. In cancer, they have roles in the control of numerous factors in cancer development and progression, including angiogenesis, stromal reaction, epithelial mesenchymal transitions, apoptosis, invasion, metastases and drug resistance. Also, we consider current information on the role of this signalling system in cancer and examine the state of the current cell, animal and clinical trials utilizing endothelin targeted drugs for cancer management. Although targeting the endothelin axis in cell lines and xenografts show some promise in retarding cellular growth, results from limited clinical trials in prostatic cancer are less encouraging and did not offer significant survival benefit. The ability to target both cancer cells and vasculature via endothelin is an important consideration that necessitates the further refining of therapeutic strategies as we continue to explore the possibilities of the endothelin axis in cancer treatment.
Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: A new treatment for metastatic soft tissue sarcoma
February 2014
Girolamo Ranieri | Maria Mammì | Eugenio Donato Di Paola | Emilio Russo | Luca Gallelli | Rita Citraro | Cosmo Damiano Gadaleta | Ilaria Marech | Michele Ammendola | Giovambattista De Sarro
Abstract: Soft tissue sarcomas (STS) are rare tumors with mesenchymal origin, accounting for 1% of all human cancer. Local control of STS can be obtained through the use of surgery and radiotherapy. In about 40% of these patients, disease will recur at distant sites, and of these more than 90% will die because of this aggressive malignancy. In advanced and/or metastatic STS patients treated with anthracycline-based regimen the median overall survival is about 12 months, and it has remained unchanged during the last 20 years. Clearly, this strongly suggests the need for discover more active compounds in STS, such as imatinib in GIST or dermatofibrosarcoma patients. In this paper we describe the crucial role of angiogenesis mechanisms in sarcomas development and progression. Consequentially, we focus on pazopanib, a novel multitargeted tyrosine kinase inhibitor with anti-angiogenic activity, mainly due to VEGFR2 pathway interference. We also analyze principal completed trials leading pazopanib approval in sarcomas pretreated patients.
Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers
February 2014
Thomas E. Kruger | Andrew H. Miller | Andrew K. Godwin | Jinxi Wang
Abstract: The mechanisms underlying malignant cell metastasis to secondary sites such as bone are complex and no doubt multifactorial. Members of the small integrin-binding ligand N-linked glycoproteins (SIBLINGs) family, particularly bone sialoprotein (BSP) and osteopontin (OPN), exhibit multiple activities known to promote malignant cell proliferation, detachment, invasion, and metastasis of several osteotropic cancers. The expression level of BSP and OPN is elevated in a variety of human cancers, particularly those that metastasize preferentially to the skeleton. Recent studies suggest that the "osteomimicry" of malignant cells is not only conferred by transmembrane receptors bound by BSP and OPN, but includes the "switch" in gene expression repertoire typically expressed in cells of skeletal lineage. Understanding the role of BSP and OPN in tumor progression, altered pathophysiology of bone microenvironment, and tumor metastasis to bone will likely result in development of better diagnostic approaches and therapeutic regimens for osteotropic malignant diseases
Targeting the MET gene for the treatment of non-small-cell lung cancer
February 2014
F. Gelsomino | F. Facchinetti | E.R. Haspinger | M.C. Garassino | L. Trusolino | F. De Braud | M. Tiseo
Abstract: Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era.In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.
Targeted therapies in metastatic esophageal cancer: Advances over the past decade
Available online 26 January 2014
Amr Mohamed | Bassel El-Rayes | Fadlo R. Khuri | Nabil F. Saba
Abstract: Esophageal cancer is one of the most aggressive malignancies of the upper aerodigestive tract. Despite advances in surgical techniques and multi-modality therapies, the 5-year survival rate remains poor (14%). Over the past decade, efforts have been focused on the field of drug development with the advancement of novel molecularly targeted therapeutic agents. These agents target a variety of cancer relevant pathways such as vascular endothelial growth factor (VEGF) or its receptor, the cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), and mammalian target of rapamycin (mTOR) pathways. The number of approved targeted agents remains few, with HER-2 inhibitors leading the list for treatment of HER-2 expressing metastatic adenocarcinomas. Novel agents have not yet been widely explored in esophageal cancer. In this review, we will provide a concise and systematic overview of the development of novel targeted therapies currently under investigation for the treatment of metastatic esophageal disease.
