Publications by authors named "Rui Batista"

46 Publications

Balancing the reactogenicity of the ChAdOx1 nCov-19 vaccine against COVID-19 and the urgent need of a large immunization in healthcare workers.

Therapie 2021 Jul 27. Epub 2021 Jul 27.

Antimicrobial Stewardship Team, Cochin Hospital, AP-HP Centre, Université de Paris, 75014 Paris, France; Université de Paris, 75006 Paris, France; Institut Pasteur, Biology of Infection Unit, French National Reference Center and WHO Collaborating Center Listeria, Inserm U1117, 75014 Paris, France.

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http://dx.doi.org/10.1016/j.therap.2021.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314864PMC
July 2021

Asciminib and ponatinib combination in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Leuk Lymphoma 2021 Aug 18:1-4. Epub 2021 Aug 18.

Pharmacology Department, Saint-Louis Hospital, Assistance Publique-Hopitaux de Paris, Université de Paris, Paris, France.

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http://dx.doi.org/10.1080/10428194.2021.1966787DOI Listing
August 2021

Prevalence of drug-drug interactions in sarcoma patients: key role of the pharmacist integration for toxicity risk management.

Cancer Chemother Pharmacol 2021 Oct 24;88(4):741-751. Epub 2021 Jul 24.

Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France.

Background: The risk of drug-drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment.

Patients And Methods: We performed a retrospective review of consecutive sarcoma patients starting chemotherapy (CT) or Tyrosine kinase inhibitor (TKI). A pharmacist performed medication reconciliation and established an early toxicity risk assessment. Potential DDI with antitumor drugs were identified using Micromedex electronic software.

Results: One hundred and twenty-two soft-tissue and 80 bone sarcoma patients (103 males, median age 50 years,) were included before CT (86%) or TKI (14%). The median number of medications was 3; 34 patients (22% of patients with medication reconciliation) reported complementary medicine use. 37 potential DDI classified as major, were identified (12% of the 243 pre-therapeutic assessments). In multivariate analysis, TKI (p < 0.0001), proton pump inhibitor (p = 0.026) and antidepressant (p < 0.001) were identified as risk factors of DDI (p < 0.02). Only marital status (p = 0.003) was associated with complementary medicine use. A pharmacist performed 157 medication reconciliations and made 71 interventions among 59 patients (37%). In multivariate analysis, factors associated with pharmacist intervention were: complementary medicines (p = 0.004), drugs number (p = 0.005) and treatment with TKI (p = 0.0002) CONCLUSIONS: Clinical interventions on DDI are more frequently required among sarcoma patients treated with TKI than CT. Multidisciplinary risk assessment including a medication reconciliation by a pharmacist could be crucial to prevent DDI with TKI.
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http://dx.doi.org/10.1007/s00280-021-04311-4DOI Listing
October 2021

Inherited Thyroid Tumors With Oncocytic Change.

Front Endocrinol (Lausanne) 2021 9;12:691979. Epub 2021 Jun 9.

Cancer Signalling and Metabolism, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.

Familial non-medullary thyroid carcinoma (FNMTC) corresponds to 5-10% of all follicular cell-derived carcinoma (FCDTC). Oncocytic thyroid tumors have an increased incidence in the familial context in comparison with sporadic FCDTC, encompassing benign and malignant tumors in the same family presenting with some extent of cell oxyphilia. This has triggered the interest of our and other groups to clarify the oncocytic change, looking for genetic markers that could explain the emergence of this phenotype in thyroid benign and malignant lesions, focusing on familial aggregation. Despite some advances regarding the identification of the gene associated with retinoic and interferon-induced mortality 19 (GRIM-19), as one of the key candidate genes affected in the "Tumor with Cell Oxyphilia" (TCO) locus, most of the mutations follow a pattern of "private mutations", almost exclusive to one family. Moreover, no causative genetic alterations were identified so far in most families. The incomplete penetrance of the disease, the diverse benign and malignant phenotypes in the affected familial members and the variable syndromic associations create an additional layer of complexity for studying the genetic alterations in oncocytic tumors. In the present review, we summarized the available evidence supporting genomic-based mechanisms for the oncocytic change, particularly in the context of FNMTC. We have also addressed the challenges and gaps in the aforementioned mechanisms, as well as molecular clues that can explain, at least partially, the phenotype of oncocytic tumors and the respective clinico-pathological behavior. Finally, we pointed to areas of further investigation in the field of oncocytic (F)NMTC with translational potential in terms of therapy.
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http://dx.doi.org/10.3389/fendo.2021.691979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220141PMC
June 2021

Genetic Determinants for Prediction of Outcome of Patients with Papillary Thyroid Carcinoma.

