Critical Reviews in Oncology / Hematology - Articles in Press

Current issues in combined modality therapy in locally advanced head and neck cancer - Corrected Proof

Anthony J. Cmelak — 2012-05-17

Abstract: Curative treatment for patients with locally advanced squamous cell carcinomas of the head and neck (SCCHN) is complex and multidisciplinary. Our understanding of the optimal management of this disease has improved over the years, incorporating refined surgical approaches, better radiotherapy delivery methods, and greater use of systemic therapies. Investigation into shifting epidemiology patterns has uncovered two biologically and clinically distinct diseases: the smoking-related entity and the increasingly common malignancy associated with human papilloma virus (HPV). Prognosis favors the latter, driving newer investigations into dose de-intensification to limit toxicities in patients with HPV-driven disease, and alternatively intensifying treatment to improve tumor control in those with a significant smoking history. In this review, I describe the most recent progress in the multi-modal integration of radiotherapy and chemoradiotherapy, and the role of targeted agents and personalized therapy, and conclude with a discussion of the relevance of these innovations with respect to HPV tumor status.

Brain metastases from gastrointestinal tumours: Tailoring the approach to maximize the outcome - Corrected Proof

2012-05-14

Abstract: Brain metastases from the gastrointestinal cancers (GI) are uncommon, but their incidence is constantly increasing due to several reasons, including improved systemic therapy and survival. Nevertheless, the average outcome of these patients is poor and related to patients’ or disease characteristics, and to the availability of treatment options. Because of the lack of evidence-based recommendations, no optimal treatment strategy has been defined. The approach to brain metastases remains often tailored, and the action plan is selected on the basis of their number, size and location, the presence of symptoms and the extra-cranial disease status. Clinical prognostic factors have been identified and grouped into index scores that can be helpful in the treatment decision making. At the same time, molecular factors contributing to brain metastases are being revealed, and the role of the unique brain microenvironment is beginning to be investigated. The aim of this review is to present and discuss available data on brain metastases from GI cancers.

Central nervous system chemotoxicity during treatment of pediatric acute lymphoblastic leukemia/lymphoma - Corrected Proof

2012-05-14

Abstract: In the last decades, increasing success rates are being obtained in the chemotherapy of pediatric leukemia and lymphoma. However, the cornerstone of this treatment is still formed by a reduced number of drugs with a highly toxic profile. In particular, central nervous system complications remain a challenging clinical problem, requiring rapid detection and prompt treatment to limit permanent damage. Furthermore, clinicians are often challenged to discriminate between CNS involvement by the disease, toxicity of drugs or infections.This clinically oriented review will help recognize and handle the main neurologic adverse effects induced by chemotherapy in pediatric patients with lymphoblastic leukemia/lymphoma. Different clinical entities and putative drugs involved are discussed in each chapter, with clinical cases illustrating the most relevant and challenging events. In addition, specific clinical-radiological patterns of some of these neurologic events are detailed. Finally, the role of pharmacogenetics, with special focus on those polymorphisms that could help explain the occurrence of neurotoxicity, is also discussed.

Angiogenesis: A promising therapeutic target for ovarian cancer - Corrected Proof

A. Bamias, S. Pignata, E. Pujade-Lauraine — 2012-05-10

Abstract: Ovarian cancer is the leading cause of death from gynecological cancers. Primary treatment of advanced ovarian cancer (FIGO stages III and IV) until recently consisted of cytoreductive surgery and paclitaxel/carboplatin chemotherapy. The results of two randomized studies, showing prolongation of progression-free survival (PFS) by the addition of the anti-VEGF monoclonal antibody, bevacizumab, led to the approval of this agent for first-line treatment of this disease and indicate that angiogenesis is a promising therapeutic target. Angiogenesis is essential for oncogenesis but also the viability and expansion of ovarian cancer. Specifically, VEGF is involved in the formation of ascites and has a direct effect on ascites tumor cells as well as an immunosuppressive function. Apart from VEGF, PDGF, FGF and angiopoietins present a therapeutic interest. We are reviewing the results of published clinical studies using anti-angiogenic factors in advanced ovarian cancer.

