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Background and Objectives: Evaluate clinical and subclinical arteriosclerotic disease in older patients with hip fracture compared with patients without fracture in order to increase knowledge about the relation between both diseases in older individuals., Patients and Methods: Age- and sex-matched case-control study of octogenarians with and without recent hip fracture. Vascular risk factors, subclinical vascular diseases (assessed by carotid plaques, carotid intima media thickness and arterial stiffness) as well as cardiovascular diseases were analyzed. Univariate and multivariate logistic models were used to estimate odds ratios (OR) with their 95% confidence intervals (CI) to assess the association of the arteriosclerosis and hip fracture., Results: We analyzed 95 patients per group with a median age of 82 [79-87] years of whom 77.9% were female. Patients in both groups have elevated rates of vascular disease (25%) without differences between them. Patients with hip fracture had higher subclinical arteriosclerotic alterations with higher percentage of carotid plaques (OR 3.25 [1.06-9.97]) compared with the control group., Conclusions: Older patients with hip fracture had significantly higher presence of subclinical alterations but not increase on rate of cardiovascular arteriosclerotic disease compared with those without hip fracture., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Background: Despite their frequency and potential impact on prognosis, cancers diagnosed via self-referral to the emergency department are poorly documented. We conducted a detailed analysis of cancer patients diagnosed following emergency self-referral and compared them with those diagnosed following emergency referral from primary care. Given the challenges associated with measuring intervals in the emergency self-referral pathway, we also aimed to provide a definition of the diagnostic interval for these cancers., Methods: A retrospective observational analysis was performed on patients diagnosed with 13 cancers, either following emergency self-referral or emergency referral from primary care. We analysed demographics, tumour stage, clinical data (including 28 presenting symptoms categorised by body systems), and diagnostic intervals by cancer site, then testing for differences between pathways., Results: Out of 3624 patients, 37 % were diagnosed following emergency self-referral and 63 % via emergency referral from primary care. Emergency self-referrals were associated with a higher likelihood of being diagnosed with cancers manifesting with localising symptoms (e.g., breast and endometrial cancer), whereas the likelihood of being diagnosed with cancers featuring nonspecific symptoms and abdominal pain (e.g., pancreatic and ovarian cancer) was higher among patients referred from primary care. Diagnostic intervals in self-referred patients were half as long as those in patients referred from primary care, with most significant differences for pancreatic cancer (28 [95 % CI -34 to -23] days shorter, respectively)., Conclusion: These findings enrich the best available evidence on cancer diagnosis through emergency self-referral and showed that, compared with the emergency referral pathway from primary care, these patients had a significantly increased likelihood of presenting with symptoms that are strongly predictive of cancer. Since the starting point for the diagnostic interval in these patients is their emergency presentation, comparing it with that of those referred from primary care as an emergency is likely to result in biased data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024. Published by Elsevier Ltd.)

The impact of exercise on pediatric tumor biology is essentially unknown. We explored the effects of regular exercise on tumor proteome profile (as assessed with liquid chromatography with tandem mass spectrometry) in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma (HR-NB). Tumor samples of 14 male mice (aged 6-8 wk) that were randomly allocated into an exercise (5-wk combined aerobic and resistance training) or nonexercise control group (6 and 8 mice/group, respectively) were analyzed. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to generate a protein-protein interaction (PPI) network and enrichment analyses. The Systems Biology Triangle (SBT) algorithm was applied for analyses at the functional category level. Tumors of exercised mice showed a higher and lower abundance of 101 and 150 proteins, respectively, than controls [false discovery rate (FDR) < 0.05]. These proteins were enriched in metabolic pathways, amino acid metabolism, regulation of hormone levels, and peroxisome proliferator-activated receptor signaling (FDR < 0.05). The SBT algorithm indicated that 184 and 126 categories showed a lower and higher abundance, respectively, in the tumors of exercised mice (FDR < 0.01). Categories with lower abundance were involved in energy production, whereas those with higher abundance were related to transcription/translation, apoptosis, and tumor suppression. Regular exercise altered the abundance of hundreds of intratumoral proteins and molecular pathways, particularly those involved in energy metabolism, apoptosis, and tumor suppression. These findings provide preliminary evidence of the molecular mechanisms underlying the potential effects of exercise in HR-NB. NEW & NOTEWORTHY We used liquid chromatography with tandem mass spectrometry to explore the impact of a 5-wk exercise intervention on the tumor proteome profile in a mouse model of one of the most aggressive childhood malignancies, high-risk neuroblastoma. Exercise altered the abundance of hundreds of proteins and pathways, particularly those involved in energy metabolism and tumor suppression. These molecular changes could mediate, at least partly, the potential antitumorigenic effects of exercise.

Purpose: The symptoms with which a patient with cancer presents and the route taken to diagnosis (emergency v nonemergency) may affect the speed with which the diagnosis of cancer is made, thereby affecting outcomes. We examined time to diagnosis by symptom for cancers diagnosed through emergency and nonemergency routes (NERs)., Methods: We performed a retrospective review of patients diagnosed with 10 solid cancers at Hospital Clínic of Barcelona between March 2013 and June 2023. Cancers were diagnosed through emergency presentation and admission (inpatient emergency route [IER]), emergency presentation and outpatient referral (outpatient emergency route [OER]), and primary care presentation and outpatient referral (NER). We assessed the effect of diagnostic routes on intervals to diagnosis for 19 cancer symptoms., Results: A total of 5,174 and 1,607 patients were diagnosed with cancer through emergency routes and NERs, respectively. Over 85% of patients presenting with alarm (localizing) symptoms such as hematuria through emergency routes were diagnosed with the expected cancer, whereas those with nonlocalizing symptoms such as abdominal pain had a more heterogeneous cancer-site composition. Median intervals were shorter for alarm than nonlocalizing symptoms and tended to be shorter in IERs than OERs. However, for most symptoms, intervals in both routes were invariably shorter than in the NER. For example, diagnostic intervals for hematuria and abdominal pain were 3 and 5 days shorter in IERs than OERs, but they were 5-8 and 17-22 days shorter than in the NER, respectively., Conclusion: For patients with alarm symptoms, intervals were shorter than for those with nonlocalizing symptoms and, for most symptoms, intervals were shorter when patients were evaluated by emergency routes rather than NERs.

Regular physical activity is associated with lower cancer incidence and mortality, as well as with a lower rate of tumour recurrence. The epidemiological evidence is supported by preclinical studies in animal models showing that regular exercise delays the progression of cancer, including highly aggressive malignancies. Although the mechanisms underlying the antitumorigenic effects of exercise remain to be defined, an improvement in cancer immunosurveillance is likely important, with different immune cell subtypes stimulated by exercise to infiltrate tumours. There is also evidence that immune cells from blood collected after an exercise bout could be used as adoptive cell therapy for cancer. In this Perspective, we address the importance of muscular activity for maintaining a healthy immune system and discuss the effects of a single bout of exercise (that is, 'acute' exercise) and those of 'regular' exercise (that is, repeated bouts) on anticancer immunity, including tumour infiltrates. We also address the postulated mechanisms and the clinical implications of this emerging area of research., (© 2023. Springer Nature Limited.)