Pharmacological management of cancer pain in children
Available online 24 January 2014
Sebastiano Mercadante | Antonello Giarratano
Abstract: The aim of this review was to assess cancer pain management in children on the basis of research published in the last ten years. Nine were papers providing clinical data, with a minimum of ten patients. No controlled studies were found. Regardless of general principles and existing recommendations, clinical data should confirm the applicability of this concept. The trials published in the last years did not provide further information to improve cancer pain management in children, because of the experience and the low number of drugs used, reflecting only meaningful opinions of experts in the field. The amount and the quality of data still remain poor, as only 737 subjects (about 80 patients per year) were surveyed with open-label designs or retrospective analysis. No comparison among possible treatments or drugs has ever been performed. Most of these trials are short-lived and assessment of adverse effects is often problematic. The experience with opioids is quite limited, and adjuvants have been seldom assessed, unless for case reports which have not been considered in this analysis. The management of breakthrough pain has never been specifically evaluated.Further clinical trials are needed to evaluate dose equivalence, clinical efficacy and safety of opioid analgesics, differences in opioid response, adjuvants and other drugs commonly used to manage opioid-related adverse effects, and dose strengths necessary for most children.
Detection methods of circulating tumor cells in cutaneous melanoma: A systematic review
Available online 24 January 2014
Stefan Rodic | Catalin Mihalcioiu | Ramy R. Saleh
Abstract: The vast majority of melanoma-related deaths are due to disseminated malignancy. Many treated patients who are clinically disease-free will go on to relapse. Therefore, new prognostic tools must be developed to better assess metastatic potential and assist in patient management. Circulating tumor cells are a widely studied metastatic biomarker with promising prognostic utility, as the shedding of cells from the primary tumor into peripheral blood is a necessary step in disease dissemination. An assortment of technologies and techniques has been developed to isolate and detect circulating melanoma cells (CMCs), but a standardized method is yet to be established. It is the aim of this study to systematically review the diverse enrichment and detection methods of circulating tumor cells in cutaneous melanoma. A literature search yielded 351 articles, of which 74 were deemed eligible according to inclusion criteria, the primary requirement being the reporting of patient CMC positivity status stratified by the stage of melanoma. Pertinent studies were used to evaluate the advantages and disadvantages of each method. Additionally, we calculated the sensitivity and specificity of seven common melanoma-associated markers based on the available literature.
BRCA1/2 mutation carriers are potentially at higher cardiovascular risk
Available online 24 January 2014
M. Arts-de Jong | A.H.E.M. Maas | L.F. Massuger | N. Hoogerbrugge | J.A. de Hullu
Abstract: BRCA1/2 mutation carriers have an elevated risk of developing breast and ovarian cancer at a relatively young age. Risk-reducing salpingo-oophorectomy is an established strategy to tremendously reduce the risk of ovarian cancer. It is recommended to perform this surgery at age 35–40 years (BRCA1) and at age 40–45 years (BRCA2) resulting in an early and abrupt menopause. BRCA1/2 mutation carriers are potentially at higher risk of cardiovascular diseases due to early surgical menopause, and cardiotoxic effects of adjuvant treatment for breast cancer. Furthermore, preliminary results of experimental studies suggest a possible causative function of the BRCA genes in cardiovascular risk. More research on cardiovascular health risks in BRCA1/2 mutation carriers is needed, especially in the field of cardio-oncology, requiring additional attention to potentially cumulative effects on cardiovascular risks in this specific group of women.
Iron overload and chelation therapy in myelodysplastic syndromes
Available online 24 January 2014
Sally Temraz | Valeria Santini | Khaled Musallam | Ali Taher
Abstract: Iron overload remains a concern in MDS patients especially those requiring recurrent blood transfusions. The consequence of iron overload may be more relevant in patients with low and intermediate-1 risk MDS who may survive long enough to experience such manifestations. It is a matter of debate whether this overload has time to yield organ damage, but it is quite evident that cellular damage and DNA genotoxic effect are induced. Iron overload may play a critical role in exacerbating pre-existing morbidity or even unmask silent ones. Under these circumstances, iron chelation therapy could play an integral role in the management of these patients. This review entails an in depth analysis of iron overload in MDS patients; its pathophysiology, effect on survival, associated risks and diagnostic options. It also discusses management options in relation to chelation therapy used in MDS patients and the impact it has on survival, hematologic response and organ function.
