The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma.

Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures (n = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.

A Cyclin D1-Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma.

PURPOSE: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1-mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1-dependent gene expression program and analyze its prognostic value. EXPERIMENTAL DESIGN: We integrated genome-wide expression analysis of cyclin D1-silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1-dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples (n = 53) and lymphoid tissues (n = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples (n = 81) by NanoString gene expression profiling to validate our findings. RESULTS: We identified a cyclin D1-dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1-dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1-dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression. CONCLUSIONS: We identified a cyclin D1-dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.

Individual income, mortality and healthcare resource use in patients with chronic heart failure living in a universal healthcare system: A population-based study in Catalonia, Spain.

BACKGROUND: To evaluate the associations between individual income, all-cause mortality and use of healthcare resources in a very large population of chronic heart failure (CHF) patients living in Catalonia (Spain), where access to public healthcare is granted by law. METHODS AND RESULTS: We used 2016 data from the Catalan Health Surveillance System, a large, exhaustive, administrative healthcare database which includes information on medical diagnoses, healthcare resource use, and individual income for all Catalan residents (N = 7,638,524). Individual annual income was categorized as high (>100,000€), medium (18,000-100,000€), low (<18,000€), and very low (welfare support). Among 155,883 CHF patients, lower individual income was associated with a shorter life expectancy at age 50 (life expectancy for high income patients 22.2 years, for very low income patients 12.8), and were independently associated with higher all-cause mortality adjusting for age, sex, comorbidities, and duration of the CHF diagnosis (odds ratio very low vs. medium income 1.21 [95% CI 1.11, 1.33]). Also, in patients with lower income levels the burden of public healthcare resource use was displaced towards urgent hospitalizations and frequent emergency department visits, as opposed to regular, specialized CHF ambulatory-based care. CONCLUSION: In a very large population of CHF patients with access to universal healthcare, lower income was independently associated with higher mortality and with lower use of ambulatory-based healthcare resources. Our findings suggest that CHF patients may benefit from systematic assessment of their socioeconomic status, as this may aid the identification of vulnerable subgroups who may benefit from tailored health education and management.

Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms.

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors.

Cost-minimization analysis favors outpatient quick diagnosis unit over hospitalization for the diagnosis of potentially serious diseases.

BACKGROUND: Quick diagnosis units (QDUs) are a promising alternative to conventional hospitalization for the diagnosis of suspected serious diseases, most commonly cancer and severe anemia. Although QDUs are as effective as hospitalization in reaching a timely diagnosis, a full economic evaluation comparing both approaches has not been reported. AIMS: To evaluate the costs of QDU vs. conventional hospitalization for the diagnosis of cancer and anemia using a cost-minimization analysis on the proven assumption that health outcomes of both approaches were equivalent. METHODS: Patients referred to the QDU of Bellvitge University Hospital of Barcelona over 51 months with a final diagnosis of severe anemia (unrelated to malignancy), lymphoma, and lung cancer were compared with patients hospitalized for workup with the same diagnoses. The total cost per patient until diagnosis was analyzed. Direct and non-direct costs of QDU and hospitalization were compared. RESULTS: Time to diagnosis in QDU patients (n=195) and length-of-stay in hospitalized patients (n=237) were equivalent. There were considerable costs savings from hospitalization. Highest savings for the three groups were related to fixed direct costs of hospital stays (66% of total savings). Savings related to fixed non-direct costs of structural and general functioning were 33% of total savings. Savings related to variable direct costs of investigations were 1% of total savings. Overall savings from hospitalization of all patients were €867,719.31. CONCLUSION: QDUs appear to be a cost-effective resource for avoiding unnecessary hospitalization in patients with anemia and cancer. Internists, hospital executives, and healthcare authorities should consider establishing this model elsewhere.

Perception of quality of care of patients with potentially severe diseases evaluated at a distinct quick diagnostic delivery model: a cross-sectional study.