Objective: This study aims to identify the risk factors associated with osteoporotic hip fractures in octogenarians and seeks to refine primary prevention strategies for these fractures., Material and Methods: We conducted a case-control study involving individuals aged 79 years and older with hip fractures, comparing them to age- and sex-matched controls without a history of hip fractures. We collected epidemiological, clinical, anthropometric, and analytical factors. We evaluated the presence of osteoporosis using bone densitometry. We defined sarcopenia according the European Working Group on Sarcopenia in Older People criteria (EWGSOP2)., Results: Ninety-five patients per group were analyzed, with a mean age of 82 years, of which 74% were women. The multivariate analysis included statistically significant factors found in the univariate analysis (p < 0.05). These factors included the Barthel Index, nutritional assessment using the CONUT tool, folic acid, vitamin D deficiency, presence of previous fractures, loss of visual acuity, bicipital circumference, sarcopenia, and osteoporosis (densitometry in the neck of the femur). The Nutritional state (OR: 0.08 [0.01-0.61]), the folic acid levels (OR 0.32 [0.1-1]), and a loss of visual acuity (OR 33.16 [2.91-377.87]) were the independent risk factors associated with hip fracture., Conclusions: The assessment of nutritional status in elderly patients, coupled with a comprehensive geriatric assessment, represents easily reproducible and cost-effective tools. These tools can effectively aid in identifying individuals at risk of hip fractures, thereby contributing to more targeted and efficient preventive measures., (Copyright © 2024 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Background: Time intervals and number of prior consultations in primary care (PC) are recognised metrics of diagnostic timeliness of cancer and are interrelated. However, whether and how the two measures correlate with each other in the emergency diagnostic pathway is unknown. We investigated the association between the number of prereferral consultations and the length of intervals from PC presentation to cancer diagnosis following emergency referral to hospital., Methods: Patients were eligible if they first consulted in PC and were diagnosed with cancer following emergency or nonemergency referral to hospital. We analysed for differences in PC and diagnostic intervals and number of consultations between emergency and nonemergency presenters and determined their associations by cancer type. Differences in presenting symptoms and stage at diagnosis between populations and according to number of consultations were also examined., Results: There were 796 emergency and 865 nonemergency presenters with comparable sociodemographic and comorbidity data. Correlation analysis in emergency presenters revealed a strong positive association between number of consultations and intervals for seven of 13 different cancers, including cancers characterised by high proportions of > 3 consultations and long intervals (pancreatic, lung, and colorectal cancer) and vice versa for others (e.g., endometrial, cervical, or oesophageal cancer). Additionally, emergency presenters with > 3 consultations were more likely than those with 1-2 to report nonspecific symptoms (60 vs. 40%, respectively) and to be diagnosed at a later stage., Conclusion: System level interventions are needed to reduce unnecessary delays in the emergency diagnostic pathway, particularly in cancer patients with multiple prereferral consultations. The findings also suggest opportunities to reduce the proportion of emergency diagnoses by targeting symptomatic individuals pre-presentation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by nuclear envelope alterations that lead to accelerated aging and premature death. Several studies have linked health and longevity to cell-extrinsic mechanisms, highlighting the relevance of circulating factors in the aging process as well as in age-related diseases. We performed a global plasma proteomic analysis in two preclinical progeroid models (Lmna G609G/G609G and Zmpste24 -/- mice) using aptamer-based proteomic technology. Pathways related to the extracellular matrix, growth factor response and calcium ion binding were among the most enriched in the proteomic signature of progeroid samples compared to controls. Despite the global downregulation trend found in the plasma proteome of progeroid mice, several proteins associated with cardiovascular disease, the main cause of death in HGPS, were upregulated. We also developed a chronological age predictor using plasma proteome data from a cohort of healthy mice (aged 1-30 months), that reported an age acceleration when applied to progeroid mice, indicating that these mice exhibit an "old" plasma proteomic signature. Furthermore, when compared to naturally-aged mice, a great proportion of differentially expressed circulating proteins in progeroid mice were specific to premature aging, highlighting secretome-associated differences between physiological and accelerated aging. This is the first large-scale profiling of the plasma proteome in progeroid mice, which provides an extensive list of candidate circulating plasma proteins as potential biomarkers and/or therapeutic targets for further exploration and hypothesis generation in the context of both physiological and premature aging., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Inappropriate medication in older patients with multimorbidity results in a greater risk of adverse drug events. Clinical decision support systems (CDSSs) are intended to improve medication appropriateness. One approach to improving CDSSs is to use ontologies instead of relational databases. Previously, we developed OntoPharma-an ontology-based CDSS for reducing medication prescribing errors. Objective: The primary aim was to model a domain for improving medication appropriateness in older patients (chronic patient domain). The secondary aim was to implement the version of OntoPharma containing the chronic patient domain in a hospital setting. Methods: A 4-step process was proposed. The first step was defining the domain scope. The chronic patient domain focused on improving medication appropriateness in older patients. A group of experts selected the following three use cases: medication regimen complexity, anticholinergic and sedative drug burden, and the presence of triggers for identifying possible adverse events. The second step was domain model representation. The implementation was conducted by medical informatics specialists and clinical pharmacists using Protégé-OWL (Stanford Center for Biomedical Informatics Research). The third step was OntoPharma-driven alert module adaptation. We reused the existing framework based on SPARQL to query ontologies. The fourth step was implementing the version of OntoPharma containing the chronic patient domain in a hospital setting. Alerts generated from July to September 2022 were analyzed. Results: We proposed 6 new classes and 5 new properties, introducing the necessary changes in the ontologies previously created. An alert is shown if the Medication Regimen Complexity Index is ≥40, if the Drug Burden Index is ≥1, or if there is a trigger based on an abnormal laboratory value. A total of 364 alerts were generated for 107 patients; 154 (42.3%) alerts were accepted. Conclusions: We proposed an ontology-based approach to provide support for improving medication appropriateness in older patients with multimorbidity in a scalable, sustainable, and reusable way. The chronic patient domain was built based on our previous research, reusing the existing framework. OntoPharma has been implemented in clinical practice and generates alerts, considering the following use cases: medication regimen complexity, anticholinergic and sedative drug burden, and the presence of triggers for identifying possible adverse events.

Patients with chronic lymphocytic leukemia (CLL) progressively develop marked immunosuppression, dampening innate and adaptive-driven antitumor responses. However, the underlying mechanisms promoting immune exhaustion are largely unknown. Herein, we provide new insights into the role of BTLA/HVEM axis promoting defects in T cell-mediated responses against leukemic cells. Increased expression of BTLA, an inhibitory immune checkpoint, was detected on the surface of CD4 + and CD8 + T lymphocytes in patients with CLL. Moreover, high levels of BTLA on CD4 + T cells correlated with diminished time to treatment. Signaling through BTLA activation led to decreased IL-2 and IFN-γ production ex vivo, whereas BTLA/HVEM binding disruption enhanced IFN-γ + CD8 + T lymphocytes. Accordingly, BTLA blockade in combination with bispecific anti-CD3/anti-CD19 antibody promoted CD8 + T cell-mediated anti-leukemic responses. Finally, treatment with an anti-BLTA blocking monoclonal antibody alone or in combination with ibrutinib-induced leukemic cell depletion in vitro. Altogether, our data reveal that BTLA dysregulation has a prognostic role and is limiting T cell-driven antitumor responses, thus providing new insights about immune exhaustion in patients with CLL., (© 2023. The Author(s).)