Cancer chemotherapy: A critical analysis of its 60 years of history - Corrected Proof

Darío Galmarini, Carlos M. Galmarini, Felipe C. Galmarini — 2012-04-30

Abstract: Chemotherapy has already proven widely effective in the treatment of cancer, occupying a prominent place in the current therapeutic arsenal. However, in recent years, there has been a plateau in the evolution of the clinical results obtained with this modality treatment. In some cases, the limitations of chemotherapy observed during the early days still apply. These facts forced us to do a thorough analysis of what happened in the past 60years. We have observed that each major advance obtained in this field was based on empirical clinical observations. We thus believe that the current results of old or new agents can only be improved by understanding the natural history of each specific cancer subtype at the clinical level and by overcoming the physiological barriers involved in chemotherapy failure. This strategy will surely allow us to enlarge the list of curable cancers by chemotherapy.

Comparison of the efficacy and safety of single-agent and doublet chemotherapy in advanced non-small cell lung cancer in the elderly: A meta-analysis - Corrected Proof

2012-04-25

Abstract: Background: In patients with advanced non-small cell lung cancer (NSCLC) aged more than 70 years, the benefit-to-risk ratio of doublet chemotherapy vs single-agent is not established.Methods: We performed a meta-analysis (MA), with a PubMed query using keywords simultaneously (Randomized controlled trial, Aged, Anti-neoplastic combined chemotherapy protocols/therapeutic use, Carcinoma, Non-small cell lung/drug therapy). Abstracts from ASCO, WCLC, and ESMO proceedings were reviewed. Articles were also obtained by cross-checking references. Third-generation agents (gemcitabine, vinorelbine, paclitaxel, docetaxel) in combination with or without platinum were included. The efficacy outcomes were Overall Response Rate (ORR) and 1-Year Overall Survival (OS). We used EasyMA software and a random-effect model in case of heterogeneity.Results: This MA comprised 10 studies including 2605 patients (mean age 74; 1866 men and 620 women; 654 stage IIIB and 1677 stage IV; 839 squamous cell cancers, 968 adenocarcinomas, 521 other pathological types). One-year OS (including the last trial by Abe) did not significantly improve for doublets compared with single-agents (HR 0.92; 95% Confidence Interval or CI: 0.82–1.03) whereas it improved significantly before inclusion of this last study, when the study by Quoix et al., the most favorable to doublets, was included. However, doublet chemotherapy significantly improved ORR after inclusion of Abe study (HR 1.51; 1.22–1.86; p<0.001). OS was not significantly improved, neither by doublets including platinum (HR 0.90, 0.70–1.16), nor by those without platinum (HR 0.94, 0.84–1.07). ORR, but not OS, was improved by doublets including a taxane (docetaxel and paclitaxel) (HR 1.72; 1.28–2.33) except for paclitaxel with a significant OS and ORR benefit. All-grade neutropenia thrombocytopenia and anemia were significantly more frequent with doublets than with single-agents (HR 1.26, 1.15–1.39; 1.75, 1.11–2.77 and 1.33, 1.17–1.52 respectively). Grade 3/4 thrombocytopenia and anemia but not neutropenia were significantly more frequent with doublets (HRs 2.13, 1.01–4.49 and 1.84, 1.29–2.63 respectively).Conclusion: Compared with single-agents, doublets significantly improved ORR but not OS. They induced significantly more frequent thrombocytopenia and anemia. The benefit-to-risk ratio of doublets in advanced NSCLC might be more favorable than that of single agents, based on ORR but not OS.

Clinical nutrition, body composition and oncology: A critical literature review of the synergies - Corrected Proof

Nathalie Jacquelin-Ravel, Claude Pichard — 2012-04-23

Highlights: ► Body composition should replace weight loss to define the nutritional status. ► Obesity and cachexia may occur simultaneously. ► Sarcopenia is the only significant predictor of chemotoxicity. ► Body composition techniques have a demonstrated positive impact in cancer treatment. ► Nutrition is not a routine care, needs to be patient-specific and fine-tuned.Abstract: Purpose of the research: Review the oncology and clinical nutrition literature to highlight the synergies between those two subjects. This review focuses on diagnostic of lean body wasting and the recent improvements in measuring body composition to monitor the response to nutrition during optimal oncology treatment.Principal results: Nutrition support in cancer patients has made major progresses. A variety of advanced tools allow monitoring and explaining weight loss, body composition changes and metabolic alterations. Body composition is more accurate than body surface area to determine chemotherapeutic drug dosing. As with any therapeutic approach, clinical nutrition has a better risk-benefit ratio if implemented when indicated rather than used routinely. Body composition measurements are helpful for a better understanding of the host-tumor interactions during cancer treatment and nutrition support.Major conclusions: Nutrition support based on body composition analysis may significantly contribute to optimize current oncology treatment and clinical outcomes.

