Time to lymphoma treatment within 24 months in 'watch and wait' follicular lymphoma is associated with inferior outcomes: A multicentre analysis.

Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, ß2 microglobulin ≥3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

Loncastuximab tesirine in Chinese patients with relapsed or refractory diffuse large B-cell lymphoma: a multicenter, open-label, single-arm, phase II trial.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase 2 LOTIS-2 study. In the China bridging pivotal phase 2 OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥ 2 lines of systemic therapies were enrolled and treated with Lonca every 3 week with 150 µg/kg for 2 cycles; then 75 µg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data-cutoff, 64 patients received Lonca (median: 4.0 cycles [range: 1 to 17]). The median number of prior lines of therapies was 3.0 (range: 2 to 12). The ORR was 51.6% (95% CI: 38.7% to 64.2%), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) Grade ≥3 treatment-emergent adverse events (TEAEs), in which increased gamma glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAEs were reported in 35 of 64 patients with 4 fatal TEAEs. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

Long-term outcomes with HLX01 (HanliKang®), a rituximab biosimilar, in previously untreated patients with diffuse large B-cell lymphoma: 5-year follow-up results of the phase 3 HLX01-NHL03 study.

HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2-76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9-87.5%) and 75.4% (95% CI: 68.9-82.6%)( HR: 0.75, 95% CI 0.47-1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4-84.6%) and 73.0% (95% CI: 66.3-80.3%) (HR: 0.84, 95% CI 0.54-1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Treatment patterns, clinical outcomes and gene mutation characteristics of hepatitis B virus-associated mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon and incurable B-cell lymphoma subtype that has an aggressive course. Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas, and is characterized by distinct clinical and genetic features. Here, we showed that 9.5% of MCL Chinese patients were hepatitis B surface antigen positive (HBsAg+). Compared to HBsAg-negative (HBsAg-) patients, HBsAg+ MCL patients had a greater incidence of elevated lactate dehydrogenase (LDH), but no difference was observed in the other clinical characteristics, including sex, age, ECOG ps, Ann Arbor stage, MIPI, extranodal involvement and Ki-67. The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens. Compared with CHOP, the HD-AraC regimen was associated with longer PFS in HBsAg+ patients. Treatment with a Bruton tyrosine kinase inhibitor (BTKi) alone can also cause HBV reactivation. Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.

Primary Central Nervous System Burkitt's Lymphoma in a Pediatric Patient: A Case Report and Literature Review.

OBJECTIVE: The objective of this research is to examine the therapy and outlook of pediatric primary central nervous system Burkitt lymphomas. METHODS: This study involves a retrospective analysis of the clinical data of a child with primary central nervous system Burkitt lymphoma who underwent treatment in our department. In addition, pertinent literature was reviewed to provide a comprehensive understanding of the topic. RESULTS: The patient was admitted to the neurosurgery department with symptoms of headache and vomiting. Brain magnetic resonance imaging (MRI) revealed multiple lesions in the right frontal and temporal lobes, dorsal thalamus, and posterior medulla oblongata. Most of the tumor mass was surgically removed from the right ventricle and diagnosed as Burkitt lymphoma. Abnormal lymph nodes were not found outside of the central nervous system. The patient achieved complete remission (CR) after receiving 6 cycles of treatment (R-AA-BB-CC-AA-BB-CC) based on the regimen of the Southern Pediatric Non-Hodgkin Lymphoma Treatment Collaboration Group 2017. As of November 23, 2023, the patient remained alive with no evidence of recurrence. CONCLUSIONS: Primary central nervous system Burkitt lymphoma is rare in children, and there is no universally accepted treatment protocol. However, the regimen outlined by the South China Children's Cancer Group-Non-Hodgkin Lymphoma in 2017 (SCCCG-NHL-2017) can serve as a useful reference for treating pediatric non-Hodgkin lymphoma.

Treatment patterns and clinical outcomes of mantle cell lymphoma: A retrospective cohort study by CHOICE.

Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B.

Chidamide plus prednisone, etoposide, and thalidomide for untreated angioimmunoblastic T-cell lymphoma in a Chinese population: A multicenter phase II trial.