Aim: Evidence on time-based metrics for cancers diagnosed through emergency presentation is lacking. We examined the duration of intervals from first symptoms to cancer diagnosis in the emergency versus primary care (PC) presentation route. Methods: Retrospective study of outpatients diagnosed with 15 solid cancers over 5 years. The outcome was the length of prediagnostic intervals by diagnostic route. Results: Median intervals in emergency presenters (n = 3167) were shorter than in PC presenters (n = 2215). However, intervals in emergency presenters with three or more prior PC consultations were similar to PC but remarkably longer than in those with one or two and no consultations. Conclusion: As we provide new interval measures for the emergency diagnostic pathway, results highlight the contribution of prior consultations to interval lengths.

Despite extensive research on cancer care during the COVID-19 pandemic, evidence on the impact on prediagnostic time intervals is lacking. To better understand how COVID-19 changed the pathway to diagnosis of cancer, we examined the length of intervals from symptom onset to diagnosis for 13 common cancer types with known clinical stage over 1-year nonpandemic period (March 2019 to March 2020; N = 844) and three biannual COVID periods (March 2020 to September 2021; N = 1172). We analyzed the patient interval (from first symptoms to presentation to a physician), the primary care/emergency department interval (from presentation with relevant symptoms to a primary care or emergency department physician to referral to a hospital-based diagnosis center) and the hospital interval (from referral to diagnosis). Compared to nonpandemic data, there were significant changes across COVID periods. The pandemic mostly impacted patient intervals for cancers diagnosed over the first 6 months after onset in March 2020. Overall median patient intervals were longest in the early COVID period (39 [IQR 22-64] days) and shortest in the nonpandemic period (20 [IQR 13-30] days; Kruskal-Wallis test [χ 2 ], P < .0001). Differences in clinical stage between periods were relevant, with cancers from the mid-period (September 2020 to March 2021) showing the most advanced stage. A shift to later stage was plausibly a result of delayed intervals in the early COVID period. Since intervals are eventually relevant to prognosis, our results provide a baseline against which the impact of improvement strategies to minimize the negative outcomes of COVID-19-associated cancer delays can be assessed and implemented., (© 2022 UICC.)

Better understanding on interactions between SARS-CoV-2 and host cells should help to identify host factors that may be targetable to combat infection and COVID-19 pathology. To this end, we have conducted a genome-wide CRISPR/Cas9-based loss-of-function screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate many findings from previous screens that used full SARS-CoV-2 viruses, but also unveil two novel critical host factors: the lysosomal efflux transporter SPNS1 and the plasma and lysosomal membrane protein PLAC8. Functional experiments with full SARS-CoV-2 viruses confirm that loss-of-function of these genes impairs viral entry. We find that PLAC8 is a key limiting host factor, whose overexpression boosts viral infection in eight different human lung cancer cell lines. Using single-cell RNA-Seq data analyses, we demonstrate that PLAC8 is highly expressed in ciliated and secretory cells of the respiratory tract, as well as in gut enterocytes, cell types that are highly susceptible to SARS-CoV-2 infection. Proteomics and cell biology studies suggest that PLAC8 and SPNS1 regulate the autophagolysosomal compartment and affect the intracellular fate of endocytosed virions., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Unprotected and fragile elderly people in nursing homes experienced the highest mortality rates during the initial coronavirus disease 2019 (COVID-19) pandemic., Objective: Our aim was to study the role of two oral anti-inflammatory drugs, colchicine and prednisone, in elderly patients with COVID-19 in geriatric centers., Methods: A phase II/III, randomized, controlled, multicenter clinical trial was performed in a geriatric population comparing the efficacy and safety of an oral combination of prednisone (60 mg/day for 3 days) and colchicine (at loading doses of 1-1.5 mg/day for 3 days, followed by 0.5 mg/day for 11 days) with the standard treatment, based on intravenous dexamethasone. Primary endpoints assessed the efficacy in reducing death or the modified endpoint death/therapeutic failure to the study drugs over a 28-day period, while secondary endpoints included safety, laboratory changes, and additional therapies used., Results: Fifty-four patients (35 female/19 male) were enrolled, 25 (46.3%) of whom were allocated to the experimental arm and 29 (53.7%) to the control arm. At day 28, no differences in deaths were observed. The combination of mortality or therapeutic failure occurred in 12 (45.13%) patients receiving dexamethasone and 6 (28.13%) patients receiving colchicine/prednisone, resulting in a reduction of risk difference (RD) of - 17% (p = 0.17), with an average reduction of 39% (risk ratio [RR] 0.61) in patients receiving colchicine/prednisone (p = 0.25). Control patients received higher amounts of additional glucocorticoids (p = 0.0095) over a longer time frame (p = 0.0003). Colchicine/prednisone significantly reduced ferritin levels at day 14, as well as D-dimer and lactate dehydrogenase (LDH) levels at day 28. Adverse events were similar in both groups., Conclusions: The combination colchicine/prednisone compared with intravenous dexamethasone has shown a remarkable trend to increase disease survival over a 28-day period in elderly patients requiring oxygen therapy in geriatric centers, without safety issues., Clinical Trial Registry: Clinical Trials Registration Number: NCT04492358., (© 2022. The Author(s).)

Although COVID-19 has had dire consequences on diagnosis of cancer, little data assessing its impact on the whole range of diagnostic activity relevant to cancer are available. We examined trends in the provision of full diagnostic tests for consecutive patients with suspected cancer referred to an academic hospital-based Quick Diagnosis Unit from January 2019 to December 2020. As weekly volumes declined, waiting times for endoscopic, imaging and biopsy/cytology procedures increased steeply during the COVID-impacted period (26 February-28 April 2020). The average weekly increase compared with the same period in 2019 was substantial for invasive procedures requiring admission (200.70%), CT scans (171.20%), GI endoscopy (161.50%), PET/CT scans (152.50%), ultrasonography (148.40%), and ambulatory biopsy/cytology procedures (111.20%). Volumes and waiting times to other procedures showed similar trends. There was a remarkable downward trend in cancer diagnosis during the COVID-impacted period, with a 54.07% reduction compared with the same weeks in 2019. Despite a modest recovery in the following months, the decline in weekly activity and cancer rates persisted until 30 December. Providing insight into how COVID-19 changed the full spectrum of diagnostic activity for suspected cancer informs resilience-building interventions to guarantee access to fast and efficient diagnostics ahead of new threats.

Purpose: Patients evaluated in the emergency department (ED) who have concerning symptoms suggestive of a cancer diagnosis are mostly referred to the quick diagnosis unit of our tertiary hospital. This study analyzed the impact of the Covid-19 pandemic on the volume, disease patterns, and accessibility to essential investigations of patients with suspected cancer referred by the ED to this unit., Methods: Trends in referrals were analyzed from January 1 to July 8, 2020 and the corresponding dates of 2019. Only non-Covid-19 conditions were evaluated. Three time-based cohorts were defined: prepandemic (January 1-February 19), pandemic (February 19-April 22), and postpandemic (April 22-July 8). Along with descriptive statistics, linear regression was used to test for time trends with weekly referrals as the dependent variable., Results: There were 384, 193, and 450 patients referred during the prepandemic, pandemic, and postpandemic periods, respectively. Following an increasing rate, referrals decreased to unprecedented levels in the pandemic period (average weekly slope: -2.1 cases), then increasing again until near normalization. Waiting times to most diagnostic procedures including radiology, endoscopic, nuclear medicine, and biopsy/cytology during the pandemic period were significantly delayed and time-to-diagnosis was considerably longer (19.72 ± 10.37 days vs. 8.33 ± 3.94 days in prepandemic and 13.49 ± 6.45 days in postpandemic period; P < 0.001 in both). Compared to other cohorts, pandemic cohort patients were more likely to have unintentional weight loss and fever of unknown origin as referral indications while anemia and lymphadenopathy were less common. Patients from the pandemic cohort had a significantly lower rate of malignancies and higher of benign gastrointestinal disorders (40.93% vs. 19.53% and 20.89% in prepandemic and postpandemic periods, respectively; P < 0.001 in both), most notably irritable bowel disease, and of mental and behavioral disorders (15.54% vs. 3.39% and 6.00% in prepandemic and postpandemic periods, respectively; P < 0.001 in both)., Conclusions: As our hospital switched its traditional care to one focused on Covid-19 patients, recognized indicators of healthcare quality of quick diagnosis units were severely disrupted. The clinical patterns of presentation and diagnosis of the pandemic period suggested that mass media-generated mental and behavioral responses with distressing symptoms played a significant role in most of these patients., Competing Interests: Declaration of Competing Interest All authors have nothing to declare on conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Due to insufficient scientific evidence, panels of tumour markers (TMs) are currently not recommended for use in suspected cancer. However, recent well-designed studies have revealed a potential clinical value in lung cancer. We analysed the diagnostic accuracy of a panel of 11 circulating TMs with clinically controlled thresholds in the differentiation of cancer from nonmalignant diseases., Methods: We prospectively recruited 4776 consecutive patients presenting with focal or nonspecific symptoms suggestive of cancer who underwent testing for 11 serum TMs before diagnosis was known. The study abided by 2015 STARD guidelines. Tumour markers included, among others, carbohydrate antigen 19-9, carcinoembryonic antigen, alpha-fetoprotein, squamous cell carcinoma-associated antigen, prostate-specific antigen (males), neuron-specific enolase, progastrin-releasing peptide and carbohydrate antigen 125. Thresholds were adjusted for the presence of kidney failure, liver disease, effusions and dermatological disorders. Results showing ≥1 TMs with concentrations above threshold were considered positive., Results: Benign diseases were diagnosed in 3281 (68.7%) patients and cancer in 1495 (31.3%), with epithelial cancers in 1214 (77% at stage IV). When applying criteria for controlled thresholds, overall specificity was 98%. Overall sensitivity of the panel in epithelial cancers was 72.2%, positive predictive value 93% and negative predictive value 90.5%. The area under the receiver operating characteristic curve was 0.920 (95% confidence interval, 0.902-0.924)., Conclusions: By using clinically controlled cut-offs, the combined panel demonstrated an excellent ability to discriminate epithelial cancers from nonmalignant diseases. However, its use in clinical practice would need formal validation through a multicentre controlled trial assessing a panel-guided strategy vs. standard diagnosis., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The inclusion of monoclonal antibodies targeting immune checkpoints such PD-1/PD-L1 or CTLA-4 has revolutionized the landscape of anti-cancer therapy. However, PD-1 and CTLA-4 blockade failed to achieve clinical benefit in CLL, thus attention has been focused on emerging checkpoints in this malignancy. LAG-3 is an immune checkpoint receptor that negatively regulates T cell-mediated responses by inducing an hyporesponsive state, thus promoting tumor escape. Patients with chronic lymphocytic leukemia (CLL) develop a profound immune suppression that leads to lessened immunosurveillance and increased risk of developing a secondary neoplasia. In the study herein, we report the profound dysregulation of LAG-3 on leukemic cells in CLL. Likewise, natural killer (NK) and T cells showed increased LAG-3 expression, hence suggesting a role for this checkpoint in CLL-associated immunosuppression. High LAG-3 expression, as well as high levels of soluble LAG-3 (sLAG-3), correlated with adverse cytogenetics and poor outcome in patients with CLL, highlighting the clinical relevance of this immune checkpoint. Treatment of peripheral blood mononuclear cells (PBMCs) from patients with CLL with relatlimab, a new anti-LAG-3 blocking antibody currently evaluated in numerous clinical trials, depleted leukemic cells and restored NK cell- and T cell-mediated responses. Moreover, combination of LAG-3 with the immunomodulatory drug (IMiD) lenalidomide significantly increased IL-2 production by T cells and antibody-dependent cytotoxicity (ADCC) mediated by NK cells. Altogether, these data provide new insights into the potential anti-leukemic effects of relatlimab, currently in clinical trials in CLL, and provides the rationale to further investigate its combination with IMiDs for the management of hematological malignancies.

Chronic lymphocytic leukemia (CLL) is characterized by progressive immunosuppression and diminished cancer immunosurveillance. Immune checkpoint blockade (ICB)-based therapies, a major breakthrough against cancer, have emerged as a powerful tool to reinvigorate antitumor responses. Herein, we analyzed the role of the novel inhibitory checkpoint BTLA and its ligand, HVEM, in the regulation of leukemic and natural killer (NK) cells in CLL. Flow cytometry analyses showed that BTLA expression is upregulated on leukemic cells and NK cells from patients with CLL, whereas HVEM is downregulated only in leukemic cells, especially in patients with advanced Rai-Binet stage. In silico analysis revealed that increased HVEM , but not BTLA , mRNA expression in leukemic cells correlated with diminished overall survival. Further, soluble BTLA (sBTLA) was found to be increased in the sera of patients with CLL and highly correlated with poor prognostic markers and shorter time to treatment. BTLA blockade with an anti-BTLA monoclonal antibody depleted leukemic cells and boosted NK cell-mediated responses ex vivo by increasing their IFN-γ production, cytotoxic capability, and antibody-dependent cytotoxicity (ADCC). In agreement with an inhibitory role of BTLA in NK cells, surface BTLA expression on NK cells was associated with poor outcome in patients with CLL. Overall, this study is the first to bring to light a role of BTLA/HVEM in the suppression of NK cell-mediated immune responses in CLL and its impact on patient's prognosis, suggesting that BTLA/HVEM axis may be a potential therapeutic target in this disease.

