It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID‐19 are concentration‐dependent. In a retrospective ...study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID‐19 (median age: 67; males: 41 63.1%), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median interquartile range: 16,600 11,430–20,842 ng/ml for lopinavir and 501 247–891 ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r‐treated patients with COVID‐19.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Whereas the immediate-release (IR) formulation of metformin has to be taken two or three times a day, the extended-release (XR) formulation enables once-daily administration and so might help to ...improve patient adherence, particularly in patients with polypharmacy.Several studies have assessed metformin XR's efficacy, safety, and pharmacokinetics (PK) in healthy people and those with type 2 diabetes (T2D).1-4 Many factors affect metformin absorption, disposition and elimination in patients with chronic kidney disease (CKD), leading to metformin accumulation. Although dose adjustment has been simulated using data from metformin XR-treated patients with various levels of kidney function,5 the pharmacodynamics (PD) and PK of metformin XR in patients with T2D and a defined CKD stage have not previously been studied. We therefore decided to comprehensively assess the efficacy, steady-state PK, and safety of three dose levels of metformin XR in people with T2D and CKD stage 3B.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Ovarian cancer is the leading cause of death from gynecologic cancer worldwide. High-grade serous carcinoma (HGSC) is the most common and deadliest subtype of ovarian cancer. While the ...origin of ovarian tumors is still debated, it has been suggested that HGSC originates from cells in the fallopian tube epithelium (FTE), specifically the epithelial cells in the region of the tubal-peritoneal junction. Three main lesions, p53 signatures, STILs, and STICs, have been defined based on the immunohistochemistry (IHC) pattern of p53 and Ki67 markers and the architectural alterations of the cells, using the Sectioning and Extensively Examining the Fimbriated End Protocol. In this study, we performed an in-depth proteomic analysis of these pre-neoplastic epithelial lesions guided by mass spectrometry imaging and IHC. We evaluated specific markers related to each preneoplastic lesion. The study identified specific lesion markers, such as CAVIN1, Emilin2, and FBLN5. We also used SpiderMass technology to perform a lipidomic analysis and identified the specific presence of specific lipids signature including dietary Fatty acids precursors in lesions. Our study provides new insights into the molecular mechanisms underlying the progression of ovarian cancer and confirms the fimbria origin of HGSC.
Epithelial-to-mesenchymal transition (EMT) has been proposed to be important for metastatic dissemination. However, recent studies have challenged the requirement of EMT for metastasis. Here, we ...assessed in different models of primary skin squamous cell carcinomas (SCCs) whether EMT is associated with metastasis. The incidence of metastasis was much higher in SCCs presenting EMT compared to SCCs without EMT, supporting the notion that a certain degree of EMT is required to initiate the metastatic cascade in primary skin SCCs. Most circulating tumor cells presented EMT, whereas most lung metastasis did not present EMT, showing that mesenchymal-to-epithelial transition is important for metastatic colonization. In contrast, immunodeficient mice transplanted with SCCs, whether displaying EMT or not, presented metastasis. Altogether, our data demonstrate that the association of EMT and metastasis is model dependent, and metastasis of primary skin SCCs is associated with EMT.
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•Primary skin SCCs with EMT have a high incidence of metastasis•Primary skin SCCs without EMT have no metastasis•Circulating tumor cells present EMT in primary tumors with metastasis•Transplanted tumors present metastasis regardless of EMT
The role of epithelial-to-mesenchymal transition (EMT) during metastasis remains controversial. Revenco et al. show that in models of primary skin tumors, only EMT tumors are associated with metastasis. In contrast, EMT is not required to induce metastasis following the subcutaneous transplantation of tumor cells, demonstrating the context dependency of EMT for metastasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Endometrial cancer (EC) is one of the most common gynecological cancers worldwide. Sentinel lymph node (SLN) status could be a major prognostic factor in evaluation of EC, but several prospective ...studies need to be performed. Here we report an in-depth proteomics analysis showing significant variations in the SLN protein landscape in EC. We show that SLNs are correlated to each tumor grade, which strengthens evidence of SLN involvement in EC. A few proteins are overexpressed specifically at each EC tumor grade and in the corresponding SLN. These proteins, which are significantly variable in both locations, should be considered potential markers of overall survival. Five major proteins for EC and SLN (PRSS3, PTX3, ASS1, ALDH2, and ANXA1) were identified in large-scale proteomics and validated by immunohistochemistry. This study improves stratification and diagnosis of individuals with EC as a result of proteomics profiling of SLNs.
