Corrigendum: Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

This corrects the article DOI: 10.1038/nature22364.

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.

Effect of intravenous iron on functional outcomes in hip fracture: a randomised controlled trial.

OBJECTIVES: to determine the safety and effect of intravenous iron sucrose on functional outcomes, delirium, nosocomial infections and transfusion requirements in older patients with hip fracture. DESIGN: single-centre randomised, double-blind, placebo-controlled clinical trial. SETTING AND PARTICIPANTS: orthogeriatric share care service at an academic tertiary care hospital. A total of 253 patients were recruited: 126 patients were assigned to intravenous iron and 127 to placebo. METHODS: on days 1, 3 and 5 after admission, the iron group received 200 mg Venofer® (iron sucrose) in 100 ml saline and the placebo group 100 ml saline. The primary outcome was absolute functional gain, considered as Barthel index (BI) at discharge minus BI on admission. Secondary outcomes included incidence of postoperative delirium according to the confusion assessment method, proportion of patients recovering prior functional status at 3 months, postoperative transfusion requirements, haemoglobin at 3 months, incidence of nosocomial infections and safety. RESULTS: the median participant age was 87 (interquartile range, 82.5-91.5) years. Most patients were female (72.7%), and the median previous BI was 81(59-95). No significant effect of intravenous iron was observed for the primary outcome: the median AFG score was 17.1 points (4.8-23.3) in the intravenous iron group and 16 points (6-26) in the placebo group (P = 0.369). No significant treatment effects were observed for other functional outcomes or secondary end points. CONCLUSION: while we found no impact of intravenous iron sucrose on functional recovery, incidence of postoperative delirium, transfusion requirements, haemoglobin at 3 months, mortality and nosocomial infections rates in older patients with hip fracture, we did find that the intervention was safe.

A Research Roadmap: Connected Health as an Enabler of Cancer Patient Support.

The evidence that quality of life is a positive variable for the survival of cancer patients has prompted the interest of the health and pharmaceutical industry in considering that variable as a final clinical outcome. Sustained improvements in cancer care in recent years have resulted in increased numbers of people living with and beyond cancer, with increased attention being placed on improving quality of life for those individuals. Connected Health provides the foundations for the transformation of cancer care into a patient-centric model, focused on providing fully connected, personalized support and therapy for the unique needs of each patient. Connected Health creates an opportunity to overcome barriers to health care support among patients diagnosed with chronic conditions. This paper provides an overview of important areas for the foundations of the creation of a new Connected Health paradigm in cancer care. Here we discuss the capabilities of mobile and wearable technologies; we also discuss pervasive and persuasive strategies and device systems to provide multidisciplinary and inclusive approaches for cancer patients for mental well-being, physical activity promotion, and rehabilitation. Several examples already show that there is enthusiasm in strengthening the possibilities offered by Connected Health in persuasive and pervasive technology in cancer care. Developments harnessing the Internet of Things, personalization, patient-centered design, and artificial intelligence help to monitor and assess the health status of cancer patients. Furthermore, this paper analyses the data infrastructure ecosystem for Connected Health and its semantic interoperability with the Connected Health economy ecosystem and its associated barriers. Interoperability is essential when developing Connected Health solutions that integrate with health systems and electronic health records. Given the exponential business growth of the Connected Health economy, there is an urgent need to develop mHealth (mobile health) exponentially, making it both an attractive and challenging market. In conclusion, there is a need for user-centered and multidisciplinary standards of practice to the design, development, evaluation, and implementation of Connected Health interventions in cancer care to ensure their acceptability, practicality, feasibility, effectiveness, affordability, safety, and equity.

Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.

Impact of a patient blood management program within an Orthogeriatric care service.

