Using Redcap to Support the Development of a Learning Healthcare System for Patients with Multiple Sclerosis.

Multiple Sclerosis is a neurodegenerative disease which shows different phenotypes making difficult for clinicians to make short-term decisions related with treatment and prognosis. Diagnosis is usually retrospective. Learning Healthcare Systems (LHS) can support clinical practice as they are devised as constantly improving modules. LHS can identify insights which allow evidence-based clinical decisions and more accurate prognosis. We are developing a LHS with the aim of reducing uncertainty. We are using ReDCAP to collect patients' data, both from Clinical Reported Outcomes (CRO) and from Patients Reported Outcomes (PRO). Once analyzed, this data will serve as a foundation to our LHS. We conducted bibliographical research to select those CRO and PRO collected in clinical practice or identified as possible risk factors. We designed a data collection and management protocol based on using ReDCAP. We are following a cohort of 300 patients for 18 months. At the moment, we have included 93 patients and received 64 complete responses and 1 partial response. This data will be used to develop a LHS, able to accurate prognosis as well as to automatically include new data and improve its algorithm.

Risk-group Classification by Recursive Partitioning Analysis of Patients Affected by Oligometastatic Renal Cancer Treated with Stereotactic Radiotherapy.

AIMS: Due to the absence of consensus on metastases-directed treatment in kidney cancer, we conducted an analysis of patients treated with stereotactic radiotherapy (SRT) on cranial or extracranial metastases to classify them in survival class risk according to pre-treatment characteristics. MATERIALS AND METHODS: We included oligometastatic kidney cancer patients treated with SRT on up to five metastases. Concomitant systemic treatment was allowed. End points included overall survival and the binary classification tree approach with recursive partitioning analysis was applied to stratify patients into overall survival risk groups. RESULTS: In total, 129 patients were treated on 242 metastases. The brain was the most common site (34.71%), followed by lung (25.62%). With a median follow-up of 19.4 months, 1- and 3-year overall survival were 82.62 and 55.11%. The recursive partitioning analysis identified four prognostic classes. Class 1 included patients aged ≤ 65 years treated on extracranial metastases, with 3-year overall survival of 82.66%. Class 2 included patients aged > 65 years, without history of metastatic bone disease, treated on extracranial metastases, with a 3-year overall survival of 67.91%. Patients aged > 65 years and a history of bone disease, treated on extracranial metastases, were classified as class 3, with a 3-year overall survival of 37.50%. Class 4 included patients treated on brain metastases, with a 3-year overall survival of 9.70%. CONCLUSION: We produced a stratification model that can predict survival of oligometastatic kidney cancer patients treated with metastases-directed SRT. Site of disease, patient's age and presence of bone disease can help clinicians in the decision-making process.

Four-year safety and effectiveness data from patients with multiple sclerosis treated with fingolimod: The Spanish GILENYA registry.

OBJECTIVE: To describe the profile of patients with multiple sclerosis (MS) treated with fingolimod in Spain and to assess the effectiveness and safety of fingolimod after 4 years of inclusion in the Spanish Gilenya Registry. METHODS: An observational, retrospective/prospective, multicenter case registry, including all patients with relapsing-remitting MS (RRMS) starting treatment with fingolimod in 43 centers in Spain. Analyses were performed in the overall population and in subgroups according to prior disease-modifying therapy (DMT): glatiramer acetate/interferon beta-1 (BRACE), natalizumab, other treatment, or naïve. RESULTS: Six hundred and sixty-six evaluable patients were included (91.1% previously treated with at least one DMT). The mean annualized relapse rate (ARR) prior to fingolimod was 1.12, and the mean EDSS at fingolimod initiation was 3.03. Fingolimod reduced the ARR by 71.4%, 75%, 75.5%, and 80.3%, after 1, 2, 3 and 4 years, respectively (p<0.001). This significant reduction in the ARR continued to be observed in all subgroups. After 4 years, the EDSS showed a minimal deterioration, with the EDSS scores from year 1 to year 4 remaining mostly stable. The percentage of patients without T1 Gd+ lesions progressively increased from 45.6% during the year prior to fingolimod initiation to 88.2% at year 4. The proportion of patients free from new/enlarged T2 lesions after 4 years of fingolimod treatment was 80.3%. This trend in both radiological measures was also observed in the subgroups. Adverse events (AEs) were experienced by up to 41.6% of patients (most commonly: lymphopenia [12.5%] and urinary tract infection [3.7%]). Most AEs were mild in severity, 3.6% of patients had serious AEs. CONCLUSIONS: The patient profile was similar to other observational studies. The results obtained from the long-term use of fingolimod showed that it was effective, regardless of prior DMT, and it had adequate safety results, with a positive benefit-risk balance.

QSAR models for biocides: The example of the prediction of Daphnia magna acute toxicity.

Biocides are multi-component products used to control undesired and harmful organisms able to affect human or animal health or to damage natural and manufactured products. Because of their widespread use, aquatic and terrestrial ecosystems could be contaminated by biocides. The environmental impact of biocides is evaluated through eco-toxicological studies with model organisms of terrestrial and aquatic ecosystems. We focused on the development of in silico models for the evaluation of the acute toxicity (EC50) of a set of biocides collected from different sources on the freshwater crustacean Daphnia magna, one of the most widely used model organisms in aquatic toxicology. Toxicological data specific for biocides are limited, so we developed three models for daphnid toxicity using different strategies (linear regression, random forest, Monte Carlo (CORAL)) to overcome this limitation. All models gave satisfactory results in our datasets: the random forest model showed the best results with a determination coefficient r2 = 0.97 and 0.89, respectively, for the training (TS) and the validation sets (VS) while linear regression model and the CORAL model had similar but lower performance (r2 = 0.83 and 0.75, respectively, for TS and VS in the linear regression model and r2 = 0.74 and 0.75 for the CORAL model).

Management of recurrent nasopharyngeal carcinoma: current perspectives.

Nasopharyngeal carcinoma is a rare disease in Western countries. Nevertheless, its incidence in China, Singapore, and other Eastern countries reaches 20 cases per 100,000 people. Being an extremely chemo- and radiosensitive disease, upfront treatment often consists in the association of intensity-modulated radiation therapy and concurrent cisplatin. Unfortunately, about 20% of the patients suffer from a radioresistant disease which recurs after upfront therapy. For these patients, mainly available therapeutic options consist in systemic therapy, in particular poly-chemotherapy. In those showing a single locoregional recurrence, chemotherapy is not considered to be the preferred approach and other different strategies may be employed. Re-irradiation and surgery are strategies that are always used more often, albeit related to high risk of morbidity. Immunotherapy and targeted therapy, such as heavy ions-based re-irradiations, are experimental but very intriguing options.

Classification of a Naïve Bayesian Fingerprint model to predict reproductive toxicity$.

Using data from the Leadscope database and Procter and Gamble researchers (1172 compounds after data curation) a new classification model to predict reproductive toxicity was developed. The model is based on Naïve Bayesian methods that use the fingerprint "extended connectivity fingerprint 2". Bits generated by the fingerprint are used from the models as descriptors to discriminate between the two classes. This technique permits the creation of a model without the use of descriptors. After a study on the probability scores, the Naïve Bayesian Fingerprint model shows a good performance on reproductive toxicity. The Matthews Correlation Coefficient value was ≥0.4 in validation. The development of new models to predict complex endpoints such as reproductive toxicity is increasingly requested, with reference also to the REACH legislation in Europe or TSCA in the USA.

Correction to: Recommendations for the follow-up care of female breast cancer survivors: a guideline of the Spanish Society of Medical Oncology (SEOM), Spanish Society of Primary Care Physicians (SEMERGEN), Spanish Society for Family and Community Medicine (SEMFYC), Spanish Society for General and Family Physicians (SEMG), Spanish Society of Obstetrics and Gynecology (SEGO), Spanish Society of Radiation Oncology (SEOR), Spanish Society of Senology and Breast Pathology (SESPM), and Spanish Society of Cardiology (SEC).

Correction to: Clin Transl Oncol https://doi.org/10.1007/s12094-017-1801-4.

Recommendations for the follow-up care of female breast cancer survivors: a guideline of the Spanish Society of Medical Oncology (SEOM), Spanish Society of General Medicine (SEMERGEN), Spanish Society for Family and Community Medicine (SEMFYC), Spanish Society for General and Family Physicians (SEMG), Spanish Society of Obstetrics and Gynecology (SEGO), Spanish Society of Radiation Oncology (SEOR), Spanish Society of Senology and Breast Pathology (SESPM), and Spanish Society of Cardiology (SEC).

The increased incidence and decreased mortality of breast cancer have produced an increased number of breast cancer survivors. The type of sequelae and comorbidities that these patients present call for a collaborative follow-up by hospital-based specialized care and primary care. In this document, we present a guideline drafted and agreed among scientific societies whose members care for breast cancer survivors. The purpose of this guideline is to achieve the shared and coordinated follow-up of these patients by specialized care and primary care professionals. In it, we review the health issues derived from the treatments performed, with recommendations about the therapeutic approach to each of them, as well as a proposal for joint follow-up by primary and specialized care.