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Diagnosis of endometrial cancer does not include sentinel lymph node mappingIn depth-proteomics analysis of sentinel lymph nodes and individuals with endometrial cancerWe identify potential biomarkers for tumor grade and overall survival
The standard of care for endometrial cancer (EC) does not currently include sentinel lymph node (SLN) mapping. Aboulouard et al. report an in-depth proteomic analysis of SLNs from individuals with grade I, II, or III EC and identify potential biomarkers for tumor grade and overall survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early ...oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of ...restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies.
Three complementary studies were performed:
) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase;
) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA
concentrations monitored monthly; and
) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4.
First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning qam +1 g in the evening qpm) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA
levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups.
Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.
Confrontée aux droits fondamentaux, l’immunité d’exécution est-elle remise en question ? Parce que la Cour internationale de Justice comme la Cour européenne des droits de l’homme estiment que ...l’immunité d’exécution ne porte pas atteinte aux droits fondamentaux, leur impact est en principe limité. Les zones de résistance paraissent d’autant plus marginales que, si certaines juridictions nationales ont marqué leur dissidence à l’égard de la jurisprudence internationale, leurs positions ont été vivement sanctionnées. Dans la perspective d’évolutions futures, elles méritent néanmoins d’être explorées.
Our study aims to evaluate the comparability of primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) patients. This single-center retrospective study includes all patients treated for ...advanced stages high-grade serous ovarian carcinomas (HGSOC) between 2007 and 2017. Preoperative characteristics and postoperative outcomes were compared after a propensity score matching analysis. Of the 221 patients included, 38% underwent PDS, and 62% received NACT. There was no age difference at diagnosis; however, CA125 levels, PCI score levels, and rates of stage IV were higher in the NACT group. There were no differences concerning the rate and the severity of complications (p = 0.29). The propensity score distribution showed a broad distinction between PDS patients and NACT patients with no significant overlap. Survival analyses demonstrate, after a median follow-up of 66.5 months, an overall survival (OS) of 105.9 and progression-free survival (PFS) of 29.2 months in the PDS group, compared to OS of 52.8 and PFS of 18.9 months in the NACT group. Advanced HGSOC is a heterogeneous population, in which inoperable patients should be differentiated from PDS patients based on many factors, primarily tumor burden.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although uremic osteoporosis is a component of mineral and bone disorder in chronic kidney disease, uremic toxin (UT) concentrations in patients with end-stage kidney disease and bone mineral density ...(BMD) changes after kidney transplantation have not previously been described. We hypothesized that elevated UT concentrations at the time of transplantation could have a negative impact on bone during the early post-transplantation period. Hence, we sought to determine whether concentrations of UTs (trimethylamine-N-oxide, indoxylsulfate, p-cresylsulfate, p-cresylglucuronide, indole-3-acetic acid, hippuric acid, and 3-carboxy-4-methyl-5-propyl-furanpropionic acid) upon transplantation are predictive markers for (i) osteoporosis one month after transplantation, and (ii) a BMD decrease and the occurrence of fractures 12 and 24 months after kidney transplantation. Between 2012 and 2018, 310 kidney transplant recipients were included, and dual-energy X-ray absorptiometry was performed 1, 12, and 24 months after transplantation. The UT concentrations upon transplantation were determined by reverse-phase high-performance liquid chromatography. Indoxylsulfate concentrations upon transplantation were positively correlated with BMD one month after transplantation for the femoral neck but were not associated with osteoporosis status upon transplantation. Concentrations of the other UTs upon transplantation were not associated with osteoporosis or BMD one month after transplantation. None of the UT concentrations were associated with BMD changes and the occurrence of osteoporotic fractures 12 and 24 months after transplantation. Hence, UT concentrations at the time of kidney transplantation were not predictive markers of osteoporosis or fractures.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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