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Salivary gland malignancies (SGMs) account for less than 5% of new diagnoses in head and neck tumors. If feasible, surgery is the preferred treatment modality. Nevertheless, some malignancies have a tendency of recurrence, with possible distant metastasis. Alternative treatment strategies, such as primary radiation or chemotherapeutics, often present low response rates. As a result, there is an unmet need for novel therapeutic approaches. Nowadays, target-based therapies (e.g., small inhibitors and immunotherapy) are used by the medical oncologist for possible treatment of advanced SGMs. Based on recent published trials, some novel treatments may provide additional disease control for some patients. However, sample sizes are small, the general findings are unsatisfactory, and a lot of uncertainties remain to be elucidated. Nevertheless, research shows that patients do not benefit from blind administration of systemic treatments and therefore a more personalized approach is highly needed. The aim of this review paper is to summarize the most recent advances in the biological understanding and molecular pathways of salivary gland cancers, the association of these pathways with the current treatments used and their implications for more personalized targeted-based therapies.

Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases yearly. The vast majority of cases present in stage IV disease, and it still bears a poor prognosis. However, since 2010, progress has been made with the introduction of targeted therapies against HER2 and with checkpoint inhibitors (PDL1). More agents interfering with other targets (FGFR2B, CLDN18.2) are being investigated. cMET is a less frequent molecular target that has been studied for gastric cancer. It is a proto-oncogene that leads to activation of the MAPK pathway and the PI3K pathway, which is responsible for activating the MTOR pathway. The prevalence of cMET is strongly debated as different techniques are being used to detect MET-driven tumors. Because of the difference in diagnostic assays, selecting patients who benefit from cMET inhibitors is difficult. In this review, we discuss the pathway of cMET, its clinical significance and the different diagnostic assays that are currently used, such as immunohistochemy (IHC), fluorescence in situ hybridization (FISH), the H-score and next-generation sequencing (NGS). Next, we discuss all the current data on cMET inhibitors in gastric cancer. Since the data on cMET inhibitors are very heterogenous, it is difficult to provide a general consensus on the outcome, as inclusion criteria differ between trials. Diagnosing cMET-driven gastric tumors is difficult, and potentially the only accurate determination of cMET overexpression/amplification may be next-generation sequencing (NGS). ispartof: CANCERS vol:15 issue:7 ispartof: location:Switzerland status: published

Immunotherapy of vulvar high‐grade squamous intraepithelial lesion (vHSIL) is investigated as an alternative for surgery, because of high comorbidity and risk of recurrence. Limited evidence exists on the role and composition of the immune microenvironment in current immunotherapeutic approaches for vHSIL. The vHSIL of 29 patients biopsied before treatment with imiquimod were analyzed by two multiplex seven‐color immunofluorescence panels to investigate the pre‐existing T‐cell and myeloid cell composition in relation to treatment response. The samples were scanned with the Vectra multispectral imaging system. Cells were automatically phenotyped and counted with inForm advanced image analysis software. Cell counts and composition were compared to that of vHSIL patients before therapeutic vaccination (n = 29) and to healthy vulva (n = 27). Our data show that the immune microenvironment of complete responders (CR) to imiquimod resembled the coordinated infiltration with type 1 CD4+ and CD8+ T cells and CD14+ inflammatory myeloid cells also found in healthy vulva. However, more CD8+ T cells and FoxP3+ regulatory T cells were present in CR. The lesions of partial responders (PR) lacked such a coordinated response and displayed an impaired influx of CD14+ inflammatory myeloid cells. Importantly, complete responses after imiquimod or therapeutic vaccination showed the same dependency on a pre‐existing coordinated type 1 T‐cell and CD14+ myeloid cell infiltration. In conclusion, a good clinical outcome after two different forms of immunotherapy for vHSIL is associated with the presence of a primary inflammatory process resulting in the coordinated influx of several types of immune cells which is then amplified., What's new? Premalignant vulvar high‐grade squamous intraepithelial lesions (vHSIL) are predominantly induced by human papilloma virus infection. The immune microenvironment in vHSIL and its role in immunotherapeutic approaches remain largely unknown. This study is the first to show that a complete clinical response in patients is associated with a pre‐existent coordinated influx of type 1 T cells and CD14+ myeloid cells, irrespective of the type of successful immunotherapy given (topical imiquimod therapy or therapeutic vaccination). This coordinated immune microenvironment closely resembles that of healthy vulvar tissue, suggesting that an impaired primary inflammatory process acts as an immune resistance mechanism in non‐complete responders.

Simple Summary Nowadays, very few systemic agents have shown clinical activity in patients with glioblastoma, making the research of novel therapeutic approaches a critical issue. Fortunately, the availability of novel compounds is increasing thanks to better biological knowledge of the disease. In this review we want to investigate more promising ongoing clinical trials in both primary and recurrent GBM. Furthermore, a great interest of the present work is focused on novel trial design strategies. Abstract Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting.

Background Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status. Methods We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA). Results By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII. Conclusion Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.

Malignant pleural mesothelioma (MPM) is a rare and orphan thoracic malignancy, with a poor prognosis as the majority of patients are diagnosed with unresectable MPM, with no significant improvements in the therapeutic strategy for over a decade. However, the recent approval of immune checkpoint inhibitors (ICI) in treatment-naive patients with unresectable MPM marks a significant step forward and hope for the treatment of this disease. In this narrative review, we discuss the biological rationale to use ICI in the treatment of MPM. We summarize the current evidence for the efficacy of ICI in MPM and discuss several unresolved challenges regarding the use of ICI in this disease, such as the best upfront immune approach in MPM (ICI versus ICI plus chemotherapy), the optimal sequential treatment strategy according to the first-line treatment, and the potential role of predictive biomarkers.

Ablation of stromal cells expressing fibroblast activation protein-α (FAP) results in cachexia and anemia, and loss of these cells is seen in transplantable tumor models., Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP+ cells, we find that they reside in most tissues of the adult mouse. FAP+ cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP+ cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP+ stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia.

