Mevalonic aciduria: Does stem cell transplant fully cure disease?

MA is a rare, autosomal recessive disorder characterized by episodes of inflammation and periodic fevers. In its most severe form, it can result in facial dysmorphism, growth inhibition, ataxia, liver dysfunction, intellectual disability, and at times can be fatal. A number of case reports exist stating that SCT is curative in these patients. We present the case of a patient diagnosed with MA at birth, who underwent SCT at the age of 14 months with intent to cure. She achieved complete engraftment and urine mevalonate became undetectable. However, 18 months following transplant, she developed frequent episodes of fevers, rashes, arthritis, and a rising urinary mevalonate. She was subsequently diagnosed with relapse. She now requires treatment with steroids and canakinumab to manage her disease. This case is the first report of disease relapse following transplant for MA. It runs contrary to prior reports that SCT is fully curative of MA and suggests that transplant may instead provide a means of decreasing disease severity without entirely eradicating the condition.     

Population pharmacokinetics of vactosertib,a new TGF-β receptor type Ι inhibitor,in patients with advanced solid tumors

Cancer Chemotherapy and Pharmacology - Vactosertib, a novel inhibitor of transforming growth factor-β type Ι receptor, is under development for the treatment of various cancers. The...     

Minimal and Maximal Extent of Band Ligation for Acute Variceal Bleeding during the First Endoscopic Session

Background/AimsThe appropriate number of band ligations during the first endoscopic session for acute variceal bleeding is debatable. We aimed to compare the technical aspects of endoscopic variceal ligation (EVL) in patients with variceal bleeding according to the number of bands placed per session.MethodsWe retrospectively reviewed multicenter data from patients who underwent EVL for acute variceal bleeding. Patients were classified into minimal EVL (targeting only the foci with active bleeding or stigmata of recent bleeding) and maximal EVL (targeting potential bleeding sources in addition to the aforementioned targets) groups. The primary endpoint was 5-day treatment failure. The secondary endpoints were 30-day rebleeding, 30-day mortality, and intraprocedural adverse events.ResultsMinimal EVL was associated with lower rates of hypoxia and shock during EVL than maximal EVL (hypoxia, 0.9% vs 2.9%; shock, 1.3% vs 3.4%). However, treatment failure was higher in the minimal EVL group than in the maximal EVL group (odds ratio, 1.60; 95% confidence interval, 1.06 to 2.41). Age ≥60 years, Model for End-Stage Liver Disease score ≥15, Child-Turcotte-Pugh classification C, presence of hepatocellular carcinoma, and systolic blood pressure <90 mm Hg at initial presentation were also associated with treatment failure. In contrast, 30-day rebleeding and 30-day mortality did not differ between the minimal and maximal EVL groups.ConclusionsGiven that minimal EVL was associated with a high risk of treatment failure, maximal EVL may be a better option for variceal bleeding. However, the minimal EVL strategy should be considered in select patients because it does not affect 30-day rebleeding and mortality.     

Radiological and clinical features of screening-detected pulmonary invasive mucinous adenocarcinoma

 Open in a separate windowOBJECTIVESThe current understanding of pulmonary invasive mucinous adenocarcinoma is largely based on studies of advanced stage patients and data about early-stage invasive mucinous adenocarcinoma are sparse. We evaluated the radiological and clinical features of screening-detected early-stage invasive mucinous adenocarcinoma (SD-IMA).METHODSData from 91 patients who underwent surgical treatment for SD-IMA (≤3 cm) from 2013 to 2019 were reviewed retrospectively. Data on radiological characteristics, clinicopathological findings, recurrence and survival were obtained. Disease-free survival rate was analysed.RESULTSRadiologically, SD-IMAs presented as a pure ground-glass nodule (6.6%), part-solid nodule (38.5%) or solid (54.9%). Dominant locations were both lower lobes (74.7%) and peripheral area (93.4%). The sensitivity of percutaneous needle biopsy was 78.1% (25/32). Lobectomy was performed in 70 (76.9%) patients, and sublobar resection in 21 (23.1%) patients. Seventy-three (80.2%), 15 (16.5%) and 3 (3.3%) patients had pathological stage IA, IB and IIB or above, respectively. Seven patients developed recurrence, and 3 died due to disease progression. Pleural seeding developed exclusively in 2 patients who underwent needle biopsy. The 5-year disease-free survival rate was 89.4%. The disease-free survival rates at 5 years were 86.3% in the lobectomy group and 100% in the sublobar resection group.CONCLUSIONSSD-IMAs were mostly radiologically invasive nodules. SD-IMAs showed favourable prognosis after surgical treatment.     

Difference between bone age at the hand and elbow at the onset of puberty

In the pubertal period, bone age advances rapidly in conjunction with growth spurts. Precise bone-age assessments in this period are important, but results from the hand and elbow can be different. We aimed to compare the bone age between the hand and elbow around puberty onset and to elucidate the chronological age confirming puberty onset according to elbow-based bone age.A total of 211 peripubertal subjects (127 boys and 84 girls) who underwent hand and elbow radiographs within 2 months was enrolled. Two radiologists and a pediatric orthopedic surgeon assessed bone age. Hand bone age was graded using the Greulich–Pyle (GP) method, and elbow bone age was determined using the Sauvegrain method. The correlation of 2 methods was evaluated by Demining regression analysis, and the mean absolute difference (MAD) with chronological age was compared between pre-pubertal and pubertal subjects. Receiver-operating characteristic curve analysis was performed to determine the chronological age confirming puberty onset.There was a statistically significant difference in bone age revealed by the GP and Sauvegrain methods in the pubertal group. In the pubertal group, the MAD was 1.26 ± 0.90 years with the GP method and 0.61 ± 0.47 years with the Sauvegrain method in boys (P < .001), while in girls, the MAD was 0.84 ± 0.60 years and 0.53 ± 0.36 years with the same 2 methods (P = .033). The chronological age for confirming puberty onset using the elbow was 12.2 years in boys and 10.3 years in girls.The bone ages of hand and elbow were different at puberty, and the elbow was a more reliable location for bone-age assessment at puberty. Puberty onset according to elbow occurred slightly earlier than expected.     

Optimal duration of antiviral treatment in patients with gastrointestinal cytomegalovirus disease at a low and high risk of relapse

We evaluated the association between antiviral treatment duration and relapse of gastrointestinal (GI) cytomegalovirus (CMV) disease by analyzing the risk factors for relapse.Patients who were diagnosed with GI CMV disease at a tertiary hospital from January 2008 to April 2019 were retrospectively enrolled. Patients with relapsed disease were those with a recurrence of GI CMV disease at least 4 weeks after the initial antiviral treatment.Of 238 participants, including 145 (51.9%) with upper and 93 (48.1%) with lower GI CMV diseases, 27 (11.3%) had experienced relapses. The difference in antiviral treatment duration between the relapsed and nonrelapsed GI CMV groups was not significant (median days, 21.0 vs 17.0, P = .13). Multivariate analysis revealed that hematologic malignancy (odds ratio, 3.73; P = .026) and ulcerative colitis (odds ratio, 4.61; P = .003) were independent risk factors for relapse. Participants with at least one of these risk factors and those with no independent risk factors were classified under the high- (relapse rate, 25.9%) and low-risk of relapse groups (relapse rate, 6.7%), respectively. Accordingly, we further stratified 180 (75.6%) and 58 (24.4%) participants under the low- and high-risk of relapse groups, respectively. There was no significant difference in relapse rates between the high- and low-risk groups according to antiviral treatment duration.Approximately 10% of the participants experienced relapses after antiviral treatment, with hematologic malignancy and ulcerative colitis featuring as risk factors. Therefore, prolonged antiviral treatment might not be helpful in preventing GI CMV disease relapse.     

Phospholipase A2 inhibitor and LY6/PLAUR domain-containing protein PINLYP regulates type I interferon innate immunity

Type I interferons (IFNs) are the first frontline of the host innate immune response against invading pathogens. Herein, we characterized an unknown protein encoded by phospholipase A2 inhibitor and LY6/PLAUR domain-containing (PINLYP) gene that interacted with TBK1 and induced type I IFN in a TBK1- and IRF3-dependent manner. Loss of PINLYP impaired the activation of IRF3 and production of IFN-β induced by DNA virus, RNA virus, and various Toll-like receptor ligands in multiple cell types. Because PINLYP deficiency in mice engendered an early embryonic lethality in mice, we generated a conditional mouse in which PINLYP was depleted in dendritic cells. Mice lacking PINLYP in dendritic cells were defective in type I IFN induction and more susceptible to lethal virus infection. Thus, PINLYP is a positive regulator of type I IFN innate immunity and important for effective host defense against viral infection.

Interferon (IFN)-mediated antiviral responses serve as the first line of the host innate immune defense against viral infection. IFNs are divided into three families based on sequence homology: type I, type II, and type III (1, 2). The type I IFN family encodes 13 subtypes of IFN-α in humans (14 in mice), a single IFN-β subtype, and several poorly defined subtypes (3, 4). Type I IFNs were originally identified based on their ability to interfere with viral replication, restrain virus dissemination, and activate adaptive immune responses (5–7). They can be induced in most cell types by microbial pathogen-associated and damage-associated molecular patterns recognized by pattern recognition receptors (PRRs) (3). By inducing the expression of IFN-stimulated genes (ISGs), type I IFNs elicit antiviral innate immunity and mediate adaptive immune responses (8, 9).The induction of antiviral type I IFN response is elicited in response to the stimulation of PRRs that detect pathogen-associated molecular patterns, such as viral nucleic acids, viral replicative intermediates, and surface glycoproteins (10, 11). There are four major subfamilies of PRRs: the Toll-like receptors (TLRs), nucleotide-binding oligomerization domain/leucine-rich repeat-containing receptors, RIG-1-like receptors (RLRs), and the C-type lectin receptors, which are located at the cell surface, in the cytosol, or endosomal compartments (11–14). Among the TLR family members, TLR3, TLR7, TLR8, and TLR9 are involved in the recognition of viral nucleotides. Viral DNA enriched in CpG-DNA motifs is recognized by TLR9, single-stranded RNA is recognized by TLR7 and TLR8, and double-stranded RNA and its synthetic analog polyinosinic-polycytidylic acid (poly I:C) are recognized by TLR3 (15, 16). Some viral envelope proteins can be recognized by TLR4 or TLR2 (16, 17).Following viral infection, cytosolic DNA can be sensed by cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) that induces the production of cyclic GMP-AMP (cGAMP) (18, 19). cGAMP functions as a second messenger that binds and activates the endoplasmic reticulum (ER) adaptor STING (19–22). Translocation of activated STING from the ER to the Golgi apparatus leads to the activation of kinase TBK1, which subsequently phosphorylates IRF3 and triggers the production of type I IFN (22–24). Cytosolic RNA can be recognized by the RLRs like RIG-1 and MDA5, which signal via mitochondrial antiviral signaling protein (MAVS; also known as CARDIF, IPS1, and VISA) and subsequently activate TBK1 and IRF3–IRF7, leading to the induction of type I IFNs and other antiviral genes (25–27).The lymphocyte antigen-6 (Ly6)/urokinase-type plasminogen activator receptor (uPAR) superfamily is characterized by the LU domain and a domain containing 10 cysteines that form distinct disulfide bridges, which create the three-fingered structural motif. The Ly6/uPAR family members regulate a wide range of functions in various cell types (28). Here, we uncovered the previously uncharacterized role of the Ly6/uPAR family member PINLYP in the induction of type I IFNs in response to DNA virus, RNA virus, and other TLR ligands. This study further defined the pivotal function of PINLYP in the effective host defense against virus infection.