Cancers (Basel) 2021 Apr 23;13(9). Epub 2021 Apr 23.

IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 Porto, Portugal.

Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002-2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTp showed increased risk of structural disease (HR = 7.0, < 0.001) and DSM (HR = 10.1, = 0.001). Combined genotypes, BRAF/TERTp (HR = 6.8, = 0.003), BRAF/TERTp (HR = 3.2, = 0.056) and BRAF/TERTp (HR = 2.2, = 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAF/TERTp (HR = 24.2, < 0.001) and BRAF/TERTp (HR = 11.5, = 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTp regardless of BRAF status (BRAF/TERTp, log-rank < 0.001; BRAF/TERTp, log-rank < 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients' outcome. BRAF/TERTp tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTp tumors were predisposed to recurrent structural disease and DSM.
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http://dx.doi.org/10.3390/cancers13092048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122921PMC
April 2021

Access and use of quinacrine (mepacrine) in the treatment of resistant giardiasis.

Infect Dis Now 2021 Mar 24. Epub 2021 Mar 24.

Pharmacy Department, Cochin Hospital, AP-HP, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.idnow.2021.03.006DOI Listing
March 2021

Analyzing the Role of DICER1 Germline Variations in Papillary Thyroid Carcinoma.

Eur Thyroid J 2021 Feb 6;9(6):296-303. Epub 2020 Aug 6.

Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal.

Introduction: DICER1 is a member of RNase III family that has a pivotal role in the biogenesis of microRNAs, being important for normal development. Dysregulation of DICER1 has been described in different human tumours; however, there is insufficient data on the risk of thyroid cancer in the presence of germline DICER1 variants, particularly when focusing on the background of papillary thyroid carcinoma (PTC). For this purpose, we ascertained the presence of DICER1 variants in 502 (PTC) cases available from The Cancer Genome Atlas (TCGA) research network in a well-characterized pathological context.

Material And Methods: in this study we analyzed 502 samples from 502 patients, described as PTC in the TCGA database. Tumour diagnoses were re-evaluated by 2 pathologists (S.C. and M.S.-S.) on slides available from the database, and clinicopathological and demographic data was examined. Data concerning germline and sporadic DICER1 gene variants as well as frequent mutations in the genes involved in thyroid carcinogenesis (e.g., and V600E) was retrieved from the database.

Results And Discussion: We report 1 new germline possibly pathogenic variant, besides 15 others already been identified in ClinVar. We found that the DICER1-positive PTC group more frequently includes PTC variants, namely the oncocytic, follicular, and aggressive (hobnail variant of PTC) variants. A previous association of DICER1 had been demonstrated, mainly with the follicular variant of PTC and follicular thyroid carcinomas. Tumours harbouring germline DICER1 mutations were more frequently "bilateral" and "encapsulated." The frequent association of DICER1 germline variants with other mutations associated with thyroid cancer can reflect an haploinsufficiency tumour suppressor gene function of DICER1, as suggested from the study of animal models.
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http://dx.doi.org/10.1159/000509183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923931PMC
February 2021

Robotic chemotherapy compounding: A multicenter productivity approach.

J Oncol Pharm Pract 2021 Feb 11:1078155221992841. Epub 2021 Feb 11.

Pharmacy Department, Fundación Onkologikoa Fundazioa, Donostia-San Sebastián, Gipuzkoa, Spain.

Introduction: The aim of this study is to compare productivity of the KIRO Oncology compounding robot in three hospital pharmacy departments and identify the key factors to predict and optimize automatic compounding time.

Methods: The study was conducted in three hospitals. Each hospital compounding workload and workflow were analyzed. Data from the robotic compounding cycles from August 2017 to July 2018 were retrospectively obtained. Nine cycle specific parameters and five productivity indicators were analysed in each site. One-to-one differences between hospitals were evaluated. Next, a correlation analysis between cycle specific factors and productivity indicators was conducted; the factors presenting a highest correlation to automatic compounding time were used to develop a multiple regression model (afterwards validated) to predict the automatic compounding time.

Results: A total of 2795 cycles (16367 preparations) were analysed. Automatic compounding time showed a relevant positive correlation (ǀr|>0.40) with the number of preparations, number of vials and total volume per cycle. Therefore, these cycle specific parameters were chosen as independent variables for the mathematical model. Considering cycles lasting 40 minutes or less, predictability of the model was high for all three hospitals (R:0.81; 0.79; 0.72).