Aim: To compare by micro-costing the costs incurred by quick diagnosis units of tertiary and second-level hospitals. Patients & methods: We included 407 patients from a tertiary and secondary hospital unit. A bottom-up approach was applied. Results: Cost per patient was €577.5 ± 219.6 in the tertiary versus €394.7 ± 92.58 in the secondary unit (p = 0.0559). Mean number of visits and ratio of successive/first visits were significantly higher in the former (3.098 and 2.07 vs 2.123 and 1.12, respectively). Personnel and indirect costs including their percent contribution to overall costs accounted for the main differences. Conclusion: A greater volume of appointments, number of staff and staff time and a greater complexity of patients from the tertiary hospital unit justified the differences in cost outcomes.

Abstract: To investigate the clinical characteristics and outcome of octogenarians with covid-19.This is a observational, retrospective, descriptive study.Consecutive patients aged >80 years who were admitted for covid-19 pneumonia during a 6 weeks period (March 20-April 30, 2020).Illness severity on admission was classified according to World Health Organization (WHO) criteria: mild, moderate, severe, and critical. Data collected included demographics, presenting symptoms, radiological and laboratory findings, comorbidities, functional status, treatment, and clinical outcome.There were 159 patients (52.2% women) with a median age of 85.99 (IQR: 80-98). The median Barthel index was 90 (40-100) and Charlson index was 5 (5-6). Most common presenting symptoms were fever, dyspnea, and cough. Patients had mild (8.2%), moderate (52.2%), or severe (39.6%) illness according to WHO criteria. A bilateral pulmonary involvement was seen in 86% of patients. Laboratory analysis revealed increased serum concentrations of inflammatory parameters (C-reactive protein, ferritin, lactate dehydrogenase, and D-dimer) with an abnormal lymphocyte count [0.88 × 109/L (0.5)]. Treatments included corticosteroids in 37%, and biological therapies in 17.6%. Fifty three (33.3%) patients died during hospitalization, with a median time from admission to death of 3 (IQR 1-6) days. Mortality was higher in men (55%). Deceased patients had a significantly higher frequency of dyspnea, increased inflammatory parameters, and illness severity compared to survivors.One-third of octogenarians with covid-19 died during hospitalization and most had bilateral lung involvement. A further knowledge of the characteristics and outcome of this population may assist clinicians in the decision-making process in these patients., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Vertebral fractures are the most prevalent osteoporotic fractures and are paradoxically the most underdiagnosed. While only one-third of patients have acute pain, they can present other associated chronic complications. Vertrebal fractures are associated with the onset of new fractures, both vertebral and nonvertebral. Radiography of the dorsal-lumbar spine is a useful tool for detecting them but depends on the subjective interpretation of the physician conducting the assessment. New techniques, such as vertebral morphometry, have recently demonstrated greater efficacy in detecting v vertebral fractures and are performed concomitantly with bone densitometry. Knowing how to identify vertebral fractures is essential for the secondary prevention of new fractures and improving our patients' quality of life., (Copyright © 2020. Published by Elsevier España, S.L.U.)

Vertebral fractures are the most prevalent osteoporotic fractures and are paradoxically the most underdiagnosed. While only one-third of patients have acute pain, they can present other associated chronic complications. Vertrebal fractures are associated with the onset of new fractures, both vertebral and nonvertebral. Radiography of the dorsal-lumbar spine is a useful tool for detecting them but depends on the subjective interpretation of the physician conducting the assessment. New techniques, such as vertebral morphometry, have recently demonstrated greater efficacy in detecting v vertebral fractures and are performed concomitantly with bone densitometry. Knowing how to identify vertebral fractures is essential for the secondary prevention of new fractures and improving our patients' quality of life., (Copyright © 2019. Publicado por Elsevier España, S.L.U.)

Background: Regular exercise, particularly moderate-intensity continuous training (MICT), can improve immune function. Natural killer (NK) cells, a subset of lymphocytes that react to infections, are the most responsive innate immune cells to exercise, but the mechanisms underlying this are poorly understood. A type of exercise training that is gaining popularity in recent years is high-intensity interval training (HIIT), but how it affects NK cells is largely unknown. In fact, intense exercise has been traditionally viewed as a potential stressor to immune homeostasis. The purpose of this study was to determine in healthy, previously untrained adults (N=8 [3 male; 40±6 years]) the effects of an intervention consisting of 4-week MICT followed by 4-week HIIT on NK cells as compared with a pre-training (baseline) state., Methods: Participants were studied at three time points: baseline, mid-intervention (after MICT), and post-intervention (after HIIT). Main assessments included cytotoxicity assays, flow-cytometry analysis of NK cell surface markers, and interrogation of the cellular proteome using a systems biology approach., Results: A significant time effect was found for NK cell cytotoxicity (p<0.001), which was increased ~10-fold at both midand post-intervention versus baseline. No significant intervention effect was found for NK surface receptor expression, except for CXCR3 determined as mean fluorescence intensity (p=0.044, although with no significant differences in post hoc pairwise comparisons). The proteins showing a higher differential expression (Log2 fold-change > 10 and false discovery rate [FDR] q-value < 0.001) were COP9 signalosome subunit 3 (COPS3), DnaJ heat shock protein family member B11 (DNAJB11), histidyl-TRNA synthetase 1 (HARS), NIMA related kinase 9 (NEK9), nucleoporin 88 (NUP88), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), regulator of chromosome condensation 2 (RCC2), TAO kinase 3 (TAOK3), transducin beta like 2 (TBL2), and ring finger protein 40 (RNF40). All were upregulated at mid-intervention compared with baseline, with the exception of HARS, which was downregulated. Four enriched pathways (FDR p<25%) were found: two related to transmembrane transport and cellular composition (downregulated at mid-intervention vs baseline), and two related to oxidation- reduction reactions (regulated at post-intervention versus baseline)., Conclusion: A progressive exercise intervention of MICT followed by HIIT induces a remarkable improvement in NK function compared with the untrained state, although at the mechanistic level the pathways involved seem to differ over time during the intervention., (Copyright © 2021 International Society of Exercise and Immunology. All rights reserved.)

Although quick diagnosis units (QDU) have become a cost-effective alternative to inpatient admission for diagnosis of potentially serious diseases, the rate of return hospitalizations among evaluated patients is unknown. This study examined the temporal trends in admissions of QDU patients through 15 years. Adult patients referred to QDU from 2004 to 2019 who were hospitalized between the first and last visit in the unit were eligible. Decisions about admissions were mainly based on the Appropriateness Evaluation Protocol and required independent validation by experienced clinicians using a customized tool. The final analysis included 825 patients. Patient characteristics and major reasons for admission were compared each year and linear trends were analyzed. Admission rates decreased from 7.2% in 2004-2005 to 4.3% in 2018-2019 ( p < 0.0001). While a significant increasing trend was observed in the rate of admissions due to cancer-related complications (from 39.5% in 2004-2005 to 61.7% in 2018-2019; p < 0.0001), those due to anemia-related complications and scheduled invasive procedures experienced a significant downward trend. A likely explanation for these declining trends was the relocation of the unit to a new daycare center in 2013-2014 with recovery rooms and armchairs for IV treatments. The facts of this study could help in the provision of anticipatory guidance for the optimal management of patients at risk of clinical complications.

Financial crisis has forced health systems to seek alternatives to hospitalization-based healthcare. Quick diagnosis units (QDUs) are cost-effective compared to hospitalization, but the determinants of QDU costs have not been studied.We aimed at assessing the predictors of costs of a district hospital QDU (Hospital Plató, Barcelona) between 2009 and 2016.This study was a retrospective longitudinal single center study of 404 consecutive outpatients referred to the QDU of Hospital Plató. The referral reason was dichotomized into suggestive of malignancy vs other. The final diagnosis was dichotomized into organic vs nonorganic and malignancy vs nonmalignancy. All individual resource costs were obtained from the finance department to conduct a micro-costing analysis of the study period.Mean age was 62 ± 20 years (women = 56%), and median time-to-diagnosis, 12 days. Total and partial costs were greater in cases with final diagnosis of organic vs nonorganic disorder, as it was in those with symptoms suggestive or a final diagnosis of cancer vs noncancer. Of all subcosts, imaging showed the stronger correlation with total cost. Time-to-diagnosis and imaging costs were significant predictors of total cost above the median in binary logistic regression, with imaging costs also being a significant predictor in multiple linear regression (with total cost as quantitative outcome).Predictors of QDU costs are partly nonmodifiable (i.e., cancer suspicion, actually one of the goals of QDUs). Yet, improved primary-care-to-hospital referral circuits reducing time to diagnosis as well as optimized imaging protocols might further increase the QDU cost-effectiveness process. Prospective studies (ideally with direct comparison to conventional hospitalization costs) are needed to explore this possibility.

Natural killer (NK) cells are major contributors to immunosurveillance and control of tumor development by inducing apoptosis of malignant cells. Among the main mechanisms involved in NK cell-mediated cytotoxicity, the death receptor pathway and the release of granules containing perforin/granzymes stand out due to their efficacy in eliminating tumor cells. However, accumulated evidence suggest a profound immune suppression in the context of tumor progression affecting effector cells, such as NK cells, leading to decreased cytotoxicity. This diminished capability, together with the development of resistance to apoptosis by cancer cells, favor the loss of immunogenicity and promote immunosuppression, thus partially inducing NK cell-mediated killing resistance. Altered expression patterns of pro- and anti-apoptotic proteins along with genetic background comprise the main mechanisms of resistance to NK cell-related apoptosis. Herein, we summarize the main effector cytotoxic mechanisms against tumor cells, as well as the major resistance strategies acquired by tumor cells that hamper the extrinsic and intrinsic apoptotic pathways related to NK cell-mediated killing.

Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

Quick diagnosis units (QDU) have become an alternative hospital-based ambulatory medicine strategy to inpatient hospitalization for potentially serious illnesses in Spain. Whether diagnosis of pancreatic cancer is better accomplished by an ambulatory or inpatient approach is unknown. The main objective of this retrospective study was to examine and compare the diagnostic effectiveness of a QDU or inpatient setting in patients with pancreatic cancer.Patients with a diagnosis of pancreatic adenocarcinoma who had been referred to a university, tertiary hospital-based QDU or hospitalized between 2005 and 2018 were eligible. Presenting symptoms and signs, risk and prognostic factors, and time to diagnosis were compared. The costs incurred during the diagnostic assessment were analyzed with a microcosting method.A total of 1004 patients (508 QDU patients and 496 inpatients) were eligible. Admitted patients were more likely than QDU patients to have weight loss, asthenia, anorexia, abdominal pain, jaundice, and palpable hepatomegaly. Time to diagnosis of inpatients was similar to that of QDU patients (4.1 [0.8 vs 4.3 [0.6] days; P = .163). Inpatients were more likely than QDU patients to have a tumor on the head of the pancreas, a tumor size >2 cm, a more advanced nodal stage, and a poorer histological differentiation. No differences were observed in the proportion of metastatic and locally advanced disease and surgical resections. Microcosting revealed a cost of &OV0556;347.76 (48.69) per QDU patient and &OV0556;634.36 (80.56) per inpatient (P < .001).Diagnosis of pancreatic cancer is similarly achieved by an inpatient or QDU clinical approach, but the latter seems to be cost-effective. Because the high costs of hospitalization, an ambulatory diagnostic assessment may be preferable in these patients.

Natural killer (NK) cells are innate lymphoid cells that, together with CD8 + T lymphocytes, are tightly correlated with immunesurveillance and the elimination of transforming and malignant cells both during early steps of tumorigenesis and metastasis. This capacity is due, but not limited to, their great cytotoxic capacity upon recognition of stress-related activating ligands of NK cells on the surface of tumor cells. Due to the emerging role of NK cells in the response to treatment with immune checkpoint blockers (ICBs) and other immunotherapies, it has become essential to deeply study this immune subset. As mentioned above, NK cell antitumor responses not only rely on their high cytotoxic capacity, cytokine production by this immune subset, such as interferon gamma (IFN-γ) or tumor necrosis factor (TNF-α), also plays a key role on NK cell function. In this chapter, we provide a detailed protocol to measure the intracellular expression of cytokines produced by NK cells upon stimulation. A step-by-step guide to isolate peripheral blood mononuclear cells, purify NK cells from whole blood, co-culture with tumor cell lines and evaluate their cytokine production capacity by flow cytometry is here provided., (© 2020 Elsevier Inc. All rights reserved.)

The immune system exerts a tight cancer surveillance to eradicate nascent and developing tumors. Natural killer (NK) cells rely on their cytotoxic activity to eliminate abnormal or stressed cells, including those undergoing malignant transformation. Thereupon, NK cells, along with CD8 + T cells, are effector immune cells with a pivotal role in cancer immunosurveillance. Due to the outstanding effectivity of immunotherapy in cancer management, strategies aimed at boosting NK cell-mediated tumor recognition and elimination are being thoroughly studied, such as approaches to induce tumor surface expression of NK cell activating ligands. Additionally, the development of methods to evaluate NK cell cytotoxic responses towards malignant cells with distinct immunogenic profiles is of paramount relevance. In this chapter, we detail a simple but highly sensitive and reproducible methodological approach to quantify in vitro NK cell-mediated lysis of a given target cell, e.g. a tumor cell, based on calcein-AM staining and fluorescence detection. Further, this method can be employed to determine the impact of chemical modulators or antibodies blocking cell surface proteins on the antitumor capacity of NK cells, with the aim to improve anticancer immune responses and elucidate the underlying mechanisms regulating NK cell activity., (© 2020 Elsevier Inc. All rights reserved.)

B-cell receptor (BCR)-dependent signaling is central for leukemia B-cell homeostasis, as underscored by the promising clinical results obtained in patients with chronic lymphocytic leukemia (CLL) treated with novel agents targeting components of this pathway. Herein, we demonstrate that the mithralog EC-7072 displays high ex vivo cytotoxic activity against leukemia cells from CLL patients independently from high-risk prognostic markers and IGHV mutational status. EC-7072 was significantly less toxic against T cells and NK cells and did not alter the production of the immune effector molecules IFN-γ and perforin. EC-7072 directly triggered caspase-3-dependent CLL cell apoptosis, which was not abrogated by microenvironment-derived factors that sustain leukemia cell survival. RNA-sequencing analyses revealed a dramatic EC-7072-driven reprograming of the transcriptome of CLL cells, including a wide downregulation of multiple components and targets of the BCR signaling pathway. Accordingly, we found decreased levels of phosphorylated signaling nodes downstream of the BCR. Crosslinking-mediated BCR activation antagonized CLL cell death triggered by EC-7072, increased the phosphorylation levels of the abovementioned signaling nodes and upregulated BCL2 expression, suggesting that the mithralog disrupts CLL cell viability by targeting the BCR signaling axis at multiple levels. EC-7072 exerted similar or higher antileukemic activity than that of several available CLL therapies and displayed additive or synergistic interaction with these drugs in killing CLL cells. Overall, our findings provide rationale for future investigation to test whether EC-7072 may be a potential therapeutic option for patients with CLL and other B-cell malignancies., (Copyright © 2019 Lorenzo-Herrero, Sordo-Bahamonde, Bretones, Payer, González-Rodríguez, González-García, Pérez-Escuredo, Villa-Álvarez, Núñez, Morís, Gonzalez and López-Soto.)

Cancer development is tightly controlled by effector immune responses that recognize and eliminate malignantly transformed cells. Nonetheless, certain immune subsets, such as tumor-associated macrophages, have been described to promote tumor growth, unraveling a double-edge role of the immune system in cancer. Cell stress can modulate the crosstalk between immune cells and tumor cells, reshaping tumor immunogenicity and/or immune function and phenotype. Infiltrating immune cells are exposed to the challenging conditions typically present in the tumor microenvironment. In return, the myriad of signaling pathways activated in response to stress conditions may tip the balance toward stimulation of antitumor responses or immune-mediated tumor progression. Here, we explore how distinct situations of cellular stress influence innate and adaptive immunity and the consequent impact on cancer establishment and progression., Competing Interests: Conflict of interest: The authors declare no conflict of interest.

The immune system is able to detect and eliminate nascent and developing tumors. Thus, T lymphocytes of the adaptive immunity recognize cancer cells by detecting tumor-associated antigens, whereas certain innate immune cells scan for molecules that are mainly overexpressed on malignant and infected cells. The best example of the latter is natural killer (NK) cells. The activity of these immune cells is strictly governed by a balance between positive and negative signals provided by stress-regulated molecules that bind NK cell membrane receptors, such as the activatory receptor NKG2D. Given the key role of NK cells in eradicating cancer cells, the development of assays to study the cellular and molecular determinants of NK cell antitumor activity are of great relevance. In this chapter, we describe a flow cytometric in vitro assay to evaluate the cytotoxic activity of NK cells against a given target cell, including tumor cells. Moreover, this method is highly versatile, as it can be complemented with the use of antibodies blocking cell surface proteins (receptors or ligands) or a variety of chemical modulators, which allows the elucidation of molecules and signaling pathways that regulate NK cell anticancer function.

Deregulated WNT signaling has been shown to favor malignant transformation, tumor progression, and resistance to conventional cancer therapy in a variety of preclinical and clinical settings. Accumulating evidence suggests that aberrant WNT signaling may also subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to multiple immunotherapeutics, including immune checkpoint blockers. Here, we discuss the molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance and present potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cancer development is under surveillance by the immune system of the host. Tumor cells can be recognized and killed by cytotoxic lymphocytes- such as CD8+ T lymphocytes and natural killer (NK) cells-mainly through the immune secretion of lytic granules that kill target cells. This process involves the fusion of the granule membrane with the cytoplasmic membrane of the immune effector cell, resulting in surface exposure of lysosomal-associated proteins that are typically present on the lipid bilayer surrounding lytic granules, such as CD107a. Therefore, membrane expression of CD107a constitutes a marker of immune cell activation and cytotoxic degranulation. In this chapter, we detail the steps required to isolate peripheral blood mononuclear cells (PBMCs), coculture them with target tumor cell lines, and evaluate the cytotoxic immune function by means of flow cytometry evaluation of CD107a expression on the surface of NK cells.

Metastasis represents the leading cause of cancer-related death mainly owing to the limited efficacy of current anticancer therapies on advanced malignancies. Although immunotherapy is rendering promising results in the treatment of cancer, many adverse events and factors hampering therapeutic efficacy, especially in solid tumors and metastases, still need to be solved. Moreover, immunotherapeutic strategies have mainly focused on modulating the activity of T cells, while Natural Killer (NK) cells have only recently been taken into consideration. NK cells represent an attractive target for cancer immunotherapy owing to their innate capacity to eliminate malignant tumors in a non-Major Histocompatibility Complex (MHC) and non-tumor antigen-restricted manner. In this review, we analyze the mechanisms and efficacy of NK cells in the control of metastasis and we detail the immunosubversive strategies developed by metastatic cells to evade NK cell-mediated immunosurveillance. We also share current and cutting-edge clinical approaches aimed at unleashing the full anti-metastatic potential of NK cells, including the adoptive transfer of NK cells, boosting of NK cell activity, redirecting NK cell activity against metastatic cells and the release of evasion mechanisms dampening NK cell immunosurveillance.

One of the cardinal features of chronic lymphocytic leukemia (CLL) is its association with a profound immunosuppression. NK cell function is markedly impaired in CLL patients, who show a significant dysregulation of the expression of activating and inhibitory receptors. Here, we analyzed the role of the novel inhibitory receptor Ig-like transcript 2 (ILT2, also termed LIR-1, LILRB1) in the regulation of NK cells in CLL. Our results show that ILT2 expression was significantly decreased on leukemic cells and increased on NK cells of CLL patients, particularly in those with advanced disease and with bad prognostic features, such as those carrying chromosome del(11q). The immunomodulatory drug lenalidomide may regulate the expression of ILT2 and its ligands in CLL since it significantly increased the expression of ILT2 and partially reestablished the expression of its ligands on leukemic cells. Furthermore, lenalidomide significantly increased the activation and proliferation of NK cells, which was strongly enhanced by ILT2 blockade. Combining ILT2 blockade and lenalidomide activated NK cell cytotoxicity resulting in increased elimination of leukemic cells from CLL patients. Overall, we describe herein the role of an inhibitory receptor involved in the suppression of NK cell activity in CLL, which is restored by ILT2 blockade in combination with lenalidomide, suggesting that it may be an interesting therapeutic strategy to be explored in this disease.