BACKGROUND: Patient blood management (PBM) performs multidisciplinary strategies to optimize red blood cell (RBC) transfusion. Orthogeriatric share care models (surgeon and geriatrician manage the patient together from admission) have the goal of improving outcomes in hip fracture patients. MATERIAL AND METHODS: A prospective observational study was conducted. Patients aged ≥70 years undergoing hip fracture (HF) surgery were consecutively included. When admitted on the orthogeriatric service a PBM protocol was applied based on: perioperative antithrombotic management, intravenous iron sucrose administration and restrictive transfusion criteria. Risk factors, clinical and functional effects of transfusion and its requirements were assessed to audit our model. RESULTS: A total of 383 patients participated (women, 78.8%; median age, 86 (82-90) years). 210 patients (54.8%) were transfused. Age (OR = 1.055, 95% CI 1.017-1.094; p = 0.004) and Hemoglobin (Hb) level on admission (OR = 0.497, 95% CI 0.413-0.597; p < 0.001) were found to be significant risk factors for transfusion. Transfusion increased length of stay (b = 1.37, 95% CI 0.543-2.196; p = 0.001) but did not have an effect on other variables. DISCUSSION: The PBM program established within an orthogeriatric service showed positive outcomes in terms of clinical complications, mortality, delirium or functional recovery in transfused patients, whereas it did not impact on shorter length of stay. The risk of transfusion on admission was predicted with the lower Hb levels on admission, along with the age of the patients. New measurements as homogenous restrictive transfusion criteria, a single-unit RBC transfusion and the assessment of the intravenous iron efficacy are need to be applied as a result of the high transfusion requirements.

Successful Pregnancy and Cancer Outcomes With Ipilimumab and Nivolumab for Metastatic Renal Cell Carcinoma: Case Report and Review of the Literature.

Pregnancy and cancer share CTLA-4 and PD-1/PD-L1 as some of the immunomodulatory pathways that reshape the immune system from a destructive response to a state of tolerance to the fetus and the tumor, respectively. Ipilimumab (anti-CTLA-4 inhibitor) and nivolumab (anti-PD-1 inhibitor) are used in combination for the treatment of metastatic renal cell carcinoma, and their use could theoretically result in an immune response against the fetus. Furthermore, these immune checkpoint inhibitors are immunoglobulin G antibodies that transfer from the mother to the fetus and may cause a direct toxicity. We present the first report of a metastatic renal cell carcinoma patient in which ipilimumab and nivolumab were successfully used starting in her first trimester of pregnancy, with sufficient follow-up to show favorable outcomes for both the mother and the child. We describe our management of this challenging case and we review the available evidence, coming from Developmental and Reproductive Toxicology Studies and case reports of metastatic melanoma patients.

Body composition and lung cancer-associated cachexia in TRACERx.

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.

Accuracy, feasibility and predictive ability of different frailty instruments in an acute geriatric setting.

PURPOSE: To analyze the feasibility, accuracy and the ability of different frailty instruments to predict adverse outcomes. METHODS: A prospective cohort study was conducted in patients ≥ 70 years admitted to the acute care setting (ACS). Feasibility and prevalence of frailty were assessed by FRAIL, Clinical Frailty Scale (CFS), hand grip strength (HGS) and the Spanish Frailty-VIG. Receiver operator characteristic (ROC) curves and area under the curve (AUC) were performed to identify frailty according to each instrument, setting VIG as the reference. For each instrument, multiple logistic regressions were used to examine the effect of frailty on primary outcome (i.e., three-month mortality) and secondary outcomes (i.e., in-hospital mortality, length of stay, institutionalization, functional decline and 30-day readmission). RESULTS: A total of 185 patients were included, with a median age of 89 years. The feasibility of the instruments was 100%, except for HGS (67%). The prevalence of frailty varied from 65.2% (FRAIL) to 86.7% (VIG). AUCs against VIG ranged from 0.69 (95% confidence interval [CI] 0.57-0.81: FRAIL) to 0.77 (95% CI 63.5-90.2: CFS). Frail patients defined by FRAIL were 2.7times more likely to have a prolonged length of stay than non-frail patients (95% CI 1.385-5.416). Three-month mortality occurred more among frail patients, either defined by FRAIL (OR 2.5; 95% CI 1.072-5.881) or CFS (OR 3.7; 95% CI 1.255-10.812), than in non-frail patients. CONCLUSION: The four instruments had high feasibility providing variable prevalence of frailty. FRAIL and CFS predicted well for three-month mortality, and FRAIL also for length of stay. However, none of the instruments predicted for the other secondary outcomes of the study.

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study.

BACKGROUND: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. PATIENTS AND METHODS: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. RESULTS: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data. CONCLUSIONS: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.

Complete response and renal cell carcinoma in the immunotherapy era: The paradox of good news.