Conclusion: Workflow differences have a remarkable incidence in the global productivity of the automated process. Total volume dosed for all preparations in a cycle is one of the variables with greater influence in automatic compounding time. Algorithms to predict automatic compounding time can be useful to help users in order to plan the cycles launched in KIRO Oncology.
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http://dx.doi.org/10.1177/1078155221992841DOI Listing
February 2021

Plasma Concentrations and Safety of Lopinavir/Ritonavir in COVID-19 Patients.

Ther Drug Monit 2021 02;43(1):131-135

Pharmacology Department, Cochin Hospital, AP-HP Centre-Université de Paris.

Background: Although the efficacy of lopinavir/ritonavir has not been proven, it has been proposed as an off-label treatment for COVID-19. Previously, it has been reported that the plasma concentrations of lopinavir significantly increase in inflammatory settings. As COVID-19 may be associated with major inflammation, assessing the plasma concentrations and safety of lopinavir in COVID-19 patients is essential.

Methods: Real-world COVID-19 data based on a retrospective study.

Results: Among the 31 COVID-19 patients treated with lopinavir/ritonavir between March 18, 2020 and April 1, 2020, higher lopinavir plasma concentrations were observed, which increased by 4.6-fold (interquartile range: 3.6-6.2), compared with the average plasma concentrations in HIV. Lopinavir concentrations in all except one patient were above the upper limit of the concentration range of HIV treatment. Approximately one to 5 patients prematurely stopped treatment mainly because of an ADR related to hepatic or gastrointestinal disorders.

Conclusions: Lopinavir plasma concentrations in patients with moderate-to-severe COVID-19 were higher than expected, and they were associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, a high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2, as suggested by previous studies. Therefore, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Caution is essential because off-label use can be associated with a new drug safety profile.
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http://dx.doi.org/10.1097/FTD.0000000000000838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808275PMC
February 2021

Clinical Validation of a Urine Test (Uromonitor-V2) for the Surveillance of Non-Muscle-Invasive Bladder Cancer Patients.

Diagnostics (Basel) 2020 Sep 24;10(10). Epub 2020 Sep 24.

i3S-Instituto de Investigação e Inovação em Saúde, R. Alfredo Allen 208, 4200-135 Porto; Portugal.

The costly and burdensome nature of the current follow-up methods in non-muscle-invasive bladder cancer (NMIBC) drives the development of new methods that may alternate with regular cystoscopy and urine cytology. The Uromonitor-V2 is a new urine-based assay in the detection of hotspot mutations in three genes (, , and ) for evaluation of disease recurrence. The aim of this study was to investigate the Uromonitor-V2's performance in detecting NMIBC recurrence and compare it with urine cytology. From February 2018 to September 2019 patients were enrolled. All subjects underwent a standard-of-care (SOC) cystoscopy, either as part of their follow-up for NMIBC or for a nonmalignant urological pathology. Urine cytology was performed in NMIBC patients. Out of the 105 patients enrolled, 97 were eligible for the study. Twenty patients presented nonmalignant lesions, 29 had a history of NMIBC with disease recurrence, and 49 had a history of NMIBC without recurrence. In NMIBC, the Uromonitor-V2 displayed a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 93.1%, 85.4%, 79.4%, and 95.3%, respectively. Urine cytology was available for 52 patients, and the sensitivity, specificity, PPV, and NPV were 26.3%, 90.9%, 62.5%, and 68.2%, respectively. With its high NPV of 95.3%, the Uromonitor-V2 revealed promising properties for the follow-up of patients with NMIBC.
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http://dx.doi.org/10.3390/diagnostics10100745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599569PMC
September 2020

Comprehensive Assessment of mRNA Expression across a Large Cohort of Benign and Malignant Thyroid Tumours.

Cancers (Basel) 2020 Jul 9;12(7). Epub 2020 Jul 9.

Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal.

The presence of promoter (p) mutations in thyroid cancer have been associated with worse prognosis features, whereas the extent and meaning of the expression and activation of in thyroid tumours is still largely unknown. We analysed frozen samples from a series of benign and malignant thyroid tumours, displaying non-aggressive features and low mutational burden in order to evaluate the presence of p mutations and mRNA expression in these settings. In this series, p mutations were found in 2%, only in malignant cases, in larger cancers, and from older patients. mRNA expression was detected in both benign and malignant tumours, with increased frequencies in the malignant tumours with aggressive histotypes, larger tumours, and from older patients. In benign tumours, mRNA expression was found in 17% of the follicular thyroid adenoma (FTA) with increased levels of expression in smaller tumours and associated with the presence of thyroiditis. p mutations and mRNA expression are correlated with worse prognosis features in malignant thyroid tumours, whereas mRNA expression in the benign tumours is associated with the presence of thyroiditis.
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http://dx.doi.org/10.3390/cancers12071846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408963PMC
July 2020

Prognostic Significance of RAS Mutations and P53 Expression in Cutaneous Squamous Cell Carcinomas.

Genes (Basel) 2020 07 6;11(7). Epub 2020 Jul 6.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal.

is considered the most commonly-altered gene in cutaneous squamous cell carcinoma (cSCC). Conversely, mutations have been reported in a low percentage of cSCC. The objective of our study was to evaluate the frequency of p53 expression and mutations in cSCC and correlate them with clinicopathological features and patient outcome. We performed immunohistochemistry for p53 and genetic profiling for mutations in a retrospective series of cSCC. The predictive value of p53 expression, mutations, and clinicopathological parameters was assessed using logistic regression models. The overall frequency of mutations was 9.3% (15/162), and 82.1% of the cases (133/162) had p53 overexpression. mutations rate was 3.2% (1/31) of in situ cSCCs and 10.7% (14/131) of invasive cSCCs. mutations were more frequently associated with an infiltrative than an expansive pattern of invasion ( = 0.046). p53 overexpression was a predictor of recurrence in the univariate analysis. Our results indicate that mutations associate with features of local aggressiveness. Larger studies with more recurrent and metastatic cSCCs are necessary to further address the prognostic significance of p53 overexpression in patients' risk stratification.
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http://dx.doi.org/10.3390/genes11070751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397334PMC
July 2020

Promoter Mutation as a Potential Predictive Biomarker in BCG-Treated Bladder Cancer Patients.

Int J Mol Sci 2020 Jan 31;21(3). Epub 2020 Jan 31.

Instituto de Investigação e Inovação em Saúde (i3S), 4200-135 Porto, Portugal.

Telomerase reverse transcriptase gene promoter () mutations are recognized as one of the most frequent genetic events in bladder cancer (BC). No studies have focused on the relevance of TERTp mutations in the specific group of tumors treated with Bacillus Calmette-Guérin (BCG) intravesical therapy. Methods - 125 non muscle invasive BC treated with BCG therapy (BCG-NMIBC) were screened for mutations, rs2853669 single nucleotide polymorphism, and Fibroblast Growth Factor Receptor 3 () hotspot mutations. Results - mutations were found in 56.0% of BCG-NMIBC and were not associated with tumor stage or grade. mutations were found in 44.9% of the cases and were not associated with tumor stage or grade nor with mutations. The rs2853669 single nucleotide polymorphism was associated with tumors of higher grade. The specific c.1-146G>A mutation was an independent predictor of nonrecurrence after BCG therapy (hazard ratio-0.382; 95% confidence interval-0.150-0.971, = 0.048). Conclusions - mutations are frequent in BCG-NMIBC and -146G>A appears to be an independent predictive marker of response to BCG treatment with an impact in recurrence-free survival.
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http://dx.doi.org/10.3390/ijms21030947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037401PMC
January 2020

Biomarkers for Bladder Cancer Diagnosis and Surveillance: A Comprehensive Review.

Diagnostics (Basel) 2020 Jan 13;10(1). Epub 2020 Jan 13.

i3S-Instituto de Investigação e Inovação em Saúde, 4200-135 Porto, Portugal.

Bladder cancer (BC) ranks as the sixth most prevalent cancer in the world, with a steady rise in its incidence and prevalence, and is accompanied by a high morbidity and mortality. BC is a complex disease with several molecular and pathological pathways, thus reflecting different behaviors depending on the clinical staging of the tumor and molecular type. Diagnosis and monitoring of BC is mainly performed by invasive tests, namely periodic cystoscopies; this procedure, although a reliable method, is highly uncomfortable for the patient and it is not exempt of comorbidities. Currently, there is no formal indication for the use of molecular biomarkers in clinical practice, even though there are several tests available. There is an imperative need for a clinical non-invasive testing for early detection, disease monitoring, and treatment response in BC. In this review, we aim to assess and compare different tests based on molecular biomarkers and evaluate their potential role as new molecules for bladder cancer diagnosis, follow-up, and treatment response monitoring.
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http://dx.doi.org/10.3390/diagnostics10010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169395PMC
January 2020

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study.

Front Genet 2019 18;10:1237. Epub 2019 Dec 18.

Department of Urology, Hospital de Mérida, Badajoz, Spain.

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70-75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. promoter mutations and hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor, capable of detecting trace amounts of promoter (c.1-124C > T and c.1-146C > T) and (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.
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http://dx.doi.org/10.3389/fgene.2019.01237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930177PMC
December 2019

Qualification of a chemotherapy-compounding robot.

J Oncol Pharm Pract 2020 Mar 18;26(2):312-324. Epub 2019 Apr 18.

Service de Pharmacie clinique, Hôpitaux Universitaires Paris Centre, Assistance Publique - Hôpitaux de Paris, Paris, France.

KIRO® Oncology (Kiro Grifols, Spain) is a robotic system for automated compounding of sterile injectable drugs including intravenous cytotoxic treatments. The present article describes the qualification procedure applied prior to production phases. Peristaltic pumps which ensure the reconstitution of drugs were tested with water and NaCl 0.9%. The performance of the robot (accuracy and precision) to prepare bags, syringes and elastomeric pumps was evaluated with three placebo solutions (aqueous, foaming and viscous) using gravimetric controls. Microbiological controls were also performed. The pumps met the requirements set for volumes ranging from 5 to 100 mL. A total of 274 preparations was compounded. For the bags, the filling accuracy was within the limit of ±10% from 1 to 48 mL with aqueous solution, from 0.6 to 48 mL with foaming solution and from 5 to 48 mL with viscous solution. For all syringes and elastomeric pumps, it was within the limit of ±10%. The precision was validated for all preparations, except for bags and syringes prepared with 0.6 and 0.25 mL, respectively. The samples of surfaces and air complied with ISO 5 class environment. Among the 24 gloves tests performed, two presented microbiological growth. All Media fill tests were validated. The qualification procedure led us to exclude injections of any active principle volume strictly lower than 1 mL. The microbiological contamination of operators' gloves remains a critical point. Our operators will be made aware of the issue during the training period.
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http://dx.doi.org/10.1177/1078155219843322DOI Listing
March 2020

Fifty shades of graft: How to improve the efficacy of faecal microbiota transplantation for decolonization of antibiotic-resistant bacteria.

Int J Antimicrob Agents 2019 May 14;53(5):553-556. Epub 2019 Mar 14.

Vedanta Biosciences Inc., Cambridge, MA, USA.

Background: Spontaneous decolonization of antibiotic-resistant bacteria (ARB) takes time: approximately 25% after 30 days for carbapenem-producing Enterobacteriaceae or extended-spectrum beta-lactamase-producing Enterobacteriaceae. Faecal microbiota transplantation (FMT) has been proposed as a new strategy to promote decolonization in order to reduce the risk of superinfection due to these ARB. This paper discusses the literature on the use of FMT for this indication, and the improvement levers available to promote its efficacy.

Methods: Literature available to date concerning the use of FMT to eradicate ARB was reviewed, and the different factors that may have influenced the efficacy of decolonization were evaluated.

Results: Four axes that could have played major roles in the efficacy of FMT were identified: bowel preparation before FMT; donor; dose; and thermal conditioning of faeces. The positive or negative impact of each on the outcome of FMT is discussed.

Conclusion: Although FMT is very efficient for the eradication of Clostridium difficile, the same 'recipe' cannot be used for the eradication of ARB. Working together with expert centres may help to improve the efficacy of FMT for this indication, and enable the reduction of in-hospital isolation precautions.
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http://dx.doi.org/10.1016/j.ijantimicag.2019.03.008DOI Listing
May 2019

Incidence of grade 3-4 liver injury under immune checkpoints inhibitors: A retrospective study.

J Hepatol 2018 12 3;69(6):1396-1397. Epub 2018 Oct 3.

Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Cochin, Hepatology Service, France; Institut Pasteur, Inserm, Unité 1223, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2018.08.014DOI Listing
December 2018

TERT promoter mutations are associated with poor prognosis in cutaneous squamous cell carcinoma.

J Am Acad Dermatol 2019 Mar 28;80(3):660-669.e6. Epub 2018 Aug 28.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal; Medical Faculty, University of Porto, Porto, Portugal. Electronic address:

Background: Telomerase reverse transcriptase gene (TERT) promoter (TERTp) mutations have been reported as potential predictors of poor prognosis in several cancers, but the prognostic value of TERTp mutations for cutaneous squamous cell carcinoma (cSCC) has not been determined.

Objective: To evaluate the frequency of TERTp mutations and correlate it with clinicopathologic features and patient outcome.

