Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial-mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication.

Post treatment imaging in patients with local advanced cervical carcinoma.

Cervical cancer (CC) is the fourth leading cause of death in women worldwide and despite the introduction of screening programs about 30% of patients presents advanced disease at diagnosis and 30-50% of them relapse in the first 5-years after treatment. According to FIGO staging system 2018, stage IB3-IVA are classified as locally advanced cervical cancer (LACC); its correct therapeutic choice remains still controversial and includes neoadjuvant chemo-radiotherapy, external beam radiotherapy, brachytherapy, hysterectomy or a combination of these modalities. In this review we focus on the most appropriated therapeutic options for LACC and imaging protocols used for its correct follow-up. We explore the imaging findings after radiotherapy and surgery and discuss the role of imaging in evaluating the response rate to treatment, selecting patients for salvage surgery and evaluating recurrence of disease. We also introduce and evaluate the advances of the emerging imaging techniques mainly represented by spectroscopy, PET-MRI, and radiomics which have improved diagnostic accuracy and are approaching to future direction.

Clinical course of Coronavirus Disease-19 in patients with haematological malignancies is characterized by a longer time to respiratory deterioration compared to non-haematological ones: results from a case-control study.

BACKGROUND: We evaluated clinical features and risk factors for mortality in patients with haematological malignancies and COVID-19. METHODS: Retrospective, case-control (1:3) study in hospitalized patients with COVID-19. Cases were patients with haematological malignancies and COVID-19, controls had COVID-19 without haematological malignancies. Patients were matched for sex, age and time of hospitalization. RESULTS: Overall, 66 cases and 198 controls were included in the study. Cases had higher prior corticosteroid use, infection rates, thrombocytopenia and neutropenia and more likely received corticosteroids and antibiotics than controls. Cases had higher respiratory deterioration than controls (78.7% vs 65.5%, p = 0.04). Notably, 29% of cases developed respiratory worsening > 10 days after hospital admission, compared to only 5% in controls. Intensive Care Unit admission and mortality were higher in cases than in controls (27% vs 8%, p = 0.002, and 35% vs 10%, p < 0.001). At multivariable analysis, having haematological malignancy [OR4.76, p < 0.001], chronic corticosteroid therapy [OR3.65, p = 0.004], prior infections [OR57.7, p = 0.006], thrombocytopenia [OR3.03, p < 0.001] and neutropenia [OR31.1, p = 0.001], low albumin levels [OR3.1, p = 0.001] and ≥ 10 days from hospital admission to respiratory worsening [OR3.3, p = 0.002] were independently associated with mortality. In cases, neutropenia [OR3.1, p < 0.001], prior infections [OR7.7, p < 0.001], ≥ 10 days to respiratory worsening [OR4.1, p < 0.001], multiple myeloma [OR1.5, p = 0.044], the variation of the CT lung score during hospitalization [OR2.6, p = 0.006] and active treatment [OR 4.4, p < 0.001] all were associated with a worse outcome. CONCLUSION: An underlying haematological malignancy was associated with a worse clinical outcome in COVID-19 patients. A prolonged clinical monitoring is needed, since respiratory worsening may occur later during hospitalization.

A forensic case of erosive cystitis and septic pulmonary embolism: is there a correlation?

Septic pulmonary embolism (SPE) is an uncommon disease in which a microorganism- containing thrombus causes an inflammatory reaction and a mechanical obstruction in the vascular system of the lungs. Usually it is associated with tricuspid valve vegetation, septic thrombophlebitis or infected venous catheters. We present a rare and fatal case of massive septic pulmonary thromboembolism occurred in a diabetic woman, who complained in previous days dyspnoea, abdominal pain and nausea. Autopsy findings showed evidence of an erosive cystitis, while lungs examination showed total occlusion of pulmonary circulation system due to thrombo-embolic clots. In literature cases report about an association between septic pulmonary thromboembolism and erosive cystitis haven't been reported. So, we here show the first reported fatal case of a septic pulmonary thromboembolism as a lethal evolution of an erosive cystitis.

Validation of the two-minute step test in obese with comorbibities and morbidly obese patients

Cardiopulmonary fitness assessment is a valuable resource to obtain quantitative indicators of an individual's physical performance. The cardiopulmonary exercise test (CPX), considered the gold standard test for this evaluation, is costly and difficult to be accessed by the general population. In order to make this evaluation more accessible, and to better reflect the performance of daily life activities, alternative tests were proposed. Morbidly obese patients present limitations that impair physical performance assessment and could benefit from a test of shorter duration, provided it is validated. This observational study aimed to validate the two-minute step test (2MST) as a tool to evaluate functional capacity (FC) in obese with comorbidities and morbidly obese patients, compared the 2MST with CPX as a measure of physical performance, and developed a predictive equation to estimate peak oxygen uptake (VO2) in the 2MST. The CPX and the 2MST were performed and metabolic and ventilatory parameters were recorded in 31 obese individuals (BMI>35 kg/m2). Pearson correlation and multiple linear regression analyses were performed to evaluate the peak VO2 best predictors. Bland-Altman analysis was performed to assess the agreement between the two methods. Peak VO2 measured by CPX and 2MST showed a strong correlation (r=0.70, P<0.001) and there was a moderate correlation between peak VO2 of the 2MST and the number of up-and-down step cycles (UDS) (r=0.55; P=0.01). The reference equation obtained was: VO2 (mL·kg-1·min-1) = 13.341 + 0.138 × total UDS - (0.183 × BMI), with an estimated standard error of 1.3 mL·kg-1·min-1. The 2MST is a viable, practical, and easily accessible test for FC. UDS and BMI can predict peak VO2 satisfactorily.

Psychopathology and neoplastic disease: medico-social and medico-legal considerations.

The cognitive disability associated with stress in patients presenting cancer disease may exert a significant impact on the psychological health of the individual and even deteriorate the clinical diagnosis. The present study consists of a review of the available literature and an analysis of the association between psychopathologic disease and cancer by selecting useful contributions to the medicosocial discussion of the topic. Interesting considerations have emerged on the epidemiology and pathogenesis of the association between psychopathology and cancer that initiated possibilities towards a greater accuracy in the assessment of the patient that is not only limited to oncologic problems and outcomes.

In Vitro Apoptotic Effects of Farnesyltransferase blockade in Acute Myeloid Leukemia Cells.

Farnesyltransferase inhibitors (FTIs) are a class of oral anti-cancer drugs currently tested in phase I-II clinical trials for treatment of hematological malignancies. The in vitro effects of various FTIs (alpha-hydroxyfarnesylphosphonic acid, manumycin-A and SCH66336) were tested on CD34+ KG1a cell line and in primary acute myeloid leukemia (AML) cells from 64 patients. By cell viability and clonogeneic methylcellulose assays, FTIs showed a significant inhibitory activity in CD34+ KG1a and primary bone marrow (BM) leukemic cells from 56% of AML patients. FTIs also induced activation of caspase-3 and Fas-independent apoptosis, confirmed by the finding that inhibition of caspase-8 was not associated with the rescue of FTI-treated cells. We concluded that other cellular events induced by FTIs may trigger activation of caspase-3 and subsequent apoptosis, but the expression of proapoptotic molecules, as Bcl-2 and Bcl-XL, and antiapoptotic, as Bcl-X(s), were not modified by FTIs. By contrast, expression of inducible nitric oxide synthase (iNOS) was increased in FTI-treated AML cells. Our results suggest a very complex mechanism of action of FTIs that require more studies for a better clinical use of the drugs alone or in combination in the treatment of hematological malignancies.

[Evaluation of liver function between indoor and outdoor workers: preliminary results].

INTRODUCTION: The aim of our study is to compare liver damage in "outdoor" environment technicians, a category occupationally exposed, and in "indoor" workers. MATERIALS AND METHODS: We studied 142 male technicians of the environment exposed to urban pollution and 142 male "indoor" workers not exposed. We compared mean and standard deviation of the following liver parameters: glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), gamma-glutamyl-traspeptidasi (γGT) and alkaline phosphatase (PHA), total bilirubin (TB) and direct (DB). We made the two groups comparable for age, length of service, BMI, alcohol consumption and smoking habits, and excluded the workers who presented confounding factors. RESULTS: We found statistically significant differences about the levels of γGT, PHA, GPT and albumin between the "outdoor" workers exposed and the "indoor" control group. In the outdoor group we observed statistically significant values, GPT (51.8 ± 30.6 I.U./l vs. 30 ± 22.3 I.U./l; p = 0.000), γ-GT (42.2 ± 29.4 I.U./l vs. 22.4 ± 20.7 I.U./l; p = 0.000) and PHA (75.7 ± 20.6 I.U./l vs. 59.1 ± 19.6 I.U./l; p= 0.000) compared to the unexposed group. No statistically significant difference emerged between the averages for the values of GOT (25.3 ± 20.7 I.U./l vs. 26 ± 17.7 I.U./l; p = 0.736) in two groups. CONCLUSIONS: It clearly emerges that the contaminants may alter the values of liver tests after prolonged exposure.

Diagnostic accuracy and interobserver agreement of Quasistatic Ultrasound Elastography in the diagnosis of thyroid nodules.

PURPOSE: To assess the best technique and the diagnostic accuracy of Quasistatic Ultrasound Elastography (QUE) in thyroid nodules. Interobserver agreement was also evaluated. MATERIALS AND METHODS: A preliminary study of 50 patients with 54 thyroid nodules was performed with quantitative software in order to define the best cut-off value of different imaging methods. All patients underwent total thyroidectomy and histopathology findings served as the standard of reference. Thereafter, 154 nodules in 137 consecutive patients were prospectively evaluated by three operators. Findings at fine-needle aspiration cytology and histopathology (N = 60) served as the standard of reference. RESULTS: The most accurate technique was the axial peri-intranodular measurement method which achieved an area under the ROC curve of 0.961 (95 %CI 0.848 - 1.00) and had an optimal cut-off value of 3.00. QUE in the differentiation of thyroid nodules showed for operator 1: sensitivity 90 % (95 %CI 73.5 - 97.9 %), specificity 92.7 % (95 %CI 86.7 - 96.6 %), LR+ 12.40 (6.54 - 23.50), LR- 0.11 (0.04 - 0.32) and accuracy 91.4 % (95 %CI 85.4 - 97.3 %); for operator 2: sensitivity 86.7 % (95 %CI 69.3 - 96.2 %), specificity 87.1 % (95 %CI 79.9 - 92.4 %), LR+ 6.72 (4.16 - 10.80), LR- 0.15 (0.06 - 0.38) and accuracy 86.9 % (95 %CI 80.0 - 93.7 %); for operator 3: sensitivity 80 % (95 %CI 61.4 - 92.3 %), specificity 83.9 % (95 %CI 76.2 - 89.9 %), LR+ 4.96 (3.20 - 7.70), LR- 0.24 (0.12 - 0.49) and accuracy 81.9 % (95 %CI 74.0 - 89.9 %). Interobserver agreement values between operator 1 and operator 2 (k = 0.79) (p < 0.05, 95 %CI 0.684 - 0.904), between operator 1 and operator 3 (k = 0.73, 95 %CI: 0.607 - 0.854) and between operator 2 and operator 3 (k = 0.71, 95 %CI: 0.584 - 0.835) were significant. CONCLUSION: QUE provides accurate quantitative evaluation of thyroid nodules with low interobserver variability.

A giant hemorragic adrenal pseudocyst: contrast-enhanced examination (CEUS) and computed tomography (CT) features.

INTRODUCTION: Adrenal pseudocysts are rare cystic masses that arise from the adrenal gland and which are usually non-functional and asymptomatic. We report a rare case of a giant hemorrhagic adrenal pseudocyst presenting with abdominal pain and we discussed the radiological features. PRESENTATION OF CASE: A 75 year old man was admitted with acute abdominal pain post mild-trauma. Computed tomography (CT) of abdomen revealed a hemorrhagic mass measuring 18 cm located in the right suprarenal region, displacing the right kidney and liver. He subsequently underwent to contrast enhancement ultrasound (CEUS), which showed features suggestive for hemorrhagic adrenal pseudocyst. A complete endocrine working didn't show any hormonal hypersecretion. The patient underwent laparotomy and right adrenal mass was excised. Histological examination revealed giant hemorrhagic adrenal pseudocyst. The abdominal pain resolved after surgery. CONCLUSIONS: to the best our knowledge, this is the first case studied with CEUS reported in the literature.

Accelerated bone mass senescence after hematopoietic stem cell transplantation.

Osteoporosis and avascular necrosis (AVN) are long-lasting and debilitating complications of hematopoietic stem cell transplantation (HSCT). We describe the magnitude of bone loss, AVN and impairment in osteogenic cell compartment following autologous (auto) and allogeneic (allo) HSCT, through the retrospective bone damage revaluation of 100 (50 auto- and 50 allo-HSCT) long-term survivors up to 15 years after transplant. Current treatment options for the management of these complications are also outlined. We found that auto- and allo-HSCT recipients show accelerated bone mineral loss and micro-architectural deterioration during the first years after transplant. Bone mass density (BMD) at the lumbar spine, but not at the femur neck, may improve in some patients after HSCT, suggesting more prolonged bone damage in cortical bone. Phalangeal BMD values remained low for even more years, suggesting persistent bone micro-architectural alterations after transplant. The incidence of AVN was higher in allo-HSCT recipients compared to auto-HSCT recipients. Steroid treatment length, but not its cumulative dose was associated with a higher incidence of bone loss. Allo-HSCT recipients affected by chronic graft versus host disease seem to be at greater risk of continuous bone loss and AVN development. Reduced BMD and higher incidence of AVN was partly related to a reduced regenerating capacity of the normal marrow osteogenic cell compartment. Our results suggest that all patients after auto-HSCT and allo-HSCT should be evaluated for their bone status and treated with anti-resorptive therapy as soon as abnormalities are detected.

Prospective comparative evaluation of quantitative-elastosonography (Q-elastography) and contrast-enhanced ultrasound for the evaluation of thyroid nodules: preliminary experience.

PURPOSE: To assess the effectiveness of semiquantitative elastosonography (Q-elastography) compared with contrast-enhanced ultrasound (CEUS) in differentiating the nature of thyroid nodules. METHODS AND MATERIALS: Forty-eight consecutive patients (35 males, 13 females, range: 34-69 years, mean: 49.4 years), candidate to surgery, previously detected at color-Doppler ultrasound (CDUS), were prospectively examined with elastosonography with dedicated semiquantitative software (Q-Elastography, Toshiba XG) and CEUS (Technos Mylab 70 Gold X, and Toshiba XG) before surgery. CEUS and elastosonography were evaluated by two investigators in consensus. Comparison between the CEUS pattern and elastonographic strain ratio observed and expected frequencies for the diagnoses was evaluated with χ(2) test or with Fisher exact test. RESULTS: Fifty-three nodules (19 papillary carcinoma, 32 hyperplasia, and 2 follicular adenoma) in 48 patients were available for analysis. Regarding echogenicity score, sensitivity, specificity, PPV and NPV of conventional US were 81%, 50%, 56%, 77%; according to Q-elastography, sensitivity, specificity, PPV and NPV were 95%, 88%, 97% and 91% respectively; whereas concerning CEUS, sensitivity specificity PPV and NPV were 79%, 91%, 83% and 89% respectively. Both CEUS and Q-elastography were more specific than US (p<0.01), with not statistical significant difference with regard to sensitivity. CONCLUSIONS: The results of the present study suggest that Q-elastography is a valuable tool in the characterization of thyroid nodules and it seems to be more sensitive than CEUS.

[Reimbursed health expenditures during the last year of life, in France, in the year 2008]. / Les dépenses de soins remboursés durant la dernière année de vie, en 2008, en France.

BACKGROUND: To measure the reimbursed health expenditures in the last year of life and the proportion it represents in total reimbursement costs in 2008, to analyse the structure of such expenditures and to identify costs by cause of death. METHODS: Data were obtained from the French national insurance information system (SNIIRAM). Data from the national hospital discharge database were linked to the outpatient reimbursement database for patients covered by the general health insurance scheme (n=49 million persons). The cost of the last year of life was calculated for the exhaustive population (361,328 deaths in 2008). The supposed cause of death was mainly derived from the primary diagnosis of the last hospital stay during which the patient died. RESULTS: The average reimbursed expenses during the last year of life were estimated at 22,000 € per person in 2008, with 12,500 € accounting for public hospital costs. Reimbursed health expenditures varied according to different medical causes of death: 52,300 € for HIV disease and about 40,000 € for tumors. A negative effect of age on the expenditure during the last year of life was observed. Health care spending increased with shorter time before death, the last month of life corresponding to 28% of reimbursed expenditures during the last year of life. Health care use in the last year of life represented 10.5% of the total health expenditures in 2008. CONCLUSION: This study found results similar to those observed in the past or in other countries. Our results show in particular that the weight of health expenditures during the last year of life on total health expenditures remains stable over the years.