Immune-checkpoint inhibitor-based therapy has revolutionized the natural history of metastatic renal cell carcinoma (mRCC) providing better survival outcomes, higher rates of complete responses (CR) and durable remissions. Along with these advances, new challenges have emerged. RECIST and new immune-response criteria may be equivocal identifying complete responses. How to define a durable response and what is the optimal treatment duration remains unclear. Furthermore, the real value of a complete and deep response, whether or not it can be considered curation and whether or not immunotherapy discontinuation should be considered after complete response, are questions that remain open. The present article reviews the current evidence regarding the impact and challenges of managing complete and durable responses in mRCC treated with immune-checkpoint inhibitors.

Clinical Characteristics, Frailty, and Mortality of Residents With COVID-19 in Nursing Homes of a Region of Madrid.

OBJECTIVES: To describe the clinical characteristics, 30-day mortality, and associated factors of patients living in nursing homes (NH) with COVID-19, from March 20 to June 1, 2020. DESIGN: This is a retrospective study. A geriatric hospital-based team acted as a consultant and coordinated the care of older people living in NHs from the hospital. SETTING AND PARTICIPANTS: A total of 630 patients aged 70 and older with Coronavirus Disease 2019 COVID-19 living in 55 NHs. METHODS: A logistic regression was performed to analyze the factors associated with mortality. In addition, Kaplan-Meier curves were applied according to mortality and its associated factors using the log-rank Mantel-Cox test. RESULTS: The diagnosis of COVID-19 was mainly made by clinical compatibility (N = 430). Median age was 87 years, 64.6% were women and 45.9% were transferred to be cared for at the hospital. A total of 282 patients died (44.7%) within the 30 days of first attention by the team. A severe form of COVID-19 occurred in 473 patients, and the most frequent symptoms were dyspnea (n = 332) and altered level of consciousness (n = 301). According to multiple logistic regression, male sex (P = .019), the Clinical Frailty Score (CFS) ≥6 (P = .004), dementia (P = .012), dyspnea (P < .001), and having a severe form of COVID-19 (P = .001), were associated with mortality, whereas age and care setting were not. CONCLUSIONS AND IMPLICATIONS: Mortality of the residents living in NHs with COVID-19 was almost 45%. The altered level of consciousness as an atypical presentation of COVID-19 should be considered in this population. A severe form of the disease, present in more than three-quarters of patients, was associated with mortality, apart from the male sex, CFS ≥6, dementia, and dyspnea, whereas age and care setting were not. These findings may also help to recognize patients in which the Advance Care Planning process is especially urgent to assist in the decisions about their care.

Association between BRCA2 alterations and intraductal and cribriform histologies in prostate cancer.

BACKGROUND: Intraductal (IDC) and cribriform (CRIB) histologies in prostate cancer have been associated with germline BRCA2 (gBRCA2) mutations in small retrospective series, leading to the recommendation of genetic testing for patients with IDC in the primary tumour. PATIENTS AND METHODS: To examine the association of gBRCA2 mutations and other tumour molecular features with IDC and/or cribriform (CRIB) histologies, we conducted a case-control study in which primary prostate tumours from 58 gBRCA2 carriers were matched (1:2) by Gleason Grade Group and specimen type to 116 non-carriers. Presence/absence of IDC and CRIB morphologies was established by two expert uropathologists blinded to gBRCA2 status. Fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS) were used to detect BRCA2 alterations, PTEN deletions and TMPRSS2-ERG fusions. Chi-squared tests were used to compare the frequency of IDC and CRIB in gBRCA2 carriers and controls and to assess associations with other variables. Logistic regression models were constructed to identify independent factors associated with both histology patterns. RESULTS: No significant differences between gBRCA2 carriers and non-carriers were observed in the prevalence of IDC (36% gBRCA2 versus 50% non-carriers, p = 0.085) or CRIB (53% gBRCA2 versus 43% non-carriers p = 0.197) patterns. However, IDC histology was independently associated with bi-allelic BRCA2 alterations (OR 4.3, 95%CI 1.1-16.2) and PTEN homozygous loss (OR 5.2, 95%CI 2.1-13.1). CRIB morphology was also independently associated with bi-allelic BRCA2 alterations (OR 5.6, 95%CI 1.7-19.3). CONCLUSIONS: While we found no association between gBRCA2 mutations and IDC or CRIB histologies, bi-allelic BRCA2 loss in primary prostate tumours was significantly associated with both variant morphologies, independently of other clinical-pathologic factors.