Procedures and recommended times in the care process of the patient with pancreatic cancer: PAN-TIME consensus between scientific societies.

PURPOSE: Pancreatic cancer (PC) is a disease with bad prognosis. It is usually diagnosed at advanced stages and its treatment is complex. The aim of this consensus document was to provide recommendations by experts that would ameliorate PC diagnosis, reduce the time to treatment, and optimize PC management by interdisciplinary teams. METHODS: As a consensus method, we followed the modified Delphi methodology. A scientific committee of experts provided 40 statements that were submitted in two rounds to a panel of 87 specialists of 12 scientific societies. RESULTS: Agreement was reached for 39 of the 40 proposed statements (97.5%). CONCLUSIONS: Although a screening of the asymptomatic population is not a feasible option, special attention to potential symptoms during primary care could ameliorate early diagnostic. It is especially important to decrease the period until diagnostic tests are performed. This consensus could improve survival in PC patients by decreasing the time to diagnose and time to treatment and by the implementation of multidisciplinary teams.

Synergic development of pharmacokinetics and bioanalytical methods as support of pharmaceutical research.

The development of pharmacokinetics led this science to achieve a relevant role in the investigation of new chemical entities for therapeutic application, and has allowed a series of new useful realizations of out of patent drugs like prolonged release and delayed release formulations, therapeutic delivery system (TDS) for drugs to be active in systemic circulation avoiding the first pass effect, orodispersible and effervescent formulations, intramuscular and subcutaneous depot formulations acting over a long period, oral inhalatory systems, and drug association at fixed dose. The above applications had pharmacokinetics as protagonist and have required the support from bioanalytical methods to assay drug concentrations, even in pg·mL(-1) of plasma, that really have paralleled the synergic development of pharmacokinetics.The complexity of the above realizations required specific guidelines from the regulatory authorities, mainly the US FDA and EU EMA, which have normalized and, in most cases, simplified the above applications admitting some waivers of in vivo bioequivalence.However, this review highlights some critical points, not yet focused on by operating guidelines, which need to be clarified by regulatory authorities. One of the most relevant issues is about the planning and conducting bioavailability and bioequivalence trials with endogenous substances, that possess own homeostatic equilibria with fluctuations, in some cases with specific rhythms, like melatonin and female sex hormones. The baseline subtraction required by guidelines to define the net contribute to the exogenous absorbed drug in most cases is a non-solvable problem.

Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.

BACKGROUND: Psoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment. AIM: To estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates. METHODS: A retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point. RESULTS: Four hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03). CONCLUSIONS: Paradoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.

Factors predictive of pelvic lymph node involvement and outcomes in melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study.

INTRODUCTION: The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement exist on dissection of pelvic LN. This study aimed at investigating predictors of pelvic LN metastasis and prognostic significance of having metastasis in the pelvic LNs. METHODS: Clinicopathologic data of 740 patients with positive groin sentinel LN who underwent ilioinguinal completion LN dissection at four Italian centre were analysed. Multivariable logistic and Cox regression analysis was used to identify independent predictors of pelvic LN metastasis and to adjust prognostic significance of pelvic LN metastasis. RESULTS: More than a quarter (26%) of patients had positive non-SLNs after inguinal and pelvic lymphadenectomy, which were located in their pelvis in the 12% of cases. Older patients [(OR) 1.69; 95% confidence interval (CI) 1.02-2.78] having thick primary (OR 1.6; 95% CI, 1.01-2.53) and ≥ 2 positive SLNs (OR 2.5; 95% CI, 1.4-4.47) were more likely to harbour pelvic LN metastasis. Interestingly, 4% of all patients (34% of patients with positive pelvic LNs) had pelvic LN metastasis with negative inguinal LNs. Pelvic LN metastasis was independently associated with higher risk of recurrence and lower survival. 5-year disease free and overall survival was 30% and 50%, respectively, for patients with pelvic LN metastasis. CONCLUSIONS: Pelvic LNs are frequently positive after ilioinguinal lymphadenectomy and it should be considered for all patients, especially those who are older, have thick primary and ≥ 2 positive SLN. Patients with pelvic LN metastasis have worse prognosis.

Development of psoriasis scalp with alopecia during treatment of Crohn's disease with infliximab and rapid response to both diseases to ustekinumab.

