Systematic review and meta-analysis on coronary calcifications in COVID-19.

Chest CT is valuable to detect alternative diagnoses/complications of COVID-19, while its role for prognostication requires further investigation. Non-pulmonary radiological findings such as cardiovascular calcifications could increase the predictivity of clinical outcomes of COVID-19 patients beyond pulmonary involvement. Several observational studies have reported mixed results on the role of coronary calcifications in COVID-19 patients as a predictor of hospitalization, ventilatory support, and mortality. The purpose of the study is to systematically review the available evidence on the predictive role of cardiovascular calcifications in SARS-CoV2 disease. The meta-analysis confirms the prognostic significance of coronary calcifications on hospital mortality, and coronary calcifications (CAC ≠ 0) were associated with an OR for mortality of 2.19 (95% CI 1.36-3.52). CAC was neutral on respiratory outcomes, but it was associated with an increased trend of cardiovascular events. Coronary calcium appears as a promising biomarker imaging even in short-term outcomes (MACEs, hospital mortality) in a non-cardiovascular disease such as Sars-CoV2 infection. Further large studies are needed to confirm promising results of this imaging biomarker in non-cardiovascular disease.

Family Pediatrician and Public Health collaboration, an alliance to increase vaccination coverage: an experience with MenB vaccination in Italy.

Background: Invasive Meningococcal Disease is a severe disease mainly affecting infants and young children. Most infections are caused by serogroups A, B, C, W, X, and Y. In the last 10 years, serogroup B has been the main cause of Invasive Meningococcal Disease in Europe. Recent data resulting from an observational study conducted in Italy show a significant reduction in the number of Invasive Meningococcal Disease cases due to Neisseria meningitidis B after the introduction of vaccine 4CMenB. Thus, the Naples Team of Federation of Italian Primary Care Pediatricians and the Public Health Department started an active collaboration focused on vaccination process management (named "Progetto Via") with the aim of increasing Meningococcal B vaccination coverage. Study design: Source of data is the regional platform "GE.VA.". Every Primary care Pediatrician uses daily to record vaccination activity. This platform is integrated with data entered by operators of the District/Vaccination Center. Methods: Time: January 2019 - December 2019. The Federation of Italian Primary Care Pediatricians/Naples organized a meeting to identify six coordinators. The pediatricians could choose to counsel in their own offices and send children to the vaccination center or to counsel and vaccinate directly in their own clinics. Results: A total of 78 pediatricians took part in the project: 46 did only counseling and 32 did both counseling and vaccination in their medical clinic. Data obtained show an overall average vaccination coverage growth of about 13% in the first 4 months of the survey, and a further growth of about 11% in the following seven months, with a total growth in the entire period of 24%. The pediatricians' counseling is essential to recover non-compliant subjects, considering both the relationship of trust with the families and the visits already scheduled as an ideal moment for vaccinations' status check. Conclusions: The project highlights how an effective collaboration between family pediatricians and the Local Health Authority becomes valuable in getting closer to reach the Ministerial goal of 95%. Vaccination coverage increased significantly when family pediatricians supported the activity of vaccine centers in distress in many regional situations. The trust relationship, the hourly availability and the capillary network of family pediatricians' clinics were key elements for the success of this project and were also recognized by parents.

Benefit of adjuvant chemotherapy in patients with special histology subtypes of triple-negative breast cancer: a systematic review.

