Critical Reviews in Oncology / Hematology - Articles in Press

Recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer - Corrected Proof

2012-01-30

Abstract: Prostate cancer is the most prevalent urogenital malignancy. However, despite initial disease control using androgen deprivation, most of patients eventually develop progressive disease that is resistant to further hormone manipulation. For these patients with castration-resistant prostate cancer (CRPC), and particularly patients with metastatic disease, options have been limited, and prognosis is grim. However, as newer regimens and agents become available, higher rates of objective and biochemical response are being achieved, providing renewed hope for the management of these patients. With the aim of facilitating the treatment of these patients, the Spanish Oncology Genitourinary Group (SOGUG) has issued a series of the recommendations which have been collected in this review. Each recommendation is accompanied by the appropriate level of evidence and grade of recommendation on the basis of the characteristics of the data available.

Individualized therapy for patients with non-small cell lung cancer: Emerging trends and challenges - Corrected Proof

Corey J. Langer — 2012-01-27

Abstract: Non-small cell lung cancer is the leading cause of cancer death in the United States. Efforts to improve outcomes have led to a greater understanding of the predictive and prognostic value of histologic and molecular characteristics of individual tumors. In standard practice, biopsy specimens are examined first on a histologic level, then on a molecular level with the recognition that both histologic subtype and gene expression profile can guide treatment decisions and have a profound effect on clinical outcomes. Epidermal growth factor activation mutations were among the first biomarkers shown to have therapeutic implications, and levels of gene expression for an array of other biomarkers are being evaluated in clinical trials. Ongoing studies underscore the need to implement molecular and histologic screening as part of routine clinical practice. To achieve an integration of clinical, histologic, and molecular parameters when making treatment decisions, collaboration between oncologists and pathologists is essential.

Tyrosine kinase inhibitors for elderly chronic myeloid leukemia patients: A systematic review of efficacy and safety data - Corrected Proof

Massimo Breccia, Mario Tiribelli, Giuliana Alimena — 2012-01-27

Abstract: The impact of age as a poor prognostic factor in chronic myeloid leukemia (CML) has been well described. In the interferon era, elderly patients diagnosed as having chronic phase chronic myeloid leukemia (CP-CML) had shorter survival compared to younger patients. With the advent of target therapy with imatinib, several reports described improved responses in elderly late CP-CML patients treated with imatinib after IFN failure, with similar overall survival compared to younger population. Imatinib in newly diagnosed older patients showed similar rate of cytogenetic and molecular responses compared to younger patients. Few data are available relating elderly CML patients subset treated with second-generation TKIs after resistance/intolerance to imatinib: both nilotinib and dasatinib have demonstrated efficacy and limited toxicity profile as in younger patients. The aim of this review is, through the revision of published data, to highlight the fact that elderly CML patients can benefit from target therapy with limited adverse events.

Octreotide for malignant bowel obstruction: Twenty years after - Corrected Proof

Sebastiano Mercadante, Giampiero Porzio — 2012-01-25

Highlights: ► We presented the original idea regarding the rationale of using octrotide in maligant bowel obstruction. ► We presented the subsequent literature supporting the efficacy of octreotide. ► Despite existing studies used different evaluation tools, in general the success rate of octrotide in managing symptoms associated with malignant bowel obstruction is high. ► No other drug has shown the same efficacy.Abstract: Malignant bowel obstruction (MBO) is a challenging complication of advanced cancer. Conservative treatment of inoperable MBO in terminal cancer patients has been found to be effective in controlling the distressing symptoms caused by this complication in inoperable cancer patients. Twenty years ago, octreotide was proposed to treat symptoms related to malignant bowel obstruction. Since then several reports have confirmed the efficacy of octreotide in the management of gastrointestinal symptoms of MBO. Fifteen randomized controlled trials or observational reports with a significant number of patients treated with octreotide have been reviewed; 281 patients were surveyed. Authors reported a therapeutic success ranging between 60% and 90%. Despite the limited number of controlled studies, the large experience acquired through 20 years suggests that octreotide is the first-choice antisecretory agent for MBO. As such, octreotide is the only drug approved by the health-care system in Italy for this treatment.

Malnutrition in childhood cancer patients: A review on its prevalence and possible causes - Corrected Proof

2012-01-24

Abstract: Purpose: To perform a systematic literature review for critical evaluation of prevalence and factors contributing to malnutrition in childhood cancer.Methods: A systematic search resulting in 46 suitable articles.Results: Due to lack of uniform criteria and adequate studies, the prevalence rates of malnutrition can only be estimated. Based on strengths and weaknesses of included references, prevalence rates are estimated to be 0–10% for leukemia, 20–50% for neuroblastoma, and 0–30% for other malignancies. Whether energy deficiency or inflammation contributed to malnutrition could not be confirmed because the occurrence of energy deficit (low energy intake, increased metabolic rate) or inflammation (related to cachexia) was not convincing. Also, a relationship between these factors and malnutrition was not studied.Conclusion: Longitudinal studies are needed to determine which children are at risk of malnutrition, and to investigate the impact of energy deficiency and inflammation on the nutritional status and body composition of childhood cancer patients.

Tumour response prediction by diffusion-weighted MR imaging: Ready for clinical use? - Corrected Proof

2012-01-24

Highlights: ► DWI shows potential for response prediction and monitoring. ► Some studies show that low pretreatment ADC is related to response to therapy. ► An increase in ADC during/after treatment is related with response in most studies. ► Validation of DWI is hampered by the lack of reproducibility and standardisation.Abstract: Background: The efficacy of anticancer therapy is usually evaluated by anatomical imaging. However, this method may be suboptimal for the evaluation of novel treatment modalities, such as targeted therapy. Theoretically, functional assessment of tumour response by diffusion weighted imaging (DWI) is an attractive tool for this purpose and may allow an early prediction of response. The optimal use of this method has still to be determined.Method: We reviewed the published literature on clinical DWI in the prediction of response to anticancer therapy, especially targeted therapy. Studies investigating the role of DWI in patients with cancer either for response prediction and/or response monitoring were selected for this analysis.Results: We identified 24 studies that met our criteria. Most studies showed a significant correlation between (changes in) apparent diffusion coefficient (ADC) values and treatment response. However, in different tumours and studies, both high and low pretreatment ADC were found to be associated with response rate. In the course of treatment, an increase in ADC was associated with response in most cases.Conclusion: The potential of DWI for (early) response monitoring of anticancer therapies has been demonstrated. However, validation is hampered by the lack of reproducibility and standardisation. We recommend that these issues should be properly addressed prior to further testing the clinical use of DWI in the assessment of treatments.

