Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma

PD-1 blockade enhances the function of anti-tumor T-cells and antibody-dependent cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 follicular lymphoma (FL) patients with rituximab-sensitive disease who relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200mg IV every 3 weeks for up to 16 cycles and rituximab was given at 375mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AE) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%) and pancreatitis (3%). Low-grade immune-related AEs were reported for 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune related AEs occurred in 13% of patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. Overall response rate (primary endpoint) was 67% and complete response rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% CI, 8.2-27.6 months), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow up of 35 months. Presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a complete response and improved PFS. In this single arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov: NCT02446457.

Examining the association between opium use, cigarette smoking and alcohol consumption with the liver enzyme levels in a population-based study: Fasa Persian cohort data

Objectives Opium use, cigarette smoking, and alcohol consumption are serious health problems in many countries including Iran. The present study aimed to examine the association between the opium use, cigarette smoking and alcohol consumption with liver enzyme levels in Southern Iran. This analytical cross-sectional study was conducted in 2020. The entire population of the Fasa Persian cohort study in the southern region of Iran was selected as the sample. Accordingly, 10,145 people participated in the study. Results Results indicated that there was a significant relationship between cigarette smoking and alcohol consumption with liver enzymes (AST, ALT, and ALP). There was also a significant relationship between inhaled opium and liver enzymes, but oral opium revealed no significant relationship with the activity of liver enzymes. Accordingly, policymakers of the health care system are recommended to hold educational programs to improve the health literacy level of the society and take effective preventative strategies in reducing the use of these substances.

Case Report: Clinical Features of Congenital Portosystemic Shunts in the Neonatal Period

Objective: The aim of this single-center retrospective study was to analyze the clinical characteristics, treatment options, and course of neonatal-onset congenital portosystemic shunts (CPSS).Methods: We included all patients with CPSS who presented with clinical symptoms within the neonatal period in our institution between 2015 and 2020.Results: Sixteen patients were identified, including 13 patients with intrahepatic portosystemic shunts (IPSS) and three patients with extrahepatic portosystemic shunts (EPSS). The median age of diagnosis was 16 days (range prenatal 24 weeks−12 months). Hyperammonemia (60%), neonatal cholestasis (44%), elevated liver enzyme (40%), hypoglycemia (40%), thrombocytopenia (38%), and coagulation abnormalities (23%) appeared in neonatal CPSS. Twelve patients (75%) presented with congenital anomalies, of which congenital heart disease (CHD) (44%) was the most common. Thirteen patients with IPSS initially underwent conservative treatment, but two of them were recommended for the catheter interventional therapy and liver transplantation, respectively, due to progressive deterioration of liver function. Spontaneous closure occurred in nine patients with IPSS. The shunt was closed using transcatheter embolization in one patient with EPSS type II. Another patient with EPSS type II underwent surgical treatment of CHD firstly. The remaining patient with EPSS type Ib received medical therapy and refused liver transplantation.Conclusion: Hyperammonemia, neonatal cholestasis, elevated liver enzyme, hypoglycemia, and thrombocytopenia are the main complications of neonatal CPSS. Moreover, CPSS is associated with multiple congenital abnormalities, especially CHD. Intrahepatic portosystemic shunts may close spontaneously, and conservative treatment can be taken first. Extrahepatic portosystemic shunts should be closed to prevent complications.

Increased Visit-to-Visit Liver Enzyme Variability Is Associated with Incident Diabetes: A Community-Based 12-Year Prospective Cohort Study

Background: Fatty liver and/or increased liver enzyme values have been reported to be associated with incident diabetes. We sought to determine whether increased visit-to-visit liver enzyme variability is associated with incident diabetes.Methods: Study participants were recruited from the Korean Genome and Epidemiologic Study (KoGES). A total of 4,151 people aged 40 to 69 years was recruited and tested every 2 years for up to 12 years. Visit-to-visit aspartate aminotransferase (AST) and alanine aminotransferase (ALT) variability was evaluated in first the 6-year period through the use of various variability measurements: standard deviation (SD), average successive variability, coefficient of variation (CV), and variation independent of mean (VIM). Oral glucose tolerance test was performed at every visit.Results: During the 6-year follow‐up appointments, 13.0% (538/4,151) of people developed incident diabetes. Visit-to-visit AST variability was associated with an increased risk of diabetes independent of conventional risk factors for diabetes (hazard ratio per 1-SD increment [95% confidence interval]: 1.06 [1.00 to 1.11], 1.12 [1.04 to 1.21], and 1.13 [1.04 to 1.22] for SD, CV, and VIM, respectively; all P<0.05); however, no such associations were observed in the visit-to-visit ALT variability. According to alcohol consumption status, both AST and ALT variability were independent predictors for incident diabetes in subjects with heavy alcohol consumption; however, neither AST nor ALT variability was associated with diabetes risk in subjects who did not drink alcohol heavily.Conclusion: Visit-to-visit liver enzyme variability is an independent predictor of incident diabetes. Such association was more evident in those who consumed significant amounts of alcohol.