Anti tumor necrosis factor antibodies are used to treat both psoriasis and inflammatory bowel disease. Several paradoxical cases of psoriatic skin lesions induced by tumor necrosis factor antagonist therapy have been described in IBD patients in the recent years. Ustekinumab, a fully human anti-interleukin-12/-23 monoclonal antibody, is the first drug of a new class of biologic therapy approved for the treatment of moderate to severe plaque psoriasis. Data on the efficacy of ustekinumab in patients with moderate-to-severe Crohn's disease, especially in patients previously treated with infliximab, have been recently published. We report about the effectiveness of ustekinumab in the treatment of both severe scalp psoriasis lesions with alopecia and active Crohn's disease.

Achievement of sustained deep remission with adalimumab in a patient with both refractory ulcerative colitis and seronegative erosive rheumatoid arthritis.

Inflammatory bowel disease (IBD) is commonly associated with peripheral inflammatory arthritis, and it has been estimated that as many as 12% of IBD patients report these manifestations. However, rheumatoid arthritis (RA) is rarely associated with ulcerative colitis (UC). Among all the biological agents available, nine have been currently approved for the treatment of RA. Conversely, only Infliximab and recently Adalimumab have been approved for UC. In particular, the efficacy of Adalimumab in UC has been demonstrated by both recent randomized controlled trials and real-life studies. Moreover, Adalimumab is a well-established treatment for RA. Herein, we describe a patient with RA and UC treated successfully with ADA.

Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-α agents: effects of combined therapy with immunosuppressants.

BACKGROUND AND AIMS: Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-α alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. METHODS: 36 patients with Crohn's disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control (HC) subjects were enrolled. 47 patients were on anti TNF-α maintenance monotherapy and 15 on anti TNF-α combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI). Disease activity was monitored at T0 and T1. RESULTS: Seroprotective titers (≥1:40) in patients were comparable to HC. Seroconvertion rate (≥4 fold increase in HAI titer) was lower than HC in IBD patients (p=0.009), either on anti TNF-α monotherapy (p=0.034) or combined with IS (p=0.011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0.0017) and versus HC (p=0.011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0.042), and in those on combined immunosuppression, both versus monotherapy (p=0.0048) and HC (p=0.0015). None of the patients experienced a disease flare. CONCLUSION: Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.

Laser ablation single-collector inductively coupled plasma mass spectrometry for lead isotopic analysis to investigate evolution of the Bilbilis mint.

This work explores the performance of laser ablation-inductively coupled plasma mass spectrometry using different types of single-collector devices (sector field and time-of-flight instrumentation) for lead isotopic analysis of bronze coins, minted in the ancient city of Bilbilis. The aim of the study was achieving sufficient discrimination power to reveal similarities and differences for coins originating from different historical periods, and to obtain information on the possible source of the lead ores used in their production, while restricting the damage inflicted to the samples such that it is not visible to the naked eye. It was found that satisfactory results (RSD in the 0.15-0.30% range for (207)Pb/(206)Pb and (208)Pb/(206)Pb ratios) could be finally obtained, despite the noisy nature of signals generated upon ablation of the highly inhomogeneous coins, by means of a methodology based on: (a) selection of the line profiling ablation mode; (b) use of a dual pass spray chamber that permits the simultaneous introduction of a solution (containing thallium of known isotopic composition), thus resulting in a wet plasma that showed an increased robustness towards matrix effects and (c) detection using a TOF-ICPMS unit, which proved to be much better suited to deal with the transient signals obtained, while being also sufficiently sensitive to obtain good counting statistics, owing to the high lead level (average around 5%) present in the samples. Moreover, under these conditions, the simultaneous aspiration of the thallium spike permitted accurate correction for mass discrimination, such that it was not necessary to use external matrix-matched standards for calibration.

New biological agents for the treatment of the "high risk" IBD patients.

BACKGROUND: Several new biological drugs have been introduced in the last decade or are under investigation for the treatment of IBD. They include anti TNFalpha agents, anti adhesion molecules, anti IL-12/23, anti IL-6R and others. Their role in IBD therapy will be discussed in regard of the association of chronic inflammation and cancer in the gut. The risk of colorectal cancer is increased in ulcerative colitis (UC) and, to some extent, in Crohn's disease (CD). This association is well known from many years. However, the mechanisms linking chronic inflammation and carcinogenesis are beginning to be elucidated only recently. RESULTS AND CONCLUSIONS: Experimental data indicate that several cytokines could play a role in promoting tumour development. In this perspective, the anti cytokine agents could be not only powerful tools in treating inflammation but also efficacious in preventing the onset of inflammation associated colorectal cancer.