Will SBRT replace conventional radiotherapy in patients with low-intermediate risk prostate cancer? A review - Corrected Proof

Stefano Arcangeli, Marta Scorsetti, Filippo Alongi — 2012-01-19

Highlights: ► We present an overview of Stereotactic Body Radiation Therapy for prostate cancer, followed by a critical evaluation of the current literature. ► We highlight the unique suitability of prostate cancer to be treated with hypofractionation (large dose per fraction) due to its intrinsic favourable radiobiology. ► We provide a brief description of the radiation therapy techniques and its evolution. ► We address the cost/effectiveness issue for the cutting-edge technology.Abstract: Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. Emerging data show the safety and efficacy of this treatment modality in prostate cancer. Preclinical data, clinical experience, and challenges are reviewed and discussed.

Target therapy in elderly breast cancer patients - Corrected Proof

2012-01-19

Abstract: Substantial progress has been made in the management of breast cancer by targeting HER2 and VEGF pathways. Although the efficacy and safety of target therapy in breast cancer have been established, no specific phase III trial has addressed these issues in the elderly population and the only data available derive from subanalyses or retrospective series. The aim of this review is to summarize the available evidence in this special population and to encourage further well designed studies in elderly breast cancer patients.

Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): A better mousetrap? A review of the clinical evidence - Corrected Proof

Sai-Hong Ignatius Ou — 2012-01-18

Highlights: ► The development of reversible EGFR inhibitors was a critical step in NSCLC therapy. ► Recently, irreversible and/or multitargeted inhibitors have also been evaluated. ►Clinical trials will help to determine the potential activity of these agents.Abstract: The discovery of activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) in 2004 heralded the era of molecular targeted therapy in NSCLC. First-generation small molecule, reversible tyrosine kinase inhibitors (TKIs) of EGFR, gefitinib and erlotinib, had been approved for second- or third-line treatment of NSCLC prior to the knowledge of these mutations. However, resistance to gefitinib and erlotinib invariably develops after prolonged clinical use. Two second-generation irreversible EGFR TKIs, afatinib (BIBW 2992) and dacomitinib (PF-00299804), that can potentially overcome the majority of these resistances are in late stage clinical development. Here I will review the clinical data of EGFR TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC: whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches.

PET/CT imaging in gynecologic malignancies: A critical overview of its clinical impact and our retrospective single center analysis - Corrected Proof

2012-01-16

Highlights: ► FDG-PET/CT is a valid instrument for the detection of recurrent or metastatic gynaecologic tumours. ► Evidence corroborates FDG-PET/CT's role in ovarian cancer in monitoring response to chemotherapy. ► In uterine cervical carcinoma, FDG-PET/CT is more sensitive than MRI for detecting nodal metastases. ► Retrospective analysis of 116 patients showed FDG-PET/CT was principally useful in the setting of suspected recurrence.Abstract: Gynecologic cancers represent a major global healthcare problem since they are associated with a significant mortality and morbidity. Over the last decade, considerable efforts have been spent in the development and optimization of novel diagnostic modalities to achieve an early diagnosis, aid in choosing appropriate treatment, improving long term surveillance, with the ultimate goal of increasing survival of gynecologic cancer patients. A growing body of evidence defines PET/CT as one of the most powerful tools for tumor, nodal and metastasis (TNM) cancer staging both in pre-treatment and in post treatment follow-up settings. At any phase of cancer evaluation, detection of metastasis represents one of the most critical impediments to the cure of tumor; traditional diagnostic imaging modalities, such as computed tomography (CT), are frequently found to inadequately stage the tumor, based on subsequent outcomes. As a consequence, patients may undergo pointless surgery for disease that could be treated with local medical therapies. In the setting of restaging, the ability to describe primary lesion, lymph nodes, possible metastases to peritoneum, bone, liver, lungs and brain renders PET/CT a potential alternative for a series of tests, including bone scanning, MRI or ultrasound, diagnostic CT, lymph node surgical sampling, that need to be used in combination in order to obtain a level of clinical confidence. In this review, we describe, the theoretical advantage and prognostic implications of PET/CT in the management of gynecologic cancer patients.

Targeted therapies in the treatment of germ cell tumors: The need for new approaches against “orphan” tumors - Corrected Proof

2012-01-10

Highlights: ► GCTs are generally highly sensitive to cisplatin-based chemotherapy and represent a model for curable neoplasms. ► Between 15%–20% of patients with metastatic disease still progress and will die as a consequence of the disease. ► New targeted therapies have been studied in a limited number of patients and the results obtained have been modest. ► Large-scale collaborations will be necessary to study new targeted therapies with clinical and translational objectives. ► Clinical trials with new targeted therapies are ongoing for the treatment of GCTs.Abstract: Germ cell tumors (GCTs) are a heterogeneous group of tumors that are highly clinically relevant to oncologists. GCTs are generally highly sensitive to cisplatin-based chemotherapy and represent a model for curable neoplasms. Cisplatin-based combination therapy followed by surgical resection of the residual tumor is the cornerstone for GCTs treatment.Although the overall cure rate is high for patients with GCTs, patients with a poor prognosis according to International Consensus Criteria or with chemoresistant disease remain a major clinical challenge. Currently, between 15% and 20% of patients with metastatic disease still progress and will die as a consequence of the disease. Therefore, the discovery of new treatment strategies or new drugs based on translational oncology remains a priority for the treatment of patients with cisplatin-refractory disease and those with a poor prognosis. Clinical trials with new targeted therapies are ongoing for the treatment of GCTs. In this article, we review some of the new targeted biologic therapies that act on the most relevant oncogenesis pathways and are in clinical development for the treatment of GCTs.

Life-expectancy of patients enrolled in phase 1 clinical trials: A systematic review of published prognostic models - Corrected Proof

2012-01-09

Highlights: ► Selection of patients for phase I clinical trials remains a critical issue. ► There is no reliable and validated guidance to estimate life-expectancy. ► Numerous scores and models for prediction of overall survival or 90-day mortality have been published. The calibration and the discrimination of these models are not explored. ► None of these models have been definitively validated on an independent cohort. ► A large multicenter study is needed.Abstract: Life-expectancy superior to 3 months is a key-eligibility criterion for contemporary oncology phase 1 trials. Nevertheless, there is no reliable and consensual guidance for estimating this criterion. We have conducted a systematic review of published studies investigating the risk factor for 90-day mortality and the inherent generated scores. Nine studies have been published on this topic. Only two of these prognostic models have been validated on an independent dataset. Most of the models are based on a very subjective and investigator-dependent parameter: the performance status. The predictive performance of these prognostic models is poorly evaluated.