Colchicine Effectiveness and Safety in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis

Introduction: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common fever syndrome in childhood. High disease activity (DA) dramatically impacts the health-related quality of life. Thus, effective and safe treatment is crucial. Colchicine might be effective, but data are still lacking. Study aimed to assess colchicine safety and effectiveness in PFAPA.Methods: This single center study was conducted between 03/2012 and 05/2021 in PFAPA patients without variants in genetic panel testing aged ≤ 18 years fulfilling Marshall criteria and classification criteria of Gattorno et al. Exclusion criteria were elevated liver enzymes, impaired kidney function, celiac disease, lactose intolerance, previous/ongoing biologics, known colchicine-intolerance. Demographics, clinical characteristics, treatment, DA, colchicine effectiveness and safety were recorded at baseline, first and last visit. Colchicine was started at 0.5–1.0 mg/day. DA was captured by physician (PGA) and patient/parent (PPGA) global assessment on a 10 cm visual analog scale, categorized as mild (&lt;2), moderate (2–4), and high (≥5). Adverse event (AE) monitoring included gastrointestinal symptoms, liver enzyme/creatinine elevation, leukopenia, neutropenia. Primary outcome included response (R; composite of PPGA + PGA decrease ≥2) at last follow-up. Secondary outcomes were partial response (PR; PGA decrease = 1 + PPGA decrease ≥1), no response (NR; unchanged/worsened PGA/PPGA), colchicine safety, flare characteristics.Results: Twenty-seven PFAPA patients were included, 52% were female, median age was 5.8 years (1–10.75), median follow-up time was 13 months. At baseline, median PPGA was high; median PGA moderate. All patients had febrile flares. Median flare frequency was every 4–5 weeks; median duration 5–6 days. Nine patients were pre-treated with corticosteroids, increasing flare frequency in 8/9. Primary Outcome: 17 patients (63%) were responders. Secondary outcomes: PR was achieved in 15%; NR in 22% at last follow-up. DA decreased significantly (p &lt;0.0001). At last follow-up, 52% reported no flares, median flare duration decreased to 1–2 days. At first follow-up, 22% reported mild abdominal pain/diarrhea. Moderate abdominal pain/diarrhea occurred with ≥1 mg/day. Mild asymptomatic liver enzyme elevation or leucopenia were rare; no severe AE or colchicine discontinuation were observed.Conclusion: Colchicine seems to be safe, well-tolerated, and effective in PFAPA patients. It can be considered in children with moderate/high DA even those without corticosteroid-benefit.

Effect of cranberry supplementation on liver enzymes and cardiometabolic risk factors in patients with NAFLD: a randomized clinical trial

Background We aimed to evaluate the effect of cranberry supplementation on serum liver enzymes, hepatic steatosis, and cardiometabolic risk factors in patients with non-alcoholic fatty liver (NAFLD). Methods In the present parallel-designed randomized controlled clinical trial, 110 patients with NAFLD were enrolled. The patients were randomized to receive 144 mg cranberry capsule or placebo for 6 months. The primary efficacy of the treatment was lipid profile, glycemic measurements, and liver enzyme levels. Results The data were reported for 46 in the supplementation group and 48 in the placebo group. The patient’s mean (SD) age was 43.16 (11.08) years. No significant differences between groups were observed regarding the post-intervention level of liver enzyme. The mean after-intervention levels of total cholesterol (p < 0.001) and triglyceride (p = 0.01) were significantly lower in the intervention group compared with the placebo group. At the end of the study, the mean insulin and HOMA-IR levels were significantly lower in the cranberry group compared with the placebo group. Significantly more patients in the cranberry group experienced a decrease in steatosis level compared with the control group. Conclusion The results of the present study showed that cranberry supplementation had a positive effect on some lipid profiles, insulin resistance, and hepatic steatosis in patients with NAFLD. Trial registration IRCT20200725048200N1; first registration date: 11.8.2020.

