Clinical Outcome and 7-Day Virological Clearance in High-Risk Patients with Mild-Moderate COVID-19 Treated with Molnupiravir, Nirmatrelvir/Ritonavir, or Remdesivir.

INTRODUCTION: We compared the effectiveness and virological clearance (VC) at day 7 (T7) post-treatment with molnupiravir, nirmatrelvir/ritonavir, and remdesivir in SARS-CoV-2-infected patients at high risk (HR) for clinical progression. METHODS: We conducted a retrospective study enrolling HR patients with mild-to-moderate COVID-19 (Jan-Oct 2022) treated with nirmatrelvir/ritonavir or molnupiravir or 3 days of remdesivir. We investigated clinical recovery at T7 (resolution of symptoms for ≥ 72 h or all-cause death), VC at T7 (PCR/antigenic negative nasopharyngeal swab), and median time to VC (days from symptom onset to the first negative swab). Factors associated with VC were investigated by logistic regression. RESULTS: In the study, 92/376 (43.8%) patients received molnupiravir, 150/376 (24.7%) nirmatrelvir/ritonavir, and 134/376 (31.5%) remdesivir. Forty-nine (13%) patients were unvaccinated or incompletely vaccinated. Patients treated with nirmatrelvir/ritonavir were younger and presented immunodeficiencies more frequently; remdesivir was used more commonly in patients hospitalized for other diseases. A high proportion of patients obtained clinical recovery without differences among the therapies (97.5% for molnupiravir, 98.3% for nirmatrelvir/ritonavir, and 93.6% for remdesivir); 12 (3.7%) patients died. Nirmatrelvir/ritonavir was associated with a higher proportion of T7 VC and a shorter time to VC compared to molnupiravir/remdesivir, also after adjustment for age and immunodeficiency (AOR 0.445 RDV vs. NMV-r, 95% CI 0.240-0.826, p = 0.010; AOR 0.222 MNP vs. NMV-r, 95% CI 0.105-0.472, p < 0.001). CONCLUSIONS: SARS-COV-2 antiviral treatments are an excellent therapeutic strategy in HR patients. Nirmatrelvir/ritonavir showed a higher proportion of VC as early as 7 days after treatment, confirming its likely superiority in indirect comparisons.

Nirmatrelvir-ritonavir, molnupiravir, and a 3-day course of remdesivir are antiviral therapies recommended in patients with a mild-to-moderate COVID-19 disease at high risk of clinical progression. Randomized controlled trials and observational studies have shown their efficacy in reducing all-cause mortality and clinical progression. Few data are available about a direct comparison among the three drugs; furthermore, the possible role of nirmatrelvir-ritonavir in increasing viral clearance and in reducing the duration of viral shedding needs to be further elucidated. We thus investigated the effectiveness, safety, and virological clearance 7 days after treatment with these three antivirals in our retrospective cohort. We included in the analysis patients that have received these treatments from January 2022 and October 2022; we observed that patients receiving nirmatrelvir-ritonavir displayed a shorter median time from symptoms' onset to virological clearance and a higher proportion of virological clearance at day 7, also after adjustment for possible confounders, compared to molnupiravir and remdesivir. Our data might help in understanding which COVID-19 patients may benefit mostly from antiviral therapies and in the choice of antiviral therapy.

Using sentiment analysis to evaluate the impact of the COVID-19 outbreak on Italy's country reputation and stock market performance.

During the recent Coronavirus disease 2019 (COVID-19) outbreak, the microblogging service Twitter has been widely used to share opinions and reactions to events. Italy was one of the first European countries to be severely affected by the outbreak and to establish lockdown and stay-at-home orders, potentially leading to country reputation damage. We resort to sentiment analysis to investigate changes in opinions about Italy reported on Twitter before and after the COVID-19 outbreak. Using different lexicons-based methods, we find a breakpoint corresponding to the date of the first established case of COVID-19 in Italy that causes a relevant change in sentiment scores used as a proxy of the country's reputation. Next, we demonstrate that sentiment scores about Italy are associated with the values of the FTSE-MIB index, the Italian Stock Exchange main index, as they serve as early detection signals of changes in the values of FTSE-MIB. Lastly, we evaluate whether different machine learning classifiers were able to determine the polarity of tweets posted before and after the outbreak with a different level of accuracy.