Turning promise into progress for antiangiogenic agents in epithelial ovarian cancer - Corrected Proof

2012-04-23

Abstract: Despite efforts to improve chemotherapeutic efficacy in epithelial ovarian cancer, outcome for patients with advanced disease has remained unchanged since the introduction of standard carboplatin and paclitaxel. Interest has therefore shifted toward molecularly targeted therapies that interfere with important features of ovarian carcinogenesis, such as angiogenesis. Several angiogenesis inhibitors, targeting vascular endothelial growth factor (VEGF) ligands (bevacizumab, VEGF-Trap) or their receptors (VEGFR-targeted tyrosine kinase inhibitors) have been clinically evaluated. These agents demonstrated efficacy in phase II clinical trials. Results from phase III trials, in which bevacizumab was added to standard frontline chemotherapy, show a modest effect. Although the initial expectations for angiogenesis inhibitors have been tempered, further research is warranted to define their precise place in the treatment of ovarian cancer. This review summarizes the performed and ongoing studies with regard to angiogenesis inhibitors in ovarian cancer, and the available data on biomarkers for response prediction. Preclinical studies evaluating alternative angiogenesis inhibitors will also be discussed.

Management of “unfavourable” carcinoma of unknown primary site: Synthesis of recent literature - Corrected Proof

2012-04-13

Abstract: Carcinomas of unknown primary (CUP) approximately represent 2–3% of all adult cancers. Various clinicopathological subsets of CUP have been identified, which may be treated with tailored approaches. Nevertheless, 80% of CUP do not fall into these subsets. Even when at least 4 prognostic models have been developed and validated in independent patient cohorts, there is no consensus or reliable guidance for estimating the prognosis of these “unfavourable” CUP. Consequently, targeting patients who benefit from palliative chemotherapy is difficult. Thirty-eight phase II trials were published between 1997 and 2011; a systematic analysis of these trials did not allow the recommendation of any of the tested regimens as a standard of care. Currently, there is only one published phase III clinical trial (Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan); without significant difference between both regimens. Thus, with the promise of molecular profiling, we are waiting for a large collaborative clinical trial that validates the concept of targeted treatment in this population of patients with “unfavourable” CUP.

Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: Where are we now and where are we going? - Corrected Proof

2012-04-12

Abstract: Endocrine therapy is the most important systemic therapy for hormone receptor positive breast cancer; however, some patients with ER+ breast cancer show intrinsic resistance to endocrine therapy, whereas others develop acquired resistance. Preclinical models have shown that endocrine resistance is associated with enhanced expression of membrane growth factor pathways or activation of various intracellular pathways involved in signal transduction and cell survival. Despite encouraging preclinical data, clinical trials investigating the combination of endocrine therapy with trastuzumab or the TKIs gefitinib, erlotinib and lapatinib have yielded varied results. This may be related to some limitations in the studies conducted so far: lack of appropriate patient selection and stratification based on previous endocrine exposure and/or sensitivity; lack of identification of a molecular biomarker; lack of appropriate clinical endpoints in the trial design.More promising results come from clinical studies which have focused on novel agents such as the mTOR inhibitor everolimus. The two randomized trials (BOLERO-2 and TAMRAD) evaluating everolimus±endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival for the combination compared to the endocrine therapy alone.The data reported so far show that the combination of target agents with endocrine therapy is effective in overcoming acquired resistance in patients with hormone receptor positive metastatic breast cancer. However, this therapeutic strategy is not yet a standard treatment for this patients. Application of more rigorous trial design, tumor and patient selection criteria will be important to better understand the complexity of endocrine resistance.

Expression, prognostic and predictive impact of VEGF and bFGF in non-small cell lung cancer - Corrected Proof

2012-04-11

Abstract: Despite major advances in cancer therapeutics, the prognosis for lung cancer patients is still poor and the median survival for patients presenting with advanced non-small cell lung cancer (NSCLC) is only 8–10months. Angiogenesis is an important biological process and a relatively early event during lung cancer pathogenesis. Anti-angiogenic agents are used in treating patients with NSCLC, and their molecular biomarkers are also being assessed to predict response. A better understanding of the biology of angiogenesis in NSCLC may reveal new targets for treating this malignancy. In this article, we review the expression and prognostic impact of the angiogenic growth factors, vascular endothelial growth factor and basic fibroblast growth factor, in NSCLC.