Compelling evidence indicates that tumors may evade immunosurveillance by subverting the metabolism of immune cells. In a recent paper in Nature, Song et al. (2018) demonstrate that ovarian cancers activate IRE1α-XBP1 signaling within CD4 + T lymphocytes, thereby disrupting their bioenergetic function and contribution to anticancer immune responses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Immunotherapy is revolutionizing the clinical management of multiple tumors. However, only a fraction of patients with cancer responds to immunotherapy, and currently available immunotherapeutic agents are expensive and generally associated with considerable toxicity, calling for the identification of robust predictive biomarkers. The overall genomic configuration of malignant cells, potentially favoring the emergence of immunogenic tumor neoantigens, as well as specific mutations that compromise the ability of the immune system to recognize or eradicate the disease have been associated with differential sensitivity to immunotherapy in preclinical and clinical settings. Along similar lines, the type, density, localization, and functional orientation of the immune infiltrate have a prominent impact on anticancer immunity, as do features of the tumor microenvironment linked to the vasculature and stroma, and systemic factors including the composition of the gut microbiota. On the basis of these considerations, we outline the hallmarks of successful anticancer immunotherapy., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Tumor cell plasticity is a major obstacle for the cure of malignancies as it makes tumor cells highly adaptable to microenvironmental changes, enables their phenotype switching among different forms, and favors the generation of prometastatic tumor cell subsets. Phenotype switching toward more aggressive forms involves different functional, phenotypic, and morphologic changes, which are often related to the process known as epithelial-mesenchymal transition (EMT). In this study, we report natural killer (NK) cells may increase the malignancy of melanoma cells by inducing changes relevant to EMT and, more broadly, to phenotype switching from proliferative to invasive forms. In coculture, NK cells induced effects on tumor cells similar to those induced by EMT-promoting cytokines, including upregulation of stemness and EMT markers, morphologic transition, inhibition of proliferation, and increased capacity for Matrigel invasion. Most changes were dependent on the engagement of NKp30 or NKG2D and the release of cytokines including IFNγ and TNFα. Moreover, EMT induction also favored escape from NK-cell attack. Melanoma cells undergoing EMT either increased NK-protective HLA-I expression on their surface or downregulated several tumor-recognizing activating receptors on NK cells. Mass spectrometry-based proteomic analysis revealed in two different melanoma cell lines a partial overlap between proteomic profiles induced by NK cells or by EMT cytokines, indicating that various processes or pathways related to tumor progression are induced by exposure to NK cells. Significance: NK cells can induce prometastatic properties on melanoma cells that escape from killing, providing important clues to improve the efficacy of NK cells in innovative antitumor therapies. Cancer Res; 78(14); 3913-25. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Mainly because of the diversity of clinical presentations, diagnostic delays in lymphoma can be excessive. The time spent in primary care before referral to the specialist may be relatively short compared with the interval between hospital appointment and diagnosis. Although studies have examined the diagnostic intervals and referral patterns of patients with lymphoma, the time to diagnosis of outpatient compared to inpatient settings and the costs incurred are unknown., Methods: We performed a retrospective study at two academic hospitals to evaluate the time to diagnosis and associated costs of hospital-based outpatient diagnostic clinics or conventional hospitalization in four representative lymphoma subtypes. The frequency, clinical and prognostic features of each lymphoma subtype and the activities of the two settings were analyzed. The costs incurred during the evaluation were compared by microcosting analysis., Results: A total of 1779 patients diagnosed between 2006 and 2016 with classical Hodgkin, large B-cell, follicular, and mature nodal peripheral T-cell lymphomas were identified. Clinically aggressive subtypes including large B-cell and peripheral T-cell lymphomas were more commonly diagnosed in inpatients than in outpatients (39.1 vs 31.2% and 18.9 vs 13.5%, respectively). For each lymphoma subtype, inpatients were older and more likely than outpatients to have systemic symptoms, worse performance status, more advanced Ann Arbor stages, and high-risk prognostic scores. The admission time for diagnosis (i.e. from admission to excisional biopsy) of inpatients was significantly shorter than the time to diagnosis of outpatients (12.3 [3.3] vs 16.2 [2.7] days; P < .001). Microcosting revealed a mean cost of €4039.56 (513.02) per inpatient and of €1408.48 (197.32) per outpatient, or a difference of €2631.08 per patient., Conclusions: Although diagnosis of lymphoma was quicker with hospitalization, the outpatient approach seems to be cost-effective and not detrimental. Despite the considerable savings with the latter approach, there may be hospitalization-associated factors which may not be properly managed in an outpatient unit (e.g. aggressive lymphomas with severe symptoms) and the cost analysis did not account for this potentially added value. While outcomes were not analyzed in this study, the impact on patient outcome of an outpatient vs inpatient diagnostic setting may represent a challenging future research.

A wide array of cell-intrinsic surveillance mechanisms maintains the homeostasis of dividing cells and the integrity of the genome. Accumulating evidence also supports a role for cell-extrinsic mechanisms. Among them, the immune system, together with cell-autonomous checkpoint processes, eliminates cells that harbor unbalanced karyotypes generated by mitotic defects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Chronic lymphocytic leukemia (CLL) is associated with a profound dysregulation of the immune system. Loss of T cell function is frequently caused in cancer by sustained signaling of inhibitory receptors. Here, we analyzed the role of the novel inhibitory receptor Ig-like transcript 2 (ILT2) in the pathogenesis of CLL. We observed that ILT2 expression was markedly reduced on leukemic cells, whereas it was increased on CD8 and CD4 T cells from CLL patients, particularly in those patients harboring chromosome 11q deletion, which includes the ATM gene. A deep dysregulation of ILT2 ligands expression in leukemia cells was also observed. ILT2 impaired the activation and proliferation of CD4 and CD8 T cells in CLL patients, but it had no effect in leukemic cells. ILT2 downregulated the production of IL-2 by CD4 T cells of CLL patients and induced the expression of cytokines that promote the survival of leukemic cells, such as IFN-γ, by T cells. Importantly, ILT2 blockade restored the activation, proliferation and cytokine production of T cells. In conclusion, we describe a novel immune inhibitory pathway that is upregulated in CLL and delineate a new potential target to be explored in this disease.

Objective: To analyse potentially inappropriate prescribing (PIP) in elderly polypathological patients (PP)., Method: Multicentre observational, prospective study of 672 patients aged 75 years and older hospitalised in Internal Medicine between April 2011 and March 2012. The Beers, STOPP-START and ACOVE criteria were used to detect potentially inappropriate prescribing and the results of PP and non-PP patients were compared., Results: Of the 672 patients included, 419 (62%) were polypathological, of which 89.3% met PIP criteria versus 79.4% of non-polypathological patients (p <0.01). 40.3% of polypathological patients met at least one Beers criteria, 62.8% at least one STOPP criteria, 62.3% at least one START criteria and 65.6% at least one ACOVE criteria. The rate of potentially inappropriate prescribing was higher in polypathological patients regardless of the tool used., Conclusions: Given the high rate of potentially inappropriate prescribing in polypathological patients, strategies to improve prescribing adequacy must be developed., (Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.)