Impact of delirium on short-term outcomes in hip fracture patients under a program of approach to delirium.

AIM: We aimed to investigate the impact of delirium on short-term outcomes in hip fracture patients. Special attention was given to patients with delirium and dementia. METHODS: A prospective observational cohort study was carried out in hip fracture patients aged ≥70 years who were admitted to a hospital unit where a multicomponents approach to delirium is established for all patients. Our population was split into delirium (n = 212) and non-delirium cohort (n = 171) according to the Confusion Assessment Method. Patients with a previous diagnosis of dementia in an outpatient appointment were also assessed within the delirium cohort. The utility of the rehabilitation was measured with the Absolute Functional Gain index. RESULTS: A total of 383 patients were entered into the study. The median age was 86 years, and most patients were women (78.8%). Delirium patients were older, presented a lower previous Barthel Index (BI), had higher rates of dementia and came more frequently from nursing homes. Comparative analysis did not show differences in mortality, complications, length of stay or walking ability between the cohorts. However, lower BI on discharge, lower Absolute Functional Gain and the presence of nosocomial infections were found more frequently in the delirium cohort. In multivariate analysis, only the BI on discharge (P = 0.010) was lower in delirium patients. Within the delirium cohort, those suffering from dementia had worse BI on discharge (P = 0.017) and lower Absolute Functional Gain (P = 0.019). CONCLUSIONS: Delirium was not associated with mortality, walking ability, length of stay and clinical complications in hip fracture patients. BI on discharge was the only short-term outcome affected. In the delirium cohort, those suffering from dementia showed worse rehabilitation results. Geriatr Gerontol Int 2020; 20: 130-137.

Recent advances in systemic therapy: Advances in systemic therapy for HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor (HER)2 over-expression is associated with a shortened disease-free interval and poor survival. Although the addition of trastuzumab to chemotherapy in the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastuzumab was used beyond the first-line setting because of multiple mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further trials to explore this concept are ongoing. New tyrosine kinase inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin homolog) pathway regulators, HER2 antibody-drug conjugates, and inhibitors of heat shock protein-90 are being evaluated to determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer.

Antinuclear antibodies and cancer: A literature review.

Antinuclear antibodies (ANAs) are a spectrum of autoantibodies targeted to various nuclear and cytoplasmic components of the cells. They are very useful as serological markers for different autoimmune disease, like systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), scleroderma, polymyositis, or mixed connective tissue disease. In these years, an increasing attention has been focussed in the relationship between tumours and autoimmunity. Different authors have demonstrated that ANAs are presented, not only in autoimmune diseases, also in serum of patients with different types of cancers. These data suggested that ANAs could be involved in the pathogenesis of cancer as well as other premalignant disease. In this review, we are going to describe all data reported about the presence of these antibodies in samples from patients with cancer as well as the potential role of some of these proteins in early detection and prognosis.

Lung cancer and peritoneal carcinomatosis.

Lung cancer is currently one of the most common malignancies in the world and peritoneal involvement is rare in these types of tumors. Clinical manifestations of these metastases are also uncommon and include intestinal perforation and obstruction. The present study reviewed certain aspects of the complication of peritoneal involvement and illustrated it with four cases of patients that were diagnosed with primary lung carcinoma and secondary peritoneal carcinomatosis (PC). The outcome of these patients is poor and they rarely respond to chemotherapy. Surgery is successful in the majority of cases.

Squamous-cell carcinoma of the lungs: is it really so different?

BACKGROUND: Squamous cell carcinoma (SCC) is the predominant histological type in men, and adenocarcinoma is the most common subtype in women in the world. The incidence of SCC is decreasing in men, while the incidence of adenocarcinoma (AC) is stable or slightly increasing in western countries. There is active research on the AC subtype but SCC remains poorly studied. CONCLUSIONS: In this review, we have studied different aspects of the SCC subtype, including epidemiology, clinical features, pathology, molecular biology markers, and new therapeutic targets, treatments and prognosis implications.

Upregulation of trefoil factor 3 (TFF3) after rectal cancer chemoradiotherapy is an adverse prognostic factor and a potential therapeutic target.

PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.