The Metabolism of Gammekane and Related Compounds

<p>1. A detailed kinetic study has been made of the glutathione S-aryl-transferases from the New Zealand grass grub (Costelytra zealandica) and from sheep liver. The insect enzyme behaves in accordance with a Michaelis-Menten model for two-substrate enzymes. It is inhibited by the sulphonphthaleins, phthaleins, fluoresceins and dicarboxylic acids competing with glutathione, while the sheep-liver enzyme is not susceptible to this type of inhibition. From this, and other data obtained from a study of the variation of kinetics with pH, it is proposed that two basic groups (possibly lysine residues) are involved in binding of glutathione to the insect enzyme, while only one such group appears in the sheep-liver enzyme. Binding of the aromatic substrate to the enzyme in both species may involve a histidine residue. 2. The accumulation of little significant radioactivity in diluant 2gamma-pentachlorocyclohexene (gamma-PCCH) during the in vitro metabolism of [14C]gamma-hexachlorohexane (gamma-HCH) suggests that the PCCH's are not formed as free intermediates during the metabolism of the HCH's. However, certain ambiguities introduced with the experimental techniques used preclude the complete exclusion of this possibility. 3. gamma-HCH, gamma-PCCH and delta-PCCH metabolized in vivo by M.domestica and C.zealandica and in vitro by preparations from both species, all produce as the principal metabolite a glutathione conjugate with chromatographic properties identical with those of authentic S-(2,4-dichlorophenyl)glutathione. There is, however some doubt as to the identity of the S-substituent moiety. 4. The in vitro metabolism of gamma-HCH and delta-PCCH is glutathione-dependent and is inhibited by various phthaleins and sulphonphthaleins. The in vivo metabolism of delta-PCCH in C.zealandica is profoundly affected by this type of compound, but its effects on the rate of metabolism in vivo of delata-HCH in M.domestica and C.zealandica are only marginal. 5. The enzyme concerned in the metabolism of delta-PCCH has been shown to differ from aryltransferase in M.domestica and C.zealandica by gel filtration techniques and by differences in activity in different enzyme preparations. The delta-PCCH-metabolising activity appears to be associated with a DDT dehydrochlorinase activity. In M.domestica, there appears to be, in addition, a second DDT dehydrochlorinase with only a low cross-specificity towards delta-PCCH.</p>

The Metabolism of Gammekane and Related Compounds

<p>1. A detailed kinetic study has been made of the glutathione S-aryl-transferases from the New Zealand grass grub (Costelytra zealandica) and from sheep liver. The insect enzyme behaves in accordance with a Michaelis-Menten model for two-substrate enzymes. It is inhibited by the sulphonphthaleins, phthaleins, fluoresceins and dicarboxylic acids competing with glutathione, while the sheep-liver enzyme is not susceptible to this type of inhibition. From this, and other data obtained from a study of the variation of kinetics with pH, it is proposed that two basic groups (possibly lysine residues) are involved in binding of glutathione to the insect enzyme, while only one such group appears in the sheep-liver enzyme. Binding of the aromatic substrate to the enzyme in both species may involve a histidine residue. 2. The accumulation of little significant radioactivity in diluant 2gamma-pentachlorocyclohexene (gamma-PCCH) during the in vitro metabolism of [14C]gamma-hexachlorohexane (gamma-HCH) suggests that the PCCH's are not formed as free intermediates during the metabolism of the HCH's. However, certain ambiguities introduced with the experimental techniques used preclude the complete exclusion of this possibility. 3. gamma-HCH, gamma-PCCH and delta-PCCH metabolized in vivo by M.domestica and C.zealandica and in vitro by preparations from both species, all produce as the principal metabolite a glutathione conjugate with chromatographic properties identical with those of authentic S-(2,4-dichlorophenyl)glutathione. There is, however some doubt as to the identity of the S-substituent moiety. 4. The in vitro metabolism of gamma-HCH and delta-PCCH is glutathione-dependent and is inhibited by various phthaleins and sulphonphthaleins. The in vivo metabolism of delta-PCCH in C.zealandica is profoundly affected by this type of compound, but its effects on the rate of metabolism in vivo of delata-HCH in M.domestica and C.zealandica are only marginal. 5. The enzyme concerned in the metabolism of delta-PCCH has been shown to differ from aryltransferase in M.domestica and C.zealandica by gel filtration techniques and by differences in activity in different enzyme preparations. The delta-PCCH-metabolising activity appears to be associated with a DDT dehydrochlorinase activity. In M.domestica, there appears to be, in addition, a second DDT dehydrochlorinase with only a low cross-specificity towards delta-PCCH.</p>

Asparaginase Induced Liver Enzyme Elevation Is More Prevalent in Hispanics Children with ALL and in Patients with SOD2 rs4880 CC Genotype

Background: Asparaginase is an integral component of treatment for pediatric patients with acute lymphoblastic leukemia (ALL). Hepatotoxicity secondary to asparaginase-based treatment is one of the most common treatment-related toxicities in ALL therapy. Hispanic children are at higher risk of ALL and ALL treatment related toxicities compared with other ethnicities. The rs4880 variant in the SOD2 gene, a critical mitochondrial enzyme that protects cells against oxidative stress, was previously found to be associated with increased incidence of hepatotoxicity following asparaginase treatment in an adult ALL cohort of largely European ancestry. Whether this association is also present in pediatric patients with ALL and in Hispanics remains unknown. Importantly, the risk genotype (CC) of rs4880 is more frequent among Hispanics. Here we aim to investigate the prevalence of hepatotoxicity and risk genotype among pediatric patients with ALL particularly of Hispanics ancestry. Method: Blood samples, demographic and clinical data were obtained from 143 pediatric patients treated for ALL between 29 January 2015 and 24 January 2020 at Children's Hospital Los Angeles. We genotyped DNA samples isolated from the patient's blood for the rs4880 variant of SOD2 using TaqMan Allelic Discrimination Assay. Liver enzyme data, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels for each subject following multiple visits before and post asparaginase-based treatment were obtained. Hepatotoxicity is defined as grade 3/4 of both AST and ALT, grade 4 of either AST or ALT, or grade 3/4 of bilirubin. We performed Cox Proportional Hazards models to evaluate the predictive factors of hepatotoxicity overtime. Results: Among the 143 patients, 13 (9.09%) patients had grade &gt; 3 elevated bilirubin levels, and 3 (2.1%) and 55 (38.46%) patients had grade &gt; 4 and &gt; 3 elevated AST levels respectively, and 19 (13.29%) and 109 (76.22%) had grade &gt; 4 and &gt; 3 elevated ALT levels respectively. Hepatotoxicity was observed in 60 (41.96%) of patients. After dichotomizing patients based on ethnicity (Hispanic and non-Hispanic), we found that BMI was significantly higher in Hispanics than non-Hispanic patients (mean BMI: 21.57 vs 18.64, p=0.002). While mean baseline levels of liver enzymes were not significantly different between Hispanic and non-Hispanic patients (bilirubin:0.69 vs 0.64, ALT: 156.06 vs 124.75, and AST: 99.98 vs 82.38), post-treatment levels were significantly higher in hispanics (ALT: 138.105 vs. 101.45, p=0.0005; AST: 84.131 vs. 64.045, p=0.0023). After chemotherapy, grade 3 or 4 elevated bilirubin was found in 11 (12.36%) of 89 Hispanic patients and only in 2 (3.7%) of 54 non-Hispanic patients. Also, there was a statistically significant difference in the frequency of elevated ALT level grade &gt; 4 and grade &gt; 3 between Hispanic and non-Hispanic patients (grade &gt; 4: 17 (19.10%) vs 2 (3.70), p= 0.01; grade &gt; 3: 74 (83.15%) vs 35 (64.8%), p=0.01). Consequently, Hepatotoxicity was more frequent among Hispanic patients than non-Hispanic, 47.19% vs 33.33%; p=0.10, respectively. We also compared hepatotoxicity parameters according to the patient's rs4880 genotypes. Among patients with the SOD2 rs4880 CC genotype 3 (6.32%) had grade &gt; 4 and 23 (50%) had grade &gt; 3 elevated AST compared with 0 (0%) and 21 (30%) among the CT and 0 (0%) and 11 (40.74%) among the TT genotype patients (CC vs. CT and TT; AST grade &gt; 4: p=0.13; grade &gt; 3 : p=0.05). In addition, elevated bilirubin grade &gt; 3 was found more frequently in patients with the SOD2 rs4880 CC genotype (15.22%) compared with those with the CT (5.71%) and TT (7.41%) genotypes. Furthermore, post-treatment bilirubin, ALT and AST median levels were significantly higher in patients with the CC genotype than in patients with CT or TT genotypes (bilirubin: 0.8275 vs. 0.6, p=0.0007; ALT: 142.555 vs. 106.038, p=0.0089; AST: 85.399 vs. 67.888, p= 0.0302). In a multivariate Cox analysis, that included ethnicity, age, gender, BMI and genotype, we identified Ethnicity (Hispanic) as the only significant predictor of hepatotoxicity (hazard ratio [HR] = 1.862, 95% confidence interval [95% CI] 1.-3.465, p=0.0499). Conclusion: Overall, these findings suggested that hepatotoxicity is highly prevalent among Hispanic pediatric patients with ALL, especially those with CC genotype of rs4880. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria.