Background: Use of inappropriate amikacin dose is one of the most important factors in inducing toxicity, prolonged hospitalization as well as in increasing patient’s mortality. Objective: The aims of this study are ...Background: Use of inappropriate amikacin dose is one of the most important factors in inducing toxicity, prolonged hospitalization as well as in increasing patient’s mortality. Objective: The aims of this study are the analysis of amikacin dose, serum level and the examination of the effectiveness of the clinical pharmacologist (CP) therapeutic drug monitoring (TDM) intervention to guarantee the safety of amikacin use. Methods: This is a one-year retrospective observational chart review study, which evaluates amikacin dose, serum drug level, development of adverse effects in patients on amikacin with or without CP TDM consultation. Results: Amikacin was prescribed for 393 complex patients, with median age 83. Amikacin group (AG) included 140 (32%) courses with CP consultation (AG1) and 292 (68%) courses without CP consultation (AG2). The distribution of most study characteristics in both groups was similar including amikacin dose (9-10 mg/kg/day), renal failure (14%) and mortality (12%). Acceptance for CP consultation was in 46% of amikacin courses and dose changes were done in 63% after CP intervention. Prolonged antibiotic course (4.6 ± 1.5 vs 3.8 ± 1.6 days, p < 0.0001) and the patient’s hemodynamic instability (15% vs 7%, p = 0.01) were more frequent in the AG1 compared to the AG2. There was a strong association between CP consultation and prolonged hospitalization (p = 0.005), while no association between it and amikacin adverse effects, renal failure or mortality. Conclusions: There was no trend to reducing amikacin toxicity, days of hospitaliza tion or mortality in patients with CP consultation. CP TDM intervention was more in the management of complicated clinical situations. However, it is necessary to optimize it.展开更多
Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this procedure.This meta-analysis aim...Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this procedure.This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC(i.e.,RAS,BRAF,SMAD4,PIK3CA)as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection.Methods:A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM,stratified according to RAS,BRAF,PIK3CA,and SMAD4 mutational status.Hazard ratios(HRs)from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined.The search was conducted in numerous databases,including MEDLINE(PubMed),Embase,Cumulative Index to Nursing and Allied Health Literature(CINAHL)(EBSCO host),and WHO Global Index Medicus,through March 18th,2022.Meta-analyses,editorials,letters to the editor,case reports,studies on other primary cancers,studies with primary metastatic sites other than the liver,studies lacking specific oncological outcome variables or genetic data,non-English language studies,and studies omitting residual disease data from liver metastasectomy were excluded.The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented.Results:RAS mutation status was negatively associated with overall survival(OS)(HR,1.68;95%CI,1.54–1.84)and recurrence free survival(RFS)(HR,1.46;95%CI,1.33–1.61).A negative association was also found for BRAF regarding OS(HR,2.64;95%CI,2.15–3.24)and RFS(HR,1.89;95%CI,1.32–2.73)and SMAD4 regarding OS(HR,1.93;95%CI,1.56–2.38)and RFS(HR,1.95;95%CI,1.31–2.91).For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted.Conclusion:RAS,BRAF,and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer.No conclusion can be drawn for PIK3CA due to the limited literature availability.These data support the integration of RAS,BRAF,and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis.Nevertheless,we have to consider several limitations,the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival(DFS)or RFS;the inclusion of patients with minimal residual disease and unconsidered potential confounding factors,such as variability in resectability definitions,chemotherapy use,and a potential interaction between biological markers and pre-and post-resection pharmacological treatments.展开更多
Context: The appointment of the M6 is crucial because it is an indicator of the prognosis of the evolution of the care and the decision-making on the continuation of the AntiRetroViral Treatment. Objective: The object...Context: The appointment of the M6 is crucial because it is an indicator of the prognosis of the evolution of the care and the decision-making on the continuation of the AntiRetroViral Treatment. Objective: The objective of this study is therefore to present the virological and molecular profile of People Living with HIV under treatment with Dolutegravir 6 months after being put on ART in Kinshasa. Methods: The present study is a cross-sectional view at the sixth month of a prospective cohort to determine the virological and molecular profile of People Living with HIV (PLHIV) after 6 months of ART based on Dolutegravir (DTG) in Kinshasa. A sample of 5 mL of blood was taken from all HIV patients included. The collection of biological data was carried out under the same conditions as at inclusion. After extraction, Quantitative Real-Time PCR was carried out to determine the quantity of HIV RNA in the samples according to the protocols previously described. Reverse Transcription PCR (RT-PCR) and Nested PCR were carried out to amplify the regions of interest for Protease and Reverse Transcriptase for sequencing. Results: The median VL value was 2.92 log<sub>10</sub> RNA copies/mL. With 17.75% of patients experiencing major failure of first-line treatment. Subtype A is dominant with 13 cases (20.98%);followed by CRF_02AG (16.13%), subtypes C (14.52%), D (9.68%) and K (6.45%). The K65R (3 cases), T69P/N (6 cases), K70R (9 cases) and M184V (8 cases) mutations were listed as existing mutations for Nucleotide Reverse Transcriptase Inhibitors. Conclusion: After 6 months of ART, 59.67% of People Living with HIV on Tenofovir-Lamivudine-Dolutegravir is in therapeutic success while 40.33% are in a state of treatment failure. Subtype A remains dominant in the population of PLHIV. Resistance mutations were detected for Lamivudine and Tenofovir, but none for Dolutegravir.展开更多
Background: For several decades, the introduction of AntiRetrovirals (ARVs) has improved the symptomatology of People Living with HIV (PLHIV), a spectacular reduction in morbidity and mortality, an improvement in life...Background: For several decades, the introduction of AntiRetrovirals (ARVs) has improved the symptomatology of People Living with HIV (PLHIV), a spectacular reduction in morbidity and mortality, an improvement in life expectancy and quality of life of PLHIV. Objective: The objective of this study was to determine the profile of PLHIV initiating AntiRetroViral Treatment (ART) in the era of Dolutegravir in Kinshasa. Methods: Cross-section of a prospective cohort to determine the profile of PLHIV initiating ART in Kinshasa. The inclusions were from October 04, 2021 to February 15, 2022. Confirmation of the diagnosis was carried out by Nested PCR. The inclusion criteria were: being at least 18 years old, confirmed HIV positive, naïve to ART, consenting and having signed an informed consent. The parameters of interest followed for the present study were: age, sex, religion, level of study, marital status, occupation, height, weight, body mass index (BMI), the clinical profile, the opportunistic infections as well as the para-clinical assessment (biochemistry and molecular biology). Results: 67 (56.3%) women and 52 (43.7%) men were included, thus 119 patients, all confirmed positive for HIV by Nested PCR on the gag, pol and env regions. The average age of the patients included is 39.87 ± 12.36 years and the most represented age group is that of 36 to 45 years with 37 patients (31.9%). The average height was 1.66 ± 0.08 meters, with an average weight of 56.41 ± 13.30 kg, giving an average Body Mass Index (BMI) of 21.54 ± 5.17 kg/m<sup>2</sup>. The majority of patients were married (46.1%), of Protestant religion (70.7%), with secondary education (66.7%), and working in the informal sector (29.4%). 49 patients (41.5%) were in clinical stage 3 and 55 patients (47.0%) had a normal clinical status. Malaria (45.4%) and tuberculosis (29.4%) were the most common Opportunistic Infections. The mean values of the patients’ assessed biochemical parameters were within the ranges. The median VL value was 4.16 log<sub>10</sub> RNA copies/ml. Subtype A (20.2%) is dominant. Mutations K65R (2 cases), T69P/N (5 cases), K70R (9 cases) and M184V (8 cases) were listed. Conclusion: In Kinshasa, PLHIV start ART late. The biochemical parameters evaluated are within normal ranges, with high VLs. Subtype A remains predominant and there are mutations conferring resistance to ART.展开更多
Introduction: The sixth month appointment (M6) is crucial because at the start of the ART course, it is an indicator of the prognosis of the evolution of care and decision-making on the continuity of treatment. Object...Introduction: The sixth month appointment (M6) is crucial because at the start of the ART course, it is an indicator of the prognosis of the evolution of care and decision-making on the continuity of treatment. Objective: The objective of this study is therefore to present the profile of People Living with HIV under treatment with Dolutegravir 6 months after starting ART in Kinshasa. Methods: The present study is a cross-sectional view at M6 of a prospective cohort to determine the profile of People Living with HIV (PLHIV) after 6 months of ARV Treatment (ART) in Kinshasa, DRC. During the M6 appointment, from April to August 2022, a sample of 5 ml of blood was taken for the various analyzes from all HIV patients included. The collection of sociodemographic data as well as biological and clinical data was carried out under the same conditions as at inclusion. The parameters recorded during M6 were: age, sex, and religion, level of study, marital status, profession, socio-economic level, height, weight, Body Mass Index (BMI), clinical profile, opportunistic infections as well as biochemical and molecular assessment. Results: In M6, 62 patients were registered including 38 women (61.3%), thus giving a sex ratio of 1.58 in favor of women. Fifty-seven (57) patients did not respond to the appointment, representing a loss rate of 47.89%. The most common age group is between 36 and 45 years old with 16 patients (26.7%). The mean age was 42.4 ± 13.3 years. The mean weight was 60.5 ± 15.4 kg with a mean BMI of 22.6 ± 5.8 kg/m<sup>2</sup>. Thirty-four (34) patients (61.82%) were in Clinical Stage 3. Thirty-six (36) patients (67.92%) had a normal clinical condition. The most common opportunistic infections among patients in M6 were: skin pruritus (25.8%), dermatitis (22.6%) and rash (21%). The mean values of biochemical parameters of patients in M6 were within normal ranges. The median VL value was 2.92 log10 RNA copies/ml with 17.75% of patients experiencing major failure of first-line treatment. Subtype A is dominant with 13 cases (20.98%);followed by CRF02_AG (16.13%) and C subtypes (14.52%). The mutations K65R (3 cases), T69P/N (6 cases), K70R (9 cases) and M184V (8 cases) were listed in M6. Conclusion: After 6 months of treatment, the majority of patients are in clinical stage 3 with a normal clinical state. Skin infections are the majority opportunistic infections. Certain biological parameters are considerably altered. A high virological failure rate with the presence of certain mutations associated with resistance to Lamivudine and Tenofovir.展开更多
Pancreatic cancer(PDAC) is an aggressive and chemoresistant disease, representing the fourth cause of cancer related deaths in western countries. Majority of patients have unresectable, locally advanced or metastatic ...Pancreatic cancer(PDAC) is an aggressive and chemoresistant disease, representing the fourth cause of cancer related deaths in western countries. Majority of patients have unresectable, locally advanced or metastatic disease at time of diagnosis and the 5-year survival rate in these conditions is extremely low. For more than a decade gemcitabine has been the cornerstone of metastatic PDAC treatment, although survival benefit was very poor. PDAC cells are surrounded by an intense desmoplastic reaction that may create a barrier to the drugs penetration within the tumor. Recently PDAC stroma has been addressed as a potential therapeutic target. Nano albumin bound(Nab)-paclitaxel is an innovative molecule depleting tumor stroma, through interaction between albumin and secreted protein acidic and rich in cysteine. Addition of nab-paclitaxel to gemcitabine has showed activity and efficacy in metastatic PDAC first-line treatment improving survival and overall response rate vs gemcitabine alone in the MPACT phase Ⅲ study. This combination represents one of the standards of care in advanced PDAC therapy and is suitable to a broader spectrum of patients compared to other schedules. Nab-paclitaxel is under investigation as a backbone of chemotherapy in novel combinations with target agents or immunotherapy in locally advanced or metastatic PDAC. In this article, we provide an updated and critical overview about the role of nab-paclitaxel in PDAC treatment based on the latest advances in preclinical and clinical research. Furthermore, we focus on the use of nab-paclitaxel within the context of metastatic PDAC treatment landscape and we discuss about future implications in the light of current clinical ongoing trials.展开更多
A new method using high-performance liquid chromatography coupled with ultra violet detection(HPLC–UV)was developed and validated for the simultaneous quantification of atazanavir,dolutegravir,darunavir,efavirenz,etr...A new method using high-performance liquid chromatography coupled with ultra violet detection(HPLC–UV)was developed and validated for the simultaneous quantification of atazanavir,dolutegravir,darunavir,efavirenz,etravirine lopinavir,raltegravir,rilpivirine and tipranavir in human plasma.For the first time we reported here the development and validation of an HPLC–UV assay to quantify the frequently administered 9antiretroviral compounds including dolutegravir and rilpivirine.A simple solid phase extraction procedure was applied to 500 μL aliquots of plasma.The chromatographic separation of the drugs and internal standard(quinoxaline) was achieved with a gradient of acetonitrile and sodium acetate buffer on a C_(18) reverse-phase analytical column with a 25 min analytical run time.Calibration curves were optimised according to the therapeutic range of drug concentrations in patients,and the coefficient of determination(r^2) was higher than0.99 for all analytes.Mean intraday and interday precisions(RSD) for all compounds were less than 15.0%,and the mean accuracy(% deviation from nominal concentration) was also found to be less than 15.0%.Extraction recovery range was between 80% and 120% for all drugs analysed.The solid phase extraction and HPLC–UV method enable a specific,sensitive,and reliable simultaneous determination of nine antiretroviral agents in plasma.Good extraction efficiency and low limit of HPLC–UV quantification make this method suitable for use in clinical trials and therapeutic drug monitoring.展开更多
Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their...Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.展开更多
AIM: To assess the efficacy and safety of antithrombotic drugs(antiplatelet or anticoagulant drugs) compared to no antithrombotic treatment or placebo in patients with heart failure(HF) and sinus rhythm. METHODS: We s...AIM: To assess the efficacy and safety of antithrombotic drugs(antiplatelet or anticoagulant drugs) compared to no antithrombotic treatment or placebo in patients with heart failure(HF) and sinus rhythm. METHODS: We searched Medline and Cochrane Library for randomized controlled trials evaluating antithrombotic treatment and no antithrombotic treatment in patients with HF and sinus rhythm. Risk ratio(RR) and 95%CIs were estimated performing meta-analysis with random effects method. RESULTS: Two studies met the inclusion criteria: Heart failure Long-term Antithrombotic Study and Warfarin/Aspirin Study in Heart failure, with 336 patients and mean follow-up 1.8-2.25 years. Stroke risk was not reduced by acetylsalicylic acid(RR = 1.18, 95%CI: 0.17-8.15), oral anticoagulation(RR = 0.30, 95%CI: 0.03-2.65) or overall antithrombotic drugs(RR = 0.52, 95%CI: 0.10-2.74). Acetylsalicylic acid showed a significant increased risk of worsening HF(RR = 1.78, 95%CI: 1.08-2.92), while oral anticoagulation had no impact in this outcome(RR = 1.03, 95%CI: 0.61-1.75). Overall antithrombotic drugs showed a significant risk increase of major bleeding(RR = 6.99, 95%CI: 0.89-54.64). CONCLUSION: Best available evidence does not support the routine use of antithrombotic drugs in patients with HF and sinus rhythm. These drugs, particularly oral anti-coagulation has the hazard of increase significantly major bleeding risk.展开更多
Tuberculosis (TB) remains an infectious disease with a high prevalence worldwide and represents a major public health issue. Although venous thromboembolism (VTE) is a rare complication of this disease, it may be a po...Tuberculosis (TB) remains an infectious disease with a high prevalence worldwide and represents a major public health issue. Although venous thromboembolism (VTE) is a rare complication of this disease, it may be a potentially life-threatening event. A 58-year-old man was admitted due to hematemesis due to inflammation at the anastomosis site after a gastrectomy years ago. After 3 days in-hospital, he showed a peroneal deep vein thrombosis and superficial thrombosis of left cephalic vein. Although reduced mobility and lack of prophylactic heparin could explain vein thrombosis, a simple etiologic workup was performed and active tuberculosis was diagnosed. This case illustrates a rare and unusual presentation form of tuberculosis, a condition that remains now-a-days one of the leading infectious causes of death worldwide. The association between tuberculosis and VTE is rare, but it should be systematically investigated.展开更多
Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and nec...Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and neck and gastric cancer.FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity.With the high number of patients receiving FP-based therapies,and the significant effects of toxicities on their quality of life,the prevention of FP-related adverse events is of major clinical interest.Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase(DPYD)gene are related to the occurrence of extremely severe,early onset toxicity in FP treated patients.The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines.Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice.Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways,TYMS and MTHFR,but no additional clinically validated genetic markers of toxicity are available to date.The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers.Moreover,the investigation of the genetic variation in the patients immunological system,a pivotal target in cancer treatment,could bring notable advances in the field.This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.展开更多
Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,in...Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,including risk-adapted intensity,have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90%in developed countries.Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes.Nevertheless,daily oral thiopurines remain the backbone maintenance or continuation therapy.Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available.Other genes of interest,such as ITPA and PACSIN2,have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols.In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.展开更多
文摘Background: Use of inappropriate amikacin dose is one of the most important factors in inducing toxicity, prolonged hospitalization as well as in increasing patient’s mortality. Objective: The aims of this study are the analysis of amikacin dose, serum level and the examination of the effectiveness of the clinical pharmacologist (CP) therapeutic drug monitoring (TDM) intervention to guarantee the safety of amikacin use. Methods: This is a one-year retrospective observational chart review study, which evaluates amikacin dose, serum drug level, development of adverse effects in patients on amikacin with or without CP TDM consultation. Results: Amikacin was prescribed for 393 complex patients, with median age 83. Amikacin group (AG) included 140 (32%) courses with CP consultation (AG1) and 292 (68%) courses without CP consultation (AG2). The distribution of most study characteristics in both groups was similar including amikacin dose (9-10 mg/kg/day), renal failure (14%) and mortality (12%). Acceptance for CP consultation was in 46% of amikacin courses and dose changes were done in 63% after CP intervention. Prolonged antibiotic course (4.6 ± 1.5 vs 3.8 ± 1.6 days, p < 0.0001) and the patient’s hemodynamic instability (15% vs 7%, p = 0.01) were more frequent in the AG1 compared to the AG2. There was a strong association between CP consultation and prolonged hospitalization (p = 0.005), while no association between it and amikacin adverse effects, renal failure or mortality. Conclusions: There was no trend to reducing amikacin toxicity, days of hospitaliza tion or mortality in patients with CP consultation. CP TDM intervention was more in the management of complicated clinical situations. However, it is necessary to optimize it.
基金partially funded by Italian Ministry of Health—Ricerca Corrente(no grant number).
文摘Objectives:Treatment of metastatic colorectal cancer(mCRC)includes resection of liver metastases(LM),however,no validated biomarker identifies patients most likely to benefit from this procedure.This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC(i.e.,RAS,BRAF,SMAD4,PIK3CA)as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection.Methods:A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM,stratified according to RAS,BRAF,PIK3CA,and SMAD4 mutational status.Hazard ratios(HRs)from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined.The search was conducted in numerous databases,including MEDLINE(PubMed),Embase,Cumulative Index to Nursing and Allied Health Literature(CINAHL)(EBSCO host),and WHO Global Index Medicus,through March 18th,2022.Meta-analyses,editorials,letters to the editor,case reports,studies on other primary cancers,studies with primary metastatic sites other than the liver,studies lacking specific oncological outcome variables or genetic data,non-English language studies,and studies omitting residual disease data from liver metastasectomy were excluded.The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented.Results:RAS mutation status was negatively associated with overall survival(OS)(HR,1.68;95%CI,1.54–1.84)and recurrence free survival(RFS)(HR,1.46;95%CI,1.33–1.61).A negative association was also found for BRAF regarding OS(HR,2.64;95%CI,2.15–3.24)and RFS(HR,1.89;95%CI,1.32–2.73)and SMAD4 regarding OS(HR,1.93;95%CI,1.56–2.38)and RFS(HR,1.95;95%CI,1.31–2.91).For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted.Conclusion:RAS,BRAF,and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer.No conclusion can be drawn for PIK3CA due to the limited literature availability.These data support the integration of RAS,BRAF,and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis.Nevertheless,we have to consider several limitations,the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival(DFS)or RFS;the inclusion of patients with minimal residual disease and unconsidered potential confounding factors,such as variability in resectability definitions,chemotherapy use,and a potential interaction between biological markers and pre-and post-resection pharmacological treatments.
文摘Context: The appointment of the M6 is crucial because it is an indicator of the prognosis of the evolution of the care and the decision-making on the continuation of the AntiRetroViral Treatment. Objective: The objective of this study is therefore to present the virological and molecular profile of People Living with HIV under treatment with Dolutegravir 6 months after being put on ART in Kinshasa. Methods: The present study is a cross-sectional view at the sixth month of a prospective cohort to determine the virological and molecular profile of People Living with HIV (PLHIV) after 6 months of ART based on Dolutegravir (DTG) in Kinshasa. A sample of 5 mL of blood was taken from all HIV patients included. The collection of biological data was carried out under the same conditions as at inclusion. After extraction, Quantitative Real-Time PCR was carried out to determine the quantity of HIV RNA in the samples according to the protocols previously described. Reverse Transcription PCR (RT-PCR) and Nested PCR were carried out to amplify the regions of interest for Protease and Reverse Transcriptase for sequencing. Results: The median VL value was 2.92 log<sub>10</sub> RNA copies/mL. With 17.75% of patients experiencing major failure of first-line treatment. Subtype A is dominant with 13 cases (20.98%);followed by CRF_02AG (16.13%), subtypes C (14.52%), D (9.68%) and K (6.45%). The K65R (3 cases), T69P/N (6 cases), K70R (9 cases) and M184V (8 cases) mutations were listed as existing mutations for Nucleotide Reverse Transcriptase Inhibitors. Conclusion: After 6 months of ART, 59.67% of People Living with HIV on Tenofovir-Lamivudine-Dolutegravir is in therapeutic success while 40.33% are in a state of treatment failure. Subtype A remains dominant in the population of PLHIV. Resistance mutations were detected for Lamivudine and Tenofovir, but none for Dolutegravir.
文摘Background: For several decades, the introduction of AntiRetrovirals (ARVs) has improved the symptomatology of People Living with HIV (PLHIV), a spectacular reduction in morbidity and mortality, an improvement in life expectancy and quality of life of PLHIV. Objective: The objective of this study was to determine the profile of PLHIV initiating AntiRetroViral Treatment (ART) in the era of Dolutegravir in Kinshasa. Methods: Cross-section of a prospective cohort to determine the profile of PLHIV initiating ART in Kinshasa. The inclusions were from October 04, 2021 to February 15, 2022. Confirmation of the diagnosis was carried out by Nested PCR. The inclusion criteria were: being at least 18 years old, confirmed HIV positive, naïve to ART, consenting and having signed an informed consent. The parameters of interest followed for the present study were: age, sex, religion, level of study, marital status, occupation, height, weight, body mass index (BMI), the clinical profile, the opportunistic infections as well as the para-clinical assessment (biochemistry and molecular biology). Results: 67 (56.3%) women and 52 (43.7%) men were included, thus 119 patients, all confirmed positive for HIV by Nested PCR on the gag, pol and env regions. The average age of the patients included is 39.87 ± 12.36 years and the most represented age group is that of 36 to 45 years with 37 patients (31.9%). The average height was 1.66 ± 0.08 meters, with an average weight of 56.41 ± 13.30 kg, giving an average Body Mass Index (BMI) of 21.54 ± 5.17 kg/m<sup>2</sup>. The majority of patients were married (46.1%), of Protestant religion (70.7%), with secondary education (66.7%), and working in the informal sector (29.4%). 49 patients (41.5%) were in clinical stage 3 and 55 patients (47.0%) had a normal clinical status. Malaria (45.4%) and tuberculosis (29.4%) were the most common Opportunistic Infections. The mean values of the patients’ assessed biochemical parameters were within the ranges. The median VL value was 4.16 log<sub>10</sub> RNA copies/ml. Subtype A (20.2%) is dominant. Mutations K65R (2 cases), T69P/N (5 cases), K70R (9 cases) and M184V (8 cases) were listed. Conclusion: In Kinshasa, PLHIV start ART late. The biochemical parameters evaluated are within normal ranges, with high VLs. Subtype A remains predominant and there are mutations conferring resistance to ART.
文摘Introduction: The sixth month appointment (M6) is crucial because at the start of the ART course, it is an indicator of the prognosis of the evolution of care and decision-making on the continuity of treatment. Objective: The objective of this study is therefore to present the profile of People Living with HIV under treatment with Dolutegravir 6 months after starting ART in Kinshasa. Methods: The present study is a cross-sectional view at M6 of a prospective cohort to determine the profile of People Living with HIV (PLHIV) after 6 months of ARV Treatment (ART) in Kinshasa, DRC. During the M6 appointment, from April to August 2022, a sample of 5 ml of blood was taken for the various analyzes from all HIV patients included. The collection of sociodemographic data as well as biological and clinical data was carried out under the same conditions as at inclusion. The parameters recorded during M6 were: age, sex, and religion, level of study, marital status, profession, socio-economic level, height, weight, Body Mass Index (BMI), clinical profile, opportunistic infections as well as biochemical and molecular assessment. Results: In M6, 62 patients were registered including 38 women (61.3%), thus giving a sex ratio of 1.58 in favor of women. Fifty-seven (57) patients did not respond to the appointment, representing a loss rate of 47.89%. The most common age group is between 36 and 45 years old with 16 patients (26.7%). The mean age was 42.4 ± 13.3 years. The mean weight was 60.5 ± 15.4 kg with a mean BMI of 22.6 ± 5.8 kg/m<sup>2</sup>. Thirty-four (34) patients (61.82%) were in Clinical Stage 3. Thirty-six (36) patients (67.92%) had a normal clinical condition. The most common opportunistic infections among patients in M6 were: skin pruritus (25.8%), dermatitis (22.6%) and rash (21%). The mean values of biochemical parameters of patients in M6 were within normal ranges. The median VL value was 2.92 log10 RNA copies/ml with 17.75% of patients experiencing major failure of first-line treatment. Subtype A is dominant with 13 cases (20.98%);followed by CRF02_AG (16.13%) and C subtypes (14.52%). The mutations K65R (3 cases), T69P/N (6 cases), K70R (9 cases) and M184V (8 cases) were listed in M6. Conclusion: After 6 months of treatment, the majority of patients are in clinical stage 3 with a normal clinical state. Skin infections are the majority opportunistic infections. Certain biological parameters are considerably altered. A high virological failure rate with the presence of certain mutations associated with resistance to Lamivudine and Tenofovir.
文摘Pancreatic cancer(PDAC) is an aggressive and chemoresistant disease, representing the fourth cause of cancer related deaths in western countries. Majority of patients have unresectable, locally advanced or metastatic disease at time of diagnosis and the 5-year survival rate in these conditions is extremely low. For more than a decade gemcitabine has been the cornerstone of metastatic PDAC treatment, although survival benefit was very poor. PDAC cells are surrounded by an intense desmoplastic reaction that may create a barrier to the drugs penetration within the tumor. Recently PDAC stroma has been addressed as a potential therapeutic target. Nano albumin bound(Nab)-paclitaxel is an innovative molecule depleting tumor stroma, through interaction between albumin and secreted protein acidic and rich in cysteine. Addition of nab-paclitaxel to gemcitabine has showed activity and efficacy in metastatic PDAC first-line treatment improving survival and overall response rate vs gemcitabine alone in the MPACT phase Ⅲ study. This combination represents one of the standards of care in advanced PDAC therapy and is suitable to a broader spectrum of patients compared to other schedules. Nab-paclitaxel is under investigation as a backbone of chemotherapy in novel combinations with target agents or immunotherapy in locally advanced or metastatic PDAC. In this article, we provide an updated and critical overview about the role of nab-paclitaxel in PDAC treatment based on the latest advances in preclinical and clinical research. Furthermore, we focus on the use of nab-paclitaxel within the context of metastatic PDAC treatment landscape and we discuss about future implications in the light of current clinical ongoing trials.
基金supported by “Ministero della Salute” “Ricerca corrente 2015” grant to E.C.
文摘A new method using high-performance liquid chromatography coupled with ultra violet detection(HPLC–UV)was developed and validated for the simultaneous quantification of atazanavir,dolutegravir,darunavir,efavirenz,etravirine lopinavir,raltegravir,rilpivirine and tipranavir in human plasma.For the first time we reported here the development and validation of an HPLC–UV assay to quantify the frequently administered 9antiretroviral compounds including dolutegravir and rilpivirine.A simple solid phase extraction procedure was applied to 500 μL aliquots of plasma.The chromatographic separation of the drugs and internal standard(quinoxaline) was achieved with a gradient of acetonitrile and sodium acetate buffer on a C_(18) reverse-phase analytical column with a 25 min analytical run time.Calibration curves were optimised according to the therapeutic range of drug concentrations in patients,and the coefficient of determination(r^2) was higher than0.99 for all analytes.Mean intraday and interday precisions(RSD) for all compounds were less than 15.0%,and the mean accuracy(% deviation from nominal concentration) was also found to be less than 15.0%.Extraction recovery range was between 80% and 120% for all drugs analysed.The solid phase extraction and HPLC–UV method enable a specific,sensitive,and reliable simultaneous determination of nine antiretroviral agents in plasma.Good extraction efficiency and low limit of HPLC–UV quantification make this method suitable for use in clinical trials and therapeutic drug monitoring.
基金Supported by Associazione Italiana per la Ricerca sul Cancro(AIRC),Special Program Molecular Clinical Oncology,5X1000,No.12214(G.T.)European Research Council,Programme‘‘Ide-as’’,Proposal No.269051(G.T.,F.R.)
文摘Colorectal cancer (CRC) is one of the most diffuse cancers worldwide and is still a clinical burden. Increasing evidences associate CRC clinical outcome to immune contexture represented by adaptive immune cells. Their type, density and location are summarized in the Immune Score that has been shown to improve prognostic prediction of CRC patients. The non-classical MHC class I human leukocyte antigen-G (HLA-G), is a crucial tumor-driven immune escape molecule involved in immune tolerance. HLA-G and soluble counterparts are able to exert inhibitory functions by direct interactions with inhibitory receptors present on both innate cells such as natural killer cells, and adaptive immune cells as cytotoxic T and B lymphocytes. HLA-G may play a prominent role in CRC strategies to avoid host immunosurveillance. This review highlights the current knowledge on HLA-G contribution in CRC, in related inflammatory diseases and in other type of cancers and disorders. HLA-G genetic setting (specific haplotypes, genotypes and alleles frequencies) and association with circulating/soluble profiles was highlighted. HLA G prognostic and predictive value in CRC was investigated in order to define a novel prognostic immune biomarker in CRC.
文摘AIM: To assess the efficacy and safety of antithrombotic drugs(antiplatelet or anticoagulant drugs) compared to no antithrombotic treatment or placebo in patients with heart failure(HF) and sinus rhythm. METHODS: We searched Medline and Cochrane Library for randomized controlled trials evaluating antithrombotic treatment and no antithrombotic treatment in patients with HF and sinus rhythm. Risk ratio(RR) and 95%CIs were estimated performing meta-analysis with random effects method. RESULTS: Two studies met the inclusion criteria: Heart failure Long-term Antithrombotic Study and Warfarin/Aspirin Study in Heart failure, with 336 patients and mean follow-up 1.8-2.25 years. Stroke risk was not reduced by acetylsalicylic acid(RR = 1.18, 95%CI: 0.17-8.15), oral anticoagulation(RR = 0.30, 95%CI: 0.03-2.65) or overall antithrombotic drugs(RR = 0.52, 95%CI: 0.10-2.74). Acetylsalicylic acid showed a significant increased risk of worsening HF(RR = 1.78, 95%CI: 1.08-2.92), while oral anticoagulation had no impact in this outcome(RR = 1.03, 95%CI: 0.61-1.75). Overall antithrombotic drugs showed a significant risk increase of major bleeding(RR = 6.99, 95%CI: 0.89-54.64). CONCLUSION: Best available evidence does not support the routine use of antithrombotic drugs in patients with HF and sinus rhythm. These drugs, particularly oral anti-coagulation has the hazard of increase significantly major bleeding risk.
文摘Tuberculosis (TB) remains an infectious disease with a high prevalence worldwide and represents a major public health issue. Although venous thromboembolism (VTE) is a rare complication of this disease, it may be a potentially life-threatening event. A 58-year-old man was admitted due to hematemesis due to inflammation at the anastomosis site after a gastrectomy years ago. After 3 days in-hospital, he showed a peroneal deep vein thrombosis and superficial thrombosis of left cephalic vein. Although reduced mobility and lack of prophylactic heparin could explain vein thrombosis, a simple etiologic workup was performed and active tuberculosis was diagnosed. This case illustrates a rare and unusual presentation form of tuberculosis, a condition that remains now-a-days one of the leading infectious causes of death worldwide. The association between tuberculosis and VTE is rare, but it should be systematically investigated.
文摘Fluoropyrimidines(FP)are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast,head and neck and gastric cancer.FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity.With the high number of patients receiving FP-based therapies,and the significant effects of toxicities on their quality of life,the prevention of FP-related adverse events is of major clinical interest.Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase(DPYD)gene are related to the occurrence of extremely severe,early onset toxicity in FP treated patients.The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines.Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice.Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways,TYMS and MTHFR,but no additional clinically validated genetic markers of toxicity are available to date.The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers.Moreover,the investigation of the genetic variation in the patients immunological system,a pivotal target in cancer treatment,could bring notable advances in the field.This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.
基金This project is supported by the Italian Ministry of Health(Progetto Ricerca Corrente 5/2012).
文摘Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,including risk-adapted intensity,have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90%in developed countries.Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes.Nevertheless,daily oral thiopurines remain the backbone maintenance or continuation therapy.Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available.Other genes of interest,such as ITPA and PACSIN2,have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols.In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.