Local ablative treatments of oligometastases from head and neck carcinomas
Available online 23 January 2014
C. Florescu | J. Thariat
Abstract: BackgroundMedian survival for recurrent/metastatic (unknown poly/oligometastatic status) head and neck cancer patients (HNSCC) is ten months with best systemic treatment. Metastatic ablation shows promising results in selected patients with several tumor types. We aimed to assess the role of surgery and stereotactic ablative body radiotherapy (SABR) with respect to survival in HNSCC.Materials and methodsPublished data on metastatic HNSCC treated ablatively were analyzed.ResultsFive-year survival rates after pulmonary/liver metastasectomy exceed 20% in selected patients. Two-year survival after lung SABRT of metastasectomy yields 35%. Interesting data on survival and tolerance are reported in other metastatic sites.ConclusionSurgery yields the best level of evidence. However, non-invasive SABR is efficient and well-tolerated in lung/liver, bone and other metastatic locations. Systemic treatment may be given sequentially with ablative treatments, or omitted in well-identified situations. Proper patient selection for local ablative treatment and optimal therapeutic sequence should be assessed in randomized trials.
Systematic review of the side effects associated with tyrosine kinase inhibitors used in the treatment of gastrointestinal stromal tumours on behalf of the EORTC Quality of Life Group
Available online 17 January 2014
Samantha C. Sodergren | Alice White | Fabio Efficace | Mirjam Sprangers | Deborah Fitzsimmons | Andrew Bottomley | Colin D. Johnson
Abstract: Tyrosine kinase inhibitors (TKIs) have revolutionised the treatment of advanced gastrointestinal stromal tumours (GISTs). Imatinib is approved as first line therapy and sunitinib is used in cases of imatinib resistance or intolerance. Compared with conventional treatments, TKIs are delivered over longer periods of time and are more specific in their targets (i.e., molecularly targeted), thus presenting different side effect profiles. We review the safety profiles of imatinib and sunitinib, documenting a total of 95 side effects including patient based as well as medically defined outcomes. Gastrointestinal complaints, particularly diarrhoea and nausea, oedema, fatigue and haematological disorders, notably anaemia, are amongst the most prevalent side effects. While there is overlap between the side effect profiles of imatinib and sunitinib, important differences emerge in the frequencies of oedema, hypertension, thyroid functioning, muscle and joint pains, as well as skin and oral conditions. Awareness of potential side effects is informative to both clinician and patient in terms of treatment decision making and can have important implications for treatment adherence and clinical outcome.
Therapeutic opportunities for castration-resistant prostate cancer patients with bone metastases
Available online 17 January 2014
Fable Zustovich | Francesca Fabiani
Abstract: Patients with castration-resistant prostate cancer are burdened not only with an unavoidable risk of mortality but also by severe mobility issues. This disease has a high tendency to induce bone metastases with concomitant general suffering, impaired mobility, and reduced self-sufficiency. The treatment of bone pain consists of opioids, nonsteroidal anti-inflammatory drugs, radiopharmaceuticals, and radiotherapy. To date, abiraterone, enzalutamide, zoledronate and denosumab are the only drugs able to delay skeletal events, and docetaxel is the only chemotherapeutic agent able to prolong survival after castration progression. Recently, 5 new drugs have proven to be efficacious in prolonging survival. Sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223 have broadened the therapeutic choices, thus changing the clinical paradigm. This review analyzes the data supporting the use of all presently available therapeutic approaches for the management of pain, skeletal events, and survival in castration-resistant prostate cancer patients with bone metastases. Data based on phase 3 trials could identify new approaches depending on patient, disease, and therapy characteristics.
Seeing the forest through the trees: A systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer
Available online 15 January 2014
Tanios Bekaii-Saab | Christina Wu
Abstract: Combinations of fluoropyrimidines with oxaliplatin or irinotecan plus a biologic agent are standard treatments for metastatic colorectal cancer (mCRC). Recent approvals of first-line cetuximab, second-line ziv-aflibercept, and regorafenib as salvage therapy have increased the complexity of the treatment armamentarium. To define optimal regimens, we systematically reviewed combination chemotherapy trials (N=83). Descriptive analyses focusing on fluoropyrimidine formulation, oxaliplatin vs irinotecan combinations, and compatibility with biologics indicated the following: infusional 5-fluorouracil (5-FU) yielded better efficacy and safety than bolus 5-FU. Capecitabine had similar outcomes and better safety than 5-FU with oxaliplatin but not irinotecan. First-line oxaliplatin and irinotecan appeared equivalent. Antiangiogenics, such as bevacizumab and ziv-aflibercept, and epidermal growth factor receptor-targeted monoclonal antibodies cetuximab and panitumumab further improved efficacy. The treatment landscape for mCRC has become complex, and we are approaching individualized therapy based on predictive factors, including KRAS mutational status. Appropriate administration of chemotherapy/biologic combinations is critical.