Correction to: Using sentiment analysis to evaluate the impact of the COVID-19 outbreak on Italy's country reputation and stock market performance.

[This corrects the article DOI: 10.1007/s10260-023-00690-5.].

Cost-Utility Analysis of Pharmacogenetic Testing Based on CYP2C19 or CYP2D6 in Major Depressive Disorder: Assessing the Drivers of Different Cost-Effectiveness Levels from an Italian Societal Perspective.

BACKGROUND AND OBJECTIVES: Major depressive disorder (MDD) is a common and severe psychiatric disorder that has enormous economical and societal costs. As pharmacogenetics is one of the key tools of precision psychiatry, we analyze the cost-utility of test screening of CYP2C19 and CYP2D6 for patients suffering from major depressive disorder (MDD) and try to understand the main drivers that influence the cost-utility. METHODS: We developed two pharmacoeconomic nonhomogeneous Markov models to test the cost-utility, from an Italian societal perspective, of pharmacogenetic testing genetic to characterize the metabolizing profiles of cytochrome P450 (CYP) 2C19 and CYP2D6 in a hypothetical case study of patients suffering from major depressive disorder (MDD). The model considers different scenarios of adjustment of antidepressant treatment according to the patient's metabolizing profile or treatment over a period of 18 weeks. The uncertainty of model parameters is tested through both a probabilistic sensitivity analysis and a one-way deterministic sensitivity analysis, and these results are used in a post-hoc analysis to understand the main drivers of three alternative cost-effectiveness levels ("poor," "standard," and "high"). These drivers are first evaluated from an exploratory multidimensional perspective and next from a predictive perspective as the probability that a patient belongs to a specific cost-effectiveness level is estimated on the basis of a restricted set of parameters used in the original pharmacoeconomic model. RESULTS: The models for CYP2C19 and CYP2D6 indicate that screening has an incremental cost-effectiveness ratio of 60,000€ and 47,000€ per quality-adjusted life year (QALY), respectively. The probabilistic sensitivity analysis shows that the treatments are cost-effective for a 75,000€ willingness to pay (WTP) threshold in 58% and 63% of the Monte Carlo replications, respectively. The post-hoc analysis highlights the factors that allow us to clearly discriminates poor cost-effectiveness from high cost-effectiveness scenarios and demonstrates that it is possible to predict with reasonable accuracy the cost-effectiveness of a genetic test and the associated therapeutic pattern. CONCLUSIONS: Our findings suggest that screenings for both CYP2C19 and CYP2D6 enzymes for patients with MDD are cost-effective for a WTP threshold of 75,000€ per QALY, and provide relevant suggestions about the most important aspects to be further explored in clinical studies aimed at addressing the cost-effectiveness of genetic testing for patients diagnosed with MDD.

Declining Mortality Rate of Hospitalised Patients in the Second Wave of the COVID-19 Epidemics in Italy: Risk Factors and the Age-Specific Patterns.

BACKGROUND: Mortality rate from COVID-19 in Italy is among the world's highest. We aimed to ascertain whether there was any reduction of in-hospital mortality in patients hospitalised for COVID-19 in the second-wave period (October 2020-January 2021) compared to the first one (February-May 2020); further, we verified whether there were clusters of hospitalised patients who particularly benefitted from reduced mortality rate. METHODS: Data collected related to in-patients' demographics, clinical, laboratory, therapies and outcome. Primary end-point was time to in-hospital death. Factors associated were evaluated by uni- and multivariable analyses. A flow diagram was created to determine the rate of in-hospital death according to individual and disease characteristics. RESULTS: A total of 1561 patients were included. The 14-day cumulative incidence of in-hospital death by competing risk regression was of 24.8% (95% CI: 21.3-28.5) and 15.9% (95% CI: 13.7-18.2) in the first and second wave. We observed that the highest relative reduction of death from first to second wave (more than 47%) occurred mainly in the clusters of patients younger than 70 years. CONCLUSIONS: Progress in care and supporting therapies did affect population over 70 years to a lesser extent. Preventive and vaccination campaigns should focus on individuals whose risk of death from COVID-19 remains high.

Protocol for a pharmacogenetic study of antidepressants: characterization of drug-metabolizing profiles of cytochromes CYP2D6 and CYP2C19 in a Sardinian population of patients with major depressive disorder.

The effectiveness of antidepressants shows high interindividual variability ranging from full symptomatologic remission to treatment-resistant depression. Many factors can determine the variation in the clinical response, but a fundamental role is played by genetic variation within the genes encoding for the enzymes most involved in the metabolism of antidepressant drugs: the CYP2D6 and CYP2C19 isoforms of the cytochrome P450 system. This study is poised to clarify whether the different metabolizing phenotypes related to CYP2D6 and CYP2C19 could have an impact on the clinical efficacy of antidepressants and whether the frequency of these phenotypes of metabolization shows differences in the population of Sardinian patients compared to other Caucasian populations. The sample is being recruited from patients followed-up and treated at the Psychiatric Unit of the Department of Medical Science and Public Health, University of Cagliari and the University Hospital Agency of Cagliari (Italy). The study design includes three approaches: (1) a pharmacogenetic analysis of 80 patients diagnosed with MDD resistant to antidepressant treatment compared to 80 clinically responsive or remitted patients; (2) a prospective arm (N = 30) of the study where we will test the impact of genetic variation within the CYP2D6 and CYP2C19 genes on clinical response to antidepressants and on their serum levels and (3) the assessment of the socio-economic impact of antidepressant therapies, and estimation of the cost-effectiveness of the pharmacogenetic test based on CYP genes.

Italian versions of the Urogenital Distress Inventory-6 and Incontinence Impact Questionnaire-7: translation and validation in women with urinary incontinence.

PURPOSE: To culturally adapt and validate the Urogenital Distress Inventory-6 and Incontinence Impact Questionnaire-7 (short forms) for use in Italian-speaking women with urinary incontinence. METHODS: We developed Italian versions of the two questionnaires through forward-backward translation, expert review and cognitive interviews. We then administered them to 100 women with urinary incontinence (mean age 58.02 ± 11.9 years) to assess the internal consistency (Cronbach's alpha), test-retest reliability (intraclass correlation coefficient), standard error of measurement, minimum detectable change, and construct validity by hypothesis testing. RESULTS: No difficulties in acceptability emerged. Internal consistency was 0.61 for Urogenital Distress Inventory-6 and 0.88 for Incontinence Impact Questionnaire-7. Test-retest reliability was respectively 0.79 and 0.91. The minimum detectable change was respectively 22.9 and 18.1 points (on a 0-100 scale). Nine out of 10 a priori hypotheses regarding construct validity were confirmed. CONCLUSIONS: The Italian versions of the Urogenital Distress Inventory-6 and Incontinence Impact Questionnaire-7 showed reliability levels in line with the literature and good construct validity. Thus, we think that the present study extends the evidence for both questionnaires as useful tools for assessing women with urinary incontinence.Implications for rehabilitationThe Italian versions of the short forms of the Urogenital Distress Inventory and the Incontinence Impact Questionnaire have never been validated in Italian-speaking women with urinary incontinence.After translation and cross-cultural adaptation, the Italian versions of these two questionnaires showed reliability levels in line with the literature and good construct validity.The Urogenital Distress Inventory-6 produces a summary index of overall symptom distress, whereas the Incontinence Impact Questionnaire-7 is a unidimensional questionnaire measuring the adverse effects of urinary incontinence on health-related quality of life.

Reliability, responsiveness and minimal clinically important difference of the two Fear Avoidance and Beliefs Questionnaire scales in Italian subjects with chronic low back pain undergoing multidisciplinary rehabilitation.

BACKGROUND: The Fear-Avoidance Beliefs Questionnaire (FABQ) is a widely used outcome measure. There is still a lack of information concerning responsiveness and minimal clinically important difference (MCID), limiting its use for clinical and research purposes. AIM: The aim of this study was to examine reliability, responsiveness and MCID of the two FABQ scales in subjects with chronic low back pain. DESIGN: Methodological research based on a prospective single-group observational study. SETTING: Outpatient, Unit of rehabilitation. POPULATION: Chronic non-specific low back pain. METHODS: At the beginning and the end of a multidisciplinary program (8-week), 129 subjects completed the FABQ scales. Reliability was determined as internal consistency (Cronbach's alpha) and test-retest reliability (96-hour interval; N.=64; Interclass correlation coefficient [ICC 2.1]). Responsiveness was calculated both by distribution-based and anchor-based methods, using as external criterion the Global Perceived Effect Scale (GPE: 7 levels), rated by each individual. RESULTS: Cronbach's alpha and ICC(2,1) were respectively: 0.75 and 0.90 for FABQ-Physical Activity Scale (FABQ-PA), and 0.85 and 0.95 for FABQ-Work Scale (FABQ-W). Minimum detectable change (MDC95) values were 3.69 points for FABQ-PA, and 5.95 points for FABQ-W. In receiver-operating characteristic curves, splitting GPE data into null/minimal/moderate improvement vs. large improvement (GPE 0-2 vs. GPE 3): 1) for FABQ-PA, the area under the curve (AUC) was 0.97 and the best cutoff score identifying meaningful change in fear-avoidance beliefs about physical activity was a change of 4 points; 2) for FABQ-W, the AUC was 0.97 and the best cutoff score for meaningful change in fear-avoidance beliefs about work activities was a change of 7 points. CONCLUSIONS: After triangulation of the above results, a change of 4 points for FABQ-PA and 7 points for FABQ-W were selected as MCID. These two values represent cutoffs that seem to accurately identify meaningful change in fear-avoidance beliefs, according to subject's judgement. CLINICAL REHABILITATION IMPACT: The present study calculated - in a sample of people with chronic low back pain - the minimal clinically important change of the two FABQ scales (FABQ-Physical Activity Scale and FABQ-Work Scale). These values increase confidence in interpreting score changes, thus enhancing their meaningful use in both research and clinical contexts.

Reliability and reproducibility of the new AO/OTA 2018 classification system for proximal humeral fractures: a comparison of three different classification systems.

BACKGROUND: The classification systems for proximal humeral fractures routinely used in clinical practice include the Neer and Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) 2007 systems. Currently used systems have low inter- and intraobserver reliability. In 2018, AO/OTA introduced a new classification system with the aim of simplifying the coding process, in which the Neer four-part classification was integrated into the fracture description. The aim of the present work is to assess the inter- and intraobserver agreement of the new AO/OTA 2018 compared with the Neer and AO/OTA 2007 classifications. MATERIALS AND METHODS: A total of 116 radiographs of consecutive patients with proximal humeral fracture were selected and classified by three observers with different levels of experience. All three observers independently reviewed and classified the images according to the Neer, AO/OTA 2007, and new AO/OTA 2018 systems. To determine the intraobserver agreement, the observers reviewed the same set of radiographs after an interval of 8 weeks. The inter- and intraobserver agreement were determined through Cohen's kappa coefficient analysis. RESULTS: The new AO/OTA 2018 classification showed substantial mean inter- (k = 0.67) and intraobserver (k = 0.75) agreement. These results are similar to the reliability observed for the Neer classification (interobserver, k = 0.67; intraobserver, k = 0.85) but better than those found for the AO/OTA 2007 system, which showed only moderate inter- (k = 0.57) and intraobserver (k = 0.58) agreement. The two more experienced observers showed better overall agreement, but no statistically significant difference was found. No differences were found between surgical experience and agreement regarding specific fracture types or groups. CONCLUSIONS: The results showed that the Neer system still represents the more reliable and reproducible classification. However, the new AO/OTA 2018 classification improved the agreement among observers compared with the AO/OTA 2007 system, while still maintaining substantial descriptive power and simplifying the coding process. The universal modifiers and qualifications, despite their possible complexity, allowed a more comprehensive fracture definition without negatively affecting the reliability or reproducibility of the classification system. LEVEL OF EVIDENCE: Level III, diagnostic studies.

The Italian version of the Quebec Back Pain Disability Scale: cross-cultural adaptation, reliability and validity in patients with chronic low back pain.

BACKGROUND AND AIM: Growing attention is being given to physical functioning measures to assess interventions for low back pain (LBP). The Quebec Back Pain Disability Questionnaire (QBPDS) has never been validated in Italian patients, and the aim of the study was culturally adapting and validating the Italian version of the QBPDS (QBPDS-I), to allow its use with Italian-speaking patients with chronic LBP. METHODS: The QBPDS-I was developed by means of forward-backward translation, a final review by an expert committee and a test of the prefinal version to evaluate its comprehensibility. The psychometric testing included structural validity by exploratory factor analysis (EFA), reliability by internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation coefficient, ICC 2.1), measurement error by calculating the minimum detectable change (MDC), construct validity by assessing hypotheses of QBPDS correlations with the Roland Morris Disability Scale (RMDQ), the Oswestry Disability Questionnaire (ODI) and a pain numerical rating scale (NRS) (Spearman's correlations). RESULTS: It took one month to develop a consensus-based version of the QBPDS-I. The questionnaire was administered to 201 subjects with chronic LBP and was well accepted. EFA suggested a one-factor 20-item solution (first factor variance explained = 54.7%). Internal consistency (α = 0.95) and test-retest reliability (ICC = 0.90) were excellent. The MDC was 12 scale points. Construct validity was good as all of the hypotheses were met; correlations: RMDQ (r = 0.40), ODI (r = 0.48) and NRS (r = 0.44). CONCLUSIONS: The QBPDS-I is unidimensional, reliable and valid in patients with chronic LBP. Its use is recommended for clinical and research purposes.

Sexual disability in patients with chronic non-specific low back pain-a multicenter retrospective analysis.

[Purpose] Oswestry Disability Index includes an item (Oswestry Disability Index-8) aiming to assess sexual disability associated to low back pain. The aim of this study is to investigate the percentage of participants who answered the Oswestry Disability Index-8, and the relevance and characteristics of sexual disability due to low back pain in Italian patients. [Participants and Methods] Design: multicenter retrospective analysis. Population: six hundred and ninety-seven outpatients with non-specific low back pain. Variables: pain characteristics (amount, localization, and duration of perceived pain), disability, and psychological variables (anxiety, depression, catastrophizing, kinesiophobia, pain acceptance, and pain vigilance and awareness). [Results] Seventy-seven participants (11.05%) did not answer the Oswestry Disability Index-8. The odds of being not responding to the Oswestry Disability Index-8 item appeared related to age (odds=7.50 for over 60), gender (odds=2.65 for females), and marital status (odds=2.33 for not married). Concerning the psychological variables, Activity Avoidance (coefficient=0.071), Depression (coefficient=0.068), and Rumination (coefficient=0.031) showed a positive impact on sexual disability. [Conclusion] In Italian patients, the percentage of not-responding to Oswestry Disability Index-8 was relatively low. In addition, sexual disability was related to depression, activity avoidance, and rumination.

High methylation levels of PCDH10 predict poor prognosis in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is not a clinically homogeneous disease, but subsets of patients with distinct prognosis and response to therapy can be identified by genome-wide analyses. Mutations in major PDAC driver genes were associated with poor survival. By bioinformatics analysis, we identified protocadherins among the most frequently mutated genes in PDAC suggesting an important role of these genes in the biology of this tumor. Promoter methylation of protocadherins has been suggested as a prognostic marker in different tumors, but in PDAC this epigenetic modification has not been extensively studied. Thus, we evaluated whether promoter methylation of three frequently mutated protocadherins, PCDHAC2, PCDHGC5 and PCDH10 could be used as survival predictors in PDAC patients. METHODS: DNA extracted from 23 PDACs and adjacent non-neoplastic pancreatic tissues were bisulfite treated. Combined Bisulfite Restriction Analysis (COBRA) coupled to denaturing high-performance liquid chromatography (dHPLC) detection and bisulfite genomic sequencing (BGS) were used to determine the presence of methylated CpG dinucleotides in the promoter amplicons analyzed. RESULTS: In an exploratory analysis, two protocadherins showed the same pattern of CpG methylation in PDAC and adjacent non-neoplastic pancreatic tissues: lack of methylation for PCDHAC2, complete methylation for PCDHGC5. Conversely, the third protocadherin analyzed, PCDH10, showed a variable degree of CpG methylation in PDAC and absence of methylation in adjacent non-neoplastic pancreatic tissues. At Kaplan-Meier analysis, high levels of PCDH10 methylation defined according to the receiver operating characteristic (ROC) curve analysis were significantly associated with worse progression-free survival (PFS) rates (P = 0.008), but not with overall survival (OS). High levels of PCDH10 methylation were a prognostic factor influencing PFS (HR = 4.0: 95% CI, 1.3-12.3; P = 0.016), but not the OS. CONCLUSIONS: In this study, we show for the first time that the methylation status of PCDH10 can predict prognosis in PDAC patients with a significant impact on the outcome in terms of progression-free survival. High levels of PCDH10 promoter methylation could be useful to identify patients at high risk of disease progression, contributing to a more accurate stratification of PDAC patients for personalized clinical management.

Development of the Italian version of the High-Activity Arthroplasty Score (HAAS-I) following hip and knee total arthroplasty: cross-cultural adaptation, reliability, validity and sensitivity to change.

BACKGROUND: The number of physically active individuals who develop knee and hip arthritis and who undergo arthroplasties of these joints ie ever increasing. It has become necessary to develop evaluation scales which address the specific issues raised by such individuals. The High Activity Arthroplasty Score is one such scales, originally developed in English. METHODS: The HAAS-I was developed by means of forward-backward translation, a final review by an expert committee and a test of the pre-final version to establish its correspondence with the original English version. The psychometric testing included reliability by means of internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation coefficients) and construct validity by Pearson's correlations with a pain intensity numerical rating scale (NRS), the Western Ontario and McMaster University index (WOMAC, for THA subjects), the Knee injury and Osteoarthritis Outcome Scale (KOOS; for TKA subjects) and the Short-Form 36 Health Survey (SF-36). RESULTS: The questionnaire was administered to 67 subjects with THA and 61 with TKA and proved to be acceptable. The questionnaire showed good internal consistency (0.85 for THA and 0.91 for TKA) and a high level of test-retest reliability (ICC = 0.97 with 95% CI 0.95-0.98 for THA; ICC = 0.95 with 95% CI 0.92-0.98 for TKA). There was a moderate correlation between the HAAS-I and NRS (r = - 0.40), there was a high correlation between the HAAS-I and WOMAC (r = - 0.68) and there were moderate to high correlations between the HAAS-I and SF-36 subscales (r = 0.34 to 0.63) for THA. There was a moderate correlation between the HAAS-I and NRS (r = - 0.77); there was a high correlation between the HAAS-I and KOOS subscales (r = - 0.79 to r = - 0.91); and there were low correlations between the HAAS-I and SF-36 subscales (r = 0.01 to 0.29) for TKA. CONCLUSIONS: The HAAS-I was successfully translated into Italian and proved to have good psychometric properties that replicated the results of existing versions. Its use is recommended for clinical and research purposes.

Responsiveness and minimal important change of the NeckPix© in subjects with chronic neck pain undergoing rehabilitation.

PURPOSE: The NeckPix© is a simple and rapid means of measuring the beliefs of subjects with chronic neck pain concerning pain-related fears of a specific set of activities of daily living. The original version showed satisfactory psychometric properties. This observational study is aimed at evaluating its responsiveness and minimal important changes (MICs) in subjects with chronic neck pain. METHODS: At the beginning, at the end of an 8-week rehabilitation programme as well as at the one-year follow-up, 153 subjects completed the NeckPix©. After the programme and at follow-up, subjects and physiotherapists also completed the global perceived effect (GPE) scale, which was divided to produce a dichotomous outcome. Responsiveness was calculated by distribution [effect size (ES); standardised response mean (SRM)] and anchor-based methods [receiver-operating characteristics (ROC) curves; correlations between change scores of the NeckPix© and GPEs]. ROC curves were also used to compute MICs. RESULTS: The ES ranged from 0.95 to 1.26 and the SRM from 0.84 to 0.98 at post-treatment and follow-up based on subjects' and physiotherapists' perspective. The ROC analyses revealed AUCs of 0.89 and 0.97 at post-treatment and follow-up, respectively; MICs (sensitivity; specificity) were of 6 (0.82; 0.88) and 8 (0.80; 0.92) at post-treatment and of 8 (0.95; 0.90 based on subjects and 0.95; 0.92 based on physiotherapists perspective) at follow-up. The correlations between change scores of the NeckPix© and GPEs ranged from -0.69 to -0.82. CONCLUSIONS: The NeckPix© was sensitive in detecting clinical changes in subjects with chronic neck pain undergoing rehabilitation. We recommend taking the MICs provided into account when assessing subjects' improvement or planning studies in this clinical context.

A tumour score with multidetector spiral CT for venous infiltration in pancreatic cancer: influence on borderline resectable.

PURPOSE: A tumour score for venous invasion in patients with pancreatic adenocarcinoma was evaluated by means of computed tomography (CT), in order to improve the assessment of medical treatment and clinical outcome with special attention to borderline resectable disease. MATERIALS AND METHODS: Fifty-six consecutive patients who underwent curative surgical resection for pancreatic cancer were analysed. On the basis of CT criteria, tumour involvement of the portal vein (PV) and superior mesenteric vein (SMV) was graded according to an adapted 4-point scale: score 1, definite absence of invasion; score 2, probable absence of invasion; score 3, probable presence of invasion; score 4, definite presence of invasion. Correlations between the venous infiltration scores and the patients' clinical features were also evaluated. RESULTS: After radiological evaluation of PV and SMV grades of infiltration, 21/56 (37 %) and 37/56 (66 %) patients, respectively, were found to have borderline resectable disease. The 4-point scale achieved a sensitivity of 80 %, a specificity of 96 % and an accuracy of 93 % in the evaluation of the PV, and a sensitivity of 100 %, a specificity of 94 % and an accuracy of 95 % in the evaluation of the SMV. Analysis of the distribution of clinical characteristics by PV and SMV infiltration showed that both scores correlated with the presence of distal metastasis (p = 0.016 and p = 0.028, respectively), and resection margins status (p = 0.015 and p = 0.006, respectively). CONCLUSIONS: This adapted tumour score is reliable for assessing venous invasion and might improve preoperative staging in patients with borderline resectable pancreatic cancer.

Changes in miR-143 and miR-21 expression and clinicopathological correlations in pancreatic cancers.

OBJECTIVES: Despite advances in clinical management of pancreatic cancer (PC), there is still room for improvement in early detection, diagnosis, and treatment strategies. The role of microRNAs (miRNAs) in tumor biology might pinpoint an alteration in expression of miRNAs as new diagnostic/prognostic biomarkers. METHODS: Expression levels of miR-143 and miR-21 and correlations with clinicopathological features were analyzed in 26 matched pairs of tumor and adjacent noncancerous tissue samples collected from patients with PCs, including 18 pancreatic ductal adenocarcinomas (PDACs) and 8 adenocarcinomas of Vater's papilla (PVACs). RESULTS: Compared to normal tissues, miR-143 was up-regulated in both PDAC and PVAC tumor samples (P = 0.0028 and P = 0.039, respectively). Conversely, alterations in miR-21 expression were significantly different in PDAC versus PVAC samples (P = 0.0049). Tumor levels of miR-21 were associated with preoperative serum levels of CA 19-9 (r = 0.63, P = 0.0022), whereas miR-143 expression was negatively correlated to lymph node spreading (r = -0.64; P = 0.0004). Correlation between miR-143 and miR-21 expression levels in patients with PDAC was observed (r = 0.53, P = 0.023). CONCLUSIONS: Deregulation of miR-143 and miR-21 may reflect histological features and biological behavior of different PCs. Association data with clinical parameters might indicate a prognostic significance for miR-143 and miR-21 in PCs.

Mirna expression profiles identify drivers in colorectal and pancreatic cancers.

BACKGROUND AND AIM: Altered expression of microRNAs (miRNAs) hallmarks many cancer types. The study of the associations of miRNA expression profile and cancer phenotype could help identify the links between deregulation of miRNA expression and oncogenic pathways. METHODS: Expression profiling of 866 human miRNAs in 19 colorectal and 17 pancreatic cancers and in matched adjacent normal tissues was investigated. Classical paired t-test and random forest analyses were applied to identify miRNAs associated with tissue-specific tumors. Network analysis based on a computational approach to mine associations between cancer types and miRNAs was performed. RESULTS: The merge between the two statistical methods used to intersect the miRNAs differentially expressed in colon and pancreatic cancers allowed the identification of cancer-specific miRNA alterations. By miRNA-network analysis, tissue-specific patterns of miRNA deregulation were traced: the driving miRNAs were miR-195, miR-1280, miR-140-3p and miR-1246 in colorectal tumors, and miR-103, miR-23a and miR-15b in pancreatic cancers. CONCLUSION: MiRNA expression profiles may identify cancer-specific signatures and potentially useful biomarkers for the diagnosis of tissue specific cancers. miRNA-network analysis help identify altered miRNA regulatory networks that could play a role in tumor pathogenesis.

R2 resection in pancreatic cancer--does it make sense?

BACKGROUND: The goal of surgical treatment in patients with pancreatic cancer is the complete resection of tumor tissue; however, the intraoperative appraisal of resectability can be difficult. Extensive surgical exploration for definitive clear resectability may lead to R2 resections in single cases. PATIENTS: We analyzed 38 patients with pancreatic cancer with remaining macroscopic tumor tissue after pancreatic resection, as R0 resection was not possible. Patients were compared to 46 patients with unresectable cancer without distant metastases or peritoneal carcinomatosis, in which a bypass procedure was performed. RESULTS: Operating time and hospital stay were significantly longer after R2 resection. Intraoperative blood loss was significantly higher; and severe surgical complications and the need for relaparotomy were significantly more frequent after R2 resection. The 30-day mortality rate was higher after R2 resection; this difference was not statistically significant. Median survival was comparable in both groups. Two years after surgery, 22.6% of the patients after R2 resection were still alive compared to 10.9% after bypass surgery. CONCLUSION: Tumor debulking is not a treatment option in patients with advanced pancreatic cancer, but the patient is not at a disadvantage compared to bypass procedures if tumor tissue remains and R0 resection cannot be achieved after surgical exploration.

Up-regulation of p75 neurotrophin receptor (p75NTR) is associated with apoptosis in chronic pancreatitis.

Activation of apoptosis in chronic pancreatitis has been demonstrated. The low-affinity neurotrophin receptor p75 (p75NTR) mediates apoptosis in many cell types in vivo and in vitro. The aim of this study was to examine whether p75NTR is involved in the apoptotic process in chronic pancreatitis. The quantity and localization of the receptor was evaluated using northern blot analysis, in situ hybridization, immunohistochemistry, and western blot analysis. Apoptosis was determined by TUNEL assay. By northern blot analysis, p75NTR mRNA levels were increased 40-fold in chronic pancreatitis compared with normal pancreas (P < 0.01). In situ hybridization revealed weak p75NTR mRNA expression in some ductal cells in the normal pancreas. In contrast in chronic pancreatitis moderate p75NTR expression was present in acinar cells next to fibrosis, ductal cells, and cells of ductular structures as well as in some islet cells. Immunostaining of p75NTR in normal pancreas and chronic pancreatitis tissue samples showed a similar intensity and distribution pattern as found by in situ hybridization. Higher p75NTR protein levels could be confirmed by western blot analysis, which revealed an 8.6-fold increase of p75NTR in chronic pancreatitis. TUNEL staining showed, in chronic pancreatitis samples, positivity in some acinar cells next to fibrosis, some ductal cells, and cells of ductular structures. Also some islet cells were positive by TUNEL staining. The presence of p75NTR immunoreactivity was positively correlated (P < 0.05) with the apoptotic index in the exocrine and endocrine pancreas. In conclusion, p75NTR, the low-affinity receptor of neurotrophins which mediates apoptosis, is up-regulated in CP and is involved in the apoptotic process of the exocrine and endocrine pancreas.