Mechanobiology of tumor invasion: Engineering meets oncology - Corrected Proof

Shawn P. Carey, Timothy M. D’Alfonso, Sandra J. Shin, Cynthia A. Reinhart-King — 2011-12-19

Highlights: ► Tumor invasion, the process by which cells physically dissociate from primary tumors, is a rate-limiting step in metastasis. ► Invasion depends on coordination of intracellular molecular machinery and response to biophysical extracellular cues. ► Mechanobiology and engineering have been used to study physical tumor cell behaviors that comprise the “invasive phenotype”. ► Understanding the invasive phenotype should enable more effective diagnostic and therapeutic strategies in the clinic.Abstract: The physical sciences and engineering have introduced novel perspectives into the study of cancer through model systems, tools, and metrics that enable integration of basic science observations with clinical data. These methods have contributed to the identification of several overarching mechanisms that drive processes during cancer progression including tumor growth, angiogenesis, and metastasis. During tumor cell invasion – the first clinically observable step of metastasis – cells demonstrate diverse and evolving physical phenotypes that cannot typically be defined by any single molecular mechanism, and mechanobiology has been used to study the physical cell behaviors that comprise the “invasive phenotype”. In this review, we discuss the continually evolving pathological characterization and in vitro mechanobiological characterization of tumor invasion, with emphasis on emerging physical biology and mechanobiology strategies that have contributed to a more robust mechanistic understanding of tumor cell invasion. These physical approaches may ultimately help to better predict and identify tumor metastasis.

Therapeutic and prognostic importance of epithelial–mesenchymal transition in liver cancers: Insights from experimental models - Corrected Proof

Olorunseun O. Ogunwobi, Chen Liu — 2011-12-19

Highlights: ► Liver cancers cause significant mortality worldwide. ► Experimental models show that liver cancers are characterized by epithelial-mesenchymal transition (EMT). ► EMT-related markers may have prognostic and therapeutic importance in liver cancers. ► Questions remain as to the definitive role of EMT in human liver cancers. ► Detailed human studies are needed to definitively clarify the role of EMT in human liver cancers.Abstract: Hepatocellular carcinoma (HCC) and hepatic metastases of colon cancers are malignant conditions of the liver that cause significant morbidity and mortality worldwide. Experimental models suggest that both conditions are characterized by epithelial–mesenchymal transition (EMT). Whilst ongoing research efforts aim to definitively clarify its role in human cancer patients, data from experimental models have unraveled a number of potential therapeutic targets as well as markers of prognostic importance. This area of research is generating intense interest amongst both basic scientists and clinicians. Some questions have been answered, but many important issues remain unresolved. We expect that in the near future, studies of human tissues can definitively clarify the role of EMT in the development and progression of human malignant diseases of the liver and that further studies can be carried out to determine how best to target aspects of the process for the treatment of patients with hepatocellular carcinoma and hepatic metastases of colon cancers.

Anti-leukemic properties of IL-12, IL-23 and IL-27: Differences and similarities in the control of pediatric B acute lymphoblastic leukemia - Corrected Proof

Claudia Cocco, Vito Pistoia, Irma Airoldi — 2011-12-16

Highlights: ► We review and discuss the role of IL-12, IL-23 and IL-27 in pediatric B-ALL. ► The cytokines show direct anti-leukemic activity with similar and different mechanisms. ► IL-27 is able to target both B-ALL blasts and TIC and inhibits their spreading in vivo. ► IL-27 appears as a good candidate for B-ALL therapy due to its multifaceted activity.Abstract: B acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy. Although patient cure has reached an excellent rate, a minority of cases relapse and need novel therapies.IL-12, IL-23 and IL-27 belong to the IL-12 superfamily and exert immunological and anti-tumor functions. The latter can be mediated by activation of immune responses or by the direct activity on cancer cells. Recently, the role of IL-12, IL-23 and IL-27 in the control of pediatric B-ALL has been unveiled. Here, we discuss in a translational perspective the role of IL-12 family cytokines in pediatric B-ALL, highlighting similarities and differences in their mechanisms of action.

How to select the optimal therapy for early-stage prostate cancer - Corrected Proof

Marisa A. Kollmeier, Michael J. Zelefsky — 2011-12-09

Abstract: Selecting the “optimal therapy” for the patient with localized prostate cancer may be one of the most challenging medical decisions facing the oncologist. Most patients will have a number of appropriate therapeutic options available to them. Before determining which therapy is most appropriate for a patient, a critical question which needs to be asked is whether any therapy is necessary, especially for those who present with early-stage, low-grade, low-volume disease. Furthermore, given the lack of randomized trials available to guide physicians regarding the superiority of one therapy over another, it is important to consider the different side-effect profiles relevant for each treatment modality. The potential toxicities of therapy impact quality-of-life outcomes and play an important role for most patients in their individual selection of a particular therapy. In addition, there are other important issues that need to be considered, which include the medical condition of the patient and emotional and psychological considerations, as well as family/peer viewpoints or perceived notions of a particular therapy. This review will discuss the relevant issues in the decision making and treatment selection for the patient.

Management of hepatocellular carcinoma with transarterial chemoembolization in the era of systemic targeted therapy - Corrected Proof

Riccardo Lencioni — 2011-12-06

Abstract: The clinical management of hepatocellular carcinoma (HCC) is often complicated by poor liver function. Treatment options for intermediate- and advanced-stage disease are limited. Transcatheter arterial chemoembolization (TACE) is an effective first-line therapy for intermediate-stage HCC. By interrupting blood flow to the tumor and administering concentrated chemotherapy locoregionally, TACE induces necrosis at the tumor site, but may create conditions that permit or encourage angiogenesis and recurrence of the tumor. Combination of TACE with new targeted agents may be an effective way to treat intermediate-stage HCC, particularly in higher risk patients. Because of the efficacy and safety of sorafenib—the first systemic therapy to show significant clinical benefit in advanced HCC—there is great interest in its potential use in combination with existing treatment modalities. The synergistic combination of TACE plus sorafenib represents a promising opportunity for tumor control.

Not all sarcomas developed in irradiated tissue are necessarily radiation-induced – Spectrum of disease and treatment characteristics - Corrected Proof

2011-12-06

Abstract: Background: Sarcomas in irradiated tissue (SITs) are often considered with second cancers, although they usually present distinct dose–response, genetic and clinical patterns. The contribution of radiation in SIT development is likely, but remains unproven in many cases.Materials and methods: We reviewed the literature for published data on SITs.Results: SITs incidence ranged between 0.03% and 0.2%. Median latency was 15years. Angiosarcoma was the second most common subtype after undifferentiated sarcomas of malignant fibrous histiocytoma (MFH). C-Myc overexpression can be used to identify radiation-induced angiosarcoma, and a recently described transcriptomic signature of genes involved in chronic oxidative stress and mitochondrial dysfunction may indicate radiation causality. Osteosarcomas were often associated with genetic predisposition. Five-year survival rates rarely exceeded 30% because the therapeutic possibilities were often limited by the first cancer. Chemotherapy response may differ from that of de novo sarcomas.Conclusion: SITs present different characteristics from non-sarcomatoid second cancers. Reporting of SIT cases and the establishment of tissue and serum banks is necessary to better understand and validate the recently discovered radiation signature.

Missing: A diagnostic technique to enumerate antigen-specific T cells - Corrected Proof

Melinda Shelley Suchard — 2011-12-05

Abstract: T lymphocytes are responsible for immune responses against pathogens, immune surveillance against cancer and maintenance of tolerance to self. While techniques available to detect antigen-specific T cells have been well described, there is a missing technique in our repertoire. While fluorescent multimers can be used for limited research applications, there is no existing technique suitable for detection of antigen-specific T cells in a diagnostic setting. The absence of such a technology has inhibited the search for “correlates of protection” against infectious, autoimmune or malignant disease. This critical review of existing methods will highlight the limitations of the data on which our current understanding of the immune system is based, in an effort to stimulate development of improved techniques.

Oral health status in children with acute lymphoblastic leukemia - Corrected Proof

2011-12-05

Abstract: Leukemia is a malignancy of the bone marrow. Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and accounts for nearly 75% of all newly diagnosed leukemias and 25% of all malignancies in childhood. The aim of the present study was to review the oral health status in children with ALL. Databases were explored using various combinations of the following keywords: “acute lymphoblastic leukemia”, “children”, “inflammation”, “pediatric”, “periodontal disease” and “periodontitis”. Oral inflammatory conditions including chelitis, gingivitis, herpetic gingivostomatitis, mucositis, oral candidiasis, periodontitis and ulcerations are common manifestations in children with ALL.Results: Periodontal inflammatory conditions and oral mucositis were reported to be significantly higher in children with ALL as compared to healthy controls. Tooth morphological disorders including agenesis, microdontia, short roots and developmental defects in the enamel and dentin were more often observed in children with ALL as compared to healthy controls. Children with ALL have a reduced salivary flow rate, which makes them more susceptible to dental caries as compared to healthy children. Malocclusion due to microdontia may also trigger temporomandibular joint disorders in children with ALL; however, this relationship needs further investigations.Conclusion: Oral inflammatory conditions including mucositis and gingivitis are common in children with ALL as compared to healthy children. Tooth morphological disorders including microdontia and enamel and dentin are common manifestations in children with ALL.

Integration of cell biology, pharmacological modeling and statistical analysis: Part I: Cell biology and PK/PD in the Oncology paradigm - Corrected Proof

Revathi Ananthakrishnan, Sandeep Menon — 2011-11-28

Abstract: The motivation of this two-part review article is to provide a comprehensive picture of cancer, cancer drugs and the detection and treatment of cancer. In order to do so, this article integrates the cell biology and biophysics of cancer as well as the modeling of preclinical Oncology drug data and statistical analysis of Oncology clinical trials data. It also discusses novel cancer diagnostic tools and standard and potential treatment options.

Polycomb genes and cancer: Time for clinical application? - Corrected Proof

Francesco Crea, Elisa Paolicchi, Victor E. Marquez, Romano Danesi — 2011-11-23

Abstract: Polycomb group genes (PcGs) are epigenetic effectors, essential for stem cell self-renewal and pluripotency. Two main Polycomb repressive complexes (PRC1, PRC2) mediate gene silencing through histone post-translational modifications.PcGs have been the focus of investigation in cancer research. Many cancer types show an over-expression of PcGs, predicting poor prognosis, metastasis and chemoresistance. Genetic polymorphisms of EZH2 (a PRC2 component) are significantly associated to lung cancer risk. Recently, 3-Deazaneplanocin A (DZNeP) was identified as an efficient inhibitor of PRC2 activity. DZNeP impairs cancer stem cell self-renewal and tumorigenicity.Despite the well-established role of PcGs in cancer stem cell biology, few studies dissected the clinical significance of these genes. In this paper, we explore PcGs as predictive and prognostic factors in oncology, with particular emphasis on what they can add to current biomarkers. We also propose a model for the rational development of DZNeP-based anticancer regimens and suggest the therapeutic applications of this drug.

New perspectives in the treatment of metastatic renal cell carcinoma - Corrected Proof

Jérôme Barrière, Benjamin Hoch, Jean-Marc Ferrero — 2011-11-18

Abstract: Since 2007, the advent of so-called “targeted” therapy has revolutionized the management of renal cell carcinoma (RCC), replacing interferon or interleukin-2 immunotherapy. The present article first reviews the fundamentals of current practice in the management of metastatic-phase RCC. It then goes on to consider the new perspectives opening up in terms of treatment strategy (sequential or combined treatments and new drugs) in what can be seen as a second phase in this ongoing revolution in treatment. In the years to come, the challenge will be to learn to optimize the use of the many drugs available, possibly in association with micro-invasive techniques, so as to achieve the third phase of the revolution: long-term remission in metastatic RCC. The search for factors predictive of response and greater knowledge of tumor biology will be essential steps, yet to be made, toward this goal.

Pleiotropic cellular, hemostatic, and biological actions of Ankaferd hemostat - Corrected Proof

Berat Z. Haznedaroglu, Yavuz Beyazit, Sharon L. Walker, Ibrahim C. Haznedaroglu — 2011-11-14

Abstract: Sustaining hemostasis in clinical hemorrhages is a challenging task and requires extensive effort to stabilize medically hard-to-treat traumatic injuries. Several hemostatic agents are preferred to control external and internal bleedings, yet commercially available products are not sufficiently effective or fast-acting to achieve hemostasis in extreme cases. Ankaferd Blood Stopper (ABS) is a herbal extract traditionally used as a hemostatic agent. Recent studies have shown that ABS could be utilized successfully as a hemostatic agent for the management of clinical hemorrhages when conventional methods were ineffective. This review serves as a basis to provide recent findings on several applications of ABS, specifically preclinical, biological, and clinical studies both in vitro and in vivo. Another section focuses on the ultrastructural morphology and protein network formation of ABS in an effort to understand the hemostatic mechanisms of this unique agent at tissue level.

Secondary malignancies in survivors of breast cancer: How to overcome the risk - Corrected Proof

Mark Shilkrut, Yazid Belkacemi, Abraham Kuten, on behalf of AROME — 2011-11-07

Abstract: Secondary radiation-induced cancers (SRIC) are rare but well-documented as long-term side effects of radiation in a large population of breast cancer survivors. The estimate of the standardized incidence ratio is 1.2, increasing with time elapsed from irradiation, and influenced by age, genetic and environmental backgrounds of the patient and systemic treatments. The majority of SRIC occurs in or close to high-dose treatment volume in the intermediate dose level. It is a dose- and rate-dependent phenomenon that rarely occurs in tissues with a cumulative dose of <3.5Gy. Careful patient selection, thorough treatment planning and modern radiation equipment can reduce the dose to the surrounding tissues and decrease the incidence of SRIC.

Current knowledge and open issues regarding Bevacizumab in gynaecological neoplasms - Corrected Proof

2011-11-07

Abstract: In the last fifty years the combining of different drugs has progressively improved response and survival rates in gynaecological malignancies. Results are, however, far from being satisfactory. Treatments used in cases of advanced or recurrent disease offer limited results in terms of long-term responses and the urgent need for new drugs has prompted researchers to investigate and propose new therapeutic modalities. One of the most important avenues that are being explored is represented by monoclonal antibodies (MoAb) directed against Vascular Endothelial Growth Factor (VEGF).Several antibodies against this target are now available and Bevacizumab appears to be one of the most promising agents. VEGF has been confirmed as an important therapeutic target in several clinical trials and in multiple disease settings, including gynaecological cancers, for its biological and clinical significance in tumour angiogenesis. The binding and blocking of VEGF growth factor is the basis of tumour growth inhibition, since angiogenesis is essential in the process of tumour growth and progression. Several clinical trials have utilized this agent successfully, either alone or in combination with other drugs. Despite initial concerns, adverse reactions have not been significant with side effects being more tolerable than those associated to conventional chemotherapy. Furthermore, the limited toxicity profile of this, as well as other target therapies, allows it to be combined with cytotoxic drugs without the requirement for a significant dose reduction of the latter. This review outlines the rationale for studying this anti-angiogenetic compound, summarizing the existing and emerging clinical evidence related to the use of Bevacizumab in the treatment of gynaecological malignancies, focusing on its potential benefits and adverse effects.

Functional imaging in predicting response to antineoplastic agents and molecular targeted therapies in lung cancer: A review of existing evidence - Corrected Proof

S. Novello, M. Giaj Levra, T. Vavalà — 2011-11-07

Abstract: The increasing use of FDG-PET (18F-2-fluoro-2-deoxy-d-glucose positron emission tomography) imaging in the staging of non-small-cell lung cancer (NSCLC) may result in a significant shift in stage distribution, with an increased percentage of patients staged as having metastatic disease and consequently a higher percentage of patients treated with systemic therapy. The amount of FDG-PET uptake in primary lung lesions has been shown to be correlated with tumour growth rate. Data suggest that tumours with increased glucose uptake are presumably more metabolically active and more biologically aggressive, and standardized uptake value (SUV) at PET may be regarded as a prognostic factor. Growing evidence suggests that PET may be used as a predictive marker to assess the activity of antineoplastic agents, allowing close monitoring of the efficacy of the treatment in order to be able to switch earlier to alternative therapies according to the individual chemosensitivity of the tumour.Currently the value of FDG-PET for monitoring response is complicated by the heterogeneity of the published data on the methods used for FDG quantification and the selection of the primary targets and clinical endpoints. As a result, objective validation of proposed thresholds of responsiveness is lacking.This article discusses the assessment of treatment response in NSCLC patients using functional imaging, and emphasizes advantages and limitations in clinical management.

Hepatosplenic gamma-delta T-cell lymphoma - Corrected Proof

Andrés J.M. Ferreri, Silvia Govi, Stefano A. Pileri — 2011-11-02

Abstract: Hepatosplenic T-cell lymphoma (HSTL) is a rare and aggressive extranodal lymphoma derived mostly from cytotoxic γδ T-cells. The peak incidence is in adolescents and young adults, and is more common in males. Up to 20% of HSTL arise in the setting of chronic immune suppression, most commonly solid organ transplantation or prolonged antigenic stimulation. Patients present with systemic symptoms (fever), abdominal pain, weakness, and marked hepatosplenomegaly in the absence of lymphadenopathy. Patients usually manifest marked thrombocytopenia, often with anaemia and leucopenia, a leukemic phase, and bone marrow involvement in 80% of cases. Lactate dehydrogenase levels are usually markedly elevated.HSTL exhibits a marked chemoresistance to currently used regimens, a rapidly progressive behavior, and dismal prognosis. Patients with post-transplant HSTL exhibit an especially poor outcome. Standard treatment has yet to be established. Anthracycline-based chemotherapy is associated with a satisfactory response in two thirds of patients, but poor long-term results. Complete remission is extremely uncommon, and most patients die from lymphoma within two years of diagnosis. A prognostic correlation between outcome and degree of thrombocytopenia has been reported. Relapsing disease is usually chemorefractory and fast growing, and patients’ performance status and clinical conditions are poor. These aspects, as well as the lack of drugs with proven activity against HSTL, render salvage treatment almost impossible. A few cases of HSTL successfully treated with autologous or allogeneic stem-cell transplantation have been reported. The use of 2′-deoxycoformycin and other targeted therapies, such as alemtuzumab, anti-γδ TCR monoclonal antibodies, and anti-CD44 therapy, have shown promising results in anecdotal reports.

Defining and predicting indolent and low risk prostate cancer - Corrected Proof

Chris H. Bangma, Monique J. Roobol — 2011-10-28

Abstract: The early detection of asymptomatic prostate cancer has led to the increased incidence of tumours that are unlikely to become symptomatic during life, so called indolent cancers. The prediction of low risk and indolent prostate cancer is needed to avoid overtreatment by unnecessary invasive therapies, and select men for active surveillance. Some of the currently available nomograms predicting these low risk tumours have been validated in independent populations. However, assessment to the compliance with their treatment advises based on the calculation of probability are scarce. The ultimate value of nomograms for the urologic practice can only be assessed by analysing their practical implementation.

Adjuvant early breast cancer systemic therapies according to daily used technologies - Corrected Proof

W. Jacot, M. Gutowski, D. Azria, G. Romieu — 2011-10-24

Highlights: ► Various adjuvant breast cancer guidelines are available. ► These consensual statements can be optimized using locally available daily used technologies. ► The conjunction of the Adjuvant! Online tool with additional predictive and prognostic factors, such as the uPA/PAI-1 complex, can be used in the routine clinical decision process.Abstract: Prognosis of early breast cancer patients is significantly improved with the use of adjuvant therapies. Various guidelines have been proposed to select patients who will derive the most benefit from such treatments. However, classifications have limited usefulness in subsets of patients such as those with node negative breast cancer.The 2007 St. Paul de Vence Clinical Practice Recommendations proposed to consider adjuvant therapy in accordance with the 10-year relapse-free survival reduction estimated by Adjuvant! Online. However, many limitations remain regarding the use of Adjuvant! Online. Among them, adverse prognostic and/or predictive factors such as vascular invasion, mitotic activity, progesterone receptor negativity, and HER-2 expression are not incorporated in the routine clinical decision process. Our group has therefore issued guidelines based on the consideration of both Adjuvant! Online calculations and the prognostic and/or predictive effects of these markers. In addition, web-accessible comprehensive tables summarizing these recommendations are provided.

Cancer prevalence and mortality in centenarians: A systematic review - Corrected Proof

Nicholas Pavlidis, Giorgio Stanta, Riccardo A. Audisio — 2011-10-24

Abstract: Life expectancy has dramatically expanded, the global population has aged unprecedentedly and the number of centenarians has significantly increased. The analysis of autopsy series, cancer registries data, vital statistics and surveys specific to this age group allows unique observations with respect to incidence and prevalence, cause of death by cancer, frequency of primary tumours, metastatic patterns, occurrence of incidental cancers and of multiple primary tumours.Data analysis demonstrates how cancer incidence and cause of death present a threefold decrease after age 90 and reach 0–4% above age 100. In addition, the number of metastatic sites are remarkably less and incidental malignant tumours or multiple primary cancers are more frequent, indicating that cancer in centenarians carries a more indolent behaviour.The unique features of malignant tumours in this population is hereby presented and discussed following a systematic review of the available literature.Cancer in the very elderly is relatively uncommon as a disease and as a cause of death. It is characterized by a slow growth and a modest life-threatening potential.

The intersection between cannabis and cancer in the United States - Corrected Proof

Daniel W. Bowles, Cindy L. O’Bryant, D. Ross Camidge, Antonio Jimeno — 2011-10-24

Abstract: In the last 15years there has been a major shift in the laws governing medical use of cannabis in the United States. Corresponding with this change there has been escalating interest in the role that cannabis, commonly referred to as marijuana, and cannabinoids play in the care of patients with cancer. This review will examine cannabis’ and cannabinoids’ current and potential roles in cancer care. Specifically, we will examine five areas of cannabis medicine: (1) pharmacologic properties of cannabis; (2) its potential role in the development of human cancers, particularly smoking-related malignancies; (3) cannabinoids’ potential as anti-cancer therapies; (4) cannabis and cannabinoids in the palliation of common cancer-associated symptoms; (5) current legal status of cannabis for medical purposes in the United States.

Neuro-cognitive impairment in breast cancer patients: Pharmacological considerations - Corrected Proof

Yin Ting Cheung, Wai Keung Chui, Alexandre Chan — 2011-10-20

Highlights: ► Duration of cognitive impairment varied across different generations of chemotherapy regimens. ► Concurrent administration of multiple cytotoxic agents could lead to a synergistic decline on cognition. ► Current clinical evidence is insufficient to evaluate the effects of dose intensities of chemotherapy regimens on cognition. ► More investigations are needed to delineate pharmacological factors as determinants of chemotherapy-associated cognitive changes.Abstract: Post-chemotherapy cognitive impairment has been an issue of concern in cancer survivors. While most reviews are focused on patient-related factors, it is proposed that drug-related factors may also be determinants. The objective of this review is to study the relationship between the types and dose intensities of chemotherapy regimens on cognitive impairment in breast cancer patients through a systematic literature search.Eighteen prospective studies were selected. The types, dose intensities and durations of chemotherapy regimens received by subjects were compared against prevalence results obtained in individual studies. It was observed that the duration of impairment varied across different generations of chemotherapy regimens. Concurrent administration of multiple cytotoxic agents can lead to a synergistic decline on cognition.Current clinical evidence is insufficient to evaluate the relationship between the types, dose intensities of chemotherapy regimens and cognitive impairment. More investigation is needed to examine the role of pharmacological factors in chemotherapy-associated cognitive changes.

Clinico-pathological and biological prognostic variables in squamous cell carcinoma of the vulva - Corrected Proof

2011-10-20

Abstract: Several clinical–pathological parameters have been related to survival of patients with invasive squamous cell carcinoma of the vulva, whereas few studies have investigated the ability of biological variables to predict the clinical outcome of these patients. The present paper reviews the literature data on the prognostic relevance of lymph node-related parameters, primary tumor-related parameters, FIGO stage, blood variables, and tissue biological variables. Regarding these latter, the paper takes into account the analysis of DNA content, cell cycle-regulatory proteins, apoptosis-related proteins, epidermal growth factor receptor [EGFR], and proteins that are involved in tumor invasiveness, metastasis and angiogenesis. At present, the lymph node status and FIGO stage according to the new 2009 classification system are the main predictors for vulvar squamous cell carcinoma, whereas biological variables do not have yet a clinical relevance and their role is still investigational.

The case for wider use of recombinant factor VIII concentrates - Corrected Proof

Cedric Hermans, Hans-Hermann Brackmann, Piercarla Schinco, Günter Auerswald — 2011-10-03

Abstract: The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.

Necroptosis: An emerging form of programmed cell death - Corrected Proof

Wei Wu, Peng Liu, Jianyong Li — 2011-10-03

Highlights: ► Necroptosis is one particular form of programmed necrosis induced by stimulating death receptors with agonists. ► Necroptosis has its own unique signaling pathway which requires the involvement of receptor interaction protein kinase 1 and 3. ► Necroptosis plays an important role in immune system regulation, tissue injury, and cancer development.Abstract: Necrosis plays an important role in multiple physiological and pathological processes. Recently, a relatively new form of necrosis has been characterized as “necroptosis”. Morphologically, necroptosis exhibits the features of necrosis; however, necroptosis exhibits a unique signaling pathway that requires the involvement of receptor interaction protein kinase 1 and 3 (RIP1 and RIP3) and can be specifically inhibited by necrostatins. Necroptosis has been found to contribute to the regulation of immune system, cancer development as well as cellular responses to multiple stresses. In this review, we will summarize the signaling pathway, biological effects and pathological significance of this specific form of programmed cell death.

Early detection, prevention and management of cutaneous adverse events due to sorafenib: Recommendations from the Sorafenib Working Group - Corrected Proof

2011-09-26

Abstract: Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice.

Evolvement of the treatment paradigm for metastatic colon cancer. From chemotherapy to targeted therapy - Corrected Proof

Santiago Aparo, Sanjay Goel — 2011-09-26

Abstract: Colorectal Cancer is the second most common cancer in incidence and mortality in the United States. In spite of current screening strategies 1 out of 5 patients still presents with metastatic disease. During the last 10–15 years there has been significant increase in the availability of chemotherapy options for this disease. The recent introduction of molecular markers to the treatment algorithm allows oncologists to tailor treatments for each particular patient. In the following article we give an overview of the landmark publications that led to our current standards and we give our view on particular situations in which the available evidence is not so helpful in making therapeutic decisions.

Second-line therapy for refractory renal-cell carcinoma - Corrected Proof

Fable Zustovich, Giuseppe Lombardi, Ornella Nicoletto, Davide Pastorelli — 2011-09-23

Abstract: In the last 5 years inhibitors of the VEGF/VEGFR and mTOR pathways have dramatically changed the therapeutic approach to metastatic renal cancer. Randomized controlled trials have shown that six targeted agents – sorafenib, sunitinib, temsirolimus, bevacizumab, everolimus and pazopanib – are able to improve patient outcome. Even if the choice of drug for first-line therapy is quite well defined, to date it is not easy to characterize and evaluate the efficacy of new therapies in second-line treatment. It is not clear whether, after first-line therapy with a VEGF/VEGFR inhibitor, use of mTOR or a second TKI inhibitor should be recommended. In this review we report on current evidence supporting the use of targeted agents in second-line therapy. Therefore we try to combine current clinical results with a practical clinical approach, with the goal of evaluating the best clinical decision for different clinical situations.

May intra-operative radiotherapy have a role in the treatment of prostate cancer? - Corrected Proof

2011-09-19

Abstract: Treatment of locally advanced prostate cancer is still a challenge. Combined treatments including hormone therapy, radiotherapy, and/or surgery can achieve less than 50% of disease free survival at 10 years. Almost 50% of patients with locally advanced disease after radical prostatectomy experience local relapse and biochemical failure occurs up to 70% of cases after radiotherapy and hormone therapy. Postoperative radiotherapy has recently demonstrated to improve biochemical and clinical outcome in pT3 and/or positive margin tumors in 3 large randomized trials. Therefore, combining surgery and intra-operative radiotherapy (IORT) might be of value in this patient population. Recently, a number of studies have shown the feasibility of IORT, delivered with dedicated linear accelerators, combined or not with external beam radiotherapy with the aim of improving clinical outcome and possibly shortening overall treatment time. Preliminary clinical results look encouraging and could be the premise for future controlled prospective phase III trials.

Chemotherapy-induced peripheral neurotoxicity (CIPN): An update - Corrected Proof

Andreas A. Argyriou, Jordi Bruna, Paola Marmiroli, Guido Cavaletti — 2011-09-12

Highlights: ► We revise the current knowledge in chemotherapy-induced peripheral neurotoxicity. ► Several effective antineoplastic drugs are harmful to peripheral nerves. ► Incidence of the damage is poorly known. ► Chemotherapy-induced peripheral neurotoxicity can be dose-limiting. ► No treatment is available.Abstract: The peripheral nervous system can be vulnerable to the toxic action of several drugs since it is not protected as effectively as the central nervous system from noxious exogenous agents. Drug-induced neurotoxicity can affect the nerve fibers or the neuronal bodies (generally the dorsal root ganglia of the primary sensory neurons). Among the neurotoxic drugs antineoplastic agents represent a major clinical problem, given their widespread use and the potential severity of their toxicity. In fact, the peripheral neurotoxicity of antineoplastic agents frequently represents one of their dose-limiting side effects. Moreover, even when antineoplastic agents’ peripheral neurotoxicity is not dose-limiting, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. Among the anticancer chemotherapy drugs, platinum derivates, antitubulins, thalidomide and bortezomib can induce the most severe effects on the peripheral nervous system of the treated patients. Therefore, we will review the features of chemotherapy-induced peripheral neurotoxicity (CIPN) resulting from the administration of these drugs with a focus on new classes of promising antineoplastic agents, such as epothilones and proteasome inhibitors.

Strategies for maintenance therapy in advanced non-small cell lung cancer: Current status, unanswered questions and future directions - Corrected Proof

Ana Custodio, Javier de Castro — 2011-09-12

Abstract: Systemic chemotherapy (CT) with platinum-based doublets result in modest improvements in both overall survival (OS) and quality of life in good performance status patients with advanced non-small cell lung cancer (NSCLC). However, although substantial progress has been made in the therapeutic options currently available for these patients, the overall outcome remains poor.Maintenance therapy for patients who achieved at least stable disease after first-line treatment has been an area of intense investigation in recent years as a way of improving outcomes in metastatic NSCLC. Several alternative strategies for prolongation of initial treatment have been evaluated. These include the prolongation of the initial combination CT regimen until disease progression, unacceptable toxicity or a predefined greater number of cycles, continuation with a lower intensity version of the first-line CT regimen or administration of a new active agent immediately after completion of the first-line therapy (switch-maintenance or early second-line therapy). Treatments that have been studied in randomized trials to date include CT, molecularly targeted agents, and immunotherapy approaches. Phase III trials have not revealed a survival benefit for extended first-line CT with combination regimens for more than 4–6 cycles. Nevertheless, early second-line therapy with pemetrexed in nonsquamous tumours and erlotinib have demonstrated to improve OS results, especially in select patient groups characterized by histology and/or molecular profile. This article reviews recent data with maintenance therapy in advanced NSCLC and discusses the implications for routine patient care and future drug development.

Nilotinib as frontline and second-line therapy in chronic myeloid leukemia: Open questions - Corrected Proof

2011-09-07

Abstract: Nilotinib is a second generation ABL tyrosine kinase inhibitor (TKI) that exerts major anti-leukemic effects in newly diagnosed patients with chronic myeloid leukemia (CML) as well as in most patients with imatinib-resistant CML. In freshly diagnosed patients, the anti-leukemic activity of nilotinib exceeds the efficacy of imatinib, and although long-term data for nilotinib are not available yet, the drug has recently been approved for firstline treatment of chronic phase CML in various countries. Still however, several questions concerning the optimal dose, follow-up parameters, long-term safety, and patient selection remain open. Likewise, it remains uncertain whether both Sokal low-risk and high-risk patients should receive nilotinib as frontline therapy in the future. Another question is whether nilotinib can completely eradicate CML in a subset of patients. Furthermore, it remains unclear whether and what comorbidity must be regarded as relative or absolute contra-indication for this TKI. To discuss these issues, the Austrian CML Working Group organized a series of meetings in 2010. In the current article, the outcomes from these discussions are summarized and presented together with recommendations for frontline use of TKIs in various groups of patients with CML. These recommendations should assist in daily practice as well as in the preparation and conduct of clinical trials.

Osteosarcomas of the mandible: Are they different from other tumor sites? - Corrected Proof

2011-08-25

Abstract: Background: Osteosarcomas of the mandible (MOS) affect 1/10millionpersons/year, mostly the young adult. Due to lack of specific data, the treatment of MOS is extrapolated from that of extragnathic OS but varies widely between institutions.Materials and methods: We aimed at providing a focused description of MOS histologies and grades through the English literature, at determining the evidence-based role of chemotherapy, of adjuvant radiation therapy and the potential of reconstructive surgery tailored through modern pre-operative multi-modal imaging.Results: The estimated proportion of high grade MOS was 58%. However, low-grade MOS may be underestimated as they are mostly reported as case reports. The intermediate grade was hardly found in the literature. Estimated weighted-mean proportions of chondroblastic and osteoblastic MOS were 37% and 46%, respectively. Multimodal imaging modalities including MRI has a great potential for accurate pre-operative assessment of tumor extensions into bone and soft tissues. Surgery is the mainstay of treatment and margins the most important factor. The role of neoadjuvant chemotherapy in treating occult systemic metastases and in increasing the probability of clear margins is controversial, as well as the histology-dependent response to chemotherapy. The role of adjuvant radiotherapy (mostly proposed for positive margins) and/or adjuvant chemotherapy is still controversial. Crude survival is around 77% and local control around 67%. Local failure is the main cause of death in MOS compared to extragnathic sites.

Building the bridge between rhabdomyosarcoma in children, adolescents and young adults: The road ahead - Corrected Proof

2011-08-01

Highlights: ► Rhabdomyosarcoma (RMS) mainly affects children, but also adolescents and (young) adults (AYA). ► As compared to children improvement in survival in AYA lags behind. ► AYA with RMS should be treated in studies whenever available. ► This review provides an overview of RMS at different ages. ► We propose age-independent global collaboration for treatment of RMS.Abstract: Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma that mainly affects children, but also occurs in adolescents and (young) adults (AYA). Despite dramatic survival improvements reported by international study groups in children over the past decades, the awareness of a dismal outcome for older patients with RMS has grown. In contrast to the world-wide organization of care for children with RMS, standard care in adults lags behind. A step forward in RMS management for patients of all ages is urgently needed. Both paediatric oncologists and medical oncologists are essential players in development of a concept of RMS care, but bringing two worlds together seems not so easy. This review provides an overview which highlights the similarities and differences in children and adults with RMS. Furthermore, it comes up with a novel concept to overcome the virtual gap between the treatment approach of children and AYA with RMS.

On the dual roles and polarized phenotypes of neutrophils in tumor development and progression - Corrected Proof

H. Piccard, R.J. Muschel, G. Opdenakker — 2011-07-28

Abstract: Inconsistencies plague our understanding of the role of neutrophils in cancer and the literature provides evidence for a duality in neutrophil activity on the outcome of cancer. Here, the different effects of neutrophils during the multiple subprocesses of cancer development and progression are overviewed, in order to gain insight into the features of both antitumoral and protumoral tumor-associated neutrophils (TAN). Neutrophils can counteract the progression of malignancies through tumor cytotoxicity, tumor rejection and enhancement of antitumoral immune memory. These cells have recently been phenotypically denominated N1 neutrophils. Recent studies indicate that cytokines, such as TGF-β and IFN-β, are involved in directing neutrophil polarization by the tumor microenvironment. With the opposite polarity, N2 neutrophils may be detrimental for the host and beneficial for tumor growth, invasion and metastasis, e.g. through proteolysis of extracellullar matrix components, promotion of angiogenesis and mediation of immunosuppression.

Her-2/neu gene amplification and over-expression in stomach and esophageal adenocarcinoma: From pathology to treatment - Corrected Proof

2011-07-25

Abstract: Discovery of the over-expression of Her-2/neu or the amplification of its regulatory gene in stomach and esophageal cancer has resulted in targeted treatment directed at this protein. The fact itself and its consequences have been the topic of an abundance of studies and clinical trials. In the present report we review the current state of the art as regards diagnosis of the over-expression and amplification of Her-2/neu, its inhibition as a new therapeutic concept, treatment toxicity, and the development of resistance to Her-2/neu as a limiting factor in stomach and esophageal adenocarcinoma.

End-of-life care across Southern Europe: A critical review of cultural similarities and differences between Italy, Spain and Portugal - Corrected Proof

2011-07-11

Abstract: Evidence from a range of sources demonstrates that end-of-life (EoL) care practices and preferences vary across countries; culture is consistently one of the main explanations given for this. In order to understand how cultural factors are used to explain similarities and differences in EoL care between Spain, Italy and Portugal, database and hand searches were performed and cross-cutting core themes identified. Similarities included higher proportions of people who wished to die at home than actually died at home, a persistent trend for partial disclosure in Italy and Spain, low use of advance directives, and low incidence of all medical EoL decisions (with the exception of terminal sedation) compared to northern European countries. The role of religion and the importance of family ties were the two main cultural factors used to explain the similarities. Further research is needed in order to interpret the important differences that were also found.

Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: A critical review - Corrected Proof

Camillo Porta, Cezary Szczylik, Bernard Escudier — 2011-07-06

Abstract: The introduction of novel anti-angiogenic therapies has greatly improved the outcome of patients with metastatic renal cell carcinoma (mRCC). The use of these therapies in combination or sequentially is proposed to provide greater efficacy.We have reviewed completed and ongoing clinical trials in mRCC that have reported efficacy and/or safety data of novel therapies used in combination or sequentially.Bevacizumab appears to be a useful partner when combined with interferon (IFN), while controversial results have been reported when combined with temsirolimus and everolimus. Other combinations appear to have unacceptable tolerability or require dose or schedule optimization. Sequencing data provide a clear indication that multiple lines of treatment may extend survival. The ‘ideal’ sequence, however, is still unknown.In conclusion, novel therapies used in combination or sequentially have potential to provide optimised treatment and patient outcomes in mRCC. The results from ongoing/planned trials are expected to help shape future therapy.

Primary plasma cell leukemia in the era of new drugs: Has something changed? - Corrected Proof

2011-06-30

Abstract: Primary plasma cell leukemia (PPCL) is a rare and aggressive variant of multiple myeloma. This disease is associated with a very poor prognosis, and unfortunately it has not significantly improved during the last three decades. Autologous stem cell transplantation is generally recommended in eligible patients, but survival in transplanted PPCL patients is significantly lower than that of multiple myeloma. Recent preliminary data indicate that new drugs, in particular lenalidomide and bortezomib, could significantly improve the clinical outcome of PPCL, increasing response rate and duration, as well as survival. In this review we report an updated literature analysis about the current therapeutic scenario of PPCL, with a particular focus on the use of novel agents.