Up to one in four patients with nasopharyngeal carcinoma present with non-metastatic stage IV disease (i.e. T4 or N3). Distinct failure patterns exist, despite the routine adoption of contemporary treatment modalities such as intensity modulated radiotherapy and systemic chemotherapy. Concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy or induction chemotherapy followed by CCRT are commonly employed in this setting, with the latter emerging as the preferred option. Additionally, emerging radiation technologies like proton therapy has become available offering new opportunities for prevention of radiation-induced side effects. This article reviews not only the current treatment strategies, but also discusses novel ways to tackle this challenging disease with respect to the patterns of failure.

Multivariate methods are known to increase the statistical power to detect associations in the case of shared genetic basis between phenotypes. They have, however, lacked essential analytic tools to follow-up and understand the biology underlying these associations. We developed a novel computational workflow for multivariate GWAS follow-up analyses, including fine-mapping and identification of the subset of traits driving associations (driver traits). Many follow-up tools require univariate regression coefficients which are lacking from multivariate results. Our method overcomes this problem by using Canonical Correlation Analysis to turn each multivariate association into its optimal univariate Linear Combination Phenotype (LCP). This enables an LCP-GWAS, which in turn generates the statistics required for follow-up analyses. We implemented our method on 12 highly correlated inflammatory biomarkers in a Finnish population-based study. Altogether, we identified 11 associations, four of which (F5, ABO, C1orf140 and PDGFRB) were not detected by biomarker-specific analyses. Fine-mapping identified 19 signals within the 11 loci and driver trait analysis determined the traits contributing to the associations. A phenome-wide association study on the 19 representative variants from the signals in 176,899 individuals from the FinnGen study revealed 53 disease associations (p

The European Society for Medical Oncology (ESMO) consensus conference onmalignant lymphoma was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the questions devised by their group. These recommendations were then presented to the entire multidisciplinary panel and a consensus was reached. This manuscript presents recommendations regarding the management of the following 'ultra-high-risk' situations: (1) early central nervous system relapse of diffuse large B-cell lymphoma, (2) primary refractory Hodgkin lymphoma and (3) plasmablastic lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. All expert panel members approved this final article.

Purpose: Target delineation in nasopharyngeal carcinoma (NPC) often proves challenging because of the notoriously narrow therapeutic margin. High doses are needed to achieve optimal levels of tumour control, and dosimetric inadequacy remains one of the most important independent factors affecting treatment outcome. Method: A review of the available literature addressing the natural behaviour of NPC and correlation between clinical and pathological aspects of the disease was conducted. Existing international guidelines as well as published protocols specified by clinical trials on contouring of clinical target volumes (CTV) were compared. This information was then summarized into a preliminary draft guideline which was then circulated to international experts in the field for exchange of opinions and subsequent voting on areas with the greatest controversies. Results: Common areas of uncertainty and variation in practices among experts experienced in radiation therapy for NPC were elucidated. Iterative revisions were made based on extensive discussion and final voting on controversial areas by the expert panel, to formulate the recommendations on contouring of CTV based on optimal geometric expansion and anatomical editing for those structures with substantial risk of microscopic infiltration. Conclusion: Through this comprehensive review of available evidence and best practices at major institutions, as well as interactive exchange of vast experience by international experts, this set of consensus guidelines has been developed to provide a practical reference for appropriate contouring to ensure optimal target coverage. However, the final decision on the treatment volumes should be based on full consideration of individual patients' factors and facilities of an individual centre (including the quality of imaging methods and the precision of treatment delivery). (C) 2017 Elsevier B.V. All rights reserved.

Assessing response to therapy in lymphoma is important for determining patients' prognosis, guiding subsequent treatment, and may be used as an outcome measure of prognostic and therapeutic trials. Traditionally, computed tomography was the mainstay for response assessment and was predominantly performed at the end of treatment, whereas the most recent guidelines propose F-18-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) for this purpose. However, the value of FDG-PET performed during treatment (interim FDG-PET) is still a topic of debate. The purpose of this scientific communication is to provide an evidence-based overview of the value of interim FDG-PET in patients with lymphoma. The article first describes the development of imaging-based response assessment in lymphoma, the rationale and limitations of using FDG-PET for this purpose, and continues with the evidence-based clinical utility of interim FDG-PET in three major lymphoma subtypes (Hodgkin lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma), and finishes with conclusions and recommendations for standard care and future research. (C) 2017 Elsevier Inc. All rights reserved.

Gastric (G) and gastro-esophageal junction (GEJ) adenocarcinomas are of the most common and deadly cancers worldwide and affect mainly patients over 70 years at diagnosis. Older age has been associated in gastric cancers with distal tumour location, well-differentiated adenocarcinoma and microsatellite instability and is not identified itself as an independent prognostic factor. As immune checkpoint inhibitors recently changed the landmark of advanced G and GEJ adenocarcinomas treatment, we decided to perform a literature review to define the evidence-level of clinical data in older patients. This work underlined the lasting low -inclusion rate of older patients and -implementation rate of frailty screening tools in clinical trials in G/GEJ carcinomas. In the first-line metastatic setting, two prospective randomized phase III studies have specifically assessed the efficacy of chemotherapy in older patients with HER2-negative gastric cancers, demonstrating the feasibility of reduced dose oxaliplatin-based chemotherapy regimen in this population. Only few data are available in HER2-positive tumors, or in the second-line setting. Furthermore, no specific trial with immune checkpoint inhibitors was performed in older frail patients whereas their benefit/adverse events ratio make them attractive candidates in this patient's population. We conclude that older fit patients can be treated in the same way as younger ones and included in clinical trials. Improving the outcome of older frail patients should be the oncology community next focus by implementing targeted interventions before initiating cancer therapy and designing specific clinical trials. Frailty screening tools and geriatric data collection have to be implemented in routine-practice and clinical trials. ispartof: CANCER TREATMENT REVIEWS vol:100 ispartof: location:Netherlands status: published

Neurofibromatosis (NF) is the umbrella term for neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN). EU-PEARL aims to create a framework for platform trials in NF. The aim of this systematic review is to create an overview of recent clinical drug trials in NF, to identify learning points to guide development of the framework. We searched Embase, Medline and Cochrane register of trials on October 1, 2020 for publications of clinical drug trials in NF patients. We excluded publications published before 2010, systematic reviews, secondary analyses and studies with

Despite a general favourable outcome in limited stage diffuse large B-cell lymphoma (DLBCL), relapses occur in about 10 to 20% of patients. Prognostic models only partially identify patients at risk for relapse. Moreover, it is not known whether the outcome after such a relapse is similar to the outcome after relapse in advanced stages. From January 2004 through December 2012, all newly diagnosed patients with stage I(E) DLBCL were retrospectively analysed from 2 clinical databases to investigate the relapse pattern and outcome in relation to initial treatment and clinical characteristics. In 126 patients (median age 64 years), histologically confirmed stage I(E) DLBCL was diagnosed. With a median follow-up of 53 months (range 5-132 months), 1 progressive disease and 18 relapses occurred. The 5-year time to tumour progression and disease-specific survival were 85% (95% CI 79-91%) and 92% (95% CI 87%-97%), respectively. We observed no significant difference in relapse localization, time to tumour progression, and disease-specific survival between patients treated with abbreviated R-CHOP plus involved field radiotherapy or with 6 to 8 cycles of R-CHOP. Analysis of relapses showed relapse >5 years after initial treatment (late relapse) in 5 of 19 patients (26%). Six of 19 patients (32%) had central nervous system relapse. Three of 11 relapsed cases available for analysis (28%) showed an MYC translocation, suggesting an overrepresentation in the relapse group. Outcome of patients with a relapse was poor with a median survival after relapse of 8 months. Only 1 patient (5%) underwent successful autologous stem cell transplantation. To improve outcome in these patients, early identification of new biological factors such as a MYC translocation or a high risk for CNS dissemination might be helpful. Moreover, treatment of any relapse after stage I disease should be taken seriously. Salvage treatment should be similar to relapses after advanced DLBCL.

// Helen J. MacKay 1 , Douglas A. Levine 2 , Victoria L. Bae-Jump 3 , Daphne W. Bell 4 , Jessica N. McAlpine 5 , Alessandro Santin 6 , Gini F. Fleming 7 , David G. Mutch 8 , Kenneth P. Nephew 9 , Nicolas Wentzensen 10 , Paul J. Goodfellow 11 , Oliver Dorigo 12 , Hans W. Nijman 13 , Russell Broaddus 14 and Elise C. Kohn 15 1 Division of Medical Oncology & Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 2 Division of Gynecologic Cancer, Department of OB/GYN, NYU Langone Laura and Isaac Perlmutter Cancer Center, New York, NY, United States 3 Division of Gynecologic Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, CA, United States 4 Reproductive Cancer Genetics Section, Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute/NIH, MSC 8000, Bethesda, ML, United States 5 University of British Columbia & BC Cancer Agency, Division of Gynecologic Oncology, Vancouver, British Columbia, Canada 6 Department of Gynecology, Obstetrics and Reproductive Sciences, Yale School of Medicine, New Haven, CT, United States 7 Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, IL, United States 8 Department of Obstetrics & Gynecology, Washington University School of Medicine, St. Louis, MO, United States 9 Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN, United States 10 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, ML, United States 11 James Comprehensive Cancer Center and The Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH, United States 12 Division Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford, CA, United States 13 Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 14 Department of Pathology, Unit 85, University of Texas M.D. Anderson Cancer Center, Houston, TX, United States 15 Clinical Investigations Branch of The Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, ML, United States Correspondence to: Elise C. Kohn, email: kohne@mail.nih.gov Keywords: endometrial cancer, molecular targets Received: March 03, 2017 Accepted: May 15, 2017 Published: August 03, 2017 ABSTRACT The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials.

Evoked potentials (EP) characterize signal conduction in selected tracts of the central nervous system in a quantifiable way. Since alteration of signal conduction is the main mechanism of symptoms and signs in multiple sclerosis (MS), multimodal EP may serve as a representative measure of the functional impairment in MS. Moreover, EP have been shown to be predictive for disease course, and thus might help to select patient groups at high risk of progression for clinical trials. EP can detect deterioration, as well as improvement of impulse propagation, independently from the mechanism causing the change. Therefore, they are candidates for biomarkers with application in clinical phase-II trials. Applicability of EP in multicenter trials has been limited by different standards of registration and assessment.

For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small-cell lung cancer (NSCLC). The recent introduction of immunotherapy (IT) in clinical practice, especially strategies targeting negative regulators of the immune system, so-called immune checkpoint inhibitors, has led to a paradigm shift in lung cancer as in many other solid tumors. Although antibodies against programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) are currently on the forefront of the immuno-oncology field, the first efforts to eradicate cancer by exploiting the host's immune system date back to several decades ago. Even then, researchers aimed to explore the addition of RT to IT strategies in NSCLC patients, attributing its potential benefit to local control of target lesions through direct and indirect DNA damage in cancer cells. However, recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Herein, the authors review the rationale of combining IT and RT across all NSCLC disease stages and summarize both historical and current clinical evidence surrounding these combination strategies. Furthermore, an overview is provided of active clinical trials exploring the IT-RT concept in different settings of NSCLC.

The RAS–RAF–MEK–ERK pathway regulates processes involved in the proliferation and survival of cells. KRAS mutations, prevalent in approximately 30% of patients with non-small-cell lung cancer (NSCLC), result in constitutive activation of the pathway. Selumetinib (AZD6244, ARRY-142886) is a potent and selective inhibitor of MEK1/2 which has demonstrated significant efficacy in combination with docetaxel in patients with KRAS mutant pretreated advanced NSCLC. Several trials in combination with other chemotherapy and targeted therapy regimens in lung cancer are ongoing. We review the development of selumetinib in patients with NSCLC, summarize the pharmacodynamic, pharmacokinetic and tolerability characteristics, and the available clinical trial data to understand the role of selumetinib in the treatment of NSCLC.

Background Locoregional advanced melanoma poses a complex clinical challenge that requires a multidisciplinary, patient-centered approach. Numerous agents have been studied for their suitability as intralesional therapy in the past decades, but few have successfully completed phase 3 clinical trial testing. Methods The relevant medical literature was searched for articles regarding use of intralesional therapies in metastatic melanoma. Therapies with data from phase 2 or higher studies were selected for review. This review also summarizes the mechanisms of action, adverse-event profiles, and clinical data for these agents. Results Intralesional therapies demonstrate promising effects in select patients with advanced melanoma. The optimal approach should be individually tailored and consist of a combination of intralesional therapies, regional perfusions, systemic immunotherapies, targeted therapies, and surgery, if necessary. Conclusions Due to its relatively good local response rates and tolerable adverse-event profile, intralesional therapy may be a treatment option for select patients with unresectable, locally advanced or metastatic melanoma.

Lung cancer is an umbrella term for a subset of heterogeneous diseases that are collectively responsible for the most cancer-related deaths worldwide. Despite the tremendous progress made in understanding lung tumour biology, advances in early diagnosis, multimodal therapy and deciphering molecular mechanisms of drug resistance, overall curative outcomes remain low, especially in metastatic disease. Nanotechnology, in particular nanoparticles (NPs), continue to progressively impact the way by which tumours are diagnosed and treated. The unique physicochemical properties of materials at the nanoscale grant access to a diverse molecular toolkit that can be manipulated for use in respiratory oncology. This realisation has resulted in several clinically approved NP formulations and many more in clinical trials. However, NPs are not a panacea and have yet to be utilised to maximal effect in lung cancer, and medicine in a wider context. This review serves to: describe the complexity of lung cancer, the current diagnostic and therapeutic environment, and highlight the recent advancements of nanotechnology based approaches in diagnosis and treatment of respiratory malignancies. Finally, a brief outlook on the future directions of nanomedicine is provided; presently the full potential of the field is yet to be realised. By gleaning lessons and integrating advancements from neighbouring disciplines, nanomedicine can be elevated to a position where the current barriers that stymie full clinical impact are lifted.

BACKGROUND: We investigated whether pre-existent goiter and well-differentiated thyroid cancer (WDTC) are associated with survival in anaplastic thyroid carcinoma (ATC).METHODS: We analyzed medical records from 94 ATC patients, drawn from the Netherlands Cancer Registry, diagnosed in 17 hospitals between 1989 and 2009.RESULTS: The 29 patients (31%) with pre-existent goiter, including 8 with WDTC, were younger than those without (median, 69 vs 76 years; P = .02). One-year overall survival was 9% (95% confidence interval [CI], 3% to 14%) with no difference between pre-existent goiter or not (overall survival, 14%; 95% CI, 1% to 26% vs overall survival, 6%; 95% CI, 0% to 13%]). Higher age was associated with a worse survival (hazard rate, 1.03; 95% CI, 1.01 to 1.06]), whereas the hazard to die was lower after surgery and/or radiotherapy (hazard rate, .37; 95% CI, .21 to.67 and hazard rate,. 22; 95% CI, .12 to .41, respectively).CONCLUSIONS: ATC patients with pre-existent goiter were younger, yet survival was not significantly different between those with or without pre-existent goiter or WDTC. (C) 2015 Elsevier Inc. All rights reserved.

ContextMany tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients.MethodsAll major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand–foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported.ResultsIn total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33–64)%, and was 17 (95% CI 12–24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14–77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34–46)% and 27 (95% CI 22–32)% respectively. Clinical benefit was found in 53 (95% CI 48–59)% of DTC patients on sorafenib, and in 84 (95% CI 79–88)% and 55 (95% CI 49–61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity.ConclusionThe currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

Purpose: Pediatric head and neck malignancies are managed with intensive multimodality therapy. Proton beam therapy (PBT) may reduce toxicity by limiting exposure of normal tissue to radiation. In this study, we report acute toxicities and early outcomes following PBT for pediatric head and neck malignancies.Materials and methods: Between 2010 and 2016, pediatric patients with nonhematologic malignancies of the head and neck were treated with PBT. Clinical and dosimetric data were abstracted from the medical record and treatment planning system with institutional review board approval.Results: Sixty-nine consecutive pediatric patients were treated with proton-based radiotherapy for head and neck malignancies. Thirty-five were treated for rhabdomyosarcoma to a median dose of 50.4 Gy relative biological effectiveness [RBE]. Ten patients were treated for Ewing sarcoma to a median dose of 55.8 Gy[RBE]. Twenty-four patients were treated for other histologies to a median dose of 63.0 Gy[RBE]. Grade 3 oral mucositis, anorexia, and dysphagia were reported to be 4, 22, and 7%, respectively. Actuarial 1-year freedom from local recurrence was 92% (95% CI 80–97). Actuarial 1-year overall survival was 93% (95% CI 79–98) in the entire cohort. Oral cavity mucositis was significantly correlated with oral cavity dose (D80 and D50 [P Conclusions: In this study, we report low rates of acute toxicity in a cohort of pediatric patients with head and neck malignancies. PBT appears safe for this patient population, with local control rates similar to historical reports. Longer follow-up will be required to evaluate late toxicity and long-term disease control.

Contains fulltext : 170335.pdf (Publisher’s version ) (Open Access) BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

Background: Adenocarcinoma of the pancreas is one of the most aggressive cancer diseases affecting the human body. Recent research has shown the importance of the perioperative phase in disease progression. Particularly during this vulnerable phase, substances such as metamizole and paracetamol are given as general anesthetics and postoperative analgesics. Therefore, the effects of metamizole and paracetamol on tumor progression should be investigated in more detail because the extent to which these substances influence the carcinogenesis of pancreatic carcinoma is still unclear. This study analyzed the influence of metamizole and its active metabolites MAA (4-N-methyl-aminoantipyrine) and paracetamol on the proliferation, apoptosis, and necrosis of the pancreatic cancer cell lines PaTu 8988t and Panc-1 in vitro. Methods: Cell proliferation was measured by means of the ELISA BrdU assay and the rate of apoptosis by flow cytometry using the Annexin V assay. Results: Metamizole and paracetamol significantly inhibited cell proliferation in pancreatic cancer cells. After the addition of metamizole to PaTu 8988t cells, the rate of apoptosis was reduced after 3 h of incubation but significantly increased after 9 h of incubation. Conclusion: The oncogenic potential of pancreatic adenocarcinoma is mainly characterized by its extreme growth rate. Non-opioid analgesics such as metamizole and paracetamol are given as general anesthetics and postoperative analgesics. The combination of metamizole or paracetamol with cytotoxic therapeutic approaches may achieve synergistic effects. Further studies are necessary to identify the underlying mechanisms so that new therapeutic options may be developed for the treatment of this aggressive tumor.

Introduction: Intralesional therapy for metastatic melanoma has some advantages over systemic therapy. Local drug administration allows for delivery of an increased concentration of the agent and reduced systemic exposure, thereby increasing local efficacy and limiting toxicity. Moreover, since in vivo tumor nodules contain the tumor antigens, this tumor tissue may serve as an autologous vaccine to induce systemic immunity. This so-called 'bystander effect', where uninjected distant lesions exhibit a response, has been reported in select intralesional therapy trials. Areas covered: This review will give an overview of the working mechanisms, clinical evidence and side effects for available intralesional and topical therapies and summarize the most recent developments in this field. Expert opinion: The ideal treatment approach for locoregionally advanced melanoma should be multidisciplinary and tailored to the patient, taking into consideration patient-related, tumor-related factors (such as location, tumor burden, mutation status) and previous treatments received. It will likely not be a single therapy, but rather a combination of injectable treatments, regional perfusions and systemic therapies.

M. Dreyling1, M. Ghielmini2, R. Marcus3, G. Salles4, U. Vitolo5 & M. Ladetto6 on behalf of the ESMO Guidelines Working Group* Department of Medicine III, University of Munich, Munich, Germany; Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland; Haematology, Kings College Hospital, London, UK; Service D’Hematologie, Centre Hospitalier Lyon-Sud, Pierre-Benite, France; Haematology II, Centro Universitario Ricerca Oncologica Ospedale Molinette, Turin; Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Malignant brain tumors including glioblastoma are incurable cancers. Over the last years a number of promising novel treatment approaches have been investigated including the application of inhibitors of receptor tyrosine kinases and downstream targets, immune-based therapies and anti-angiogenic agents. Unfortunately so far the major clinical trials in glioblastoma patients did not deliver clear clinical benefits. Systemic brain tumor therapy is seriously hampered by poor drug delivery to the brain. Although in glioblastoma, the blood brain barrier is disrupted in the tumor core, the major part of the tumor is largely protected by an intact blood brain barrier. Active cytotoxic compounds encapsulated into liposomes, micelles, and nanopartides constitute novel treatment options because they can be designed to facilitate entry into the brain parenchyma. In the case of biological therapeutics, encapsulation of therapeutic cells and their implantation into the surgical cavity represents another promising approach. This technology provides long term release of the active compound at the tumor site and reduces side effects associated with systemic delivery. The proof of principle of encapsulated cell factories has been successfully demonstrated in experimental animal models and should pave the way for clinical application. Here we review the challenges associated with the treatment of brain tumors and the different encapsulation options available for drugs and living cells, with an emphasis on alginate based cell encapsulation technology. (C) 2014 Elsevier B.V. All rights reserved.

With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level.

Background Fatigue is a prevalent and burdensome symptom for patients with incurable cancer receiving cancer treatment with palliative intent and is associated with reduced quality of life. Psychosocial interventions seem promising for management of fatigue among cancer patients. Objectives To assess the effects of psychosocial interventions for fatigue in adult patients with incurable cancer receiving cancer treatment with palliative intent. Search methods We searched the following databases: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, and seven clinical trial registries; we also searched the reference lists of articles. The date of our most recent search was 29 November 2016. Selection criteria We included randomised controlled trials that compared psychosocial interventions in adults aged 18 years or over undergoing cancer treatment with palliative intent for incurable cancer versus usual care or other controls. Psychosocial interventions were defined as various kinds of interventions provided to influence or change cognitions, emotions, behaviours, social interactions, or a combination of these. Psychosocial interventions of interest to this review had to involve at least two interactions between the patient and the care provider in which the care provider gave the patient personal feedback concerning changes sought by these interventions. We included trials that reported fatigue as an outcome of interest. Data collection and analysis We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data, including information on adverse events. We assessed the quality of evidence using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) and created a 'Summary of findings’ table. Main results We identified 14 studies (16 reports) that met inclusion criteria for this review and involved 3077 randomised participants in total. Most of these studies included a mixed sample of participants; we obtained data for the subset of interest for this review (diagnosis of incurable cancer and receiving cancer treatment) from the study investigators of 12 studies, for which we included 535 participants in the subset meta-analysis for fatigue post intervention. Researchers investigated a broad range of psychosocial interventions with different intervention aims and durations. We identified sources of potential bias, including lack of description of methods of blinding and allocation concealment and inclusion of small study populations. Findings from our meta-analysis do not support the effectiveness of psychosocial interventions for reducing fatigue post intervention (standardised mean difference (SMD) -0.25, 95% confidence interval (CI) -0.50 to 0.00; not significant; 535 participants, 12 studies; very low-quality evidence). First follow-up findings on fatigue suggested benefit for participants assigned to the psychosocial intervention compared with control (SMD -0.66, 95% CI -1.00 to -0.32; 147 participants, four studies; very low-quality evidence), which was not sustained at second follow-up (SMD -0.41, 95% CI -1.12 to 0.30; not significant; very low-quality evidence). Results for our secondary outcomes revealed very low-quality evidence for the efficacy of psychosocial interventions in improving physical functioning post intervention (SMD 0.32, 95% CI 0.01 to 0.63; 307 participants, seven studies). These findings were not sustained at first follow-up (SMD 0.37, 95% CI -0.20 to 0.94; not significant; 122 participants, two studies; very low-quality evidence). Findings do not support the effectiveness of psychosocial interventions for improving social functioning (mean difference (MD) 4.16, 95% CI -11.20 to 19.53; not significant; 141 participants, four studies), role functioning (MD 3.49, 95% CI -12.78 to 19.76; not significant; 143 participants, four studies), emotional functioning (SMD -0.11, 95% CI -0.56 to 0.35; not significant; 115 participants, three studies), or cognitive functioning (MD -2.23, 95% CI -12.52 to 8.06; not significant; 86 participants, two studies) post intervention. Only three studies evaluated adverse events. These studies found no difference between the number of adverse events among participants in the intervention versus control group. Using GRADE, we considered the overall quality of evidence for our primary and secondary outcomes to be very low. Therefore, we have very little confidence in the effect estimate, and the true effect is likely to be substantially different from the estimate of effect. Limitations in study quality and imprecision due to sparse data resulted in downgrading of the quality of data. Additionally, most studies were at high risk of bias owing to their small sample size for the subset of patients with incurable cancer (fewer than 50 participants per arm), leading to uncertainty about effect estimates. Authors' conclusions We found little evidence around the benefits of psychosocial interventions provided to reduce fatigue in adult patients with incurable cancer receiving cancer treatment with palliative intent. Additional studies with larger samples are required to assess whether psychosocial interventions are beneficial for addressing fatigue in patients with incurable cancer.

Background Selective cyclooxygenase-2 (COX-2) inhibitors are analgesic, antipyretic, and anti-inflammatory drugs. They have been found to inhibit the development of glioma in laboratory investigations. Whether these drugs reduce the risk of glioma incidence in humans is unknown. Methods We conducted a matched case-control analysis using the U.K.-based Clinical Practice Research Datalink (CPRD). We identified 2,469 cases matched to 24,690 controls on age, sex, calendar time, general practice, and number of years of active history in the CPRD prior to the index date. We conducted conditional logistic regression analyses to determine relative risks, estimated as odds ratios (ORs) with 95% confidence intervals (CIs) of glioma in relation to use of selective COX-2 inhibitors, adjusted for several confounding variables. Results Use of selective COX-2 inhibitors was unrelated to risk of glioma (adjusted OR for 1-9 versus 0 prescriptions = 1.02; 95% CI = 0.92-1.13, 10-29 versus 0 prescriptions = 1.01; 95% CI = 0.80-1.28, >= 30 versus 0 prescriptions = 1.16; 95% CI = 0.86-1.55). Trends for increasing numbers of prescriptions for other non-steroidal anti-inflammatory drugs (NSAIDs), and non-NSAID analgesics were also not associated with glioma risk. Conclusion Further epidemiologic studies are needed to confirm the null relation of use of selective COX-2 inhibitors to glioma risk and to explain the discrepancy between laboratory investigations and our observational study. Impact: Use of selective COX-2 inhibitors is unrelated to glioma risk.

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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Correction: Volume: 211 Pages: 233-233 DOI: 10.1016/j.ajo.2019.11.027 Published:‏ MAR 2020 PURPOSE: To validate a staging system for metastatic uveal melanoma that will facilitate planning, reporting, and interpreting the results of clinical trials. DESIGN: Reliability and validity study. METHODS: The performance index, the largest diameter of the largest metastasis and alkaline phosphatase level at the time of diagnosis of metastases, and overall survival of 249 patients from 7 ocular oncology centers who died of dissemination were analyzed. Predicted median survival time calculated according to the Helsinki University Hospital Working Formulation was used to assign patients to stages IVa, IVb, and IVc, which correspond to predicted survival times of >= 12

OBJECTIVE: An increasing number of patients with locally advanced gastric carcinomas (GC) are being treated with preoperative chemotherapy before surgery. BACKGROUND: Histopathological tumor regression may have an important prognostic impact in addition to the UICC-TNM classification system. METHODS: We evaluated the histopathological tumor regression in 480 surgical resection specimens of GC after neoadjuvant cisplatin-based chemotherapy, using an established system encompassing three tumor regression grades based on the estimation of the percentage of residual tumor tissue at the primary tumor site in relation to the macroscopically identifiable former tumor bed. Tumor regression was correlated to clinicopathological characteristics and patient survival. RESULTS: Of the patients in this study, 102 (21.2%) had complete or subtotal tumor regression (50% residual tumor). Tumor regression was significantly associated with posttreatment tumor category (pT), lymph node status (pN), lymphatic invasion status (pL), and resection status (P < 0.001). Major histopathological regression was less frequent in tumors of the distal stomach and tumors of nonintestinal type (P = 0.003). Tumor regression (P = 0.009) and postoperative Lymph node status (P < 0.001) were independent prognostic factors for survival in a multivariate analysis of tumor regression, ypT/N/L category, resection status, grading and Lauren´s classification. CONCLUSIONS: Assessment of histological tumor regression after preoperative chemotherapy in GC provides objective and highly valuable prognostic information in addition to posttherapeutic lymph node status. A standardized tumor regression grading system should be implemented in pathological reports of these tumors.

Meningiomas are the most common type of primary central nervous system tumors. Approximately, 80% of meningiomas are classified by the World Health Organization (WHO) as grade I, and 20% of these tumors are grade II and III, considered high-grade meningiomas (HGMs). Clinical control of HGMs, as well as meningiomas that relapse after surgery, and radiation therapy is difficult, and novel therapeutic approaches are necessary. However, traditional chemotherapies, interferons, hormonal therapies, and other targeted therapies have so far failed to provide clinical benefit. During the last several years, next generation sequencing has dissected the genetic heterogeneity of meningioma and enriched our knowledge about distinct oncogenic pathways driving different subtypes of meningiomas, opening up a door to new personalized targeted therapies. Molecular classification of meningioma allows a new design of clinical trials that assign patients to corresponding targeted agents based on the tumor genetic subtypes. In this review, we will shed light on emerging medical treatments of meningiomas with a particular focus on the new targets identified with genomic sequencing that have led to clinical trials testing novel compounds. Moreover, we present recent development of patient-derived preclinical models that provide platforms for assessing targeted therapies as well as strategies with novel mechanism of action such as oncolytic viruses.

Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward.

Context: High-grade T1 (formerly T1G3) bladder cancer (BCa) has a high propensity to recur and progress. As a result, decisions pertaining to its treatment are difficult. Treatment with bacillus Calmette-Guerin (BCG) risks progression and metastases but may preserve the bladder. Cystectomy may offer the best opportunity for cure but is associated with morbidity and a risk of mortality, and it may constitute potential overtreatment for many cases of T1G3 tumours. For purposes of this review, we continue to refer to high-grade T1 lesions as "T1G3.'' Objective: To review the current literature on the management of T1G3 BCa and to provide recommendations for its treatment. Evidence acquisition: A National Center for Biotechnology Information (NCBI) PubMed search for relevant articles published between 1996 and 9 January 2009 was performed using the Medical Subject Headings "T1G3'' or "T1'' and "Bladder cancer.'' Articles relevant to the treatment of T1G3 BCa were retained. Evidence synthesis: The diagnosis of T1G3 disease is difficult because pathologic staging is often unreliable and because of the risk of significant understaging at initial transurethral resection (TUR) of bladder tumour. A secondary restaging TUR is recommended for all cases of T1G3. A single dose of immediate post-TUR chemotherapy is recommended. For a bladder-sparing approach, intravesical BCG should be given as induction with maintenance dosing. Immediate or early radical cystectomy (RC) should be offered to all patients with recurrent or multifocal T1G3 disease, those who are at high risk of progression, and those failing BCG treatment. Conclusions: Both bladder preservation and RC are appropriate options for T1G3 BCa. Risk stratification of patients based on pathologic features at initial TUR or at recurrence can select those most appropriate for bladder preservation compared to those for whom cystectomy should be strongly considered. (C) 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.

After the implementation of standard first line chemotherapy with platinum and antifolates in pleural mesothelioma, patients are confronted with a need for second line treatment at relapse or progression. We conducted a systematic review of the literature for the activity, effectiveness and toxicity of second line treatment. The results are presented according to the class of drugs: chemotherapy and targeted or biological agent. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy and radiotherapy. However, immunotherapy appears to be effective in 15—20% of cases, with interleukin-2 becoming the standard therapy for this disease. As a consequence of the immune susceptibility of RCC, other avenues of immunotherapy are being explored, such as nonmyeloablative allogeneic stem cell transplantation (NST). A number of trials have shown NST to be effective in varying degrees, causing partial or complete regression. Although nonmyeloablative conditioning is safer than myeloablative conditioning, its role has yet to be clearly proven as many studies have shown variable effect. Alongside this limitation, transplant-related toxicity also forms obstacles. Regardless of the limitation of NST, further refinement of the technique, with appropriate patient selection, may lead to this being an effective therapeutic choice for a significant number of individuals.

The estrogen receptor a (ER alpha) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ER alpha expression with the tracer 16 alpha-F-18-fluoro-17 beta-estradiol (F-18-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of F-18-FES PET to determine tumor ERa expression noninvasively in epithelial ovarian cancer patients. Methods: F-18-FES PET/CT was performed shortly before cytoreductive surgery. Tumor F-18-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. F-18-FES PET/CT findings were compared with histology and immunohistochemistry for ER alpha, ER beta, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells Chi staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. Results: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor F-18-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative F-18-FES uptake correlated with the semiquantitative immunoscore for ER alpha (rho = 0.65, P

Historically, locally advanced rectal cancer is known for its dismal prognosis. The treatment of locally advanced rectal cancer is subject to continuous change due to development of new and better diagnostic tools, radiotherapeutic techniques, chemotherapeutic agents and understanding of the subject. It is clear, that a multimodality approach is the only way to achieve satisfactory local recurrence and survival rates in this type of cancer. However, which multimodality strategy is to be used still remains a point of controversy. This review summarises recent developments in imaging, (neo-) adjuvant therapy and surgical techniques in the treatment of primary locally advanced rectal cancer. (C) 2004 Elsevier Ltd. All rights reserved.

Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherapies are reviewed, and next steps in the development of clinical therapeutics are discussed.

Background: We investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) treated with lapatinib and capecitabine (LC). Patients and Methods: A total of 203 patients with HER2+ MBC, who had progressed after trastuzumab-containing chemotherapy, were retrospectively evaluated in 11 centers between September 2009 and May 2011. 85 patients who had developed BMs before the initiation of treatment with LC were included. All patients had received prior cranial radiotherapy. All patients were treated with the combination of lapatinib (1,250 mg/day continuously) and capecitabine (2,000 mg/m(2) on days 1-14 of a 21-day cycle). Results: The median follow-up was 10.5 months (range 1-38 months). An overall response rate of 27.1% was achieved, including complete response in 2 (2.4%) and partial response in 21 (24.7%) patients. Median progression-free survival was 7 months (95% confidence interval (CI) 5-9), with a median overall survival of 13 months (95% Cl 9-17). The most common side effects were hand-foot syndrome (58.8%), nausea (55.3%), fatigue (48.9%), anorexia (45.9%), rash (36.5%), and diarrhea (35.4%). Grade 3-4 toxicities were hand-foot syndrome (9.4%), diarrhea (8.3%), fatigue (5.9%), and rash (4.7%). There were no symptomatic cardiac events. Conclusion: LC combination therapy was effective and well-tolerated in patients with HER2+ MBC with BMs, who had progressive disease after trastuzumab-containing therapy., BACKGROUND: We investigated the clinical outcome of patients with brainmetastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+)metastatic breast cancer (MBC) treated with lapatinib and capecitabine (LC).PATIENTS AND METHODS: A total of 203 patients with HER2+ MBC, who had progressed after trastuzumab-containing chemotherapy, were retrospectively evaluated in 11centers between September 2009 and May 2011. 85 patients who had developed BMsbefore the initiation of treatment with LC were included. All patients hadreceived prior cranial radiotherapy. All patients were treated with thecombination of lapatinib (1,250 mg/day continuously) and capecitabine (2,000mg/m(2) on days 1-14 of a 21-day cycle).RESULTS: The median follow-up was 10.5 months (range 1-38 months). An overallresponse rate of 27.1% was achieved, including complete response in 2 (2.4%) and partial response in 21 (24.7%) patients. Median progression-free survival was 7months (95% confidence interval (CI) 5-9), with a median overall survival of 13months (95% Cl 9-17). The most common side effects were hand-foot syndrome(58.8%), nausea (55.3%), fatigue (48.9%), anorexia (45.9%), rash (36.5%), anddiarrhea (35.4%). Grade 3-4 toxicities were hand-foot syndrome (9.4%), diarrhea(8.3%), fatigue (5.9%), and rash (4.7%). There were no symptomatic cardiacevents.CONCLUSION: LC combination therapy was effective and well-tolerated in patientswith HER2+ MBC with BMs, who had progressive disease after trastuzumab-containingtherapy.

Aims: Tumours depend on angiogenesis for enhanced tumour cell survival and progression. Vascular endothelial growth factor receptor (VEGFR) signalling plays a major part in this process. Previously, we evaluated tyrosine kinase activity in paediatric brain tumour tissue lysates using a peptide microarray containing 144 different tyrosine kinase peptide substrates. When applied to paediatric pilocytic astrocytoma tissue, this analysis revealed extensive phosphorylation of VEGFR-derived peptides. The aim of the current study was to validate this result and determine the presence of VEGFR-2 activity in paediatric pilocytic astrocytoma as the main VEGFR in terms of mitogenic signalling. In addition, the localization of VEGFR1-3 mRNA expression was assessed. Methods: VEGFR-2 phosphorylation was determined by adopting a proximity ligation assay approach. Enrichment of endothelial markers and VEGFRs in tumour endothelium was determined by quantitative polymerase chain reaction (qPCR) analysis of laser-microdissected blood vessels. Results: Proximity ligation assays on tumour cryosections showed the presence of phosphorylation of VEGFR-2, which primarily localized to vascular endothelium. qPCR analysis of endothelial markers and VEGFRs showed a 13.6-fold average enrichment of VEGFR-2 expression in the laser-microdissected endothelium compared to whole tumour. Also the expression of VEGFR-1 and -3 was highly enriched in the endothelium fraction with an average fold-enrichment of 16.5 and 50.8 respectively. Conclusions: Phosphorylated VEGFR-2 is detected on endothelial cells in paediatric pilocytic astrocytoma. Furthermore, endothelial cells are the main source of VEGFR1-3 mRNA expression. This suggests a crucial role for VEGF/VEGFR-induced angiogenesis in the progression and maintenance of these tumours.

Background Combinations of trastuzumab with either docetaxel or vinorelbine are considered valuable treatment options for HER2-positive metastatic breast cancer patients. We performed a retrospective comparison of the clinical outcomes associated with either one of these combinations. Methods From a multi-institutional database we retrieved 179 patients treated with either docetaxel or vinorelbine plus trastuzumab as first-line therapy for HER2-positive advanced breast cancer. Results Docetaxel-trastuzumab was superior to vinorelbine-trastuzumab in terms of response rate (RR: 77 vs 57%, p = 0.01) and median overall survival (OS: 35 vs 23 months, p = 0.04), but not in median time to progression (TTP: 12 vs 10 months, p = 0.53). At multivariate analysis, type of treatment was not associated with TTP but was an independent predictor of OS, with a significant reduction in the risk of death in favor of docetaxel-trastuzumab (HR 0.474, 95% IC 0,303-0.742, p < 0.01). Conclusion Docetaxel or vinorelbine, when combined with trastuzumab, provide excellent rates of tumor control in patients with previously untreated HER2-positive advanced breast cancer. Docetaxel may offer some advantage in terms of response rate and resulted in a significantly prolonged overall survival, which, because of the retrospective design of our study, deserves further investigation in prospective trials.

To investigate the correlation between O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma.A real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence.A subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p=0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma.MGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.

In Europe, renal cancer (that is neoplasia of the kidney, renal pelvis or ureter (ICD-9 189 and ICD-10 C64-C66)) ranks as the seventh most common malignancy in men amongst whom there are 29,600 new cases each year (3.5% of all cancers). Tobacco, obesity and a diet poor in vegetables are all acknowledged risk factors, along with specific occupational and environmental factors. A familial history of renal carcinoma is also likely to increase the risk. Renal carcinoma may remain clinically occult for Most of its Course, The classic presentation of pain, haematuria. and flank mass occurs in only 9% of patients and is often indicative of advanced disease. Approximately 30% of patients with renal carcinoma present with metastatic disease, 25% with locally advanced renal carcinoma and 45% with localized disease. Metastases are typically found in the lung, soft tissue, bone, liver, cutaneous sites, and central nervous system. The most important staging technique is a computed tomography (CT) scan of the whole abdomen. Survival rates are more favourable Cor patients with tumours confined to the kidney. Five-year survival for patients with metastatic renal carcinoma is comprised between 0 and 20%. Radical nephrectomy is the standard intervention for renal cancer. Intrinsic resistance to chemotherapy has long been a hallmark of renal carcinoma. Limited options are available for the systemic therapy, and no chemotherapeutic regimen is accepted as a standard of care. Biologic agents represent the major effective therapies for widespread metastatic renal cancer. An antiangiogenic strategy. the neutralization of VEGF. can slow the growth rate of advanced cancer. (C) 2007 Published by Elsevier Ireland Ltd.

Purpose: A study was designed to define the therapeutic efficacy, safety, and toxicity of two sequential high-dose treatments of radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell carcinoma. Here, we report the dosimetric analysis and the relationship between the development of a human antichimeric antibody response and altered pharmacokinetics. Experimental Design: Patients (n = 29) with progressive metastatic renal cell carcinoma received a low dose (222 MBq) of [131I]cG250 for dosimetric analysis, followed by the first radioimmunotherapy with 2,220 MBq/m2 [131I]cG250 (n = 27) 1 week later. If no grade 4 hematologic toxicity was observed, a second low dose of [131I]cG250 (n = 20) was given 3 months later. Provided that no accelerated blood clearance was observed, a second radioimmunotherapy of [131I]cG250 was administered at an activity-dose level of 1,110 MBq/m2 (n = 3) or 1,665 MBq/m2 (n = 16). After each administration, whole-body images were obtained and the pharmacokinetics and the development of human antichimeric antibody responses were determined. Radiation-absorbed doses were calculated for whole body, red marrow, organs, and metastases. Results: No correlation was found between hematologic toxicity and radiation-absorbed dose to the whole body or bone marrow, nor administered activity (MBq and MBq/kg). The tumor-absorbed doses varied largely. An inverse relation between tumor size and radiation-absorbed dose was found. Most tumor lesions received 50 Gy. A relatively high number of patients developed a human antichimeric antibody response (8 of 27) with altered pharmacokinetics, hampering additional radioimmunotherapies in four of these patients. Conclusions: Dosimetric analysis did not adequately predict the degree of bone marrow toxicity. When human antichimeric antibody developed, the rapid clearance of radioactivity from the blood and body prohibited further treatment. According to the calculated absorbed dose in metastatic lesions, future radioimmunotherapy studies with radiolabeled cG250 should aim at treatment of small-volume disease or treatment in an adjuvant setting.