A Recursive Partitioning Approach to Hospital Case Mix Classification

The present dissertation was focused on the study and development of a clinical data mining methodology for hospital case mix iso-resource classification. Several recursive partitioning methodologies were applied on Emilia-Romagna Region hospital discharge database. Here, the need for developing several alternative iso-resource subgroups was a critical point in the development of case mix classification systems, due to the presence of clinical coherence requirements. Two major classes of trees were assessed: constant-fit trees and model-based trees, with a particular focus on the latter class, which peculiarity is to fit regression models in the nodes of the tree. After an extensive literature review, the traditional regression tree (constant-fit) and four model-based tree algorithms were assessed: two modifications of the Model-Based Recursive Partitioning (MOB) algorithm which were given additional flexibility by performing a within-node model selection step, respectively using count regression and continuous response regression GLMs; a two-step composite algorithm which fits regression trees and models in terminal nodes; quantile-model-based regression trees, by means of the Generalized Unbiased Interaction Detection and Estimation (GUIDE) algorithm. These algorithms were compared under several points of view. Statistical performance, measured via bootstrap out-of-bag performance curves, was in favor of model-based trees, while, among them, competing performances were found. Implications for the design of hospital case mix classification systems were also evaluated, since the two classes of trees can be conceptually linked to different refunding schemes. Moreover, application and advantages of two different ensemble methods were discussed. All the recursive partitioning methods employed resulted in the definition of iso-resource clinically similar subgroups of patients. Different interpretations were given to these alternative subgroups, due to differences in the rationale of the various splitting criteria. In particular, model-based trees identified subgroups with differential effects of patient’s age and clinical severity on resource consumption, here measured with hospital length of stay

Subxiphoid thymectomy with a double sternum retractor: a pilot study.

Background: Our study aims to describe the experience of a single team in terms of the potential and benefits of subxiphoid thymectomy using a double sternum hook retractor. Methods: From November 2016 to July 2018, 34 patients have been undergone subxiphoid thymectomy at our Department. Twenty patients were diagnosed with Masaoka Stage I–III thymomas, 12 with thymic hyperplasia or cysts of the thymus, 2 with thymic tumors. All patients underwent a chest computed tomography (CT) with enhancement. 18-Fludeoxyglucose positron emission tomography (18FDG-PET) was performed when recurrence was suspected. Neurological examinations were set. Patients underwent video-assisted thoracoscopic surgery (VATS) subxiphoid thymectomy with a double sternum retractor. A retrospective analysis of clinical, perioperative data, and follow-up was performed. Incidence rates for death or recurrence were calculated. Average pain score (NRS scale), average mental health, and physical health scores (SF-12) were analyzed. Results: Thirty-four patients (mean age 54; 12 men and 22 women) with thymic neoformation (from 1.0 cm × 1.0 cm × 1.0 cm to 14.0 cm × 9.0 cm × 4.5 cm) were enrolled. All patients underwent subxiphoid thymectomy. No mortality or recurrence was observed. Median follow-up time was 17.9 months (range, 2.2–23.3 months). The morbidity rate was 9.7 events per 100 person-years. Average pain scores after surgery and after follow-up were 1.7±0.4 and 0.1±0.4, respectively; average mental health and physical health scores on the SF-12 scale were 45.6±2.4 and 33.6±2.4, respectively. Conclusions: Subxiphoid thymectomy is a high satisfaction approach with positive aesthetic outcomes and low pain. Double sternum retractors are especially useful for creating space during thymectomy. However, the qualified experience is needed

Cancer stem-neuroendocrine cells in an atypical carcinoid case report.

Lung neuroendocrine cells tumor (NET) classification and diagnosis, particularly for typical and atypical carcinoids, are complicated by a variable natural history and nonspecific symptoms. Mechanisms for the development and progression of well-differentiated lung NETs are still unclear. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and impact on prognosis. One of the main unclear point is the definition of these cells’ composition. In fact, it is known that carcinoids are mainly constituted by neuroendocrine cells. Aim of our report is to show for the first time the presence of a high percentage of cancer stem cells (CSCs) in an atypical carcinoid. The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. SOX2 was additionally determined by immunohistochemistry. All specimens contained the 53.10% of ALDHhigh cells among all viable lung cancer cells, which indicates that more than half of the entire tumor cell population was composed by CSCs. As expected also in immunohistochemistry, about a half of the nuclei of the cells were positive for SOX2. We strongly support the hypothesis of the presence of cancer stem-neuroendocrine cells (CSCs-NETs) as subpopulation in these types of tumors

Cancer stem cells and their microenvironment.

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Cancer stem cells and macrophages: molecular connections and future perspectives against cancer.

Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies

CD44+/EPCAM+ cells detect a subpopulation of ALDHhigh cells in human non-small cell lung cancer: A chance for targeting cancer stem cells?

Objectives: Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells. Materials and Methods: This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC. Results: There was a highly positive correlation between the expressions of ALDHhigh and CD44+/EPCAM+ cells, with a Pearson\u2019s correlation coefficient equal to 0.69 (95% CI 0.39\u20130.86; P = 0.0002), and Spearman\u2019s correlation coefficient equal to 0.52 (P = 0.0124). The average paired difference between the expression of ALDHhigh and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = \u20131.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDHhigh and CD44+/EPCAM+ cells. Conclusions: Our study is the first attempt which identifies a high correlation between the ALDHhigh and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.Objectives: Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells. Materials and Methods: This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC. Results: There was a highly positive correlation between the expressions of ALDHhigh and CD44+/EPCAM+ cells, with a Pearson\u2019s correlation coefficient equal to 0.69 (95% CI 0.39\u20130.86; P = 0.0002), and Spearman\u2019s correlation coefficient equal to 0.52 (P = 0.0124). The average paired difference between the expression of ALDHhigh and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = \u20131.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDHhigh and CD44+/ EPCAM+ cells. Conclusions: Our study is the first attempt which identifies a high correlation between the ALDHhigh and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells

Isolation and Identification of Cancer Stem-Like Cells in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: A Pilot Study

Background: Lung cancer stem cells (CSCs) share many characteristics with normal stem cells, such as self-renewal and multipotentiality. High expression of aldehyde dehydrogenase (ALDH) has been detected in many tumors, particularly in the CSC compartment, and it plays an important role in tumor proliferation, metastasis, and drug resistance. CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumors. The aim of this study was to isolate and analyze cancer stem-like cells from surgically removed specimens to compare lung adenocarcinoma (ADENO) and squamous (SQUAMO) cell carcinoma. Methods: The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. Fluorescence-activated cell sorting analysis for CD44 was performed with tumor cells. Quantitative real-time PCR was performed to assess the expression of SOX2 and NANOG as stemness markers. ALDH1A1 expression was additionally determined by immunohistochemistry. Anchorage-independent ALDHhigh cell growth was also evaluated. ALDHhigh ADENO and SQUAMO cells were cultured to analyze spheroid formation. Results: All specimens contained 0.5–12.5% ALDHhigh cells with 3.8–18.9% CD44-positive cells. SOX2 and NANOG relative expression in ALDHhigh compared to ALDHlow cells in ADENO and SQUAMO was analyzed and compared between the histotypes. Immunohistochemistry confirmed the presence of ALDH1A1 in the sections. SOX2 and NANOG were expressed at higher levels in the ALDHhigh subpopulation than in the ALDHlow subpopulation only in ADENO cells, and the opposite result was seen in SQUAMO cells. In vitro functional assays demonstrated that ALDHhigh cells exhibited migration capacity with distinct behaviors between ALDHhigh spheres in ADENO vs. SQUAMO samples. Conclusions: Our results highlight the importance of a better characterization of cancer stem-like cells in ADENO and SQUAMO histotypes. This may suggest new differential approaches for prognostic and therapeutic purposes in patients with non-small-cell lung cancer

Cancer Stem Cells and Cell Cycle Genes as Independent Predictors of Relapse in Non-small Cell Lung Cancer: Secondary Analysis of a Prospective Study.

Purpose: Cancer stem cells (CSCs) are described as resistant to chemotherapy and radiotherapy. It has been shown that CSCs infuence disease-free survival in patients undergoing surgery for lung cancer (NCT04634630). We recently described an overexpression of CSCs recurrence-related genes (RG) in lung cancer. This study aims to investigate CSC frequency and RG expression as predictors of disease-free survival in lung cancer. Experimental Design: This secondary analysis of a prospective cohort study involved 22 surgical tumor specimens from 22 patients harboring early (I-II) and locally advanced (IIIA) stages ACL and SCCL. Cell population frequency analysis of ALDHhigh (CSCs) and ALDHlow (cancer cells) was performed on each tumor specimen. In addition, RG expression was assessed for 31 target genes separately in ALDHhigh and ALDHlow populations. CSCs frequency and RG expression were assessed as predictors of disease-free survival by Cox analysis. Results: CSCs frequency and RG expression were independent predictors of disease-free survival. CSC frequency was not related to diseasefree survival in early-stage patients (HR = 0.84, 95%CI = 0.53-1.33, P = .454), whereas it was a risk factor for locally advanced-stage patients (HR = 1.22, 95%CI = 1.09-1.35, P = .000). RG expression—if measured in CSCs—was related to a higher risk of recurrence (HR = 1.19, 95%CI = 1.03-1.39, P = .021). The effect of RG expression measured in cancer cells on disease-free survival was lower and was not statistically significant (HR = 1.12, 95%CI = 0.94-1.33, P = .196). Conclusions: CSCs frequency and RG expression are independent predictors of relapse in lung cancer. Considering these results, CSCs and RG may be considered for both target therapy and prognosis

Expression of ALDH and SOX-2 in Pulmonary Sclerosing Pnemocytoma (PSP) of the Lung: Is There a Meaning Behind?

Background: Pulmonary sclerosing pneumocytoma (PSP) is a rare benign pulmonary tumor that derives from primitive respiratory epithelium of the pulmonary alveolus. The etiology and pathogenesis are still unclear. Histopathological diagnosis focuses on cells that are positive for TTF1, EMA, cytokeratin-7, and CAM 5.2. The aim of our study is to highlight the elevated expression of ALDH and the presence of SOX-2 in pulmonary sclerosing pneumocytoma. Methods: We report five cases of pulmonary sclerosing pneumocytoma undergone surgery at our Division of Thoracic Surgery, during a period between 1994 and 2011. ALDH and SOX-2 markers were also tested for positivity in all the patients. Results: Patients showed elevated expression of ALDH during immunohistochemistry and mild expression of SOX-2, although in two cases in which SOX-2 was highly expressed. Among these two patients, one presented with lymph node recurrence while the other had no recurrence with a PET-positive nodule. In particular, the patient who had developed recurrence had an ALDH score of 4 and a SOX-2 score of 3, whereas the patient with the PET-positive nodule showed an ALDH score of 4 with a mild SOX-2expression of score 1. Conclusions: This is the first attempt demonstrating the elevated expression of ALDH in this disease. SOX-2 expression was noted in both the patient who developed recurrence and the patient with a PET-positive nodule. We believe that further investigation may be highly useful to better characterize these two markers as well as understandtheir function