Sorafenib-based combination as a first line treatment for advanced hepatocellular carcinoma: A systematic review of the literature
Available online 7 January 2014
Omar Abdel-Rahman | Mona Fouad
Abstract: BackgroundHepatocellular carcinoma is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Advanced HCC is a distinct disease entity with limited approved treatment options and grave prognosis. So, we will explore in this systematic review the value of using sorafenib-based combination in this poor prognosis subset of HCC.MethodsPubMed, Medline, the Cochrane Library, trip database and Google Scholar were searched using the terms "Hepatocellular carcinoma" OR "Hepatoma" or "Liver cancer" AND "systemic anticancer therapy" AND "Sorafenib" and specifying only English literature. Outcomes of interest included progression free survival and overall survival (PFS and OS), tumor response, and toxicities.ResultsA total of 17 potentially relevant trials was identified, of which 9 studies were excluded. Hence, eight trials involving 272 patients were included.Median PFS was reported in 6 out of the 8 trials ranging from 3.7 to 7.5 months. Median OS was reported in 6 out of the 8 studies ranging from 7.4 to 40.1 months.The DCR was reported in the 8 studies, ranging from 48.7% to 76%. Frequently reported Grade 3/4 toxicities were increased AST/ALT, fatigue, hypertension, hand foot skin reaction and diarrhea. However, some chemotherapy-specific side effects were noted in some studies.ConclusionsThe current evidence from the available clinical trials suggests that sorafenib-based combination with some anticancer agents (especially mTOR inhibitors) could be a more effective and tolerable treatment for advanced HCC in the future. However, such sorafenib-based combination cannot be recommended outside the setting of clinical trials.
Oxaliplatin induced-neuropathy in digestive tumors
January 2014
María Sereno | Gerardo Gutiérrez-Gutiérrez | César Gómez-Raposo | Miriam López-Gómez | Maria Merino-Salvador | Francisco Zambrana Tébar | Cristina Rodriguez-Antona | Enrique Casado
Abstract: Oxaliplatin is one of the main drugs used in digestive tumors treatment. Peripheral neuropathy is a well-recognized dose-limiting toxicity of OXL. Two types of neuropathy have been described with this agent: acute or transient and chronic or persistent, with different etiology, clinical manifestations and prognosis.This paper is an exhaustive review about the main aspects of oxaliplatin induced peripheral neuropathy, focus in clinical features, treatment, prevention strategies and future approach.
Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities
January 2014
Barbara Merelli | Daniela Massi | Laura Cattaneo | Mario Mandalà
Abstract: A dynamic interplay exists between host and tumor, and the ability of the tumor to evade immune recognition often determines the clinical course of the disease. Significant enthusiasm currently exists for a new immunotherapeutic strategy: the use of immunomodulatory monoclonal antibodies that directly enhance the function of components of the anti-tumor immune response such as T cells, or block immunologic checkpoints that would otherwise restrain effective anti-tumor immunity. This strategy is based on the evidence that development of cancer is facilitated by the dis-regulation and exploitation of otherwise physiological pathways that, under normal circumstances, down-regulate immune activation and maintain tolerance to self. Among these pathways an important role is covered by the Programmed death-1 (PD-1)/PD-Ligand (L) 1 axis. An emerging concept in cancer immunology is that inhibitory ligands such as PD-L1 are induced in response to immune attack, a mechanism termed "adaptive resistance". This potential mechanism of immune resistance by tumors suggests that therapy directed at blocking the interaction between PD-1 and PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity. The anti-PD-1 strategy can be effective in several solid tumors such as renal cell carcinoma (RCC) or non-small cell lung cancer (NSCLC), however in this review we summarize the biological role of PD-1/PD-L1 on cancer by focusing our attention in the biological rationale, clinical challenges and opportunities to target the PD-1/PD-L1 axis in melanoma.
Drug interactions with solid tumour-targeted therapies
January 2014
Audrey Thomas-Schoemann | Benoit Blanchet | Christophe Bardin | Gaëlle Noé | Pascaline Boudou-Rouquette | Michel Vidal | François Goldwasser
Abstract: Drug interactions are an on-going concern in the treatment of cancer, especially when targeted therapies, such as tyrosine kinase inhibitors (TKI) or mammalian target of rapamycin (mTOR) inhibitors, are being used. The emergence of elderly patients and/or patients with both cancer and other chronic co-morbidities leads to polypharmacy. Therefore, the risk of drug–drug interactions (DDI) becomes a clinically relevant issue, all the more so as TKIs and mTOR inhibitors are essentially metabolised by cytochrome P450 enzymes. These DDIs can result in variability in anticancer drug exposure, thus favouring the selection of resistant cellular clones or the occurrence of toxicity. This review provides a comprehensive overview of DDIs that involve targeted therapies approved by the FDA for the treatment of solid tumours for more than 3 years (sorafenib, sunitinib, erlotinib, gefitinib, imatinib, lapatinib, everolimus, temsirolimus) and medicinal herb or drugs. This review also provides some guidelines to help oncologists and pharmacists in their clinical practice.


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Pat Greenhouse / GLobe Staff
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text:
Advocates for children with special needs are backing legislation aimed at reducing the use of physical restraints and locked isolation rooms to discipline students.
The bill, authored by Republican state Sen. Randy Head of Logansport, would require all schools in Indiana to develop seclusion and restraint policies that meet certain standards and to train staff in their appropriate use.
Senate Bill 345 would also require schools to document and report to both parents and the state when those techniques are used.
The push for the legislation started last year, after the U.S. Department of Education released a study that found tens of thousands of students across the U.S. — most of them disabled — had been strapped down, physically restrained or locked into isolation rooms by teachers or school staff to keep order in their classrooms. In some cases, the techniques led to injury and death.
Head wants the legislation to apply to all schools – public, charter and private – but some private and charter schools are lobbying to be excluded. His bill was scheduled for a committee hearing Tuesday but was postponed.
"No one should be able to put a kid in a sleeper hold or lock him in a closet, no matter where parents decide to place their kids," Head said.
Though the legislation would cover all students – not just those with physical, mental or emotional disabilities – it has its strongest backing from organizations that advocate for children with special needs.
The U.S. Department of Education study released last year found that about 70 percent of the nearly 40,000 students who were restrained or isolated in seclusion rooms during the 2009-10 school year had learning, behavioral, physical or developmental needs.
The study also found that African-American and Hispanic students were also disproportionately isolated or restrained.
Kim Dodson, assistant executive director of The Arc of Indiana, said Indiana has laws that cover the use of physical restraints and isolation rooms in state prisons, juvenile facilities and nursing homes. But no law that sets the standards for when they can be used in school.
"Schools should be required to have a policy where every child, disabled or not, has the right to education and is treated with dignity and respect and a healthy and safe environment in which to learn," Dodson said.
Dodson said the need for such legislation was made evident by an incident that occurred last week, when an 8-year-old child with Down Syndrome was sent from an Indianapolis area school with her shoes and socks duct-taped tightly to her ankles to prevent her from removing them. The child's parents said the tape was wrapped so tightly that the child couldn't walk and was placed in a wheelchair by school staff when she was sent home on a school bus.
Head's bill would allow schools to develop their own policies as long as they meet certain standards spelled out in the legislation. Those standards include a requirement that school personnel be trained in the appropriate use of restraints and isolation rooms, and that those techniques be used as a last resort to keep a student from harming himself or others.
Currently, the Indiana Department of Education encourages local school corporations to develop their own policies on the use of restraints and isolation techniques. But there is no requirement to do so, leaving the state with a patchwork of policies and practices.
"It's hard to write a law that plans for every circumstance and every teacher is going to tell you that things are unpredictable so we want each school corporation to come up with policies that will work," said Head. "But we want those policies made public, we want parents to understand how they will be used, and we want to make sure they're not going to harmful to a child."
Maureen Hayden covers the Statehouse for CNHI, the Tribune-Star's parent company. She can be reached at firstname.lastname@example.com.
Local & Bistate
Legislation would reduce use of restraints, isolation rooms in schools
- Local & Bistate
Purdue shooting leaves one person dead
A Purdue University engineering student opened fire inside a basement classroom Tuesday, killing a teaching assistant and prompting officials to put the campus on lockdown, police and the university said.
Inmates part of new Legion post
Wearing khaki-colored matching uniforms, more than 20 veterans inside a maximum-security prison stood tall to salute the flag of the United States at an event that welcomed them as new American Legion members.
THS grad Miller among students in adjacent building when shooting occurs
Kris Miller and his roommate were in a computer lab of Purdue's mechanical engineering building Tuesday when they received a call that a shooting had occurred next door.
Bosma moves gay marriage ban bill to friendlier committee
Republican House of Representatives Speaker Brian Bosma sent a bill that proposes a constitutional ban on gay marriage to a more conservative-leaning legislature committee Tuesday, because it lacked support on the first committee to which it was assigned.
We enter the deep freeze again
If you had to step outside to get your newspaper this morning, you might have noticed it's painfully cold once again.
Levy redirects school funds
If the new "protected levy" legislation goes into effect later this year, it would mean "a substantial reduction" in revenue for Vigo County School Corp. bus transportation, capital projects and bus replacement funds, according to the district's chief financial officer.
School debt levy redirects funds across Indiana
School officials and state legislators from around the state are searching for ways to keep the school buses running — and children safe on the streets — pending the loss of millions of dollars for school transportation.
More than 50 school districts in Indiana stand to lose at least 20 percent of their revenues for transportation, new buses and other big-ticket projects under a new law that requires them to first pay off their debts. -
VIDEO: Sen. Donnelly updates T-S editorial board
Passage of a long overdue U.S. farm bill could be completed by the end of this month, Sen. Joe Donnelly, D-Ind., said Tuesday.
Vigo coroner tries again for salary increase
After being denied last year, Vigo County Coroner Dr. Susan Amos is again seeking to have her county salary increased to match that of several other county office holders.
Putnam deputy released; April trial set
A Putnam County Sheriff's deputy accused in federal criminal cases of excessive force against suspects in four arrests has been released to pre-trial supervision.
Parent group hoping to keep day care open
When Grace Finley takes her 4-year-old son to The Woods Day Care/Pre-School, she is reassured knowing that he's receiving quality care, he's safe and he's loved. So when she, and other parents, learned Wednesday that the nationally accredited program is scheduled to close June 6, they were stunned by the news.
SCORE gets new home base
The Greater Wabash Valley SCORE Chapter 661 has moved to the former Indiana State Police Post building at the southwest corner of U.S. 41 and Jessica Drive on the Ivy Tech Community College-Wabash Valley campus.
Mayor Bennett drops veto threat over financial consultant
Mayor Duke Bennett has dropped a threat to use his veto power in the matter of the Terre Haute City Council seeking to hire its own financial consultant.
Gas leak closes city streets
A natural gas leak caused the temporary evacuation of three homes in Terre Haute on Thursday morning.
Police records provide details into arrests in case
Police records provide more details of four arrests that are at the center of federal civil rights abuse allegations against a Putnam County sheriff's deputy.
Law firm to provide free cab rides home from St. Pat's Day celebrations
Terre Haute law firm Fleschner, Stark, Tanoos & Newlin encourages St. Patrick's Day revelers to make smart decisions for this year's festivities. The firm will offer free cab rides to adults who have had one too many drinks on March 15 and 17.
Pence signs military relief fund changes into law
INDIANAPOLIS (AP) — Gov. Mike Pence has signed into law a measure allowing more of Indiana's veterans and their families access to a fund that helps them pay for food, housing and other expenses.
Vigo County Jail Log: March 13, 2014
The following individuals were booked into the Vigo County Jail by area law enforcement on Wednesday and Thursday, based on jail records.
Vectren repairs natural gas leak near 16th and Crawford
A natural gas leak caused the temporary evacuation of three homes in Terre Haute earlier today.
New lawsuit challenges Indiana gay marriage ban
INDIANAPOLIS (AP) — Indiana's ban on same-sex marriages faces a new challenge in a lawsuit filed by a national gay rights group.
Sentencing overhaul passes Indiana Legislature
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Putnam deputy released from jail, awaits trial on federal charges
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Indiana lawmakers eyeing roads, preschool deals
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MARK BENNETT: First BaconFest sure to cure your salty fried meat cravings
Bacon taught me a life lesson.
I wrapped strips of it around chicken livers and secured the cold, gooey bundles with toothpicks to earn money. -
New rules may keep moped riders on road
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Nearly half of Indiana students get meal aid
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Hearing date set for Dugger charter school
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Sullivan County ambulance overturns on Interstate 70
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New trustee appointed to Indiana State board
Kathleen G. Cabello, president and co-founder of Cabello Associates Inc., has been appointed by Gov. Mike Pence to serve on the Indiana State University Board of Trustees.
Car from home invasion recovered
A stolen vehicle believed to have been used by suspects in a March 4 home invasion has been recovered.
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Brandon Martin collects first career 410 feature win at Attica Raceway Park.
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Alessandra Rizzotti commented 21 minutes ago
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Did you know that your strongest weapon against cancer may be in your own blood?
Because of advances in genetic science, researchers are now starting to see positive results from harvesting the "killing power" of the body's natural defenders against disease which are called T-cells.
They are a certain type of white blood cell that grows in the Thymus (thus 'T'-Cell) and goes on the hunt for tumors and cell mutations.
Now, we're starting to see amazing non-toxic cancer-killing results.
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President Obama responded with a fist bump after Crist signed the papers, the Tampa Bay Times reported. Crist, an independent for more than two years, endorsed the president in this year's election over his Republican challenger, Mitt Romney.
"I've had friends for years tell me, 'You know Charlie, you're a Democrat and you don't know it,'" Crist told the newspaper.
Crist served in the state Legislature before winning the governorship in 2006. Trailing Marco Rubio in a Republican primary for the U.S. Senate, Crist became an independent in 2010. He ran behind Rubio and ahead of the Democratic candidate in the general election.
The Times said Crist is believed to be considering another run for governor in 2014. He would be likely to have competition in the Democratic primary.
Florida has been split between the two parties in recent years. Obama carried the state narrowly in November, Gov. Rick Scott and Rubio are both conservative Republicans while Democratic Sen. Bill Nelson won a third term this year with 55 percent of the vote.
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Eleanor gets avg. rating
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Underneath the mask you've buried yourself into
It's coal-black
I am tired of the gulping that you do
Every day a new face
What if I unscrew
Your own identity
Wouldn's you guess there's nothing left of you?
The quicksand of life drags us
Down into the circle
One day we might not catch you
I feel sorry, for what you try to do
Breaking others down, to try and to pursue
Your own selfish interests
I am starting to get sick of you
Whatever happened ever since you left
You make yourself and me look like fools
If you believe the lyrics are not correct you can Submit Corrections to us


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Houzz is the new way to design your home.
190,977 antique furniture Home Design Photos
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Masters Residence
dark, antique William and Mary highboy and a Calcutta gold and black marble basketweave tile floor. Faux gray and light blue walls lend a clean, crisp feel to the room, compounded by a white pedestal tub and polished nickel faucet.
Staying true to the original 1920s style, this room was given fresh
wooden furniture from the moist in the bathroom?
on my antiques.....and even ordinary vintage wood item. Although, like wax, eventually needs to be reapplied. It does not require the buffing that beeswax needs for a lovely finish.
I have used in our steamy bathroom on the wood cabinets and it refreshes their appearance remarkably.
I do not
beautiful vintage bathroom using and antique piece of furniture
combinatie mobila in baie — Olga Radu
Bosworth Hoedemaker
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tiful furniture, it can add charm to your rooms
piece of furniture and the baskets
of the antique piece. Use this color in our kitchen cabinets
Antiquing: Look the merchant in the eye and ask if the piece is a good value for the money. How the question is received is more important than the answer itself. If the dealer is offended or avoids your gaze, chances are that it's not a
welcome antiques into your home:Unlike most new furniture, which decreases in value over time, your antique purchases will hold their value — and even increase in value over the years.Antique furniture was built to last; expect to find better materials and higher-quality construction than in new mass-produced
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Armoire — jonraynor
Urban Orchard Interiors
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Big sink, French windows, antique side table
colors, new furniture and light fixtures combine in her kitchen's new look. A vintage-style pendant and antique furniture with plenty of patina complete the 11-by-20-foot space.
Cabinet and chairs — michaelpoteet
Brian Dittmar Design, Inc.
Presidio Heights traditional
Like the color or the walls and I like the furniture arrangement
James with antique pieces gives the room a comfortable, lived-in feel that isn't always achievable with all-new pieces. "Patina refers to a level of age and wear, such as you find in antique furniture," says Dittmar. "Having pieces with patina instantly gives the room a lived-in feeling. The worst thing is
resembles a furniture store, not a home."
Color of walls — dlopiccolo210
Walter Studio Interior Design
Fairview Road NE
The antique round pedestal table with marble inlay is part of my client's collection.
The antique bronze and crystal chandelier was part of my client's collection. You can find a similar style on 1stdibs.com
The benches are from a local antique dealer. I don't think they reproduced this bench
The antique porcelain table lamps are part of my client's collection.
full of antique furniture, vases, sculpture, potted plants and throw pillows galore. For others, that sort of living space would be incredibly unappealing.
Hallway — honeytorres
Volz O'Connell Hutson
Bastrop County Plantation House
fixtures, antique furniture, custom cabinetry and millwork, encaustic tile, new and vintage reproduction appliances, and historic reproduction carpets and drapes.
© Copyright 2011, Rick Patrick Photography
fixtures, antique furniture, custom cabinetry and millwork, encaustic tile, new and vintage reproduction appliances, and historic reproduction carpets and drapes. © Copyright 2011, Rick Patrick Photography
fixtures, antique furniture, custom cabinetry and millwork, encaustic tile, new and vintage reproduction appliances, and historic reproduction carpets and drapes. The original Greek revival–style house was built in 1857; one of the new additions, seen here on the right side, doubles the square footage of
The style — allysonmburden
Andrea Schumacher Interiors
2010 Colorado Homes & Lifestyles "Home of the Year"
to many antique pieces over the internet in my search for a specific piece of furniture.
numerous antiques - I'm sure this is one of them.
homeowners' antique furniture and art collection. In this bar and lounge area next to the entryway, she created a welcoming space for guests with a custom bar and beautifully worn leather sofa. Custom bar: Sergey Antique ReproductionsRug: Shaver-Ramsey
face paint — 1963voloshin
Amy Lau Design
West Chelsea Loft
I have light maple stairs and light maple hardwood upstairs. Our basement had carpet but we are changing to antique maple laminate. How do I merge the new colours. The stairs to basement will be new darker
Nakashima furniture or wall unit, black/rice paper sliding doors
Knoll furniture company began distributing Pennsylvania craftsman George Nakashima's polished cherrywood tables and softly geometric chairs. Nakashima's furniture (like the side table and chair shown here) was museum quality, but he refused to treat it as precious. "A certain amount of scratching and
young, 'antique' furniture in record time. To me, there is nothing quite so uninteresting as a shining, perfectly smooth surface that looks as though it has never been used."Nakashima's daughter, Mira, explained how wabi-sabi influenced him (and continues to guide the work of his studio following his death)
Buffett — june2494


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Is it legal to lie about your age when filling an online application of a home-based job, in Ontario, Canada?
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Is it legal to lie about your age when filling an online application of a home-based job, in Ontario, Canada?I wanna get a home-based job, but is it legal to lie about your age on the online application of the job, in Ontario Canada? So is it legal or not? And how could they find out I'm lying exactly?
Asked By: Zitos - 2/3/2010
Best Answer - Chosen by Asker
who cares Canadian Lows don't count for anything anyways.
Answered By: WJ - 2/3/2010
Additional Answers (4)
Answered By: Kenny - 2/3/2010
Alright, firstly, the term "home-based job" just jumps out at me as a scam. I would not submit the application...
Answered By: Catarate - 2/3/2010
Since they really aren't going to give you a job it is OK to not really give them your age.
That said if this is the 1 in 10,000 home based job that isn't a scam then when and if they find out that you are not the age you said you were they will fire you and may take other action.
Answered By: WRG - 2/3/2010
why would you want to lie about a thing like that. it will make you look bad. if this is a job then they will find out. if its a survey then no they won't find out. but lieing makes you look bad any way you look at it
Answered By: jjt - 2/3/2010
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oy. i hadn't read the responses prior to mine (they didn't show up before), so i hope you guys don't think i'm responding to you. i'm responding to the article itself. i think you guys are spot on. and keep the faith!
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oy. i hadn't read the responses prior to mine (they didn't show up before), so i hope you guys don't think i'm responding to you. i'm responding to the article itself. i think you guys are spot on. and keep the faith!
This is clearly not the right move on Correa's part. Entirely the wrong thing, actually. He should have just outed the guy as a wacko Bill O'Reilly-type. But the stakes are waaay higher in Ecuador. Do you know anything about Ecuador? About Latin American history? Ecuador (like most Latin American countries who haven't resisted) has a long history of being run by US-supported right wing fascists who have no problem torturing and killing dissidents. Now that the left is finally on the rise, they are extremely concerned that their country will slip back into its former US-supported ways (keeping the poor extremely poor and ensuring that the 1% will prosper and will never have to worry about anything). This is the context that you, and for that matter, very few US media outlets provide. It's not pretty, and it's not perfect, but that's kinda the way it is. And it makes a bit more sense, even if it doesn't vindicated anyone. Oh, and we (i.e., the US) did precisely the same thing, but faaar worse when we were a fledgling democracy, trying to make its way in the world after a period of being the backyard of a major empire.
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Researchers have developed a mechanism for filtering water using an element of wood.
Researchers have tested the Blue Stones, and found them to have musical properties.
Newly discovered species is the biggest land predator ever found and one of the largest of the Jurassic Era.
A new process is able to convert carbon dioxide into methanol.
As the Earth's ice levels decline, more viruses may resurface.
Anger may trigger a heart attack or stroke, with a "danger window" of about two hours after an outburst.
Beringia is the land mass connecting Siberia and the U.S.
Over 90% of the newly-discovered worlds are smaller than Neptune.
Scientists point to a specific crater on Mars that is the source of meteorites on Earth.


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Camera: | Cannon Powershot A570 IS |
Recording media: | JPEG (digital) |
Title: | Salmon Crested Cockatoo |
Username: | SusanKing |
Uploaded: | 26 Sep 2008 - 6:41 AM |
Tags: | Bird, Cockatoo, General, Parrot, Pets / captive animals, Wildlife / nature |
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Nice capture Sue but the wrong angle nearly all good bird shots need to see the eye to bring the photo to life and it would have given you a better focusesing point, as you can see shotting up into the sky with a white bird is no easy matter, well done.
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