PURPOSE: Breast cancer (BC) is a leading cause of morbidity, disability, and mortality in women, worldwide; triple-negative BC (TNBC) is a subtype traditionally associated with poorer prognosis. TNBC special histology subtypes present distinct clinical and molecular features and sensitivity to antineoplastic treatments. However, no consensus has been defined on the best adjuvant therapy. The aim of the review is to study the evidence from literature to inform the choice of adjuvant treatments in this setting. METHODS: We systematically searched literature assessing the benefit of adjuvant chemotherapy in patients with TNBC special histotypes (PROSPERO: CRD42020153818). RESULTS: We screened 6404 records (15 included). All the studies estimated the benefit of different chemotherapy regimens, in retrospective cohorts (median size: 69 patients (range min-max: 17-5142); median follow-up: 51 months (range: 21-268); mostly in Europe and USA). In patients with early-stage adenoid cystic TNBC, a marginal role of chemotherapy was reported. Similar for apocrine TNBC. Medullary tumors exhibited an intrinsic good prognosis with a limited role of chemotherapy, suggested to be modulated by the presence of tumor-infiltrating lymphocytes. A significant impact of chemotherapy on the overall survival was estimated in patients with metaplastic TNBC. Limitations were related to the retrospective design of all the studies and heterogeneous treatments received by the patients. CONCLUSIONS: There is potential opportunity to consider treatment de-escalation and less intense therapies in some patients with early, special histology-type TNBC. International efforts are indispensable to validate prospective clinical decision models.

Robotic versus laparoscopic distal pancreatectomy: multicentre analysis.

BACKGROUND: The role of minimally invasive distal pancreatectomy is still unclear, and whether robotic distal pancreatectomy (RDP) offers benefits over laparoscopic distal pancreatectomy (LDP) is unknown because large multicentre studies are lacking. This study compared perioperative outcomes between RDP and LDP. METHODS: A multicentre international propensity score-matched study included patients who underwent RDP or LDP for any indication in 21 European centres from six countries that performed at least 15 distal pancreatectomies annually (January 2011 to June 2019). Propensity score matching was based on preoperative characteristics in a 1 : 1 ratio. The primary outcome was the major morbidity rate (Clavien-Dindo grade IIIa or above). RESULTS: A total of 1551 patients (407 RDP and 1144 LDP) were included in the study. Some 402 patients who had RDP were matched with 402 who underwent LDP. After matching, there was no difference between RDP and LDP groups in rates of major morbidity (14.2 versus 16.5 per cent respectively; P = 0.378), postoperative pancreatic fistula grade B/C (24.6 versus 26.5 per cent; P = 0.543) or 90-day mortality (0.5 versus 1.3 per cent; P = 0.268). RDP was associated with a longer duration of surgery than LDP (median 285 (i.q.r. 225-350) versus 240 (195-300) min respectively; P < 0.001), lower conversion rate (6.7 versus 15.2 per cent; P < 0.001), higher spleen preservation rate (81.4 versus 62.9 per cent; P = 0.001), longer hospital stay (median 8.5 (i.q.r. 7-12) versus 7 (6-10) days; P < 0.001) and lower readmission rate (11.0 versus 18.2 per cent; P = 0.004). CONCLUSION: The major morbidity rate was comparable between RDP and LDP. RDP was associated with improved rates of conversion, spleen preservation and readmission, to the detriment of longer duration of surgery and hospital stay.

Robotic Dual-Console Distal Pancreatectomy: Could it be Considered a Safe Approach and Surgical Teaching even in Pancreatic Surgery? A Retrospective Observational Study Cohort.

BACKGROUND: The study aims to assess the safety and feasibility of the robotic dual-console during a robotic distal pancreatectomy METHODS: The data of the consecutive patients submitted to RDP from 2012 to 2019 at the Verona University were retrieved from a prospectively maintained database. The patients submitted to RDP were divided into the dual-console platform group (DG) and compared to the standard robotic procedure group (SG). RESULTS: In the study period, 102 robotic distal pancreatectomies were performed, of whom 42 patients (41%) belonged to the DG and 60 patients (59%) to the SG. Higher operation time was recorded in the DG compared to the SG (410 vs. 265 min, p < 0.001). The overall conversion rate of the series was 7% (n 7 patients). All the conversions were observed in the SG (p = 0.021). No differences in morbidity or pancreatic fistula rate were recorded (p > 0.05). No mortality events in the 90th postoperative days were reported in this series. CONCLUSIONS: The robotic dual-console approach for distal pancreatectomy is safe, feasible, and reproducible. The postoperative surgical outcomes are comparable to the standard RDP with the single-console da Vinci Surgical System®. This surgical technique can widely and safely improve the robotic surgical training program.

French maritime pine bark extract (pycnogenol) in association with triple combination cream for the treatment of facial melasma in women: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Melasma can be recalcitrant to treatment, and relapses are common. Pycnogenol has been reported to be effective in treating melasma. OBJECTIVE: To compare the efficacy, safety and tolerability of 75 mg pycnogenol taken orally twice a day vs. a placebo, in association with the triple combination and broad-spectrum sunscreen for the treatment of facial melasma. METHODS: A randomized, double-blind, parallel, placebo-controlled study was conducted on 44 women with facial melasma in a single centre from May 2019 through November 2019. Patients with melasma were randomly assigned to orally take 75 mg pycnogenol (PYC) or a placebo (PLAC) twice a day for 60 days. Both groups also received tinted sunscreen [Sun Protection Factor (SPF) 50; Persistent Pigment Darkening (PPD) 17] for daytime use and a topical triple combination at bedtime. The primary outcome was a change from the baseline Modified Melasma Area Severity Index (mMASI) score. Secondary outcomes were improvements in the patients' quality of life (MELASQoL), colorimetric indices and Global Aesthetic Improvement Scale (GAIS). RESULTS: All participants completed the trial. The mean (SD) age of the participants was 39 (7) years, and 91% were phototypes III-IV. Both groups exhibited a reduction in mMASI scores, MELASQoL scores and colour contrast (P < 0.01). The mean (CI 95%) reductions of the mMASI scores were 49% (36-61%) for PYC and 34% (16-47%) for PLAC. The reductions in mMASI scores and colorimetric contrast were superior for the PYC group (P < 0.05). The analysis of GAIS resulted in an improvement of 86% (CI 95%: 68-96%) for the participants in the PYC group and 55% (CI 95%: 32-73%) for those in the PLAC group. There were no adverse effects related to oral treatment. CONCLUSION: Pycnogenol is well-tolerated and increases the effectiveness of broad-spectrum sunscreen and the triple combination in the treatment of facial melasma in women.

Efficacy and safety of topical isobutylamido thiazolyl resorcinol (Thiamidol) vs. 4% hydroquinone cream for facial melasma: an evaluator-blinded, randomized controlled trial.

BACKGROUND: Melasma can be refractory to treatment, and relapses are frequent. Thiamidol is a new potent tyrosinase inhibitor that has been found effective as a cosmeceutical for the depigmenting of melasma. OBJECTIVE: This study compared the efficacy and tolerability of topical 0.2% Thiamidol vs. 4% hydroquinone for facial melasma. METHODS: Fifty women with facial melasma participated in a randomized, evaluator-blinded, controlled study from September through November 2020. Patients were randomly assigned to apply a double layer of 0.2% Thiamidol twice a day or 4% hydroquinone cream at bedtime, for 90 days. Both groups received tinted sunscreen (sun protection factor 60, PPD 20). The primary outcome was the change from the baseline Modified Melasma Area Seve:rity Index (mMASI) score. Secondary outcomes were improvements in the patients' quality of life [Melasma Quality of Life Index (MELASQoL)], colourimetry, and Global Aesthetic Improvement Scale (GAIS) evaluation. RESULTS: One participant, from the hydroquinone group, did not complete the study (unrelated to adverse effects). The mean (SD) age of the participants was 43 (6) years, and 86% were phototypes III-IV. Both groups exhibited a reduction in mMASI, MELASQoL, and colour contrast scores (P < 0.01). The mean [95% confidence interval (CI 95%)] reductions of the mMASI scores were 43% (35-50%) for Thiamidol and 33% (23-42%) for hydroquinone. There was no difference between the groups in the reductions in mMASI, MELASQoL, colourimetric contrast and GAIS scores (P ≥ 0.09). The GAIS analysis resulted in an improvement of 84% (CI: 95% 67-97%) for participants in the Thiamidol group and 74% (CI: 95% 61-93%) for those in the hydroquinone group. There were only mild adverse effects in the Thiamidol group, but allergic contact dermatitis was evidenced in two (8%) participants. CONCLUSION: The melasma improvement achieved using 0.2% Thiamidol did not differ from that of 4% hydroquinone cream. Thiamidol can be considered a suitable option for melasma patients with poor tolerability or treatment failure with hydroquinone.

Use of an intraoperative wound protector to prevent surgical-site infection after pancreatoduodenectomy: randomized clinical trial.

BACKGROUND: Surgical-site infection (SSI) increases treatment costs, duration of hospital stay and readmission rate after pancreatic surgery. This study aimed to assess whether a wound protector could reduce the risk of superficial incisional SSI after pancreatoduodenectomy. METHODS: This RCT included patients undergoing pancreatoduodenectomy at Verona University Hospital, between 2017 and 2018. The experimental group had a dual-ring wound protector, whereas the control group had standard surgical drapes. The groups were stratified by preoperative biliary stent placement. The primary outcome was the overall rate of superficial SSI. RESULTS: An interim analysis was conducted after 212 patients had been enrolled; 22 patients (10·4 per cent) were excluded owing to inability to complete the pancreatoduodenectomy, or the need for postoperative reintervention. Some 94 patients (49·5 per cent) had a wound protector and 96 (50·5 per cent) had standard drapes. There were no differences between groups in demographics, or in intraoperative findings, pathological data or surgical outcomes. The overall superficial SSI rate was 7·4 per cent, which did not differ between groups (7 per cent in each group; P = 0·585). Subanalysis of patients with a preoperative biliary stent showed a similar outcome (superficial SSI rate 9 versus 8 per cent with wound protector versus surgical drapes respectively; P = 0·536). The trial was stopped prematurely on the grounds of futility. CONCLUSION: Use of a wound protector did not reduce the rate of superficial SSI after pancreatoduodenectomy. Registration number: NCT03820648 (http://www.clinicaltrials.gov).

ANTECEDENTES: La infección de la herida quirúrgica (surgical-site infection, SSI), especialmente de la incisión, aumenta sobremanera los costes del tratamiento, la duración de la estancia y la tasa de reingresos en la cirugía de páncreas. En los últimos años se han introducido los protectores de las heridas (wound protectors, WP) con la intención de reducir la tasa de SSI. Este estudio tuvo como objetivo evaluar si un WP podría reducir la incidencia de la SSI superficial de la incisión (superficial incisional surgical-site infection, SI-SSI) en pacientes sometidos a duodenopancreatectomía cefálica (pancreaticoduodenectomy, PD). MÉTODOS: Ensayo aleatorizado controlado en el que se incluyeron los pacientes a los que se realizó una PD en la Universidad de Verona entre 2017 y 2018. En el grupo experimental se utilizó un WP de doble anillo, mientras que el grupo control se utilizaron tallas quirúrgicas convencionales (standard drape, SD). Los grupos se estratificaron también según la colocación preoperatoria de una prótesis biliar. RESULTADOS: Se incluyeron 212 pacientes, de los que 22 (10%) abandonaron el estudio debido a la imposibilidad de realizar la DP o a la necesidad de una reintervención durante el curso postoperatorio. Los pacientes se dividieron en 94 (49%) en el grupo WP y 96 (51%) en el grupo SD. No se detectaron diferencias entre grupos en cuanto a las variables demográficas y a los resultados intraoperatorios, patológicos o quirúrgicos. La tasa global de SI-SSI fue del 7,4%, que no difirió entre los grupos (WP 7,5% versus SD 7,3%, P = 0,585). Teniendo en cuenta los resultados descritos, se cumplieron los criterios de futilidad del análisis y el ensayo se interrumpió prematuramente. CONCLUSIÓN: En el entorno de un centro de alto volumen, la WP por si sola no redujo la tasa de SI-SSI. Cabría plantear su utilización dentro de un programa multimodal, que debería incluir un replanteamiento interno de la institución encaminado a la reducción de complicaciones infecciosas.

MRI prediction of pathological response in locally advanced rectal cancer: when apparent diffusion coefficient radiomics meets conventional volumetry.

AIM: To investigate the role of diffusion-weighted imaging (DWI), T2-weighted (W) imaging, and apparent diffusion coefficient (ADC) histogram analysis before, during, and after neoadjuvant chemoradiotherapy (CRT) in the prediction of pathological response in patients with locally advanced rectal cancer (LARC). MATERIALS AND METHODS: Magnetic resonance imaging (MRI) at 1.5 T was performed in 43 patients with LARC before, during, and after CRT. Tumour volume was measured on both T2-weighted (VT2W) and on DWI at b=1,000 images (Vb,1,000) at each time point, hence the tumour volume reduction rate (ΔVT2W and ΔVb,1,000) was calculated. Whole-lesion (three-dimensional [3D]) first-order texture analysis of the ADC map was performed. Imaging parameters were compared to the pathological tumour regression grade (TRG). The diagnostic performance of each parameter in the identification of complete responders (CR; TRG4), partial responders (PR; TRG3) and non-responders (NR; TRG0-2) was evaluated by multinomial regression analysis and receiver operating characteristics curves. RESULTS: After surgery, 11 patients were CR, 22 PR, and 10 NR. Before CRT, predictions of CR resulted in an ADC value of the 75th percentile and median, with good accuracy (74% and 86%, respectively) and sensitivity (73% and 82%, respectively). During CRT, the best predictor of CR was ΔVT2W (-58.3%) with good accuracy (81%) and excellent sensitivity (91%). After CRT, the best predictors of CR were ΔVT2W (-82.8%) and ΔVb, 1,000 (-86.8%), with 84% accuracy in both cases and 82% and 91% sensitivity, respectively. CONCLUSIONS: The median ADC value at pre-treatment MRI and ΔVT2W (from pre-to-during CRT MRI) may have a role in early and accurate prediction of response to treatment. Both ΔVT2W and ΔVb,1,000 (from pre-to-post CRT) can help in the identification of CR after CRT.

MpMRI of the prostate: is there a role for semi-quantitative analysis of DCE-MRI and late gadolinium enhancement in the characterisation of prostate cancer?

AIM: To assess whether there is a significant difference in perfusion parameters between benign and malignant prostatic lesions, focusing on semi-quantitative analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and presence of late gadolinium enhancement (LGE). MATERIAL AND METHODS: Three hundred and thirteen patients who underwent multiparametric MRI (mpMRI) of the prostate and with available corresponding histology (prostatectomy or biopsy) were selected retrospectively for this study. The MRI protocol consisted of multiplanar T2-and diffusion-weighted imaging, DCE and delayed axial T1 images. Images were reviewed independently by two radiologists for LGE assessment and Prostate Imaging - Reporting and Data System (PI-RADS) scoring. For each lesion, semi-quantitative analysis of DCE-MRI was performed and the following data were evaluated: time to peak, wash-in rate, wash-out rate, brevity of enhancement, and area under the curve. The presence or absence of LGE in delayed axial T1 images was assessed qualitatively. MRI results were compared to histology. The presence of significant prostate cancer was based both on Epstein criteria (SPC) and Gleason score (GS ≥7). RESULTS: SPC and Gleason score ≥7 tumours showed significant lower time to peak and brevity of enhancement (p<0.001) with higher wash-in rate (p=0.001). LGE was observed in 152/313 (49%) cases; among them 103/152 (68%) did not show SPC whereas 49/152 (32%) had SPC (p<0.001). The presence of LGE determined a risk reduction of SPC resulting as an independent predictor at multivariate analysis (logOR=-0.78, SE 0.33, p=0.02). CONCLUSION: Semi-quantitative perfusion analysis and LGE may help to predict the presence/absence of a significant prostate tumour and represent a promising tool to improve mpMRI diagnostic performance.

Could perfusion heterogeneity at dynamic contrast-enhanced MRI be used to predict rectal cancer sensitivity to chemoradiotherapy?

AIM: To evaluate whether perfusion heterogeneity of rectal cancer prior to chemoradiotherapy (CRT) using histogram analysis of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) quantitative parameters can predict response to treatment. MATERIALS AND METHODS: Twenty-one patients with histologically proven rectal adenocarcinoma were enrolled prospectively. All patients underwent 1.5 T DCE-MRI before CRT. Tumour volumes were drawn on Ktrans and Ve maps, using T2-weighted (W) images as reference, and the following first-order texture parameters of Ve and Ktrans values were extracted: 25th, 50th, 75th percentile, mean, standard deviation, skewness, and kurtosis. After CRT, patients underwent surgery and according with Rödel's tumour regression grade (TRG), they were classified as poor responders "non-GR" (TRG 0-2) and good responders "GR" (TRG 3-4). Differences between GR and non-GR in DCE-MRI first-order texture parameters were evaluated using the Mann-Whitney test, and their role in the prediction of response was investigated using receiver operating characteristic (ROC) curve analysis. RESULTS: Sixteen (76%) patients were classified as GR and five (24%) were non-GR. Skewness and kurtosis of Ve was significantly higher in non-GR (4.886±1.320 and 36.402±24.486, respectively) than in GR patients (1.809±1.280, p=0.003 and 6.268±8.130, p= 0.011). Ve skewness <3.635 was able to predict GR with an area under the ROC curve (AUC) of 0.988, sensitivity 93.8%, specificity 80%, and accuracy 90.5%. Ve kurtosis <21.095 was able to predict response with an AUC of 0.963, sensitivity 93.8%, specificity 80%, and accuracy 90.5%. Other parameters were not different between groups or predictors of response. CONCLUSION: Ve skewness and kurtosis seem to be promising in the prediction of response to CRT in rectal cancer patients.

Could early tumour volume changes assessed on morphological MRI predict the response to chemoradiation therapy in locally-advanced rectal cancer?

AIM: To investigate the potential role of an additional magnetic resonance imaging (MRI) examination performed during neoadjuvant chemoradiation therapy (CRT) in the prediction of pathological response in locally advanced rectal cancer (LARC). MATERIAL AND METHODS: Forty-eight consecutive patients with LARC underwent neoadjuvant CRT. MRI studies at 1.5 T, including high-resolution T2-weighted sequences that were acquired parallel and perpendicular to the main axis of the tumour were performed before (preMRI), during (midMRI), and 6-8 weeks after the end of CRT (postMRI). Cancer volumes (Vpre, Vmid, Vpost) were drawn manually and the reduction rate calculated (ΔVmid, ΔVpost). According to Rödel's pathological tumour regression grade (TRG), patients were considered non-responders (NR; TRG0-2), partial responders (PR; TRG3), and complete responders (CR; TRG4). Multivariate regression analysis was performed to identify the best MRI predictors of NR, PR, and CR. RESULTS: Twenty-five patients were considered PR (52%), 13 CR (27%), and 10 NR (22%). Tumour shrinkage mainly occurred shortly after CRT (ΔVmid: CR: 80±10% versus PR: 56±19% versus NR: 28±22%, p=2.2×10-16). Vmid, Vpost, ΔVmid, and ΔVpost correlated with TRG (p<0.001). At multivariate analysis, the combined assessment of Vmid and ΔVmid was selected as the best predictor of response to CRT, in that it distinguishes CR, PR, and NR early and accurately (81.5%). CONCLUSION: MidMRI allows final response assessment to neoadjuvant CRT earlier and better than the MRI performed after the end of CRT. MRI findings at midMRI may be useful to tailor patient treatment.

Exploring pathways for sustained melanogenesis in facial melasma: an immunofluorescence study.

BACKGROUND: The physiopathology of epidermal hypermelanization in melasma is not completely understood. Several cytokines and growth factors are increased in skin with melasma, nevertheless, nor the pathways involved in the increased αMSH expression have been adequately evaluated, nor a model for sustained focal melanogenesis is available. OBJECTIVE: To explore stimulatory pathways for epidermal pigmentation in facial melasma related to αMSH: those linked to ultraviolet radiation, oxidative stress, inflammation, neural crest pigmentation cell differentiation and antagonism of αMSH. METHODS: Paired skin biopsies (3 mm) from 26 women with facial melasma and from normal adjacent skin (<2 cm far) were processed for immunofluorescence with markers for p53, p38, αMSH, MC1R, Melan-A, IL-1α, COX2, Wnt1, WIF-1 and ASIP. RESULTS: The fluorescence intensity in the skin from melasma was higher for MC1R, αMSH at epidermis as at melanocytes (P < 0.05). There were no differences between the sites in epidermal protein expression of COX2, IL-1α, p53, WIF-1 and ASIP (P > 0.1). P53 was expressed only in epidermis, without difference between sites (P = 0.92). WNT1 was remarkable in the epidermis of melasma (P < 0.01), but not in dermis. Positive p38 cells were prominent in the upper dermis of melasma (P < 0.01), despite no marking in epidermis. CONCLUSION: Melanogenesis in melasma involves epithelial secretion of αMSH and activation of the Wnt pathway; nevertheless, it seems to be independent of the stimulation by ultraviolet radiation/p53, IL-1α, COX2/PgE2 , WIF-1 and ASIP. Damaged cells at upper dermis suggest the role of senescence/autophagy in sustained pigmentation in melasma.

Modeling the Iatrogenic Pancreatic Cancer Risk After Islet Autotransplantation in Mouse.

Iatrogenic pancreatic cancer metastasis after islet infusion is a potential risk of islet autotransplantation performed after pancreatectomy. To model this risk, islets and/or pancreatic exocrine clusters obtained from a genetically engineered mouse model for pancreatic ductal adenocarcinoma (the LSL-KrasG12D/+ ;LSL-Trp53R172H/+ ;Pdx-1-Cre, termed KPC mouse) were transplanted via the portal vein in syngeneic wild type (WT) severely diabetic recipients in the following treatment groups: group A (n = 11) received KPC exocrine clusters in volume equal to 250 islet equivalents (IEQs); group B (n = 12) received 250 WT IEQs mixed with KPC exocrine clusters (1:1 volume ratio); group C (n = 5) received 250 KPC IEQs, and group D (n = 7) received 250 WT IEQs. The incidence of hepatic metastasis was assessed by magnetic resonance imaging and histology over the 13 months of follow-up. Overall survival was not different in the four groups. No mice developed liver metastases during the follow-up. Two mice developed spontaneous tumors: a liver hepatocellular tumor in group A and a malignant lymphoma in group D. Islets and/or exocrine clusters obtained by KPC mouse, a model that develops pancreatic cancer with 100% penetrance, do not retain the same risk of tumor development when transplanted via the portal vein in a syngeneic diabetic recipient.

Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis.

OBJECTIVE: We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA). METHOD: We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter. RESULTS: Testing early vs delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks (wks) following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1-4 wks post-surgery or moderate, 4-8 wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped. CONCLUSIONS: Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.

Short-term in vivo modifications of platelet NADPH oxidase 2 (NOX2) and prostaglandin F2α in HIV-1 patients on abacavir-based therapies.

OBJECTIVES: The aim of the study was to investigate the in vivo effect of abacavir (ABC) on platelet oxidative stress. METHODS: We performed a randomized pilot study including 39 HIV-1-infected patients, 17 on zidovudine/lamivudine (ZDV/3TC) and 22 on tenofovir/emtricitabine (TDF/FTC). Ten patients on ZDV/3TC and eight patients on TDF/FTC were randomly allocated to switching the nucleoside backbone to ABC/3TC. At baseline and after 6 months, platelet oxidative stress was assessed by platelet NADPH oxidase 2 (NOX2)-derived peptide (sNOX2-dp), a marker of NOX2 activation, and platelet prostaglandin F2α (8-iso-PGF2α ). Platelet activation was measured by soluble CD40L (sCD40L). RESULTS: At baseline, no differences between ZDV/3TC or TDF/FTC recipients were found. After 6 months, patients switching from ZDV/3TC showed a decrease of sNOX2-dp (from 20.9±5.7 to 12.5±3.8 pg/ml, p=0.002) and 8-iso-PGF2α (from 154.3±41.9 to 122.9±28.0 pmol/l, p=0.025). No effects on platelet oxidative stress biomarkers were observed in subjects from TDF/FTC, who showed a significant increase in blood glucose (p=0.043) and total cholesterol (p=0.027). ABC showed no effect on sCD40L levels in both groups. CONCLUSIONS: ABC reduced platelet sNOX2-dp and 8-iso-PGF2α in HIV-1 subjects switching from ZDV/3TC but not in those from TDF/FTC after 6 months. No changes in platelet activation were found in both groups.

Does cyclic guanosine monophosphate induce autophagy in thyroid malignant carcinoma through down-regulation of cyclic guanosine monophosphate phosphodiesterase?

The aim of this study was to evaluate whether or not the expression of cGMP- phosphodiesterases (cGMP-PDE) varies in different thyroid pathologies and to elucidate the relationship between the expression of cGMP-PDE, cGMP, and autophagy. Fifty-four thyroid biopsy samples, excised to perform the biopsy, were split into two parts and randomly assigned: one part was microscopically examined and histological classified, and the other was frozen and analysed in order to evaluate the cGMP-PDE activity. Intracellular cGMP was also measured. A strong expression of intracellular cGMP and cGMP-PDE activity was observed in carcinoma in respect to controls and benign pathologies. The level of cGMP-PDE in papillary carcinoma without lymph node involvement (N-) was approximately four-fold higher compared to those with lymph node invasion (N±). On the contrary, the cGMP was one and a half times higher in N± than N-. Our results are promising, although further epigenetical studies are needed to confirm this association. A correlation between the cGMP-degrading activity and the severity of thyroid pathology has been shown. The decrease of cGMP-PDE and the increase of cGMP in N± papillar carcinoma could be an autophagic stimulus, a defence mechanism of the body, against the cancer that is expanding and invading other tissues and organs.

Accelerated bone turnover identifies hemiplegic patients at higher risk of demineralization.

Immobilization osteoporosis represents a severe complication in hemiplegic patients (HPs), causing fragility fractures, which may occur during rehabilitation reducing functional recovery and survival. The aim of the study was to investigate determinants of bone loss, independent from length of immobilization, which may be useful in early identification of HPs at higher risk of demineralization. Forty-eight HPs of both sexes underwent anthropometric measurements, evaluation of scores of spasticity and of lower limb motory capacity. Laboratory tests were performed. On serum: calcium; phosphorus; creatinine; ALP; iPTH; 25(OH) vitamin-D; sex hormones; Δ4-androstenedione; DHEA-S; insulin; IGF-1; FT3; FT4; TSH; c-AMP. On urine: c-AMP and calcium/creatinine ratio. Two bone turnover markers were measured: serum osteocalcin (BGP) and urinary deoxypyridinoline (DPD). Bone mineral density was determined at both femoral necks, defining a percentage difference in bone loss between paretic and non-paretic limb, thus controlling for the complex cofactors involved. Only bone turnover markers significantly and directly correlated with the entity of demineralization, controlling for age, sex and length of immobilization in the multivariate analysis (BGP coefficient estimate=0.008; SE=0.003; p=0.020; DPD coefficient estimate=0.005; SE=0.002; p=0.036). BGP and DPD are not dependent on anthropometric and endocrine-metabolic parameters, disability patterns and duration of immobilization, thus represent independent determinants of the degree of demineralization. A cutoff was defined for BGP and DPD above which subjects show significantly greater risk of demineralization. The immobilization event generates more severe bone loss when it occurs in subjects with higher bone turnover. BGP and DPD measurements may be of primary importance for early identification of HPs at risk, with relevant preventive implications.