Angioimmunoblastic T-cell lymphoma (AITL) is a common type of peripheral T-cell lymphoma (PTCL) with a poor prognosis, and an effective first-line therapy is lacking. Chidamide is a selective histone deacetylase inhibitor and has been approved by the China Food and Drug Administration for relapsed or refractory PTCL. We conducted a multicenter phase II clinical trial combining chidamide with prednisone, etoposide, and thalidomide (CPET regimen) for a total of eight cycles in untreated AITL patients in China. The primary objectives were the overall response rate (ORR) and complete remission (CR) rate after eight cycles of the CPET regimen. The secondary endpoints were progression-free survival (PFS) and safety. Of the 71 enrolled patients, 51 completed the eight cycles of the CPET regimen. The ORR and CR of the 51 patients were 90.2 and 54.9%, respectively. After a median follow-up of 11.4 months (95% confidence interval [CI], 9.9-17.0), the median PFS of the 51 patients was 42.6 months (95% CI, 27.7-not reached) and the median overall survival (OS) was not reached. The 2-year PFS rate and OS rate were 66.5 and 82.2%, respectively. Sixty-eight patients received at least one cycle of CPET regimen and were included as the safety assessment population. The most common grade 3/4 adverse event was neutropenia (n = 22, 32.3%). Twelve patients showed treatment-related infections and recovered from antibiotic therapy; the other adverse events were mostly mild and reversible. The oral CPET regimen is an effective, tolerable, and economical choice for untreated AITL in a Chinese population. This trial was registered in www.clinicaltrials.gov as NCT03273452.

ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1.

While combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) cures most patients with diffuse large B-cell lymphoma (DLBCL), those with high-risk international prognostic index disease have inferior survival. Enzastaurin as a potent inhibitor of PKC-ß and PI3K/AKT pathway suppressor has been tested in many clinical trials including two key studies in DLBCL: Phase III maintenance study (Preventing Relapse in Lymphoma Using Daily Enzastaurin [PRELUDE]) and a first-line Phase II study (S028). DNA extracted from PRELUDE patients' blood samples was retrospectively genotyped identifying a novel genetic biomarker, DGM1 that showed high correlation with response to enzastaurin. A similar finding observed in the S028 study suggested that addition of enzastaurin to R-CHOP may significantly improve outcomes as frontline therapy for high-risk DGM1 positive DLBCL patients. ENGINE is a global, multicenter, placebo-controlled and randomized study to compare the effect of R-CHOP/enzastaurin as frontline treatment in high-risk DLBCL patients. The primary end point for this study is overall survival in patients who are DGM1 positive. Clinical Trial Registration Identifier: NCT03263026.

Effective remission of chidamide on treatment of advanced mycosis fungoides: An unusual case report.

Mycosis fungoides (MF) and Sézary syndrome are the most common types of primary cutaneous T cell lymphoma, which primarily involves skin without curative treatment. We report a case of a 29-year-old female Chinese patient, who developed multiple cutaneous lesions gradually for 5 years. However, the patient could not tolerate pruritus and ulceration of cutaneous lesions, so she was admitted to hospital and diagnosed with advanced MF based on clinical manifestation, laboratory, and image results. Then she received four cycles of COPE regimen (cyclophosphamide, vincristine, prednisolone, and etoposide). Although the skin lesions shrinked and sense of pruritus alleviated quickly after the chemotherapy, the effective remission duration was not satisfactory. Therefore, the patient received gemcitabine and thalidomide for three cycles subsequently. Still the remission duration was not long lasting. After that, she took chidamide orally two times a week. By the time of 7 weeks, the patches almost diminished and the patient did not feel itching for almost 6 months. And, she did not have any adverse effect and had a better quality of life than the period of chemotherapy.

Primary breast diffuse large B-cell lymphoma in the rituximab era: Therapeutic strategies and patterns of failure.

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare subtype of DLBCL with limited data on patterns of failure. This multicenter study aimed to define the optimum treatment strategy and patterns of failure for PB-DLBCL patients. We retrospectively reviewed data on 108 PB-DLBCL patients from 21 Chinese medical centers. Only patients with localized disease (involvement of breast and localized lymph nodes) were included. After a median follow-up of 3.2 years, 32% of patients developed progression or relapse. A continuous pattern of relapse was observed, characterized by frequent late relapses in the contralateral breast and central nervous system (CNS). Although rituximab significantly reduced the overall cumulative risk of progression or relapse (5-year cumulative risk 57% vs 24%, P = .029), it had limited effect on the reduction of breast relapse (P = .46). Consolidative radiotherapy significantly decreased the risk of breast relapse, even in the subgroup of patients treated with rituximab (5-year cumulative risk 21.2% vs 0%, P = .012). A continuous risk of CNS progression or relapse up to 8.2 years from diagnosis was observed (10-year cumulative risk 28.3%), with a median time to CNS relapse of 3.1 years. Neither rituximab nor prophylactic intrathecal chemotherapy significantly decreased the risk of CNS relapse. In summary, our study indicates that PB-DLBCL has a continuous pattern of relapse, especially with frequent late relapses in the CNS and contralateral breast. Rituximab and RT confer complementary benefit in the reduction of relapse. However, neither the addition of rituximab nor prophylactic intrathecal chemotherapy could effectively prevent CNS relapse for PB-DLBCL patients.