Changing the Risk Paradigms Can be Good for Our Health: J-Shaped, Linear and Threshold Dose-Response Models.

Both the linear (at low doses)-no-threshold (LNT) and the threshold models (S-shapes) dose-response lead to no benefit from low exposure. We propose three new models that allow and include, but do not require - unlike LNT and S-shaped models - this strong assumption. We also provide the means to calculate benefits associated with bi-phasic biological behaviors, when they occur and propose:THREE HORMETIC (PHASIC) MODELS: the J-shaped, inverse J-shaped, the min-max, andMethod for calculating the direct benefits associated with the J and inverse J-shaped models.The J-shaped and min-max models for mutagens and carcinogenic agents include an experimentally justified repair stage for toxic and carcinogenic damage. We link these to stochastic transition models for cancer and show how abrupt transitions in cancer hazard rates, as functions of exposure concentrations and durations, can emerge naturally in large cell populations even when the rates of cell-level events increase smoothly (e.g., proportionally) with concentration. In this very general family of models, J-shaped dose-response curves emerge. These results are universal, i.e., independent of specific biological details represented by the stochastic transition networks. Thus, using them suggests a more complete and realistic way to assess risks at low doses or dose-rates.

[The contribution of cancer registries in environmental health studies]. / Il contributo dei Registri tumori negli studi su ambiente e salute.

Cancer incidence is an outcome of interest in studies assessing the health impact of polluted sites, for which an example is represented by SENTIERI Project. Incidence data are characterized by better diagnostic quality and are not influenced by survival factors, furthermore they allow the investigation of high-survival neoplasms (i.e. childhood cancer) and rare malignancies. Furthermore, the study of incidence is more informative than mortality for non-lethal tumours, therefore it represents an advancement in respect to the study of mortality completed in SENTIERI Project. In the last decade in Italy some environmental epidemiology studies used cancer register data, for example the Biancavilla (Sicily) investigation on fluoro-edenite related mesothelioma and the study in an area of Naples Province where hazardous waste was extensively dumped. In this frame, ISS planned some collaborative studies with Siracusa, Mantua and Ferrara cancer Registries, where three major polluted sites are located. Following these pilot studies an ISS-AIRTUM (Italian Association of Cancer Registries) collaborative study has been planned. For a description of SENTIERI, refer to the 2010 supplement of Epidemiology & Prevention, devoted to the Project.

[Scientific collaboration between Istituto Superiore di Sanità and Italian Association of Cancer Registries for the study of cancer incidence in Italian polluted sites]. / Collaborazione scientifica ISS-AIRTUM per lo studio dell'incidenza dei tumori nei siti di interesse nazionale per le bonifiche.

The collaborative study between Istituto superiore di sanità and Associazione italiana registri tumori (ISS-AIRTUM) aims at investigating cancer incidence in polluted sites for adults and for children (0-14 years) and adolescents (15-19 years) to comment the study results in the light of a set of a priori hypotheses. On the whole, 141 out of 298 municipalities included in SENTIERI Project are served by a Cancer Register participating to the AIRTUM network. For a description of SENTIERI, refer to the 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI Project. The time window of the study is the period 1996-2005. The number of expected cases in each polluted site will be estimated by applying incidence rates of the national pool of cancer registries and of the pool of the geographic macroarea in which each site is located: Northern, Central, Southern Italy and Islands. Cancer incidence in children and adolescents is one of the main priorities of international public health institutions, because of the need to protect childhood health from involuntary exposure to environmental risk factors. Standardized incidence ratios (SIRs) will be computed using expected figures derived from the national pool of cancer registries.