Immune cell infiltration and inflammatory landscape in primary brain tumours.

BACKGROUND: Primary malignant brain tumours are more than one-third of all brain tumours and despite the molecular investigation to identify cancer driver mutations, the current therapeutic options available are challenging due to high intratumour heterogeneity. In addition, an immunosuppressive and inflammatory tumour microenvironment strengthens cancer progression. Therefore, we defined an immune and inflammatory profiling of meningioma and glial tumours to elucidate the role of the immune infiltration in these cancer types. METHODS: Using tissue microarrays of 158 brain tumour samples, we assessed CD3, CD4, CD8, CD20, CD138, Granzyme B (GzmB), 5-Lipoxygenase (5-LOX), Programmed Death-Ligand 1 (PD-L1), O-6-Methylguanine-DNA Methyltransferase (MGMT) and Transglutaminase 2 (TG2) expression by immunohistochemistry (IHC). IHC results were correlated using a Spearman correlation matrix. Transcript expression, correlation, and overall survival (OS) analyses were evaluated using public datasets available on GEPIA2 in Glioblastoma (GBM) and Lower Grade Glioma (LGG) cohorts. RESULTS: Seven out of ten markers showed a significantly different IHC expression in at least one of the evaluated cohorts whereas CD3, CD4 and 5-LOX were differentially expressed between GBMs and astrocytomas. Correlation matrix analysis revealed that 5-LOX and GzmB expression were associated in both meningiomas and GBMs, whereas 5-LOX expression was significantly and positively correlated to TG2 in both meningioma and astrocytoma cohorts. These findings were confirmed with the correlation analysis of TCGA-GBM and LGG datasets. Profiling of mRNA levels indicated a significant increase in CD3 (CD3D, CD3E), and CD138 (SDC1) expression in GBM compared to control tissues. CD4 and 5-LOX (ALOX5) mRNA levels were significantly more expressed in tumour samples than in normal tissues in both GBM and LGG. In GBM cohort, GzmB (GZMB), SDC1 and MGMT gene expression predicted a poor overall survival (OS). Moreover, in LGG cohort, an increased expression of CD3 (CD3D, CD3E, CD3G), CD8 (CD8A), GZMB, CD20 (MS4A1), SDC1, PD-L1, ALOX5, and TG2 (TGM2) genes was associated with worse OS. CONCLUSIONS: Our data have revealed that there is a positive and significant correlation between the expression of 5-LOX and GzmB, both at RNA and protein level. Further evaluation is needed to understand the interplay of 5-LOX and immune infiltration in glioma progression.

Adenogenesis Factors FGF7, FGF10, FGF23, IFN-τ and HGF in Endometriosis Tissue Respect to Eutopic Endometrium: An Immunohistochemical Study.

Endometriosis is a pathological condition defined by the occurrence of endometrial glandular and stromal structures in anatomical compartments different from the uterine cavity. Endometriosis is a genetic polymorphism, estrogen-dependent inflammatory disease. This very common pathological entity causes a high level of morbidity in patients; it is also considered one of the most important causes of infertility. We and others have proposed as a pathogenetic mechanism of endometriosis a modification in the fine tuning of the processes of organogenesis of the uterus. We have correlated the immunohistochemical expression in deep endometriotic lesions and in normal endometrial tissue of several molecular factors that are implicated in the embryonic development of the uterine glands. We noticed a significant higher expression both for epithelium and stroma in the controls respect to the endometriosis samples for FGF7, FGF-10 and HGF. Interestingly, regarding FGF-23 and IFN-τ, we observed a significant higher expression in the ectopic endometrial stroma compared to the eutopic endometrium, while thepithetlium expression did not display a significant differential expression in endometriosis tissues respect to normal endometrium. The data generated support the fact that endometriosis tissues, both the epithelial and stromal component, have a different phenotype respect to the eutopic endometrium and sustain the hypothesis that alterations in the molecular mechanisms in control for adenogenesis and survival of endometrial structures are linked to the genesis and survival of endometriosis lesions outside of the uterus.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes from Pathology to Bedside: Part 2-Peripheral Nervous System.

PURPOSE OF REVIEW: Peripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV. RECENT FINDINGS: Progress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Pulmonary leiomyosarcoma arising in pulmonary hamartoma: an exceptional occurrence in a rare tumor.

A solitary peripheral lung nodule was found in the left lung of a 52-year-old man. It was located in the lower lobe and measured 18.5 cm of major axis on chest computed tomography. A tru-cut core biopsy was obtained and a proliferation of bland, monomorphic, spindle cells in interlacing fascicles was observed. Accordingly, a surgical resection of the neoplasm was subsequently carried out. Macroscopically, the tumor appeared as a well-circumscribed nodule with a firm and whitish cut surface. Histologically, the neoplasm was predominantly composed of bland and monomorphic spindle cells, with a predominantly fascicular growth pattern, in which many tubular and cleft-like spaces of entrapped normal respiratory epithelium were involved. Myxoid change, stromal hyalinization and scattered bizarre mononucleated and multinucleated cells were also observed. Based on clinico-morphological, immunophenotypical and molecular features, we made a diagnosis of malignant transformation of pulmonary adenoleiomyomatous hamartoma into pulmonary leiomyosarcoma. As far as we know, this is the first described case of this exceptionally rare occurrence in an already rare neoplasm.

Central and Peripheral Nervous System Complications of Vasculitis Syndromes From Pathology to Bedside: Part 1-Central Nervous System.

PURPOSE OF REVIEW: The aim of this review is to provide a comprehensive update on the clinical assessment, diagnosis, complications, and treatment of primary central nervous system vasculitis (PCNSV). RECENT FINDINGS: The developments in neuroimaging, molecular testing, and cerebral biopsy have enhanced clinical assessment and decision making, providing novel insights to prevent misdiagnosis increasing diagnostic certainty. Advances in imaging techniques visualizing the wall of intracranial vessels have improved the possibility to distinguish inflammatory from non-inflammatory vascular lesions. Large recent studies have revealed a more varied histopathological pictures and disclosed an association with amyloid angiopathy. Unfortunately, therapy remains largely empiric. PCNSV is a heterogeneous group of disorders encompassing different clinical subsets that may differ in terms of prognosis and therapy. Recent evidence has described a more benign course, with good response to therapy. New diagnostic techniques will play soon a pivotal role in the appropriate diagnosis and prompt management of PCNSV.

Structured reporting of computed tomography in the staging of colon cancer: a Delphi consensus proposal.

BACKGROUND: Structured reporting (SR) in radiology is becoming increasingly necessary and has been recognized recently by major scientific societies. This study aims to build structured CT-based reports in colon cancer during the staging phase in order to improve communication between the radiologist, members of multidisciplinary teams and patients. MATERIALS AND METHODS: A panel of expert radiologists, members of the Italian Society of Medical and Interventional Radiology, was established. A modified Delphi process was used to develop the SR and to assess a level of agreement for all report sections. Cronbach's alpha (Cα) correlation coefficient was used to assess internal consistency for each section and to measure quality analysis according to the average inter-item correlation. RESULTS: The final SR version was built by including n = 18 items in the "Patient Clinical Data" section, n = 7 items in the "Clinical Evaluation" section, n = 9 items in the "Imaging Protocol" section and n = 29 items in the "Report" section. Overall, 63 items were included in the final version of the SR. Both in the first and second round, all sections received a higher than good rating: a mean value of 4.6 and range 3.6-4.9 in the first round; a mean value of 5.0 and range 4.9-5 in the second round. In the first round, Cronbach's alpha (Cα) correlation coefficient was a questionable 0.61. In the first round, the overall mean score of the experts and the sum of scores for the structured report were 4.6 (range 1-5) and 1111 (mean value 74.07, STD 4.85), respectively. In the second round, Cronbach's alpha (Cα) correlation coefficient was an acceptable 0.70. In the second round, the overall mean score of the experts and the sum of score for structured report were 4.9 (range 4-5) and 1108 (mean value 79.14, STD 1.83), respectively. The overall mean score obtained by the experts in the second round was higher than the overall mean score of the first round, with a lower standard deviation value to underline greater agreement among the experts for the structured report reached in this round. CONCLUSIONS: A wide implementation of SR is of critical importance in order to offer referring physicians and patients optimum quality of service and to provide researchers with the best quality data in the context of big data exploitation of available clinical data. Implementation is a complex procedure, requiring mature technology to successfully address the multiple challenges of user-friendliness, organization and interoperability.

Structured reporting of x-ray mammography in the first diagnosis of breast cancer: a Delphi consensus proposal.

BACKGROUND: Radiology is an essential tool in the management of a patient. The aim of this manuscript was to build structured report (SR) Mammography based in Breast Cancer. METHODS: A working team of 16 experts (group A) was composed to create a SR for Mammography Breast Cancer. A further working group of 4 experts (group B), blinded to the activities of the group A, was composed to assess the quality and clinical usefulness of the SR final draft. Modified Delphi process was used to assess level of agreement for all report sections. Cronbach's alpha (Cα) correlation coefficient was used to assess internal consistency and to measure quality analysis according to the average inter-item correlation. RESULTS: The final SR version was built by including n = 2 items in Personal Data, n = 4 items in Setting, n = 2 items in Comparison with previous breast examination, n = 19 items in Anamnesis and clinical context; n = 10 items in Technique; n = 1 item in Radiation dose; n = 5 items Parenchymal pattern; n = 28 items in Description of the finding; n = 12 items in Diagnostic categories and Report and n = 1 item in Conclusions. The overall mean score of the experts and the sum of score for structured report were 4.9 and 807 in the second round. The Cronbach's alpha (Cα) correlation coefficient was 0.82 in the second round. About the quality evaluation, the overall mean score of the experts was 3.3. The Cronbach's alpha (Cα) correlation coefficient was 0.90. CONCLUSIONS: Structured reporting improves the quality, clarity and reproducibility of reports across departments, cities, countries and internationally and will assist patient management and improve breast health care and facilitate research.

Myoepithelial sialadenitis with metachromatic matrix: A diagnostic pitfall. A case of salivary gland swelling in a paediatric patient evaluated by fine needle aspiration cytology.

Fine needle aspiration cytology (FNAC) is generally characterized by a high diagnostic accuracy in differentiating non-neoplastic/inflammatory lesions from neoplastic lesions of the salivary glands. Lymphoepithelial sialadenitis/myoepithelial sialadenitis is exceedingly rare in paediatric patients and is characterized by a diffuse, often bilateral, salivary gland enlargement and the differential diagnosis may sometimes be difficult. We report the case of a 10-year-old boy who presented with a swelling of the left parotid gland investigated by ultrasound salivary gland FNAC.

Atypical cytological presentation of granular cell tumour: Tumour-associated fibrosis may affect fine-needle aspiration cytology accuracy.

The cytological features of granular cell tumour (GCT) are generally quite typical but, in some cases, the fine needle aspiration cytology (FNAC) diagnosis of GCT may be difficult or impossible because of unusual sites of onset or equivocal cytological features. In this report, two GCTs with atypical FNAC features are described in order to investigate the causes and provide possible diagnostic tips. From a series of nine histologically proven GCTs, two inconclusive FNAC cases were retrieved. Smears were poorly cellular showing isolated naked nuclei, anisonucleosis, granular chromatin and occasional small nucleoli. The background was finely granular in one case. Histological controls of these cases revealed marked fibrosis. Tumour-associated fibrosis in GCT is variable and does not seem to influence clinical behaviour but it influences the harvest and the integrity of granular cells collected by FNAC. When GCT smears are poorly cellular, attention should be paid to the granular background and to the few granular cells, if any, as they might be the only features to suggest a GCT.

Interventional cytopathology in the COVID-19 era.

INTRODUCTION: The dramatic spread of COVID-19 has raised many questions about cytological procedures performed in and out of the laboratories all over the world. METHODS: We report a heterogeneous series of fine needle aspirations performed during the period of phase 1 of the lockdown for the COVID-19 pandemic to describe our experience and measures taken during this period. RESULTS: A total of 48 fine needle aspirations (ultrasound, computed tomography and endoscopic ultrasound guided) were processed and reported. CONCLUSIONS: Pre-existing procedures have been modified to allow healthcare professionals to work safely ensuring patients the necessary assistance with samples suitable for cellularity, fixation and staining for an accurate cytological diagnosis.

Surgical Treatment of Oral Cavity Nodular Fasciitis.

BACKGROUND: Nodular fascitiis is a myofibroblastic neoplasm of the soft tissue that rarely affects oral cavity. With a broad pattern of presentation, sometimes Nodular Fascitiis can have a rapid growth and appear highly cellular with local aggressiveness on biopsies, thus simulating a sarcoma. The aim of this paper is to present a case of troublesome diagnosis of nodular fascitiis mimicking a Malignant Fibrous Histiocytoma, with the purpose of alert clinicians and pathologists on the difficulties that can be met in the differential diagnosis between these 2 lesions. A 42-year-old male presented an exophytic lesion on the cheek. After the excisional biopsy, histological and immunohistochemical evaluations revealed a picture of doubtful significance. With a careful analysis, the diagnosis of nodular fasciitis was made and the patient was not further treated. At a 3-year follow-up, no recurrence was found. Differential diagnosis within myofibroblastic neoplasm can be a real challenge for both Clinicians and Pathologist. A coordinated team-work is mandatory to avoid clinical malpractice and unnecessarily aggressive treatment.

NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine.

In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.

Medullary thyroid carcinoma with double negative calcitonin and CEA: a case report and update of literature review.

BACKGROUND: Medullary thyroid carcinoma is a malignant uncommon and aggressive tumour of the parafollicular C cells. In about 75% of cases it is sporadic while, in case of RET mutation, it is associated to multiple endocrine neoplasia type 2 (25% of cases). The biochemical features of medullary thyroid carcinoma include the production of calcitonin and carcinoembryogenic antigen. The above-mentioned features are useful in the diagnostic process as well as in the follow up and in the prognostication of the disease. Even if calcitonin elevation is strongly associated to MTC, it can also be found increased in many pathological different conditions as pregnancy, lactation, C-cells hyperplasia, autoimmune thyroiditis, end stage renal disease, lung and prostate cancer and several neuroendocrine tumours. Major medullary thyroid tumours are usually connected to high doses of circulating calcitonin, in fact non-secretory variants have hardly been described. CASE PRESENTATION: We herein report the case of a 59 years old male, who had undergone total thyroidectomy for multinodular goiter with negative preoperative calcitonin, showing medullary thyroid carcinoma at definitive pathology. To the best of our knowledge, this is the first case documenting a non-secretory medullary thyroid carcinoma, with double negative markers at the time of diagnosis and at the relapse. CONCLUSION: A Literature review underlining pathological hypothesis, differential diagnosis and alternative and innovative biomarkers to identify non-secretory medullary thyroid carcinoma was carried out.

A rat model of acute kidney injury through systemic hypoperfusion evaluated by micro-US, color and PW-Doppler.

AIM: To create an animal model of acute renal ischemia induced by systemic hypoperfusion, controllable and reproducible to study, in real time, hemorrhagic shock changes with micro-imaging. ANIMALS AND METHODS: Hemorrhagic shock was induced in rats activating a syringe pump setup to remove 1 mL/min of blood, through the femoral artery catheter. The withdrawal was continued until the mean arterial pressure (MAP) dropped to 25-30 mmHg. For the next 60 min, the MAP was maintained at a constant pressure value, by automatic pump infusion and withdrawal. Micro-ultrasound imaging was performed using the Vevo 2100 system with the MS250 transducer (13-24 MHz). Renal size, morphology and echogenicity were evaluated in B-mode. Renal blood flow was evaluated using color and PW-Doppler. RESULTS: After 1 h of ischemia, B-mode images documented slight changes in kidney echogenicity. Color and PW-Doppler analysis showed a reduction in renal blood flow in kidneys during the hypoperfusion with a progressive and significant change from baseline values of resistive index (RI). At the histological evaluation, 60 min of hypoperfusion resulted in ischemic changes in the kidneys. CONCLUSIONS: The results of this experimental study encourage the use of the described model to study acute renal ischemia trough severe hypoperfusion. The histological data confirmed that the model was able to produce injury in renal parenchyma. It can be used to assess acute ischemic damage not only in the kidney but also in other organs by using all available dedicated small animals imaging techniques.

Extrapleural solitary fibrous tumor: A distinct entity from pleural solitary fibrous tumor. An update on clinical, molecular and diagnostic features.

Solitary fibrous tumor (SFT) is a mesenchymal neoplasm that was originally described to be localized in the pleura, but thereafter, this has been reported in several anatomic sites. Although the etiology of the neoplasm remains largely unknown, the pathogenesis seems to be related to an NAB2-STAT6 fusion gene due to paracentric inversion on chromosome 12q13. The diagnosis of extrapleural SFT is challenging, owing to its rarity, and requires an integrated approach that includes specific clinical, histological, immunohistochemical, and even molecular findings. Histologically, extrapleural SFT shares morphological features same as those of the pleural SFT because it is characterized by a patternless distribution of both oval- and spindle-shaped cells in a variable collagen stroma. In addition, morphological variants of mixoid, fat-forming, and giant cell-rich tumors are described. A correct diagnosis is mandatory for a proper therapy and management of the patients with extrapleural SFT, as extrapleural SFT is usually more aggressive than pleural form, particularly cases occurring in the mediastinum, retroperitoneum, pelvis, and meninges. Although SFT is usually considered as a clinically indolent neoplasm, the prognosis is substantially unpredictable and only partially related to morphological features. In this context, cellularity, neoplastic borders, cellular atypias, and mitotic activity can show a wide range of variability. We review extrapleural SFT by discussing diagnostic clues, differential diagnosis, recent molecular findings, and prognostic factors.

Multidisciplinary Diagnostic and Surgical Management of Adenocarcinoma Gingival Metastases.

Colon cancer is the third leading cause of cancer-related mortality worldwide and colon cancer metastases in rare sites, such as the oral cavity, lead to a worse prognosis. Oral metastasis is a rare clinical condition and it represents only the 1% among all oral cavity neoplasms. A multidisciplinary approach is recommended to carry out a correct diagnostic procedure that allows distinguishing between metastatic and primitive lesions of the oral cavity. Quick diagnosis and management are fundamental to take an appropriate action as early as possible, as usually the prognosis in patients with oral metastases of colon carcinoma is poor. Aim of this brief clinical report is to underline how the quick diagnosis and management of gingival lesions can be crucial for the correct management of those uncommon oral diseases and for having a better prognosis of the primary cancer.

Parotid squamous cell carcinoma metastases: Application of human papillomavirus-DNA test on liquid-based cytology to recognize oropharyngeal origin of the neoplasm.

Malignancies of the parotid gland are relatively uncommon and in most cases are primary neoplasms; intraparotid metastases are rare. Oral and oropharyngeal squamous cell carcinoma (O- and OP-SCC) can potentially metastasize to the parotid gland or intraparotid lymph nodes. Fine-needle aspiration cytology (FNAC) serves as the initial diagnostic approach for this purpose. HPV status in FNAC specimens is relevant and can guide the diagnostic workup, indicating a potential oropharyngeal origin of the primary tumor. A small series of occult SCC metastases is presented below, in which HPV-DNA testing of FNAC specimens helped identify primary neoplasms located in the oropharynx. US-guided FNAC of parotid nodules was conducted by an experienced interventional cytopathologist in three cases. Each patient underwent assessment of direct smears, cell blocks, and liquid-based samples for HPV testing. The morphological and immunocytochemical features of SCC were documented, and real-time PCR was employed for the detection and genotyping of HPV. The role of HPV testing on FNAC specimens in pinpointing the primary neoplasms in the oropharynx is highlighted. Consequently, FNAC samples emerge as valuable diagnostic and prognostic tools in this context, providing essential insights for patient management.

Associations between Radiomics and Genomics in Non-Small Cell Lung Cancer Utilizing Computed Tomography and Next-Generation Sequencing: An Exploratory Study.

BACKGROUND: Radiomics, an evolving paradigm in medical imaging, involves the quantitative analysis of tumor features and demonstrates promise in predicting treatment responses and outcomes. This study aims to investigate the predictive capacity of radiomics for genetic alterations in non-small cell lung cancer (NSCLC). METHODS: This exploratory, observational study integrated radiomic perspectives using computed tomography (CT) and genomic perspectives through next-generation sequencing (NGS) applied to liquid biopsies. Associations between radiomic features and genetic mutations were established using the Area Under the Receiver Operating Characteristic curve (AUC-ROC). Machine learning techniques, including Support Vector Machine (SVM) classification, aim to predict genetic mutations based on radiomic features. The prognostic impact of selected gene variants was assessed using Kaplan-Meier curves and Log-rank tests. RESULTS: Sixty-six patients underwent screening, with fifty-seven being comprehensively characterized radiomically and genomically. Predominantly males (68.4%), adenocarcinoma was the prevalent histological type (73.7%). Disease staging is distributed across I/II (38.6%), III (31.6%), and IV (29.8%). Significant correlations were identified with mutations of ROS1 p.Thr145Pro (shape_Sphericity), ROS1 p.Arg167Gln (glszm_ZoneEntropy, firstorder_TotalEnergy), ROS1 p.Asp2213Asn (glszm_GrayLevelVariance, firstorder_RootMeanSquared), and ALK p.Asp1529Glu (glcm_Imc1). Patients with the ROS1 p.Thr145Pro variant demonstrated markedly shorter median survival compared to the wild-type group (9.7 months vs. not reached, p = 0.0143; HR: 5.35; 95% CI: 1.39-20.48). CONCLUSIONS: The exploration of the intersection between radiomics and cancer genetics in NSCLC is not only feasible but also holds the potential to improve genetic predictions and enhance prognostic accuracy.

Role of ejection fraction in patients at risk for advanced heart failure: insights from the HELP-HF registry.

AIMS: Patients with heart failure (HF) with reduced ejection fraction (EF) (HFrEF), mildly reduced EF (HFmrEF), and preserved EF (HFpEF) may all progress to advanced HF, but the impact of EF in the advanced setting is not well established. Our aim was to assess the prognostic impact of EF in patients with at least one 'I NEED HELP' marker for advanced HF. METHODS AND RESULTS: Patients with HF and at least one high-risk 'I NEED HELP' criterion from four centres were included in this analysis. Outcomes were assessed in patients with HFrEF (EF ≤ 40%), HFmrEF (EF 41-49%), and HFpEF (EF ≥ 50%) and with EF analysed as a continuous variable. The prognostic impact of medical therapy for HF in patients with EF < 50% and EF > 50% was also evaluated. All-cause death was the primary endpoint, and cardiovascular death was a secondary endpoint. Among 1149 patients enrolled [mean age 75.1 ± 11.5 years, 67.3% males, 67.6% hospitalized, median follow-up 260 days (inter-quartile range 105-390 days)], HFrEF, HFmrEF, and HFpEF were observed in 699 (60.8%), 122 (10.6%), and 328 (28.6%) patients, and 1 year mortality was 28.3%, 26.2%, and 20.1, respectively (log-rank P = 0.036). As compared with HFrEF patients, HFpEF patients had a lower risk of all-cause death [adjusted hazard ratio (HRadj ) 0.67, 95% confidence interval (CI) 0.48-0.94, P = 0.022], whereas no difference was noted for HFmrEF patients. After multivariable adjustment, a lower risk of all-cause death (HRadj for 5% increase 0.94, 95% CI 0.89-0.99, P = 0.017) and cardiovascular death (HRadj for 5% increase 0.94, 95% CI 0.88-1.00, P = 0.049) was observed at higher EF values. Beta-blockers and renin-angiotensin system inhibitors or sacubitril/valsartan were associated with lower mortality in both EF < 50% and EF ≥ 50% groups. CONCLUSIONS: Among patients with HF and at least one 'I NEED HELP' marker for advanced HF, left ventricular EF is still of prognostic value.

Clinical burden and predictors of non-cardiovascular mortality and morbidity in advanced heart failure.

BACKGROUND: The changing demographic of heart failure (HF) increases the exposure to non-cardiovascular (non-CV) events. We investigated the distribution of non-CV mortality/morbidity and the characteristics associated with higher risk of non-CV events in patients with advanced HF. METHODS: Patients from the HELP-HF registry were stratified according to the number of 2018 HFA-ESC criteria for advanced HF. Endpoints were non-CV mortality and non-CV hospitalization. Competing risk analyses were performed assessing the association between HFA-ESC criteria and study outcomes and the additional predictors of non-CV endpoints. RESULTS: One thousand one hundred and forty-nine patients were included (median age 77 years-IQR 69-83). At 6, 12, 18 and 22 months, cumulative incidence of CV vs non-CV mortality was 13% vs 5%, 17% vs 8%, 20% vs 12%, 23% vs 12%, and of CV vs non-CV hospitalization was 26% vs 11%, 38% vs 17%, 45% vs 20%, 50% vs 21%. HFA-ESC criteria were associated with increasing adjusted risk of CV death, whereas no association was observed for CV hospitalization, non-CV death and non-CV hospitalization. Predictors of non-CV death were age, chronic obstructive pulmonary disease, dementia, preserved ejection fraction, >1 HF hospitalization and hemoglobin. CONCLUSIONS: Patients with advanced HF are exposed to high, even though not predominant, burden of non-CV outcomes. HFA-ESC criteria aid to stratify the risk of CV death, but are not associated with lower competing risk of non-CV outcomes. Alternative factors can be useful to define the patients with advanced HF at risk of non-CV events in order to better select patients for treatments specifically reducing CV risk.