Methods: We performed genetic profiling of TERTp mutations in a retrospective series of cSCCs. The predictive value of TERTp mutations and clinicopathologic parameters were assessed by using logistic regression models.

Results: A total of 152 cSCCs from 122 patients were analyzed for TERTp mutations; the mutation rate was 31.6% (48 of 152), and it was higher in invasive cSCC (42 of 121 [34.7%]) than in in situ cSCC (6 of 31 [19.4%]). Age older than 75 years (odds ratio [OR], 14.84; P = .013] and TERTp mutation (OR, 8.11; P = .002) were independent predictors of local recurrence. TERTp mutation (OR, 15.89; P = .022) was independently associated with higher risk of lymph node metastasis.

Limitations: The restricted number of metastatic cases.

Conclusion: TERTp mutations may prove to be a molecular biomarker with prognostic significance in invasive cSCC, but larger studies are needed.
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http://dx.doi.org/10.1016/j.jaad.2018.08.032DOI Listing
March 2019

mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and mRNA Expression.

Int J Mol Sci 2018 May 13;19(5). Epub 2018 May 13.

Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto 4099-002, Portugal.

The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase mRNA levels, whereas Torin2 caused a ~6 fold increase in mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho-AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of mRNA expression.
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http://dx.doi.org/10.3390/ijms19051448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983778PMC
May 2018

Multinodular Goiter Progression Toward Malignancy in a Case of DICER1 Syndrome: Histologic and Molecular Alterations.

Am J Clin Pathol 2018 Mar;149(5):379-386

Department of Pathology Pediatric Department, Centro Hospitalar São João, Porto, Portugal.

Objectives: Multinodular goiter (MNG) and well-differentiated thyroid carcinoma (WDTC) are emerging phenotypes of DICER1 syndrome.

Methods: Histologic and molecular findings of botryoid-type embryonal rhabdomyosarcoma (bERMS) and thyroid nodules from a 12-year-old DICER1 mutation carrier (p.Arg1060Ilefs*7) were investigated, providing interesting clues for understanding thyroid carcinogenesis.

Results: The patient had bERMS at age 7 years. The thyroid was enlarged and multinodular (61 g). Histologically, some nodules were classified as adenomatous and others as tumors with "intermediate" nuclei. One displayed vascular invasion and was classified as WDTC not otherwise specified (NOS). Somatic DICER1 mutations were identified in bERMS, two tumors with "intermediate" nuclei and WDTC. No somatic DICER1 mutations were found in adenomatous nodules. No molecular alterations were detected in BRAF600, NRAS61, HRAS12/61, KRAS12/61, TERT promoter, RET/PTC1, RET/PTC3, and PAX8/PPARγ.

Conclusions: The findings obtained from this single case support the assumption that DICER1 syndrome-related WDTC NOS may develop on a background of MNG, via a stepwise process, involving DICER1 somatic mutations and additional molecular events, distinct from the classic pathways of papillary/follicular carcinoma.
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http://dx.doi.org/10.1093/ajcp/aqy004DOI Listing
March 2018

NIS expression in thyroid tumors, relation with prognosis clinicopathological and molecular features.

Endocr Connect 2018 Jan;7(1):78-90

Instituto de Investigação e Inovação em Saúde (i3S)Porto, Portugal

Thyroid cancer therapy is based on surgery followed by radioiodine treatment. The incorporation of radioiodine by cancer cells is mediated by sodium iodide symporter (NIS) (codified by the gene), that is functional only when targeted to the cell membrane. We aimed to evaluate if NIS expression in thyroid primary tumors would be helpful in predicting tumor behavior, response to therapy and prognosis. NIS expression was addressed by qPCR and immunohistochemistry. In order to validate our data, we also studied expression on 378 primary papillary thyroid carcinomas from The Cancer Genome Atlas (TCGA) database. In our series, expression was lower in carcinomas with vascular invasion and with extrathyroidal extension and in those harboring V600E mutation. Analysis of expression from TCGA database confirmed our results. Furthermore, it showed that larger tumors, with locoregional recurrences and/or distant metastases or harboring , and/or promoter (p) mutations presented significantly less expression. Regarding immunohistochemistry, 12/211 of the cases demonstrated NIS in the membrane of tumor cells, those cases showed variable outcomes concerning therapy success, prognosis and all but one were wild type for , and p mutations. mRNA lower expression is associated with features of aggressiveness and with key genetic alterations involving , and p. Mutations in these genes seem to decrease protein expression and its targeting to the cell membrane. mRNA expression is more informative than NIS immunohistochemical expression regarding tumor aggressiveness and prognostic features.
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http://dx.doi.org/10.1530/EC-17-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754505PMC
January 2018

Impact of Fecal Microbiota Transplantation for Decolonization of Multidrug-Resistant Organisms May Vary According to Donor Microbiota.

Clin Infect Dis 2018 04;66(8):1316-1317

Maladies Infectieuses, Hôpital Raymond-Poincaré, Assistance Publique-Hôpitaux de Paris (AP-HP), Garches, France.

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http://dx.doi.org/10.1093/cid/cix963DOI Listing
April 2018

Inhibitory Effects of Antagonists of Growth Hormone-Releasing Hormone (GHRH) in Thyroid Cancer.

Horm Cancer 2017 12 18;8(5-6):314-324. Epub 2017 Sep 18.

Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal.

Growth hormone-releasing hormone (GHRH) is a peptide hormone secreted by the hypothalamus that regulates the synthesis and secretion of growth hormone (GH) in the pituitary. The extra-hypothalamic GHRH and its cognate receptors (GHRHR and splice variants) play a mitogenic role by stimulating cell proliferation and preventing apoptotic cell death. It is well established that GHRH antagonists inhibit the growth, tumorigenicity, and metastasis of various human malignancies. In this work, we studied the effect of two new GHRH antagonists, MIA602 and MIA690, on thyroid cancer. We studied the effect of MIA602 and MIA690 on thyroid cancer in vitro, using human thyroid cancer cell lines, and in vivo, using chicken embryo chorioallantoic membrane (CAM) assays. We found that mRNA for GHRH and GHRH receptor is expressed in thyroid cell lines and in samples of thyroid tumors. Immunohistochemistry confirmed the expression of GHRHR protein in specimens of thyroid tumor. We observed that GHRH antagonists inhibited the growth and increased apoptosis of thyroid cancer cells. In vivo, the antagonists inhibited growth and angiogenesis of engrafted thyroid tumors. Our results suggest that GHRH expression may play a role in growth of thyroid cancer and that GHRH antagonists can be a therapeutic option for thyroid cancer patients.
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http://dx.doi.org/10.1007/s12672-017-0307-4DOI Listing
December 2017

Etiopathogenesis of oncocytomas.

Semin Cancer Biol 2017 12 4;47:82-94. Epub 2017 Jul 4.

Cancer Signalling and Metabolism Research Group, Instituto de Investigação e Inovação em Saúde - i3S (Institute for Research and Innovation in Health), University of Porto, Porto, Portugal; Cancer Signalling and Metabolism Research Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal; Department of Pathology, Faculdade de Medicina da Universidade do Porto - FMUP (Medical Faculty of University of Porto), Porto, Portugal. Electronic address:

Oncocytomas are distinct tumors characterized by an abnormal accumulation of defective and (most probably) dysfunctional mitochondria in cell cytoplasm of such tumors. This particular phenotype has been studied for the last decades and the clarification of the etiopathogenic causes are still needed. Several mechanisms involved in the formation and maintenance of oncocytomas are accepted as reasonable causes, but the relevance and contribution of each one for oncocytic transformation may depend on different cancer etiopathogenic contexts. In this review, we describe the current knowledge of the etiopathogenic events that may lead to oncocytic transformation and discuss their contribution for tumor progression and mitochondrial accumulation.
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http://dx.doi.org/10.1016/j.semcancer.2017.06.014DOI Listing
December 2017

SDHD promoter mutations are rare events in cutaneous melanomas but SDHD protein expression is downregulated in advanced cutaneous melanoma.

PLoS One 2017 29;12(6):e0180392. Epub 2017 Jun 29.

Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal.

Background: SDHD promoter mutations were reported in 4-10% of cutaneous melanomas. The advanced clinico-pathological and patient survival association with SDHD mutation and/or expression in cutaneous melanoma remains controversial.

Objectives: To evaluate the presence of SDHD promoter mutations and SDHD protein expression in a melanoma series and its possible association with prognosis and survival of the patients.

Methods: We assessed SDHD promoter status in cutaneous melanomas (CM), ocular melanomas (OM) and melanoma cell lines, and the expression of SDHD protein by immunohistochemistry in CM and OM, and by western blot in melanoma cell lines. We explored the putative association between SDHD protein expression and clinico-pathological and prognostic parameters of melanoma.

Results: We detected 2% of SDHD promoter mutations in CM, but none in OM and cell lines. SDHD protein expression was present in all CM, in OM and in all CM and OM derived cell lines analysed. A significant association between lower SDHD mean protein expression and presence of ulceration and higher pT stage was found.

Conclusions: SDHD promoter mutation seems to be a rare event in CM but SDHD lower expression might associate with worst prognostic features in CM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180392PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491217PMC
October 2017

Impact of faecal microbiota transplantation to eradicate vancomycin-resistant enterococci (VRE) colonization in humans.

J Infect 2017 10 7;75(4):376-377. Epub 2017 Jun 7.

Infectious Diseases Unit, Raymond Poincaré Teaching Hospital, APHP, Versailles Saint-Quentin University, Garches, France.

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http://dx.doi.org/10.1016/j.jinf.2017.06.001DOI Listing
October 2017

Methods and Reporting Studies Assessing Fecal Microbiota Transplantation: A Systematic Review.

Ann Intern Med 2017 Jul 23;167(1):34-39. Epub 2017 May 23.

From INSERM U1153, Assistance Publique-Hôpitaux de Paris, Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes-Sorbonne Paris Cité, French Cochrane Centre, and Hôpital Cochin, Paris, France, and Mailman School of Public Health, Columbia University, New York, New York.

Background: Fecal microbiota transplantation (FMT) could be a novel treatment option for several chronic diseases associated with altered gut microbiota.

Purpose: To examine the conduct and reporting of studies assessing FMT.

Data Sources: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science from inception to 31 January 2017.

Study Selection: Two reviewers independently examined titles and abstracts to identify all English-language reports of human clinical studies assessing the safety or efficacy of FMT.

Data Extraction: Three reviewers independently assessed study types and characteristics and the reporting of important methodological components of the FMT intervention.

Data Synthesis: Most (84%) of the 85 published reports found addressed the use of FMTs for Clostridium difficile infection or inflammatory bowel disease, and most (87%) were non-randomized controlled trials. Important methodological components that were not reported in published studies included the following: eligibility criteria for donors (47%), materials used for collecting stools and the period of collection (96%), methods used for conservation of stools (76%), the amount and type of stools used (for example, fresh or frozen), and duration of stool conservation (67%). Many (58%) did not report an analysis of microbiota composition.

Limitations: Lack of universal consensus regarding the most important methodological components of FMT and inability to assess the actual conduct of studies and whether the publication process affected the completeness of reporting.

Conclusion: Key components of FMT interventions, which are necessary to replicate and understand study findings about efficacy and safety, are poorly reported.

Primary Funding Source: No specific funding.
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http://dx.doi.org/10.7326/M16-2810DOI Listing
July 2017

Validation of self - confidence scale for clean urinary intermittent self - catheterization for patients and health - caregivers.

Int Braz J Urol 2017 May-Jun;43(3):505-511

Divisão de Urologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo- USP - Ribeirão Preto,SP, Brasil.

Objective: To validate a measurement instrument for clean intermittent self-catheterization for patients and health-caregivers.

Material And Methods: Methodological study of instrument validation performed at a Rehabilitation Center in a University hospital for patients submitted to clean intermittent self-catheterization and their health-caregivers. Following ethical criteria, data were collected during interview with nurse staff using a Likert question form containing 16 items with 5 points each: "no confidence"=1, "little confidence"=2, "confident"=3, "very confident"=4 and "completely confident"=5. Questionnaire called "Self- Confident Scale for Clean Intermittent Self-catheterization" (SCSCISC) was constructed based on literature and previously validated (appearance and content).

Results: The instrument was validated by 122 patients and 119 health-caregivers, in a proportion of 15:1. It was observed a good linear association and sample adequacy KMO 0.931 and X2=2881.63, p<0.001. Anti-image matrix showed high values at diagonal suggesting inclusion of all factors. Screen plot analysis showed a suggestion of items maintenance in a single set. It was observed high correlation of all items with the total, alpha-Cronbach 0.944. The same results were obtained in subsamples of patients and health-caregivers.

Conclusion: The instrument showed good psychometric adequacy corroborating its use for evaluation of self-confidence during clean intermittent self-catheterization.
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http://dx.doi.org/10.1590/S1677-5538.IBJU.2015.0468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462142PMC
October 2017

TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease.

J Clin Endocrinol Metab 2017 06;102(6):1898-1907

i3S Instituto de Investigação e Inovação em Saúde, Porto 4200-135, Portugal.

Context: Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype.

Objectives: To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases.

Design And Patients: Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue.

Results: We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations.

Conclusions: When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.
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http://dx.doi.org/10.1210/jc.2016-2785DOI Listing
June 2017
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