The expanding options for front-line treatment in patients with newly diagnosed CML - Corrected Proof

Javier Pinilla-Ibarz, Ian Flinn — 2012-04-09

Abstract: The past decade has seen remarkable advances in the treatment of chronic myeloid leukemia (CML). The discovery of the underlying cause of CML, a chromosomal translocation resulting in the expression of an aberrant tyrosine kinase, has enabled the rational development of targeted therapy with tyrosine kinase inhibitors (TKIs). The first available TKI, imatinib, dramatically improved survival rates and demonstrated the potential for long-term treatment. A number of additional strategies have been tested to further maximize outcomes in patients with newly diagnosed CML, including newer TKIs, imatinib dose escalation, and combination therapy. The advanced, more potent TKIs, nilotinib and dasatinib, have proven effective for newly diagnosed patients and for those who experience inadequate response or intolerance to imatinib. Randomized phase 3 studies have shown that nilotinib and dasatinib are more efficacious than imatinib in achieving primary study endpoints. Nilotinib was superior to imatinib in the rate of major molecular response at 12 months; dasatinib was superior to imatinib in the rate of complete cytogenetic response by 12 months. These phase 3 studies are ongoing to further define longer-term efficacy and safety. Research on additional contributing signaling pathways in CML, T315I mutations, and other causes of treatment resistance has identified additional potential treatments that are now in early stages of clinical development, with encouraging preliminary results. With continued advances, it is conceivable that the ultimate goal – a cure for CML – is in our sights.

Tailored strategies for radiation therapy in classical Hodgkin's lymphoma - Corrected Proof

Stephanie A. Terezakis, Yvette L. Kasamon — 2012-04-05

Abstract: Radiotherapeutic advances have contributed to the evolution of Hodgkin's lymphoma (HL) treatment paradigms. A reduction in radiation therapy (RT) field size and dose has the potential to significantly impact the therapeutic ratio by diminishing late toxicities while maintaining curability. Substantial progress in risk stratification has contributed to the development of tailored RT strategies which address both field design as well as dose. Technologic improvements have also enhanced the ability to adapt the RT technique to the individual patient. The refinement of the RT approach and its incorporation into current combined modality strategies in adult classical HL is the subject of ongoing investigation and is critically reviewed.

Symptoms tell it all: A systematic review of the value of symptom assessment to predict survival in advanced cancer patients - Corrected Proof

2012-04-02

Abstract: Purpose: To determine the prognostic meaning of symptoms in patients with advanced cancer.Design: Medline, Embase, Cochrane and Cinahl databases were systematically explored. The predicting symptoms were also evaluated in the three stages of palliative care: disease-directed palliation, symptom-oriented palliation and palliation in the terminal stage.Results: Out of 3167 papers, forty-four papers satisfied all criteria. Confusion, anorexia, fatigue, cachexia, weight loss, cognitive impairment, drowsiness, dyspnea, dysphagia, dry mouth and depressed mood were associated with survival in ≥50% of the studies evaluating these symptoms. Multivariate analysis showed confusion, anorexia, fatigue, cachexia, weight loss, dyspnea and dysphagia as independent prognostic factors in 30–56% of the studies.In the stage of disease-directed palliation anorexia, cachexia, weight loss, dysphagia and pain and in the stage of symptom-oriented palliation confusion, fatigue, cachexia, weight loss, dyspnea, dysphagia and nausea were shown to be independent predictors of survival in >30% of the studies.Conclusion: Symptoms with independent predictive value are confusion, anorexia, fatigue, cachexia, weight loss, dyspnea and dysphagia. New insights are added by the variance between the three palliative stages.

The ticking time-bomb of asbestos: Its insidious role in the development of malignant mesothelioma - Corrected Proof

Anthony Linton, Janette Vardy, Stephen Clarke, Nico van Zandwijk — 2012-03-29

Abstract: The relationship between asbestos exposure and malignant mesothelioma (MM) has been well established. Despite bans on asbestos use in an increasing number of nations, the prolonged latency from exposure to diagnosis, and the ongoing presence and use of these dangerous fibres, have led to the increasing prevalence of this deadly disease worldwide. Whilst occupational contact has been implicated in the bulk of diagnosed cases over the past 50 years, a significant proportion of disease has been linked to para-occupational, domestic and environmental exposure. In this review, we will provide an update on the impact of historical and ongoing asbestos contact in both occupational and non-occupational settings. Furthermore, we will address the unresolved controversies surrounding the use of chrysotile asbestos, the effect of gender and genetics on development of this disease, childhood mesothelioma and co-aetiological factors including SV40 exposure.

Anaplastic large cell lymphoma, ALK-positive - Corrected Proof

Andrés J.M. Ferreri, Silvia Govi, Stefano A. Pileri, Kerry J. Savage — 2012-03-22

Highlights: ► Anaplastic large cell lymphoma ALK+ is an aggressive CD30+ T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene. ► This lymphoma occurs in young subjects, and frequently presents at an advanced stage, with systemic symptoms and extranodal involvement. ► It has the best prognosis among T-cell lymphomas. First-line doxorubicin-based chemotherapy is associated with a 90% ORR, and a 5-year OS of 70%. ► High-dose chemotherapy and ASCT lead to favourable results in patients in first remission, but superiority to standard chemotherapy is unproven. ► The development of novel therapies targeting CD30 and ALK appear promising.Abstract: Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) is an aggressive CD30-positive T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene and the expression of ALK protein. No particular risk factor has been clearly identified for ALCL. ALK+ ALCL shows a broad morphologic spectrum, but all cases contain a variable proportion of cells with eccentric, horseshoe- or kidney-shaped nuclei often with an eosinophilic region near the nucleus (hallmark cells). Five morphologic patterns can be recognized. ALK+ ALCL occurs in young subjects (median age ∼35years), with male predominance, and frequently presents at an advanced stage, with systemic symptoms and extranodal involvement. Near 40% of patients are low risk according to the International Prognostic Index (IPI). Overall, the prognosis of ALK+ ALCL is remarkably better than other T-cell lymphomas. The IPI and the PIT scores in general predict survival in patients with ALK+ ALCL. Standard first-line treatment for ALK+ ALCL consists of doxorubicin-containing polychemotherapy, which is associated with an overall response rate of ∼90%, a 5-year relapse-free survival of ∼60%, and a 5-year overall survival of 70%. Excellent results have been reported with a variety of anthracycline-based chemotherapy regimens including CHOP, CHOEP or MACOP-B. Consolidative high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) has also been evaluated in patients in first remission with favourable results, however, superiority to standard chemotherapy is unproven and this approach remains investigational. Following universally accepted guidelines for the treatment of failed aggressive lymphomas, HDC/ASCT can effectively salvage a proportion of patients with relapsed or refractory ALK+ ALCL. Recently, the development of novel therapies targeting CD30 and ALK appear promising.

Update on the optimal management of patients with colorectal liver metastases - Corrected Proof

Steven R. Alberts — 2012-03-19

Abstract: Patients with colorectal liver metastases represent a distinct subset of metastatic colorectal cancer. Optimal management requires a multidisciplinary approach, local and systemic. Curative hepatic surgery is standard for resectable cases, but unfortunately, the majority of patients are not initially resectable due to the size, location, and/or extent of disease, inadequate remnant liver volume, or comorbidities. Other local approaches may be complementary (such as portal vein embolization) or alternative (such as ablation, hepatic arterial infusion, selective internal radiation therapy, and stereotactic body radiotherapy) to surgery. Systemic therapy can downsize disease, allowing surgical resection and, potentially, long-term survival, but it must be balanced against the potential for hepatotoxicity. Current standard approaches including cytotoxics and biologics, such as bevacizumab and particularly anti-epidermal growth factor receptor therapy, improve response rates and may enhance downsizing and resection rates. Optimization of local therapies and systemic conversion strategies via controlled, randomized trials is still a pending question.

HPV-related (pre)malignancies of the female anogenital tract in renal transplant recipients - Corrected Proof

F. Hinten, K.A.P. Meeuwis, M.M. van Rossum, J.A. de Hullu — 2012-03-19

Abstract: Renal transplantations (RTs) are performed routinely in many countries. After RT, the administration of lifelong immunosuppressive therapy is required. As a consequence, renal transplant recipients (RTRs) have a high risk to develop virus-associated (pre)malignancies, such as Human papillomavirus (HPV) related anogenital (pre)malignancies. It is known that the majority of the RTRs are infected with HPV and that these women have a 14-fold increased risk of cervical cancer, up to 50-fold of vulvar cancer and up to 100-fold of anal cancer. Often, treatment of these lesions requires concessions and may be suboptimal as radiation therapy and extensive surgery may damage the renal transplant. Therefore, prognosis may be compromised due to inadequately treated malignancies. Especially for these immunocompromised patients prevention is of utmost importance. Yearly cervical cancer screening for RTRs is advised, but appears to be executed poorly. For the future, optimizing screening and prevention of anogenital (pre)malignancies is an important issue for women after RT. This review gives a broad overview of all aspects regarding HPV-related (pre)malignancies of the female anogenital tract in RTRs.

Metabolomics in cancer: A bench-to-bedside intersection - Corrected Proof

2012-03-19

Abstract: The field of oncology is a rapidly evolving science mostly due to extensive basic, translational and clinical research which have provided more insights into the tumor biology and set grounds for the development of new therapies. Metabolomics is the upcoming new science in the omics field with the potential to further increment our knowledge of cancer biology. In this review we intend to explore the potential role of metabolomics in understanding cancer process, improving cancer staging, refining tumor characterization and in the search for predictive biomarkers of response and toxicity.

Targeting insulin-like growth factor in breast cancer therapeutics - Corrected Proof

Michalis V. Karamouzis, Athanasios G. Papavassiliou — 2012-03-19

Abstract: The insulin-like growth factor (IGF) pathway holds crucial role in cell growth, differentiation and proliferation. Aberrant regulation of the IGF system has been attributed to the pathogenesis of breast cancer and has been shown to contribute to various stages of breast carcinogenesis. Therefore, targeting the IGF-related axis represents a promising strategy, mainly aiming to bypass the resistance of currently employed treatment options in breast cancer patients. Nevertheless, major limitations have aroused despite the early stage of clinical development of various IGF-system modulators. The present review highlights the current status and considers the future perspectives of IGF-system targeting in breast cancer therapeutics.

Multitargeted anti-angiogenic agents and NSCLC: Clinical update and future directions - Corrected Proof

Peter M. Ellis, Khalid Al-Saleh — 2012-03-14

Abstract: Increasing understanding of the molecular abnormalities driving cell growth and proliferation has resulted in extensive research into molecularly targeted therapies. Angiogenesis is an appealing target for the treatment of non small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody against circulating vascular endothelial growth factor (VEGF), is already approved for the treatment of NSCLC. Many other anti-angiogenic agents under development form the focus of this review. A variety of agents, including sorafenib, sunitinib, cediranib, axitinib, motesanib, linifinib and brivanib inhibit VEGF in addition to either platelet derived growth factor (PDGF), or fibroblast derived growth factor (FGF). To date, none of these agents in combination with chemotherapy have resulted in improvements in overall survival for patients with advanced NSCLC. Triple angiokinase inhibitors, which inhibit VEGF, PDGF and FGF, have potential to improve the therapeutic outcomes for patients with NSCLC. However, there is a need for identification of appropriate biomarkers to improve patient selection and identify those patients benefiting from anti-angiogenesis therapy.

Comparative analysis of multiparametric magnetic resonance and PET-CT in the management of local recurrence after radical prostatectomy for prostate cancer - Corrected Proof

2012-03-09

Abstract: Purpose: Our aim was to assess whether multiparametric magnetic resonance and PET-CT can have a role in detecting local recurrence in patients with biochemical recurrence after radical prostatectomy.Methods: We reviewed the recent international literature by carrying out a PUBMED search.Results: We critically reviewed 11 recent original studies about the use of PET-CT and 5 recent studies about the use of multiparametric magnetic resonance. PET-CT has not shown significant results in terms of detection rate for local recurrence in patients with low level of PSA. Multiparametric magnetic resonance showed encouraging results to detect local recurrence in patients with low PSA and with small diameter lesions.Conclusions: Currently, most important urological societies do not consider multiparametric magnetic resonance and PET-CT in the follow-up of patients with suspected local recurrence after radical prostatectomy. We can assert that multiparametric magnetic resonance seems to have excellent results in detecting local recurrence in patients submitted to radical prostatectomy and PSA<1.5ng/ml.

Cancer education for medical students in developing countries: Where do we stand and how to improve? - Corrected Proof

Mohamed Amgad, Emad Shash, Rabab Gaafar — 2012-03-05

Abstract: Background: This article is a review of the literature regarding the state of oncology education for medical students in developing countries, and possible solutions to the problems at hand.Methods: Ovid MEDLINE, PubMed, ERIC, The Cochrane CENTRAL Register of Controlled Trials (CENTRAL) and Google Scholar were searched using the terms oncology, undergraduate, cancer, education and teaching.Results: The search resulted in 40 relevant articles in total. Ten articles showed that there is a lack of adequate knowledge in the scientific, clinical and psychological aspects of oncology and palliative care amongst students and physicians in developing countries. Eight articles describe the relevance and usefulness of summer schools, workshops and trainings. The rest of them discuss possible methods of addressing the issue, the most important of which is the inclusion of a clinical oncology rotation in the undergraduate syllabus.Conclusion: Graduated physicians and medical students are a long way from reaching the standard knowledge and skills required in oncology. Thus, there is a pressing need to reform the undergraduate medical curricula in developing countries in order to increase cancer awareness for better graduated future physicians.

Long-term survivors among patients with cancer of unknown primary - Corrected Proof

2012-03-05

Abstract: There is a general conception among oncologists that CUP patients behave poorly to treatment and carry a dismal survival. In this paper we are trying to elucidate the different groups of CUP patients and to describe in details the diagnostic and therapeutic management of the prognostically favorable patients.Clinicians should be aware that the favorable CUP cases must be treated according to recent guidelines with either specific locoregional and/or systemic therapy and that they commonly enjoy a long survival. Survival data of 219 CUP patients treated at Ioannina University Hospital from 1995 until 2011 are also presented.

Regulatory T cells in stem cell transplantation: Main characters or walk-on actors? - Corrected Proof

Claudio Fozza, Francesco Dazzi — 2012-03-05

Abstract: Almost 10 years have passed since the first experiments specifically addressing the role of regulatory T cells (Treg) in stem cell transplantation (SCT). It is now time to try to dissect what is their actual impact in such a therapeutic context. In the present review we will initially remind the preliminary experiments exploring the Treg behavior in murine models of SCT, then moving to the first studies evaluating their influence on graft versus host disease and graft versus leukemia in humans. After focusing on some interesting aspects of Treg mechanisms of action after SCT, we will evaluate their activity after donor lymphocyte infusion as well as after reduced intensity conditioning and autologous SCT. We will conclude by briefly discussing possible therapeutic applications of Treg and highlighting biological and clinical issues which deserve to be further assessed in the next future.

Vaccines in non-small cell lung cancer: Rationale, combination strategies and update on clinical trials - Corrected Proof

2012-02-27

Abstract: Non-small cell lung cancer (NSCLC) remains the leading cause of cancer related mortality worldwide and despite some advances in therapy the overall prognosis remains disappointing. New therapeutic approaches like vaccination have been proposed and several clinical trials are ongoing.Many tumor antigens have been identified so far and specific tumor vaccines targeting these antigens have been developed. Even if the ideal setting for vaccine therapy might be the adjuvant one, vaccines seem to be potentially beneficial also in advanced disease and combination therapy could be a promising treatment option.In the advanced setting anti-MUC-1 vaccine (belagenpumatucel) and anti-TGF-β2 vaccine (BPL-25) have entered in phase III trials as maintenance therapy after first line chemotherapy. In the adjuvant setting the most relevant and promising vaccines are directed against MAGE-A3 and PRAME, respectively.We will review the key points for effective active immunotherapies and combination therapies, giving an update on the most promising vaccines developed in NSCLC.

Surveillance for hereditary cancer: Does the benefit outweigh the psychological burden?—A systematic review - Corrected Proof

Jessica P. Gopie, Hans F.A. Vasen, Aad Tibben — 2012-02-27

Abstract: Individuals at risk for developing hereditary cancer are offered surveillance in order to improve the prognosis. An important question is whether the benefit of surveillance outweighs the psychological burden. In this review, we evaluated all studies that investigated psychological distress and the quality of life in individuals under surveillance for hereditary cancer of the breast, ovarian, prostate, pancreas, colorectum, melanoma, and various rare syndromes such as familial adenomatous polyposis, Li–Fraumeni and Peutz–Jeghers syndrome.Thirty-two studies were identified. Surveillance for most hereditary cancers was associated with good psychological outcomes. However, surveillance of individuals at high risk for developing multiple tumors appeared to be associated with increased distress and a lower quality of life. Common factors associated with worse psychological outcomes included a personal history of cancer, female gender, having a first degree relative with cancer, negative illness perceptions and coping style. The use of a simple screening tool to identify distressed individuals is recommended.

Parenteral nutrition in advanced cancer patients - Corrected Proof

2012-02-24

Abstract: Parenteral nutrition (PN) is a medical treatment aimed at providing intravenous nutrients in patients in whom gastrointestinal function is partially or totally impaired. An obvious indication of PN in advanced cancer patients is the prevention and/or treatment of malnutrition in hypo-aphagic patients with intestinal failure due to the disease itself or the consequences of antineoplastic treatments. However, PN may also improve compliance with palliative radio/chemotherapy, reduce its side effects, enhance quality of life and prolong survival. A careful evaluation of patients’ clinical conditions and families’ expectations is mandatory before the decision to initiate PN in ACPs is taken, in order to avoid administration of an inappropriate or even life-threatening medical treatment. Current available evidence indicates that patients expected to die earlier from the underlying tumour rather than from starvation gather no benefit from intravenous nutritional support. Although it is likely that intravenous nutrients provided to feed the patients are also utilized by cancer cells, at present there is no evidence that this translates into a clinically relevant harm to the patient. Fear of tumour growth stimulation must not be a reason for not considering parenteral nutrition in advanced cancer patients. The risk of septic, metabolic and mechanical complications has to be considered when PN support is prescribed, although a specialized and well trained medical and nursing staff may dramatically reduce complication rate. Decisions regarding treatment initiation and its possible withdrawal should be made based on the best available evidence and non on cultural and personal attitudes.

Erratum to “B.I. Rini, E.J. Small, The potential for prostate cancer immunotherapy” [Crit. Rev. Oncol./Hematol. 46 (2003) S117–S127] - Corrected Proof

B.I. Rini, E.J. Small — 2012-02-17

The article named above did not include a reference to a paper published in Current Oncology Reports in 2001 (Rini BI, Small EJ, Immunotherapy for prostate cancer. Curr Oncol Reports, 2001:3;418–423) from which some of the material for the paper published in Critical Reviews in Oncology/Hematology had been drawn.

The role of second-generation 5-HT3 receptor antagonists in managing chemotherapy-induced nausea and vomiting in hematological malignancies - Corrected Proof

2012-02-10

Abstract: Compared with solid tumor patients, those with hematological malignancies are at particular risk of chemotherapy-induced nausea and vomiting (CINV) because of their young age, exposure to highly-emetogenic induction, consolidation and salvage regimens, the high-dose conditioning regimens used before stem cell transplantation (SCT), and the heavy psychological burden of such treatments. In the absence of prophylaxis, around 75% of patients undergoing SCT experience delayed CINV. With first-generation 5-HT3 receptor antagonists, only about 20% are completely protected from nausea and vomiting, and this frequent and debilitating adverse event has not been fully addressed. In contrast to solid tumors, there are no internationally agreed guidelines for the prevention and treatment of CINV in hematological malignancies. Work on a consensus is urgently required. The second-generation 5-HT3 antagonist palonosetron is highly effective in preventing CINV in patients with solid tumors. The extended half-life of this agent and its mechanisms of action including allosteric binding, positive cooperativity and 5-HT3 receptor internalization, may make it particularly effective in controlling delayed CINV. Although controlled comparisons against first-generation 5HT3 agents have not yet been conducted in the setting of SCT, available evidence suggests that palonosetron may prove beneficial in preventing CINV in high risk patients with hematological malignancies.

Oxaliplatin as a radiosensitiser for upper and lower gastrointestinal tract malignancies: What have we learned from a decade of translational research? - Corrected Proof

Esme J. Hill, Nils H. Nicolay, Mark R. Middleton, Ricky A. Sharma — 2012-02-10

Highlights: ► Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy. ► Oxaliplatin's effects on cell cycle kinetics and on DNA damage repair pathways advocate its administration frequently during radiotherapy. ► Clinical trials testing oxaliplatin with radiotherapy have not demonstrated statistically significant improvements in primary endpoints used. ► Predictive tests are needed to select patients who will benefit most from oxaliplatin and radiotherapy.Abstract: Some of the greatest advances in the treatment of solid malignancies have resulted from the combination of chemotherapy and radiotherapy treatments. This article comprehensively reviews the current clinical evidence for oxaliplatin-based chemo-radiotherapy that may improve local control and survival. In order to understand how clinical studies should be designed, the pre-clinical evidence for the use of oxaliplatin chemotherapy as a radiosensitising agent is appraised. Particular focus is placed on oxaliplatin's biological mechanisms of action, including cell cycle effects, the formation of DNA adducts and interstrand cross-links and the role of DNA repair proteins. At a clinical level, there is currently no evidence to suggest that oxaliplatin provides an additional benefit to concurrent chemo-radiation regimes that utilise fluoropyrimidines; we evaluate the reasons for this observation, the limitations of clinical trial design and the opportunities that currently exist to design clinical trials which are underpinned by an understanding of the basic biology.

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.