Younger poor ovarian response women achieved better pregnancy results in the first three IVF cycles.

This retrospective cohort study observed the live birth rates as well as cumulative live birth rates in women with poor ovarian response (POR) undergoing IVF-embryo transfer treatment, stratified for age and cycle number. Four hundred and one patients with POR diagnosed according to the Bologna criteria were enrolled and 700 IVF-ET cycles were analysed. The overall live-birth rate per cycle was 18.3%. From cycle 1 up to cycle 3, the live-birth rates decreased significantly from 22.2% to 11.1%. The live-birth rate fell to 2.4% in cycles 4 and over. When age advanced, the live birth rates decreased obviously (P < 0.01): 30.0% for women < 35 years old, 17.0% for those 35-40 years old, and 9.0% for women older than 40 years. Similarly, the cumulative live birth rates dropped from 48.0% (< 35 years) to 16.9% (≥ 40 years) accordingly. Younger patients (< 35 years old) with POR achieved better pregnancy results compared with patients of advanced age. Extremely low live-birth rates could be anticipated after three unsuccessful cycles; therefore it may not be appropriate to suggest more IVF cycles in POR women.

Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice.

BACKGROUND & AIMS: Effective therapies for alcoholic liver disease are currently unavailable. The present study tested the efficacy of Alda-1, a specific aldehyde dehydrogenase 2 (ALDH2) activator, in treating alcoholic liver disease. METHODS: Male C57BL/6J mice were exposed to alcohol for a time-course study on aldehyde metabolism. The specificity and efficacy of Alda-1 on activating hepatic ALDH2 and aldehyde clearance were determined by acute treatments. Then, mice were fed alcohol for 8 weeks with Alda-1 administration for the last 10 days to test the therapeutic potential of Alda-1. Lastly, H4IIEC3 cells were treated with ethanol, acetaldehyde, or 4-hydroxynonenal to define the link between aldehydes and hepatotoxicity. RESULTS: Alcohol feeding for 8 weeks induced hepatic ALDH2 dysfunction and aldehyde accumulation. One dose of Alda-1 administration elevated hepatic ALDH activity, which was blocked by the specific ALDH2 inhibitor, daidzin. Alda-1 accelerated acetaldehyde clearance after acute alcohol intoxication. Alda-1 treatment in the 8-week alcohol feeding model reversed liver damage along with reduction of hepatic aldehydes. Alda-1 re-activated transcription factors, upregulated fatty acid oxidation enzymes, and reversed steatosis. Alcohol-induced endoplasmic reticulum stress and apoptotic cell death were also attenuated by Alda-1. Acetaldehyde or 4-hydroxynonenal treatment to H4IIEC3 cells inactivated transcription factors and induced endoplasmic reticulum stress and apoptosis, while ethanol per se showed limited effects. CONCLUSIONS: Pharmacological activation of ALDH2 by Alda-1 reversed alcoholic steatosis and apoptosis through accelerating aldehyde clearance. This study indicates that ALDH2 is a promising molecular target and Alda-1 has therapeutic potential for treating alcoholic liver disease.

Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways.

Hepatic zinc deficiency has been well documented in alcoholic patients, but the mechanisms by which zinc deficiency mediates cell death have not been well defined. The objectives of this study were to determine whether alcohol perturbs subcellular zinc homeostasis and how organelle zinc depletion may link with cell death pathways. Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure significantly reduced zinc level in isolated hepatic endoplasmic reticulum (ER) and mitochondria. Among the detected zinc transporters, ER Zrt/Irt-like protein (ZIP)13 and mitochondrial ZIP8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. Mitochondrial zinc transporter (ZnT) 4, which transports zinc from cytosol to mitochondria, was also increased. ER phosphorylated eukaryotic initiation factor 2α, activating transcription factor 4, and C/EBP homologous protein were significantly upregulated, and mitochondrial cytochrome c release and Bax insertion were detected in association with caspase-3 activation and apoptotic cell death. To define the role of zinc deficiency in ER and mitochondrial stress, H4IIEC3 cells were treated with 3 µM N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine for 6 h with or without supplementation with zinc or N-acetylcysteine (NAC). The results demonstrated that zinc deprivation induced caspase-3 activation and apoptosis in association with ER and mitochondria dysfunction, which were inhibited by zinc as low as 10 µM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced in ER and mitochondrial zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment.

