Encorafenib and binimetinib, a combination of BRAF and MEK inhibitors, is a standard of care for patients with advanced BRAFV600-mutant melanoma. This combination is known to have gastrointestinal ...side effects, most of which are mild and managed symptomatically. However, very few studies have reported severe colitis.
We report here 2 patients with advanced melanoma who developed severe ulcerated right colitis manifested by diarrhea and hematochezia while being treated with encorafenib and binimetinib after immune checkpoint therapy.
This rare but serious adverse event was not described in early phase 3 trials but has emerged in recent years, particularly with the sequential use of immune checkpoint inhibitors followed by BRAF/MEK inhibitors. In a comprehensive review of the existing literature, we identified 20 cases of severe colitis due to BRAF/MEK inhibitors. Clinical, endoscopic, and histological features are described to provide insight into the current understanding of this poorly understood clinical entity.
Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the ...contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever ...case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease.
We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease.
In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5–1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer.
In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer.
In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.
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•Low-phospholipid-associated cholelithiasis (LPAC) syndrome affects approximately 1% of adults with symptomatic cholelithiasis.•Normal weight, common bile duct stones, and lack of cholecystitis are clinical features significantly associated with this syndrome.•ABCB4 variants in patients with LPAC may be associated with an increased personal or family risk of hepato-biliary cancer.
The low-phospholipid-associated cholelithiasis (LPAC) syndrome is a recently described peculiar form of cholelithiasis associated with the ATP-binding-cassette subfamily B, member 4 (ABCB4) gene ...deficiency. The purpose of our study was to analyse the relationship between magnetic resonance (MR) features and the genetic status of ABCB4 in people with LPAC syndrome.
A total of 233 individuals with proven LPAC syndrome were enrolled between January 2003 and June 2018 in a retrospective single-centre study. Inclusion criteria included availability of clinical files, MR images, and genetic data. MR images were analysed by consensus among 3 senior radiologists blinded to the status of ABCB4 gene mutation.
A total of 125 individuals (mean age at first MR imaging 40.8 years; 66% females; 48% ABCB4 variant) were included. MR abnormalities were found in 61 (49%) of the 125 individuals. Forty (67%) of the 60 individuals with an ABCB4 gene variant had MR abnormalities as compared with 21 (33%) of the 65 individuals without an ABCB4 gene variant (odds ratio OR 4.1, 95% CI 1.9–9.5, p = 0.0001). Compared to individuals with no variant, individuals with an ABCB4 variant were more likely to show intrahepatic macrolithiasis (56 vs. 17%; OR 6.3, 95% CI 2.6–16.2, p <0.0001), bile duct dilatation (60 vs. 18%; OR 6.5, 95% CI 2.7–16.3, p <0.0001), and at least 1 MR feature of complication (35 vs. 15%; OR 2.9, 95% CI 1.1–7.8, p <0.05).
ABCB4-related LPAC syndrome is associated with more frequent and severe hepatobiliary MR abnormalities. This finding strongly supports the major role of the ABCB4 gene in the pathogenesis of LPAC syndrome and highlights a genotype–phenotype association in this inherited disease with genetic heterogeneity.
ABCB4-related LPAC syndrome associated with an ABCB4 gene variant demonstrates more frequent and severe hepatobiliary MR abnormalities. This finding supports the major role of the ABCB4 gene in the pathogenesis of LPAC syndrome.
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•We analysed the relationship between MRI and the genetic status of ABCB4 in LPAC.•MR abnormalities were found in 61 (49%) of the 125 individuals with LPAC syndrome.•Forty (67%) of the 60 individuals with an ABCB4 gene variant had MR abnormalities.•Twenty-one (33%) of the 65 individuals without an ABCB4 gene variant had MR abnormalities.•ABCB4-related LPAC is associated with more frequent and severe MR abnormalities.
Summary
Background
Ustekinumab and vedolizumab are commonly used after anti‐tumour necrosis factor (TNF) failure in patients with Crohn’s disease (CD). No randomised controlled trial has compared ...these drugs.
Aims
To compare the effectiveness of ustekinumab and vedolizumab in CD patients refractory to anti‐TNF.
