Radiological findings in Erdheim Chester disease: A very rare multisistemic disease.

Erdheim-Chester disease is an uncommon non-Langerhans cell histiocytosis affecting multiple systems. There is limited knowledge on the imaging capabilities of this disease. We present an extremely rare case of Erdheim-Chester illness in a 67-year-old man with multisystem involvement, including the cardiovascular system, skeleton, retroperitoneum (renal and adrenal infiltration) and the neurologic system. The involvement of the various organs was thoroughly assessed using multimodal imaging modalities such as computed tomography, magnetic resonance imaging, positron emission tomography and bone scintigraphy. Erdheim-Chester illness was revealed by a bone biopsy. Especially when there is cardiac and cerebral involvement, Erdheim-Chester illness is a rare condition with a poor prognosis. Knowing the imaging characteristics of Erdheim-Chester disease may be helpful in understanding the radiological results of many organs affected by the disease as described and discussed in the current case report.

Lipomatous hypertrophy of the interatrial septum: A potential pitfall resolved on comparing previous PET/CT.

In this case report, we describe a rare case of inter-atrial septal lipomatosis occasionally found in a PET-CT scan performed in an 81-year-old patient with a history of periprosthetic endocarditis post aortic prosthesis implantation. The patient reappeared in 2022 in the emergency department complaining of symptomatology of worsening asthenia, fever, and elevated inflammatory indices. He was hospitalized in Cardiology department on suspect of recurrence of endocarditis and underwent PET-CT examination that showed an increased metabolic finding at the interatrial septum. On possible suspicion of recurrence of infective endocarditis or cardiac tumor pathology, further diagnostic investigation by cardio-RM examination was requested. However, after radiologic consultation, the previous performed FDG-PET/TC examinations were re-evaluated and a misdiagnosed uptake at this level was revealed, which was assumed to be due to the endocarditis condition because of widespread uptake throughout the perivalvular area.

GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery.

Canonical Wnt signaling is emerging as a major regulator of endocytosis. Here, we report that Wnt-induced macropinocytosis is regulated through glycogen synthase kinase 3 (GSK3) and the ß-catenin destruction complex. We find that mutation of Axin1, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCl), CHIR99021, or dominant-negative GSK3 triggers macropinocytosis. GSK3 inhibition causes a rapid increase in acidic endolysosomes that is independent of new protein synthesis. GSK3 inhibition or Axin1 mutation increases lysosomal activity, which can be followed with tracers of active cathepsin D, ß-glucosidase, and ovalbumin degradation. Microinjection of LiCl into the blastula cavity of Xenopus embryos causes a striking increase in dextran macropinocytosis. The effects of GSK3 inhibition on protein degradation in endolysosomes are blocked by the macropinocytosis inhibitors EIPA or IPA-3, suggesting that increases in membrane trafficking drive lysosomal activity.

The Brain Metabolic Correlates of the Main Indices of Neuropsychological Assessment in Alzheimer's Disease.

BACKGROUND: The study aimed to investigate the relationships between F-18 fluorodeoxyglucose (18F)FDG uptake and neuropsychological assessment in Alzheimer's disease (AD). METHODS: We evaluated 116 subjects with AD according to the NINCDS-ADRDA criteria. All the subjects underwent a brain PET/CT with (18F)FDG, cerebrospinal fluid (CSF) assay, mini-mental state examination (MMSE) and further neuropsychological tests: Rey auditory verbal learning test, immediate recall (RAVLT immediate); Rey auditory verbal learning test, delayed recall (RAVLT, delayed); Rey complex figure test, copy (RCFT, copy); Rey complex figure test, delayed recall (RCFT, delayed); Raven's colored progressive matrices (RCPM); phonological word fluency test (PWF) and Stroop test. We performed the statistical analysis by using statistical parametric mapping (SPM12; Wellcome Department of Cognitive Neurology, London, UK). RESULTS: A significant relationship has been reported between (18F)FDG uptake and RAVLT immediate test in Brodmann area (BA)37 and BA22 and with RCFT, copy in BA40, and BA7. We did not find any significant relationships with other tests. CONCLUSION: In the AD population, brain (18F)FDG uptake is moderately related to the neuropsychological assessment, suggesting a limited impact on statistical data analysis of glucose brain metabolism.

Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties.

Defining the interplay between the genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavour in cancer biology. We found that receptor tyrosine kinase (RTK)-Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumour precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix. Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumour emergence. However, RTK-Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell's environment, such that when cells experience even subtle supra-physiological extracellular-matrix rigidity they are converted into tumour-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signalling. This work lays the groundwork for exploiting oncogenic mechanosignalling as a vulnerability at the onset of tumorigenesis, including tumour prevention strategies.

Publisher Correction: Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ.

Inactivation of ARID1A and other components of the nuclear SWI/SNF protein complex occurs at very high frequencies in a variety of human malignancies, suggesting a widespread role for the SWI/SNF complex in tumour suppression1. However, the underlying mechanisms remain poorly understood. Here we show that ARID1A-containing SWI/SNF complex (ARID1A-SWI/SNF) operates as an inhibitor of the pro-oncogenic transcriptional coactivators YAP and TAZ2. Using a combination of gain- and loss-of-function approaches in several cellular contexts, we show that YAP/TAZ are necessary to induce the effects of the inactivation of the SWI/SNF complex, such as cell proliferation, acquisition of stem cell-like traits and liver tumorigenesis. We found that YAP/TAZ form a complex with SWI/SNF; this interaction is mediated by ARID1A and is alternative to the association of YAP/TAZ with the DNA-binding platform TEAD. Cellular mechanotransduction regulates the association between ARID1A-SWI/SNF and YAP/TAZ. The inhibitory interaction of ARID1A-SWI/SNF and YAP/TAZ is predominant in cells that experience low mechanical signalling, in which loss of ARID1A rescues the association between YAP/TAZ and TEAD. At high mechanical stress, nuclear F-actin binds to ARID1A-SWI/SNF, thereby preventing the formation of the ARID1A-SWI/SNF-YAP/TAZ complex, in favour of an association between TEAD and YAP/TAZ. We propose that a dual requirement must be met to fully enable the YAP/TAZ responses: promotion of nuclear accumulation of YAP/TAZ, for example, by loss of Hippo signalling, and inhibition of ARID1A-SWI/SNF, which can occur either through genetic inactivation or because of increased cell mechanics. This study offers a molecular framework in which mechanical signals that emerge at the tissue level together with genetic lesions activate YAP/TAZ to induce cell plasticity and tumorigenesis.

Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4.

Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.

De Novo Generation of Somatic Stem Cells by YAP/TAZ.

Here we present protocols to isolate primary differentiated cells and turn them into stem/progenitor cells (SCs) of the same lineage by transient expression of the transcription factor YAP. With this method, luminal differentiated (LD) cells of the mouse mammary gland are converted into cells that exhibit molecular and functional properties of mammary SCs. YAP also turns fully differentiated pancreatic exocrine cells into pancreatic duct-like progenitors. Similarly, to endogenous, natural SCs, YAP-induced stem-like cells ("ySCs") can be eventually expanded as organoid cultures long term in vitro, without further need of ectopic YAP/TAZ, as ySCs are endowed with a heritable self-renewing SC-like state. The reprogramming procedure presented here offers the possibility to generate and expand in vitro progenitor cells of various tissue sources starting from differentiated cells. The straightforward expansion of somatic cells ex vivo has implications for regenerative medicine, for understanding mechanisms of tumor initiation and, more in general, for cell and developmental biology studies.

Crosstalk between YAP/TAZ and Notch Signaling.

How the behavior of cells in living tissues is orchestrated according to tissue needs, size, and developmental stage is still poorly understood. Advances in these directions are essential to understand morphogenesis, 'self-organization' phenomena, to build new tissues for regenerative medicine or to reverse the changes in deranged organs, such as in cancer or in genetic disorders. This review outlines a new scenario by which the crosstalk between the Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) transcription factors and Notch signaling influences cell self-renewal, stem cell differentiation, cell fate decisions, epithelial-stromal interactions, inflammation, morphogenesis, and large-scale gene oscillations.

Evaluation of recurrent disease in the re-staging of colorectal cancer by 18F-FDG PET/CT: Use of CEA and CA 19-9 in patient selection.

The aim of the present retrospective study was to evaluate the sensitivity and specificity of fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing the recurrence of colorectal cancer (CRC) with regard to carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). 18F-FDG PET/CT was performed in 100 patients for the re-staging of CRC. Therapy was discontinued prior to the examination. The mean (± standard deviation) CEA value (measured ~30 days prior to PET/CT examination) was 23.71 (±107) ng/ml, whereas the CA 19-9 value was 72 (±190.3) U/ml. Differences in CEA and CA 19-9 values in patients with scans that were positive or negative for recurrence were analyzed by means of a receiver operating characteristic (ROC) curve. ROC curves were used for the calculation of the sensitivity and specificity of 18F-FDG PET/CT for the CEA and CA 19-9 levels. The results of the 18F-FDG PET/CT were found to be associated with the CEA level (P=0.001), but not with the CA 19-9 level (P=0.43). PET/CT was positive for recurrence in 60 patients (60.0%), whose mean CEA and CA 19-9 values were 33.07±136.7 ng/ml and 75.24±192.3 U/ml, respectively. PET/CT was negative for recurrence in 40 patients (40.0%), whose mean CEA and CA 19-9 values were 10.15±30 ng/ml and 67.76±190 U/ml, respectively. On the basis of ROC curve analysis, the best compromise between sensitivity and specificity was achieved for CEA levels of 3.5 ng/ml [sensitivity, 80%; 95% confidence interval (CI), 67-89%; and specificity, 60%; 95% CI, 45-78%]. The study concluded that the detection of recurrence by 18F-FDG PET/CT in patients treated for CRC is associated with CEA, but not CA 19-9 serum levels. Moreover, 18F-FDG PET/CT should be recommended in patients with suspected CRC recurrence even when they present with CEA levels below the normal cut-off.

Induction of Expandable Tissue-Specific Stem/Progenitor Cells through Transient Expression of YAP/TAZ.

The ability to induce autologous tissue-specific stem cells in culture could have a variety of applications in regenerative medicine and disease modeling. Here we show that transient expression of exogenous YAP or its closely related paralogue TAZ in primary differentiated mouse cells can induce conversion to a tissue-specific stem/progenitor cell state. Differentiated mammary gland, neuronal, and pancreatic exocrine cells, identified using a combination of cell sorting and lineage tracing approaches, efficiently convert to proliferating cells with properties of stem/progenitor cells of their respective tissues after YAP induction. YAP-induced mammary stem/progenitor cells show molecular and functional properties similar to endogenous MaSCs, including organoid formation and mammary gland reconstitution after transplantation. Because YAP/TAZ function is also important for self-renewal of endogenous stem cells in culture, our findings have implications for understanding the molecular determinants of the somatic stem cell state.

PET/CT with (18)F-choline after radical prostatectomy in patients with PSA ≤2 ng/ml. Can PSA velocity and PSA doubling time help in patient selection?

PURPOSE: To investigate the performance of (18)F-fluorocholine ((18)F-FCH) PET/CT in relation to the prostate-specific antigen (PSA) kinetic indexes, PSA doubling time (PSAdt) and PSA velocity (PSAve), in detecting recurrent prostate cancer (PC) in a selected population of patients treated with radical prostatectomy and with PSA ≤2 ng/ml. METHODS: The study group comprised 79 patients (mean age 70 ± 7 years, range 58 - 77 years) who had been treated with radical surgery 30 to 90 months previously and with biochemical failure (defined as a measurable serum PSA level) who were evaluated with (18)F-FCH PET/CT. In order to establish the optimal threshold for PSAdt and PSAve, the diagnostic performance of PSA, PSAdt and PSAve were compared by receiver operating characteristic analysis. RESULTS: In the population examined, PSA (mean ± SD) was 1.37 ± 0.44 ng/ml (range 0.21 - 2 ng/ml) before PET/CT examination, PSAdt was 10.04 ± 16.67 months and PSAve was 2.75 ± 3.11 ng/ml per year. (18)F-FCH PET/CT was positive in 44 patients (55 %). PSAve and PSAdt were significantly different between patients with a positive and a negative (18)F-FCH PET/CT scan. Thresholds of 6 months for PSAdt and 1 ng/ml per year for PSAve were selected. For PSAdt ≤6 months the detection rate (DR) was 65 %, and for PSAve >1 ng/ml per year the DR was 67 %. PSA values were not significantly different between patients with a positive and a negative PET/CT scan. CONCLUSION: The results of our study suggest that (18)F-FCH PET/CT could be considered for the evaluation of patients with biochemical recurrence of PC and with low PSA levels. Fast PSA kinetics could be useful in the selection of these patients.

Detection of local recurrence of prostate cancer after radical prostatectomy: Is there a role for early ¹8F-FCH PET/CT?

AIM: To investigate the diagnostic performance of early acquisition compared to late imaging for the detection of local recurrence of prostate cancer by means of ¹8F-FCH PET/CT. MATERIALS AND METHODS: 99 patients with radical prostatectomy (mean PSA 3.9 ± 5.03) were subjected to early dynamic PET/CT acquisition of the pelvis and a whole body PET/CT in the same exam session. None of the patients examined was subjected to radiotherapy for local or distant recurrence. All the subjects were taken off hormonal therapy. RESULTS: 58 subjects did not show local recurrence in both early and late acquisition, 22 were positive in both modalities, 10 showed a positive early and a negative late acquisition while 9 showed a negative early and a positive late acquisition (Cohen's k = 0.558). When the results of imaging modalities were considered separately, sensitivity, specificity, positive predictive value and negative predictive value resulted: 78.9, 96.7, 93.8 and 88.1 % for early acquisition and 73.7, 95.1, 90.3 and 85.3 % for late acquisition, respectively. When the results of early and late acquisition were considered together, results were 97.4, 93.4, 90.2 and 98.3 %, respectively. CONCLUSIONS: The combination of early acquisition with late acquisition lead to an increase of the diagnostic accuracy of ¹8F-FCH PET/CT for the diagnosis of local recurrence in prostate cancer.

Functional correlates of t-Tau, p-Tau and Aß1₋42 amyloid cerebrospinal fluid levels in Alzheimer's disease: a ¹8F-FDG PET/CT study.

AIM: The aim of the study was to investigate the relationships between cerebrospinal fluid (CSF) levels of t-Tau, p-Tau and amyloid-ß (Aß1₋42) amyloid peptide and fluorine-18 fluorodeoxyglucose (¹8F-FDG) brain distribution in a group of patients with Alzheimer's disease. MATERIALS AND METHODS: The study included 81 newly diagnosed Alzheimer's disease patients according to the NINCDS-ADRDA criteria. The mean (±SD) age of the patients was 70 (±6) years; 44 were male and 37 were female. All patients underwent a CSF assay and MRI before ¹8F-FDG PET scanning. The relationships were evaluated by means of statistical parametric mapping (SPM8). RESULTS: Increased t-Tau CSF levels were related to reduced glucose consumption in a wide portion of the right frontal lobe [Brodmann area (BA 47)] and limbic lobe bilaterally (BA 31,32), whereas no areas of increased ¹8F-FDG uptake related to t-Tau levels were detected. Elevated p-Tau concentrations in CSF were related to increased glucose consumption in both the right and the left limbic lobe and in the left frontal lobe (BA 32 and 8). We did not find any specific cortical area of reduced glucose consumption being related to low levels of Aß1₋42 in CSF, whereas a spawn of ¹8F-FDG uptake was detectable in BA 18,19 and in the right cerebellum. CONCLUSION: The results of our study suggest that reduced Aß1₋42 concentrations in CSF are related to a wide cortical dysfunction, whereas t-Tau and p-Tau are related to more selective cortical metabolic patterns that mainly involve the cingulate cortex.

Brain metabolic changes in Hodgkin disease patients following diagnosis and during the disease course: An 18F-FDG PET/CT study.

The aim of the present study was to investigate brain glucose metabolism in patients with Hodgkin disease (HD) after diagnosis and during chemotherapy treatment. Following the administration of first-line doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy, 74 HD patients underwent 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography brain scans, both baseline (PET0) and interim (PET2) at the Department of Biomedicine and Prevention, University of Rome Tor Vergata (Rome, Italy). Fifty-seven patients were further evaluated 15±6 days after four additional cycles (PET6). Furthermore, a control group (CG) of 40 chemotherapy-naïve subjects was enrolled. Differences in brain 18F-FDG uptake between the CG, PET0, PET2 and PET6 scans were analyzed using statistical parametric mapping. Compared with the PET0 and CG scans, the PET2 scan demonstrated a higher metabolic activity in Brodmann area (BA) 39, and a metabolic reduction in BA 11 bilaterally and in left BA 32. All of these changes disappeared at PET6. The results of the present study indicate that ABVD chemotherapy has a limited impact on brain metabolism.

Cardiac sympathetic denervation is not related to nigrostriatal degeneration in Parkinson's disease.

AIM: The aim of our study was to investigate the relationship between myocardial sympathetic degeneration and nigrostriatal impairment in patients affected by Parkinson's disease (PD) by means of (123)I-metaiodobenzylguanidine ((123)I MIBG) scintigraphy and N-(3-fluoropropyl)-2ß-carbomethoxy-3ß-(4-[(123)I]iodophenyl)nortropane ((123)I FP-CIT) scintigraphy. PATIENTS AND METHODS: The study involved 37 patients with clinical diagnosis of PD (22 males and 15 females, mean age 62 years (±10), evaluated with (123)I FP-CIT single photon emission computed tomography (SPECT) followed by (123)I MIBG scintigraphy within 20 (±3) days. Early and delayed anterior chest images were acquired and the heart/mediastinum ratio (H/M ratio) was calculated. Furthermore, the population has been divided on the basis of the main clinical pattern to investigate the possible role of a tremor-dominant or an akinetic-dominant phenotype in this comparison. RESULTS: In PD population, there were no statistical relationships between early and delayed (123)I MIBG cardiac and (123)I FP-CIT striatal uptake in contralateral caudate (P > 0.05) and in contralateral putamen (P > 0.05) to the side mainly affected; no statistically significant relationships have been found at any level when considering ipsilateral striatum. We did not find statistically significant relationships when considering the single PD phenotypes. CONCLUSIONS: The results of our study suggest that cardiac sympathetic system and nigrostriatal system are differently affected in PD. In particular, the sympathetic neurodegeneration rate is not related to nigrostriatal degeneration rate and vice versa in our series as detectable scintigraphically.

Translation and validation of the Italian version of the European Heart Failure Self-care Behaviour Scale.

BACKGROUND: Heart failure (HF) patients can benefit from management programmes that include education, discharge planning and structured follow-up. Therefore, it is important to evaluate the improvement of self-care as a result of these interventions. The European Heart Failure Self-care Behaviour Scale (EHFScBS) was developed as a reliable and valid instrument for self-care evaluation. OBJECTIVES: The aims were to translate and validate the Italian version of the EHFScBS and to evaluate factors related to self-care. METHODS: The translation and validation were performed as follows: translation and back-translation; evaluation by four bilingual cardiologists; administration to healthy individuals of different ages and education to test language comprehension; final correction by cardiologists experienced in cognitive assessment; and administration in HF patients to test validity and internal consistency. RESULTS: A sample of 93 HF patients (mean age 77 +/- 6 years, 53% women) was considered for the validation procedure. Fifty-four (58%) patients were already followed in the HF clinic (HFC), with previous HF education, and 39 (42%) were evaluated at baseline. The reliability analysis showed a Cronbach's alpha of 0.82. At multivariate analysis, age, not already followed in HFC and female sex were associated to worse self-care behaviour. When HFC patients were considered separately, an association between self-care and cognitive dysfunction was observed. CONCLUSION: The EHFScBS appears to be a valid and reliable instrument in the Italian version also. Self-care behaviour appears to depend on age and sex and a previous HF education. Mild to moderately impaired cognitive function seems to influence self-care in patients who have already received HF education.