BACKGROUND: Although hospital-based outpatient quick diagnosis units (QDU) are an increasingly recognized cost-effective alternative to hospitalization for the diagnosis of potentially serious diseases, patient perception of their quality of care has not been evaluated well enough. This cross-sectional study analyzed the perceived quality of care of a QDU of a public third-level university hospital in Barcelona. METHODS: One hundred sixty-two consecutive patients aged ≥ 18 years attending the QDU over a 9-month period were invited to participate. A validated questionnaire distributed by the QDU attending physician and completed at the end of the first and last QDU visit evaluated perceived quality of care using six subscales. RESULTS: Response rate was 98 %. Perceived care in all subscales was high. Waiting times were rated as 'short'/'very short' or 'better'/'much better' than expected by 69-89 % of respondents and physical environment as 'better'/'much better' than expected by 94-96 %. As to accessibility, only 3 % reported not finding the Unit easily and 7 % said that frequent travels to hospital for visits and investigations were uncomfortable. Perception of patient-physician encounter was high, with 90-94 % choosing the positive extreme ends of the clinical information and personal interaction subscales items. Mean score of willingness to recommend the Unit using an analogue scale where 0 was 'never' and 10 'without a doubt' was 9.5 (0.70). On multivariate linear regression, age >65 years was an independent predictor of clinical information, personal interaction, and recommendation, while age 18-44 years was associated with lower scores in these subscales. No schooling predicted higher clinical information and recommendation scores, while university education had remarkable negative influence on them. Having ≥4 QDU visits was associated with lower time to diagnosis and recommendation scores and malignancy was a negative predictor of time to diagnosis, clinical information, and recommendation. DISCUSSION: It is worthy of note that the questionnaire evaluated patient perception and opinions of healthcare quality including recommendation rather than simply satisfaction. It has been argued that perception of quality of care is a more valuable approach than satisfaction. In addition to embracing an affective dimension, satisfaction appears more dependent on patient expectations than is perception of quality. CONCLUSIONS: While appreciating that completing the questionnaire immediately after the visit and its distribution by the QDU physician may have affected the results, scores of perceived quality of care including recommendation were high. There were, however, significant differences in several subscales associated with age, education, number of QDU visits, and diagnosis of malignant vs. benign condition.

A quick diagnosis unit as an alternative to conventional hospitalization in a tertiary public hospital: a descriptive study.

INTRODUCTION:  Reports indicate that a significant number of patients admitted to internal medicine units could be studied on an outpatient basis. OBJECTIVES:  This article assesses a quick diagnosis unit (QDU) as an alternative to acute hospitalization for the diagnostic study of patients with potentially serious diseases and suspected malignancy.  PATIENTS AND METHODS:  Between March 2008 and June 2012, 1226 patients were attended by the QDU. Patients were referred from the emergency department, primary health care centers, and outpatient clinics according to well­defined criteria. Clinical information was prospectively registered in a database.  RESULTS:  There were 634 men (51.7%), with a mean age of 60.5 ±17.5 years. The mean time to the first visit was 3.5 ±5.3 days. Most patients (65.7%) required only 2 visits. The mean interval to diagnosis was 12.2 ±14.7 days. A total of 324 patients (26.4%) had cancer. The diagnosis was  solid tumor in 81.5% of the cases, lymphoma in 19.8%, and various hematologic malignancies in 4.3%. The second most common diagnosis was anemia not associated with cancer (8.6% of the cases). Admission to the QDU allowed to avoid conventional hospitalization for diagnostic studies in 71.5% of the patients, representing a mean freeing­up rate of 7 internal medicine beds per day. In a satisfaction survey, 97% of the patients were completely or very satisfied and 96% preferred the QDU to conventional hospitalization.  CONCLUSIONS:  A QDU may be a feasible alternative to conventional hospitalization for the diagnosis of otherwise healthy patients with suspected severe disease. Appropriately managed and supported, QDUs can lighten the burden of emergency departments and reduce the need for hospitals beds.