Methods
From PubMed, EMBASE and the Cochrane Library, through March 27, 2021, we identified studies that compared ustekinumab and vedolizumab in patients with CD refractory to anti‐TNF. The main outcomes were clinical remission and steroid‐free clinical remission at weeks 14 and 52. Secondary outcomes were biological remission and treatment persistence. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) using random effects meta‐analysis.
Results
We identified 1513 reports. Among them, 38 studies were assessed for eligibility and five studies were included. All studies included were of high quality: four were retrospective and one was prospective. Among 1026 patients, 659 received ustekinumab and 367 received vedolizumab. At week 14, clinical remission (OR 1.36; 95%CI: 0.74‐2.47; I2 = 50%), steroid‐free clinical remission (OR 1.24; 95%CI: 0.79‐1.92; I2 = 52%) and biological remission (OR 0.80; 95%CI: 0.50‐1.28; I2 = 0%) rates were similar between the two treatments. At week 52, ustekinumab was associated with higher rates of clinical remission (OR 1.87; 95% CI: 1.18‐2.98; I2 = 0%), steroid‐free clinical remission (OR 1.56; 95% CI: 1.23‐1.97; I2 = 0%), biological remission (OR 1.86; 95% CI: 1.03‐3.37; I2 = 29%) and treatment persistence (OR 2.37; 95% CI: 1.56‐3.62; I2 = 0%).
Conclusion
In patients with CD refractory to anti‐TNF, ustekinumab and vedolizumab are similarly effective in induction, but as maintenance treatment, ustekinumab appears to be more effective than vedolizumab.
In patients with Crohn’s disease refractory to anti‐TNF, ustekinumab appears to be more effective than vedolizumab as maintenance treatment.
Summary
Background
The risk of lymphoma in patients with inflammatory bowel disease (IBD) treated with anti‐TNF agents remains unclear.
Aim
To assess the comparative risk of lymphoma with anti‐TNF ...agents and/or thiopurines in IBD
Methods
We searched PubMed, EMBASE and Cochrane Library to identify studies that evaluated lymphoproliferative disorders associated with anti‐TNF agents with or without thiopurines. The risk of lymphoma was assessed through four comparator groups: combination therapy (anti‐TNF plus thiopurine), anti‐TNF monotherapy, thiopurine monotherapy and control group. Pooled incidence rate ratios (IRR) were estimated through Poisson‐normal models.
Results
Four observational studies comprising 261 689 patients were included. As compared with patients unexposed to anti‐TNF and thiopurines, those exposed to anti‐TNF monotherapy, thiopurine monotherapy or combination therapy had pooled IRR (per 1000 patient‐years) of lymphoma of 1.52 (95% CI: 1.06‐2.19; P = 0.023), 2.23 (95% CI: 1.79‐2.79; P < 0.001) and 3.71 (95% CI: 2.30‐6.00; P ≤ 0.01), respectively. The risk of lymphoma associated with combination therapy was higher than with thiopurines or anti‐TNF alone with pooled IRR of 1.70 (95% CI: 1.03‐2.81; P = 0.039) and 2.49 (95% CI: 1.39‐4.47; P = 0.002), respectively. The risk did not differ between anti‐TNF monotherapy and thiopurine monotherapy with pooled IRR of 0.72 (95% CI: 0.48‐1.07; P = 0.107). All observational studies were of high quality according to the Newcastle‐Ottawa scale.
Conclusions
There is an increased risk of lymphoma in IBD patients treated with anti‐TNF agents, either alone or when combined with thiopurines.
Summary
Background
Acute severe ulcerative colitis (ASUC) is a life‐threatening condition. Mortality in ASUC decreased in published series but there is uncertainty as to whether this also applies to ...the real‐life setting.
Aim
To perform a systematic review and meta‐analysis of mortality in ASUC in studies from referral centres and in population‐based studies, separately and combined. A second aim was to identify risk factors of mortality in ASUC.
Methods
We searched pubmed and embase from 1998 to 2016, to identify studies that reported 3‐month or 12‐month mortalities of acute UC in adult patients treated in referral centres, and in population‐based studies.
Results
Six population‐based studies with 741 743 patients and 47 referral centre‐based studies with 2556 patients were included. The pooled 3‐month and 12‐month mortalities were respectively 0.84% and 1.01%. Advanced age was significantly associated with both 3 month and 12 month mortalities (OR = 1.15 per year, 95% CI: 1.10‐1.20 and OR = 1.19 per year, 95% CI: 1.15‐1.23 respectively). The pooled 3‐month and 12‐month mortalities were 0.78% and 0.85% in studies with median age of less than 50 and 2.81% and 4.17% in studies with median age of 50 or more, respectively. After adjustment for age, 3‐month and 12‐month mortalities did not differ between population‐based and referral centre‐based studies.
Conclusions
Mortality in acute severe ulcerative colitis is approximately 1%; it is higher in older patients. Efforts should be made to improve the care of elderly patients with severe UC.
There has been a previous case report of peri-arrest muscle rigidity in the setting of severe salicylate poisoning (serum salicylate concentration 1,500 mg/L), described as paratonia or rapid rigor ...mortis. We present an image of rapid rigor mortis in another fatal salicylate poisoning.
We report a 42-year-old male with severe salicylate poisoning (peak salicylate concentration 1,600 mg/L). During the peri-arrest period, the patient developed isotonic flexion of the upper and lower extremities, the clinical signs of rapid-occurring rigor mortis. Despite resuscitative efforts, the patient died.
Our patient is exhibiting peri-arrest rigidity in the upper extremities.
Peri-mortem rigidity is due to depletion of adenosine triphosphate. Severe salicylate poisoning causes uncoupling of oxidative phosphorylation which prevents the production of adenosine triphosphate, which is required to release myosin from actin to allow the muscle to relax. A limitation of our report is that we did not definitively exclude other uncouplers of oxidative phosphorylation, such as 2,4-dinitrophenol. However, the history of aspirin ingestion was provided by the patient and corroborated by his mother, and it was confirmed by measurement of his salicylate concentration.
We hypothesize that in our patient, rapid-occurring rigor mortis likely resulted from depletion of adenosine triphosphate. This occurred as a result of uncoupling of oxidative phosphorylation in the mitochondria from severe salicylate poisoning, as adenosine triphosphate is required for muscle relaxation.
Cannabinoids are the most commonly abused illicit drugs worldwide. While cannabis can be beneficial for certain heath conditions, abuse of potent synthetic cannabinoids has been on the rise. Exposure ...to cannabinoids is also prevalent in women of child-bearing age and pregnant women. These compounds can cross the placental barrier and directly affect the fetus. They mediate their effects primarily through G-protein coupled cannabinoid receptors, CB1 and CB2. In addition to significant neurological effects, cannabinoids can trigger robust immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells and inducing suppressor cells of the immune system. Profound effects of cannabinoids on the immune system as discussed in this review, suggest that maternal exposure during pregnancy could lead to dysregulation of innate and adaptive immune system of developing fetus and offspring potentially leading to weakening of immune defenses against infections and cancer later in life. Emerging evidence also indicates the underlying role of epigenetic mechanisms causing long-lasting impact following cannabinoid exposure in utero.
Mechanistic target of rapamycin （mTOR） complex 1 （mTORC1） integrates signals from growth factors, cel- lular energy levels, stress and amino acids to control cell growth and proliferation through ...regulating trans- lation, autophagy and metabolism. Here we determined the cryo-electron microscopy structure of human mTORC1 at 4.4 A resolution. The mTORCI comprises a dimer of heterotrimer （mTOR-Raptor-mLST8） mediated by the mTOR protein. The complex adopts a hollow rhomboid shape with 2-fold symmetry. Notably, mTORC1 shows intrinsic conformational dynamics. Within the complex, the conserved N-terminal caspase- like domain of Raptor faces toward the catalytic cavity of the kinase domain of mTOR. Raptor shows no caspase activity and therefore may bind to TOS motif for sub- strate recognition. Structural analysis indicates that FKBP12-Rapamycin may generate steric hindrance forsubstrate entry to the catalytic cavity of mTORCI. The structure provides a basis to understand the assembly of mTORC1 and a framework to characterize the regu- latory mechanism of mTORC1 pathway.
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