Visceral white adipose tissue is susceptible to alcohol-induced lipodystrophy in rats: role of acetaldehyde.

BACKGROUND: Chronic alcohol exposure causes lipid dyshomeostasis at the adipose-liver axis, reducing lipid storage in white fat and increasing lipid deposit in the liver. Previous studies have shown that visceral fat, rather than subcutaneous fat, is a risk factor for metabolic diseases. This study was conducted to determine whether chronic alcohol exposure differentially affects lipid metabolism in visceral (epididymal) and subcutaneous fat, and the mechanisms underlying the alcohol effects. METHODS: Male Wistar rats were pair-fed the Lieber-DeCarli control or alcohol liquid diet for 12 weeks to determine the effects of alcohol on the white fat. Tissue explants culture and 3T3-L1 culture were conducted to define the role of acetaldehyde in alcohol-induced adipose tissue dysfunction. RESULTS: Chronic alcohol feeding significantly reduced visceral fat mass and down-regulated peroxisome proliferator activator receptor-γ and CCAAT/enhancer binding protein-α, 2 important transcription factors in regulation of lipogenesis. The protein levels of lipogenic enzymes including phospho-ATP-citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, lipin1, and diacylglycerol acyltransferase 2 in the visceral fat were reduced. In contrast, chronic alcohol exposure did not affect subcutaneous fat mass and had less effect on the protein levels of lipogenic enzymes and regulators. Accordingly, the visceral fat showed a lower protein level of aldehyde detoxification enzymes compared to the subcutaneous fat. Acetaldehyde treatment to either visceral fat explants or 3T3-L1 adipocytes produced similar effects on lipogenic enzymes and regulators as observed in animal model. CONCLUSIONS: These results demonstrated that visceral fat is more susceptible to alcohol toxicity compared to subcutaneous fat, and disruption of adipose lipogenesis contributes to the pathogenesis of alcoholic lipodystrophy.

Dysregulation of hepatic zinc transporters in a mouse model of alcoholic liver disease.

Zinc deficiency is a consistent phenomenon observed in patients with alcoholic liver disease, but the mechanisms have not been well defined. The objective of this study was to determine if alcohol alters hepatic zinc transporters in association with reduction of hepatic zinc levels and if oxidative stress mediates the alterations of zinc transporters. C57BL/6 mice were pair-fed with the Lieber-DeCarli control or ethanol diets for 2, 4, or 8 wk. Chronic alcohol exposure reduced hepatic zinc levels, but increased plasma and urine zinc levels, at all time points. Hepatic zinc finger proteins, peroxisome proliferator-activated receptor-α (PPAR-α) and hepatocyte nuclear factor 4α (HNF-4α), were downregulated in ethanol-fed mice. Four hepatic zinc transporter proteins showed significant alterations in ethanol-fed mice compared with the controls. ZIP5 and ZIP14 proteins were downregulated, while ZIP7 and ZnT7 proteins were upregulated, by ethanol exposure at all time points. Immunohistochemical staining demonstrated that chronic ethanol exposure upregulated cytochrome P-450 2E1 and caused 4-hydroxynonenal accumulation in the liver. For the in vitro study, murine FL-83B hepatocytes were treated with 5 µM 4-hydroxynonenal or 100 µM hydrogen peroxide for 72 h. The results from in vitro studies demonstrated that 4-hydroxynonenal treatment altered ZIP5 and ZIP7 protein abundance, and hydrogen peroxide treatment changed ZIP7, ZIP14, and ZnT7 protein abundance. These results suggest that chronic ethanol exposure alters hepatic zinc transporters via oxidative stress, which might account for ethanol-induced hepatic zinc deficiency.

Dietary nicotinic acid supplementation ameliorates chronic alcohol-induced fatty liver in rats.

BACKGROUND: Alcohol abuse frequently causes niacin deficiency in association with the development of alcoholic liver disease. The objective of the present study was to determine whether dietary nicotinic acid (NA) deficiency exaggerates and whether dietary NA supplementation alleviates alcohol-induced fatty liver. METHODS: Male Sprague-Dawley rats were pair-fed with 4 isocaloric liquid diets: control, ethanol (EtOH), EtOH with dietary NA deficiency, and EtOH with dietary NA supplementation, respectively, for 8 weeks. The control and EtOH diets contained normal levels of NA (7.5 mg/l). Dietary NA deficiency (0 mg NA/l) was achieved by removing NA from the vitamin mix, while NA was added to the liquid diet at 750 mg/l for dietary NA supplementation. RESULTS: Chronic EtOH feeding induced significant lipid accumulation in the liver, which was not worsened by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Liver total NAD, NAD(+) , and NADH levels were remarkably higher in the NA supplemented group than the NA deficient or EtOH alone groups. Dietary NA supplementation to EtOH-fed rats increased the protein levels of hepatic cytochrome P450 4A1 (CYP4A1) and acyl-coenzyme A oxidase 1 without affecting their mRNA levels. Interestingly, we found dietary NA supplementation reduced the ubiquitination level of CYP4A1. In addition, hepatic fatty acid synthase expression was reduced, while the serum ß-hydroxybutyrate and adiponectin concentrations were significantly elevated by dietary NA supplementation. Moreover, dietary NA supplementation modulated EtOH-perturbed liver and serum metabolite profiles. CONCLUSIONS: These results demonstrate that alcoholic fatty liver was not exaggerated by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Increased hepatic fatty acid oxidation and decreased hepatic de novo lipogenesis contribute to the effects of dietary NA supplementation.

Partial remission with sintilimab monotherapy in a patient carrying a CD274 amplification in refractory diffuse large B­cell lymphoma: A case report.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with varying characteristics, in terms of genomic variation, cell morphology and clinical presentation. At present, only ~66% of patients are cured with initial treatment and those with refractory DLBCL exhibit a poor prognosis. Thus, further investigations into novel effective treatment options for DLBCL are required. The present study reports the case of a patient resistant to multiple therapies, including rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus enzastaurin (trial no. CTR20171560), GemOx plus lenalidomide and selinexor (trial no. ATG-010-DLBCL-001). The patient harbored a CD274 amplification, as identified via next-generation sequencing (NGS), and exhibited a high programmed death-ligand 1 Tumor Proportion Score of up to 95%. Consequently, the patient was treated with sintilimab monotherapy and the response lasted for 12 months of follow-up without major immune-related adverse events. This case highlights the role of NGS technology in selecting treatment options for refractory DLBCL. Furthermore, the results of the present study suggest that sintilimab may have potential in the treatment of patients with refractory DLBCL.

Enhancer of Zeste Homolog 2 Inhibitor SHR2554 in Relapsed or Refractory Peripheral T-cell Lymphoma: Data from the First-in-Human Phase I Study.

PURPOSE: Patients with peripheral T-cell lymphomas (PTCL) in the relapsed or refractory (r/r) setting have only a limited number of therapies available, and the prognosis is extremely poor. SHR2554 is an oral inhibitor against EZH2, a rational therapeutic target for lymphomas. PATIENTS AND METHODS: This was a multicenter, two-part, phase I study of SHR2554 in r/r mature lymphoid neoplasms. In part I, 350 mg twice daily was established as the recommended phase II dose (RP2D) based on the findings during dose escalation and expansion; subsequently, selected lymphoma subtypes were recruited in clinical expansion cohorts to receive SHR2554 at RP2D. Here, we provide an in-depth assessment of SHR2554 at RP2D in subpopulation with r/r PTCL. RESULTS: Twenty-eight patients were included for analysis (17 angioimmunoblastic T-cell lymphoma and 11 not otherwise specified). Eighteen (64%) patients had received ≥2 lines of previous anticancer therapies. The objective response rate was 61% [95% confidence interval (CI), 41-78]. Responses were still ongoing in 59% (10/17) of the responders; estimated median duration of response was 12.3 months (95% CI, 7.4-not reached). Median progression-free survival was 11.1 months (95% CI, 5.3-22.0), and 12-month overall survival rate was 92% (95% CI, 72-98). The most common grade 3 or 4 treatment-related adverse events were decreased platelet count [nine (32%)] as well as decreased white blood cell count, decreased neutrophil count, and anemia [four (14%) for each]. No treatment-related deaths were reported. CONCLUSIONS: This extended follow-up analysis further supports SHR2554 as a therapeutic opportunity for patients with r/r PTCL.

Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats.

Endotoxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague-Dawley rats were pair fed control or ethanol liquid diet for 8 wk. The liquid diets were based on a modified Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long-chain saturated fatty acids) or medium-chain triglycerides (MCT, exclusively medium-chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanol-induced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression, and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and zonula occludens-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent.