Future care for long-term cancer survivors: towards a new model

PurposeThe increase in the prevalence "long-term cancer survivor” (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care.MethodsThis qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report.Results232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions.ConclusionThe role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.

Future care for long-term cancer survivors: towards a new model.

PURPOSE: The increase in the prevalence "long-term cancer survivor" (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care. METHODS: This qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report. RESULTS: 232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions. CONCLUSION: The role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.

Treatment patterns for metastatic colorectal cancer in Spain.

PURPOSE: The primary aim of this retrospective study was to describe the treatment patterns according to the type of treatment received by patients with metastatic colorectal cancer (mCRC) in Spain. METHODS: This was a retrospective, observational, multicenter study performed by 33 sites throughout Spain that included consecutive patients aged 18 years or older who had received or were receiving treatment for mCRC. RESULTS: At the time of inclusion, of the 873 evaluable patients, 507 (58%) had received two lines, 235 (27%) had received three lines, 106 (12%) had received four lines, and the remaining patients had received up to ten lines. The most frequent chemotherapy schemes were the FOLFOX or CAPOX regimens (66%) for first-line treatment, FOLFOX, CAPOX or FOLFIRI (70%) for second-line treatment, and FOLFOX, FOLFIRI or other fluoropyrimidine-based regimens for third- and fourth-line (over 60%) treatment. Sixty percent of patients received targeted therapy as part of their first-line treatment, and this proportion increased up to approximately 70% of patients as part of the second-line of treatment. A relevant proportion of patients were treated with unknown KRAS, and especially the BRAF, mutation statuses. CONCLUSIONS: This study reveals inconsistencies regarding adherence to the recommendations of the ESMO guidelines for the management of mCRC in Spain. Improved adherence to the standard practice described in such guidelines for the determination of RAS and BRAF mutation statuses and the use of targeted therapies in first-line treatment should be considered to guarantee that patients can benefit from the best therapeutic approaches available.

A translational approach to design effective intervention tools for informal caregivers of dependent cancer patients.

OBJECTIVES: Caregivers of terminal patients often report a higher prevalence of unmet needs than cancer survivors. However, very few interventions have been carried out to support caregivers of patients in advanced stages, and, in most cases, they have not been rigorously designed and evaluated. The ultimate aim of this research was to obtain specific information about the sociodemographic characteristics, the different types of care provided, the symptoms due to burdens, the impact of caring on the quality of life, and the unmet needs of informal caregivers of dependent patients with cancer. This is to design effective intervention programs that can be implemented from the hospital setting itself and therefore, to improve their quality of life and prevent the deterioration of their health. STUDY DESIGN: A cross-sectional design and survey methodology were used for descriptive purposes. METHODS: The sample was composed of 132 informal caregivers of dependent patients with cancer, from a public hospital in Valencia, Spain, who were identified through the patient database of the oncology service, over the 4-month data collection period. Self-administered questionnaires were combined with personal interviews: Interview Protocol for the main caregiver, Questionnaire ICUB97, and survey of hospital quality. RESULTS: The most frequently provided types of care included the following: keeping the patient company, acting as an intermediary between them and healthcare workers, and helping them to do basic daily life activities. The main negative consequences caregivers reported were the following: feeling more tired, having less free time, changing their daily routines, and having fewer social relationships/interactions and various emotional and physical symptoms. Many of the needs of informal caregivers were not being met: resolution of doubts about illness, training in the care they should provide to the patient, and psychological help. CONCLUSIONS: Recommendations for the development of effective intervention programs are offered: increasing the psychological services provided in oncology units, training medical staff in communication skills, facilitating access to information about the disease through different means, training for informal caregivers in care techniques, coping and communication skills, self-care, and organization of time. On the one hand, implementing effective intervention programs for informal caregivers will reduce the amount withdrawing from their care duties and on the other hand, the proliferation of what are known as secondary patients.

Clinical utility of plasma-based digital next-generation sequencing in patients with advance-stage lung adenocarcinomas with insufficient tumor samples for tissue genotyping.

BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.

The burden of cancer in Spain.

INTRODUCTION: Cancer imposes a huge financial burden in all developed countries. This study estimates the burden of cancer in Spain in 2015. METHODS: The most recent available epidemiological data on prevalence, incidence and mortality, and the economic data on direct (hospital, drugs, and primary care) and indirect (productivity) costs was used from the social perspective. RESULTS: Prevalence, incidence, and mortality were, respectively, 1240, 478, and 218 per 100,000 inhabitants. Mortality was higher for men, while disability rates were higher for women. Direct costs accounted for 4818 million euros and indirect costs were 640 million euros in 2015. Direct costs were almost completely borne by the hospital (94%). Total burden of cancer in Spain was 5458 million euros in 2015. CONCLUSIONS: In Spain, the costs of cancer were mainly borne by the hospital and these costs might increase in the future due to the expected increase in longevity. Further research would be needed to investigate whether it is possible to redistribute the economic burden of cancer.

This is a call to oncologists for action

Cancer cases are growing in an exponential way, likewise the prices of new cancer drugs. Continuing in this way, in the near future, it will be impossible to provide optimum care for all cancer patients. Therefore, it is important to establish mechanisms that enable the National Health Systems to provide the best options of treatment, either through the elaboration of decision-binding frameworks or through other initiatives that guarantee the best quality care for all oncology patients to overcome, in the best possible way, this difficult illness. Here, we review current proposals that have been established by different cancer organizations worldwide, their similarities, their differences and whether they are helpful in a real clinical setting. Facing present reality and despite these organizations’ huge efforts, these proposals are not being implemented at all and it does not seem feasible that they will in the short run. In the same way, we support and argue why oncologists should have a crucial and a preponderant role to establish the best way of guaranteeing an equal access to the latest oncology care

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This is a call to oncologists for action.

Cancer cases are growing in an exponential way, likewise the prices of new cancer drugs. Continuing in this way, in the near future, it will be impossible to provide optimum care for all cancer patients. Therefore, it is important to establish mechanisms that enable the National Health Systems to provide the best options of treatment, either through the elaboration of decision-binding frameworks or through other initiatives that guarantee the best quality care for all oncology patients to overcome, in the best possible way, this difficult illness. Here, we review current proposals that have been established by different cancer organizations worldwide, their similarities, their differences and whether they are helpful in a real clinical setting. Facing present reality and despite these organizations' huge efforts, these proposals are not being implemented at all and it does not seem feasible that they will in the short run. In the same way, we support and argue why oncologists should have a crucial and a preponderant role to establish the best way of guaranteeing an equal access to the latest oncology care.

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project.

Background: Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival). Methods: Clinically annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test. Results: Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases. Conclusion: Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.

BACKGROUND: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. RESULTS: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. CONCLUSIONS: Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer

Prostate cancer is the second most diagnosed cancer in males in the world. Plasma quantification of prostate-specific antigen substantially improved the early detection of prostate cancer, but still lacks the required specificity. Clinical management of prostate cancer needs advances in the development of new non-invasive biomarkers, ameliorating current diagnosis and prognosis and guiding therapeutic decisions. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. These miRNAs are expressed in the cells and are also present in cell-derived extracellular vesicles such as exosomes. Exosomes have been shown to act as mediators for cell to cell communication because of the regulatory functions of their content. High levels of exosomes are found in several body fluids from cancer patients and could be a potential source of non-invasive biomarkers. In this review, we summarize the diagnostic and prognostic utility of exosomal miRNAs in prostate cancer (AU)

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European edition of the NCCN clinical practice guidelines: relevance of the translation and adaptation into Spanish

The NCCN-evidence-based oncology guidelines are consensus-based management documents, to ensure that all patients receive the most appropriate diagnosis, treatment and support services to achieve the best results. However, the use of these guidelines for decision-making by physicians in Spain is sometimes controversial, as treatments or diagnostic procedures are recommended which might not be authorised in our country, or other management options may exist. In March 2015, the ECO Foundation reached an agreement to translate and adapt the NCCN’s clinical practice guidelines in oncology for the Spanish sector. Consequently, ECO is the first European organization to reach an agreement of this type with the NCCN. This agreement will allow all agents involved in managing the cancer patients to have available guidelines that are adapted to the specific needs of Spain (AU)

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Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer.

Prostate cancer is the second most diagnosed cancer in males in the world. Plasma quantification of prostate-specific antigen substantially improved the early detection of prostate cancer, but still lacks the required specificity. Clinical management of prostate cancer needs advances in the development of new non-invasive biomarkers, ameliorating current diagnosis and prognosis and guiding therapeutic decisions. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. These miRNAs are expressed in the cells and are also present in cell-derived extracellular vesicles such as exosomes. Exosomes have been shown to act as mediators for cell to cell communication because of the regulatory functions of their content. High levels of exosomes are found in several body fluids from cancer patients and could be a potential source of non-invasive biomarkers. In this review, we summarize the diagnostic and prognostic utility of exosomal miRNAs in prostate cancer.

European edition of the NCCN clinical practice guidelines: relevance of the translation and adaptation into Spanish.

The NCCN-evidence-based oncology guidelines are consensus-based management documents, to ensure that all patients receive the most appropriate diagnosis, treatment and support services to achieve the best results. However, the use of these guidelines for decision-making by physicians in Spain is sometimes controversial, as treatments or diagnostic procedures are recommended which might not be authorised in our country, or other management options may exist. In March 2015, the ECO Foundation reached an agreement to translate and adapt the NCCN's clinical practice guidelines in oncology for the Spanish sector. Consequently, ECO is the first European organization to reach an agreement of this type with the NCCN. This agreement will allow all agents involved in managing the cancer patients to have available guidelines that are adapted to the specific needs of Spain.

[Treatment of intra-articular malunion of the distal radius of young active patients]. / Traitement des cals vicieux articulaires de l'extrémité distale du radius du sujet jeune actif.

Management of malunion of the distal radius remains difficult. Planning of the correction of the articular displacement requires a comprehensive analysis by CT arthrography to analyze bone, cartilage and ligaments. Arthroscopy is a valuable tool in the context of joint trauma. In the absence of osteoarthritis, the correction can be carried out as early as possible in the weeks or months following the initial fracture. The use of locking plates allows early mobilization after surgery. This correction aims to prevent the development of secondary osteoarthritis.

[Treatment of partial articular fractures of the distal radius in active young adults]. / Traitement des fractures articulaires partielles de l'extrémité distale du radius du sujet jeune actif.

The wrist's function is at stake in young active adults with partial intra-articular fractures of the distal radius. The high energy nature of these injuries, displaced fractures with risk of malunion in case of insufficient treatment, and associated ligament or cartilage damage all hinder the prognosis of these fractures. Many classification systems exist to help us analyze and in some cases, select a treatment. Optimal management requires a high-quality preoperative assessment and a precise surgical technique coupled with the use of arthroscopy to deal with joint and ligament injuries in the same operation. Devices that address the fragmented nature of these fractures provide the best fixation. The primary treatment goal is reduction with less 1mm intra-articular step-off in order to reduce the risk of secondary osteoarthritis and to treat associated ligament damage, which is very common and often under-estimated. Treating the fracture and any associated lesions during the same operation is the best way to ensure a good functional outcome.

Complement activation product C4d in oral and oropharyngeal squamous cell carcinoma.

OBJECTIVE: Complement C4d-containing fragments have been proposed as diagnostic markers for lung cancer. The purpose of this study was to evaluate the presence of C4d in oropharyngeal (OPSCC) and oral (OSCC) squamous cell carcinomas. SUBJECTS AND METHODS: C4d staining was analyzed by immunohistochemistry in 244 OPSCC surgical specimens. C4d levels were quantified by ELISA in resting saliva samples from 48 patients with oral leukoplakia and 62 with OSCC. Plasma samples from 21 patients with leukoplakia and 30 with oral carcinoma were also studied. RESULTS: C4d staining in OPSCC specimens was associated with nodal invasion (P = 0.001), histopathologic grade (P = 0.014), disease stage (P = 0.040), and focal-adhesion kinase expression (P < 0.001). No association was found between C4d and prognosis. Saliva C4d levels were higher in patients with oral cancer than in subjects with leukoplakia (0.07 ± 0.07 vs 0.04 ± 0.03 µg ml(-1) , P = 0.003). The area under the ROC curve was 0.63 (95%CI: 0.55-0.71). Salivary C4d levels in stage IV patients were higher than in patients with earlier stages (P = 0.028) and correlated with tumor size (P = 0.045). Plasma C4d levels also correlated with salivary C4d levels (P = 0.041), but differences between patients with oral cancer and subjects with leukoplakia were not significant (1.26 ± 0.59 vs 1.09 ± 0.39 µg ml(-1) , P = 0.232). CONCLUSION: C4d-containing fragments are detected in oral primary tumors and are increased in saliva from patients with OSCC.

Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival.

Correction to: Oncogene (2015) 34, 4482­4490; doi:10.1038/onc.2014.378; published online 24 November 2014. Following the online publication of this article, the authors have noticed a misspelt surname: S Hider should read S Haider. There is also an addition to the acknowledgements to read 'This study makes use of data generated by the Molecular Taxonomy of Breast Cancer International Consortium, which was funded by Cancer Research UK and the British Columbia Cancer Agency Branch'. The corrected article appears in this issue. The authors would like to apologise for any inconvenience this may cause.

Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival.

Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.