Infection perturbs Bach2- and Bach1-dependent erythroid lineage 'choice' to cause anemia.

Elucidation of how the differentiation of hematopoietic stem and progenitor cells (HSPCs) is reconfigured in response to the environment is critical for understanding the biology and disorder of hematopoiesis. Here we found that the transcription factors (TFs) Bach2 and Bach1 promoted erythropoiesis by regulating heme metabolism in committed erythroid cells to sustain erythroblast maturation and by reinforcing erythroid commitment at the erythro-myeloid bifurcation step. Bach TFs repressed expression of the gene encoding the transcription factor C/EBPß, as well as that of its target genes encoding molecules important for myelopoiesis and inflammation; they achieved the latter by binding to their regulatory regions also bound by C/EBPß. Lipopolysaccharide diminished the expression of Bach TFs in progenitor cells and promoted myeloid differentiation. Overexpression of Bach2 in HSPCs promoted erythroid development and inhibited myelopoiesis. Knockdown of BACH1 or BACH2 in human CD34+ HSPCs impaired erythroid differentiation in vitro. Thus, Bach TFs accelerate erythroid commitment by suppressing the myeloid program at steady state. Anemia of inflammation and myelodysplastic syndrome might involve reduced activity of Bach TFs.

Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma.

Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

The transcription repressors Bach2 and Bach1 promote B cell development by repressing the myeloid program.

Mature lymphoid cells express the transcription repressor Bach2, which imposes regulation on humoral and cellular immunity. Here we found critical roles for Bach2 in the development of cells of the B lineage, commencing from the common lymphoid progenitor (CLP) stage, with Bach1 as an auxiliary. Overexpression of Bach2 in pre-pro-B cells deficient in the transcription factor EBF1 and single-cell analysis of CLPs revealed that Bach2 and Bach1 repressed the expression of genes important for myeloid cells ('myeloid genes'). Bach2 and Bach1 bound to presumptive regulatory regions of the myeloid genes. Bach2(hi) CLPs showed resistance to myeloid differentiation even when cultured under myeloid conditions. Our results suggest that Bach2 functions with Bach1 and EBF1 to promote B cell development by repressing myeloid genes in CLPs.

Benralizumab treatment in an elderly patient with eosinophilic esophagitis resulted in remission: a case report.

BACKGROUND: Interleukin-5 (IL-5) has recently been shown to play a crucial role in eosinophil-mediated diseases, implying that an IL-5 receptor alpha chain (IL-5Rα) antibody (benralizumab) can be effective against eosinophilic esophagitis (EoE). Here, we present a case in which benralizumab significantly improved the symptoms and signs of an elderly Asian woman with EoE who had inadequate response to existing treatments. Case presentation A 73-year-old woman with an 8-year history of bronchial asthma (BA) and a 7-year history of dysphagia presented to our hospital with worsening dysphagia, vomiting, chest pain, and difficulty in eating. Blood biochemical findings revealed an increase in the eosinophil fraction of white blood cells (42.2%), and a conventional chest computed tomography scan revealed esophageal wall thickening. An upper gastrointestinal endoscopy revealed mucosal edema as well as multiple esophageal rings, and esophageal biopsy specimens showed an eosinophilic infiltrate of more than 15 cells/ high power field. Based on these findings, she was diagnosed as EoE complicated by BA. We firstly administrated 20 mg/day of prednisolone, rabeprazole sodium and liquid budesonide oral suspension for 5 months; however, they were ineffective and her dysphagia worsened over time. Then, benralizumab treatment in combination with these drugs was started. Her dysphagia completely disappeared 2 weeks after starting benralizumab, and an upper endoscopy showed that the clinical findings had completely disappeared after another 6 weeks. Benralizumab was then given to her for 41 months, and her symptoms remained in remission. In addition, she had no EoE recurrence for more than 12 months after discontinuing benralizumab. CONCLUSIONS: Benralizumab in combination with other multiple drugs significantly improved the symptoms and examination findings of an elderly patients with EoE. Furthermore, she experienced no recurrence even after discontinuing benralizumab withdrawal, suggesting that benralizumab could be an appropriate therapeutic option for EoE.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Disease-Free Interval and Tumor Stage Complementarily Predict the Biological Behavior of Recurrent Hepatocellular Carcinoma.

BACKGROUND: Currently used treatment algorithms were originally established based on the clinical outcomes of the initial treatment for primary hepatocellular carcinoma (HCC), and no strong evidence exists yet to suggest if these algorithms could also be applicable to patients with recurrent HCC after surgery. As such, this study sought to explore an optimal risk stratification method for cases of recurrent HCC for better clinical management. METHODS: Among the 1616 patients who underwent curative resection for HCC, the clinical features and survival outcomes of 983 patients who developed recurrence were examined in detail. RESULTS: Multivariate analysis confirmed that both the disease-free interval (DFI) from the previous surgery and tumor stage at recurrence were significant prognostic factors. However, the prognostic impact of DFI seemed different according to the tumor stages at recurrence. While curative-intent treatment showed strong influence on survival [hazard ratio (HR), 0.61; P < 0.001] regardless of the DFI in patients with stage 0 or stage A disease at recurrence, early recurrence (< 6 months) was a poor prognostic marker in patients with stage B disease. The prognosis of patients with stage C disease was exclusively influenced by the tumor distribution or choice of treatment than by the DFI. CONCLUSIONS: The DFI complementarily predicts the oncological behavior of recurrent HCC, with its predictive value differing depending on the tumor stage at recurrence. These factors should be considered for selection of the optimal treatment in patients with recurrent HCC after curative-intent surgery.

Effects of Hyphomonas Strains on the Growth of Red Algae Pyropia Species by Attaching Specifically to Their Rhizoids.

Bacteria and marine macroalgae form close associations, while various bacteria affect the morphogenesis and growth of macroalgae. Hyphomonas strains exhibit normal morphogenetic activity in protoplasts of the red alga Pyropia yezoensis (nori). However, the effects of the bacteria on the growth of Pyropia from protoplast cells to regenerated thalli remain unknown. Here, we assessed the growth of P. yezoensis and Pyropia tenera using combined cultures of three Hyphomonas strains (LNM10-16, SCM-2, and LNM-9) and three algal media (artificial seawater with vitamins, artificial seawater, and natural seawater) over 7 weeks. Third week after culture, the three Hyphomonas strains showed almost similar levels of normal growth activity for both Pyropia species. However, at 7 weeks, significant differences were observed among the three Hyphomonas strains in terms of length, length-to-width ratio, and normal morphology of Pyropia thalli. LNM10-16 significantly promoted the thalli length and length-to-width ratios of both Pyropia species in artificial seawater without vitamins and natural seawater, compared with the other two Hyphomonas strains. P. yezoensis cultured in artificial seawater with vitamins showed a much higher demand for LNM10-16 in development of the thalli length than P. tenera. These results may be explained by differences in the growth activities of Hyphomonas strains and the nutrient requirements of Pyropia species. Furthermore, the bacteria were more specifically attached to the rhizoid surfaces of both species. This study is the first to reveal that Hyphomonas strains affect the growth of Pyropia species by attaching to their rhizoids.

Efficacy and safety of postoperative preemptive use of tolvaptan for patients with cirrhosis undergoing hepatectomy for hepatocellular carcinoma.

PURPOSE: Optimal choice of diuretics in perioperative management remains unclear in enhanced recovery after liver surgery. This study investigated the efficacy and safety of tolvaptan (oral vasopressin V2-receptor antagonist) in postoperative management of patients with liver injury and hepatocellular carcinoma. METHODS: The patients clinically diagnosed with liver cirrhosis were included in this study. Clinical outcomes of 51 prospective cohort managed with a modified postoperative protocol using tolvaptan (validation group) were compared with 83 patients treated with a conventional management protocol (control group). RESULTS: Postoperative urine output were significantly larger and excessive body weight increase were reduced with no impairment in renal function or serum sodium levels in the validation group. Although the total amount of discharge and trend of serum albumin level were not significantly different among the groups, global incidence of postoperative morbidity was less frequent (19.6% vs. 44.6%, P=0.005) and postoperative stay was significantly shorter (8 days vs.10 days, P=0.008) in the validation group compared with the control group. CONCLUSIONS: Tolvaptan could be safely used for the patients with injured liver in postoperative management after hepatectomy and potentially advantageous in the era of enhanced recovery after surgery with its strong diuretic effect and better fluid management.

Suspected Immune Thrombocytopenic Purpura Induced by Lenalidomide for the Treatment of Myelodysplastic Syndrome with Deletion of Chromosome 5q: A Case Report.

Lenalidomide (LEN), one of the key drugs in the treatment of myelodysplastic syndromes (MDS) with 5q deletion, as well as multiple myeloma (MM), has various immunomodulatory effects and has been associated with autoimmune diseases, including immune thrombocytopenic purpura (ITP). A 78-year-old man presented with pancytopenia and was diagnosed with MDS with 5q deletion and other chromosomal abnormalities. Two cycles of LEN therapy (one cycle: 10 mg/day for 21 days) resulted in a transient improvement in anemia, followed by MDS progression with severe thrombocytopenia (4 × 109/L) refractory to platelet transfusions. As other non-immune and alloimmune causes of transfusion-refractory thrombocytopenia were excluded, and the level of platelet-associated immunoglobulin G was extremely high compared with the level before treatment with LEN, the diagnosis of ITP was highly suspected. Despite treatment with prednisolone (PSL), eltrombopag, and repeated platelet transfusions, his platelet count did not increase, and he died of a gastrointestinal hemorrhage. Several cases of ITP induced by LEN used to treat MM had been reported, but the platelet count recovered after administration of PSL in these previous cases. However, we should be mindful of using LEN for patients with MDS because its treatment may become extremely difficult if ITP develops.

Pretreatment Positron Emission Tomography with 18F-Fluorodeoxyglucose May Be a Useful New Predictor of Early Progressive Disease following Atezolizumab plus Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND AND AIMS: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of early progressive disease (e-PD) in patients with hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). METHODS: Twenty consecutive patients with measurable intrahepatic target nodules who received Atezo/Bev treatment were reviewed. The oncological aggressiveness of tumors estimated by 18F-FDG-PET/CT was analyzed using the rate of e-PD within 12 weeks and early progression-free survival (e-PFS) and overall survival (OS). Multivariate analysis was used to identify potential confounders for PD during Atezo/Bev therapy. RESULTS: Using the Response Evaluation Criteria in Solid Tumors version 1.1, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with lower objective response rates compared with TLR values <2 (18% vs. 33%, respectively). Moreover, TLR values ≥2 were significantly associated with higher e-PD rates compared with TLR values <2 (64% vs. 11%, respectively) and worse e-PFS (p = 0.021). In multivariate analysis, TLR ≥2 showed marginal significance as a predictor of e-PD (p = 0.053), and utility as a predictor for worse e-PFS (hazard ratio, 7.153; 95% confidence interval, 1.258-40.689; p = 0.027). In contrast, no significant differences in OS with/without e-PD were observed during the treatment course. In this study, 8 patients experienced e-PD and almost 40% of patients experienced acceptable disease control following subsequent lenvatinib treatment. CONCLUSION: Pretreatment 18F-FDG-PET/CT may be a useful new predictor of e-PD and may enable early decision-making based on early treatment changes following Atezo/Bev treatment of HCC.

Dynamics of Circulating miR-122 Predict Liver Cancer and Mortality in Japanese Patients with Histopathologically Confirmed NAFLD and Severe Fibrosis Stage.

INTRODUCTION: It is unclear whether the relationships between changes in fibrosis and circulating microRNA-122 (miR-122) dynamics might influence the prognosis of nonalcoholic fatty liver disease (NAFLD). METHODS: This study investigates the impact of serum miR-122 dynamics and histological changes on the incidence of liver cancer and mortality in 81 Japanese NAFLD patients who underwent serial liver biopsies. The median interval between the first and second liver biopsies was 2.9 years. RESULTS: The fibrosis stage scores indicated progression, no change, and improvement (a decrease of one point or more) in 21.0%, 56.8%, and 22.2% of the patients, respectively. There were 64 patients in the high-risk group who had no improvement in stage scores. Among these, the miR-122 levels were significantly lower in 7 patients with liver cancer than those of the 54 patients who had no liver cancer at the second liver biopsy. The cumulative rates of liver cancer were significantly higher in cases with miR-122 ratios <0.5 (serum miR-122 level at second biopsy to that at first biopsy) than those with ratios ≥0.5. The cumulative survival rates in cases with miR-122 ratios <0.5 tended to be lower than those with ratios ≥0.5. Of the 64 high-risk patients, 39 indicated stage 2 or greater (severe fibrosis stage) at the first liver biopsy and also showed similar results of cumulative liver cancer and survival rates. CONCLUSIONS: Longitudinal examination of serial liver biopsies indicated that the circulating miR-122 dynamics might be useful in predicting the prognosis for NAFLD patients with severe fibrosis stage and no improvement of the stage scores.

Renal safety and biochemical changes for 2 years after switching to tenofovir alafenamide from long-term other nucleotide analog treatment in patients with chronic hepatitis B.

BACKGROUND: Long-term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long-term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B. METHODS: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long-term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF. RESULTS: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1-2 and 3a-4 at baseline. In patients with CKD stages 3a-4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m2 /year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1-2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1. CONCLUSIONS: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a-4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized.

A case of primary multidrug-resistant pulmonary tuberculosis with high minimum inhibitory concentration value for bedaquiline.

Bedaquiline is a new ATP synthesis inhibitor developed as an anti-tuberculosis agent. It has resistance-associated variants (RAV), regardless of preceding bedaquiline exposure. Herein, we describe the case of a patient with multidrug-resistant tuberculosis (MDR-TB) who had no history of bedaquiline therapy but presented a relatively high minimum inhibitory concentration (MIC) of bedaquiline (1 µg/mL). Whole genome sequencing revealed a mutation in the resistance-associated gene Rv0678. The patient was first treated with a five-drug regimen (bedaquiline, delamanid, levofloxacin, cycloserine, and amikacin), which induced negative sputum culture conversion. Despite the successful treatment outcome, several questions remain regarding the efficacy of bedaquiline in this patient. Bedaquiline is an indispensable drug for MDR-TB treatment, but its clinical efficiency in the presence of Rv0678 mutations remains unclear. Therefore, evaluating the MIC of bedaquiline even in patients without a history of bedaquiline use is important for therapeutic regimen selection and may emphasize the importance of therapeutic drug monitoring in cases of bedaquiline RAV.

Comparison of Human Tissue Gadolinium Retention and Elimination between Gadoteridol and Gadobenate.

Background Linear gadolinium-based contrast agents (GBCAs) are known to be retained at higher levels of gadolinium than macro-cyclic GBCAs. However, very little is known regarding their relative elimination rates and retained fraction of injected gadolinium. Purpose To quantify and compare gadolinium retention and elimination rates in human brain tissue, skin, and bone obtained from cadavers exposed to single-agent administration of either gadoteridol (macrocyclic GBCA) or gadobenate dimeglumine (linear GBCA). Materials and Methods Autopsy cases from August 2014 to July 2019 of patients exposed to a single type of GBCA, either gadoteridol or gadobenate dimeglumine, either single or multiple doses, were included. Gadolinium levels in the brain, skin, and bone were analyzed with inductively coupled plasma mass spectrometry. Linear regression was used to compare gadolinium retention between agents and estimate elimination rates of the retained gadolinium using the time between last injection and death. Results Twenty-eight cadavers with gadoteridol exposure and nine with gadobenate dimeglumine exposure were identified (22 men; age range, 19-83 years). The median gadolinium retention of gadobenate dimeglumine was 3.0-6.5 times higher than that of gadoteridol in the brain (P < .02), 4.4 times higher in bone (P = .002), and 2.9 times higher in skin (P = .05). Gadolinium retention in the globus pallidus (GP), dentate nucleus (DN), white matter (WM), bone, and skin decreased with time elapsed from last administration to death in both the gadobenate dimeglumine (GP: -3% per twofold increase in time, P = .69; DN: -2%, P = .83; WM: -20%, P = .01; bone: -22%, P = .07; skin: -47%, P < .001) and gadoteridol (GP: -17%, P = .11; DN: -16%, P = .15; WM: -30%, P < .001; bone: -11%, P = .16; skin: -24%, P = .01) groups (P values for elimination are compared with a null hypothesis of no elimination). Conclusion The linear agent gadobenate dimeglumine retains several-fold higher levels of gadolinium in the brain and bone compared with the macrocyclic agent gadoteridol. Nonzero elimination of retained gadolinium was detected in the white matter and skin for both agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Prognostic Impact of Surgical Intervention After Lenvatinib Treatment for Advanced Hepatocellular Carcinoma.

BACKGROUND: With the introduction of new molecular-targeted agents, an increasing number of patients with advanced hepatocellular carcinoma (HCC) are benefiting from salvage interventions; however, the actual rate of conversion surgery and its prognostic advantages remain unclear. METHODS: The clinical outcomes of 107 consecutive patients who underwent lenvatinib treatment for advanced HCC were reviewed and the efficacy of additional therapy, including surgery, was investigated. RESULTS: Of the 107 patients who were initially unsuitable for curative-intent therapy or transarterial chemoembolization (TACE), 54 (50.5%) received further therapy after lenvatinib treatment (surgery [n = 16] and TACE or other treatments [n = 38]). Of the 16 patients who received surgical intervention, R0 resection was achieved in 9 (8.4%) patients. Survival analysis confirmed that successful conversion to R0 resection was associated with a longer time to treatment failure (hazard ratio [HR] 0.04, 95% confidence interval [CI] 0.01-0.29; p = 0.002) and better disease-specific survival (HR 0.04, 95% CI 0.01-0.30; p = 0.002) compared with no additional treatment, while additional treatment other than surgery or R2 resection was associated with only a marginal or no prognostic advantage. Multivariate analysis confirmed that a decrease in plasma des-gamma-carboxyprothrombin levels compared with baseline levels (odds ratio 22.22, 95% CI 3.42-144.29; p = 0.001) was significantly correlated with successful R0 resection after lenvatinib treatment, irrespective of the tumor response as assessed by imaging analysis. CONCLUSIONS: In selected patients with advanced HCC, conversion surgery after lenvatinib treatment may offer significant survival benefit as long as R0 resection is achieved.

TERT Promoter Mutation in Serum Cell-Free DNA Is a Diagnostic Marker of Primary Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease.

INTRODUCTION: It remains unclear whether TERT promoter mutation (TERT C228T) in serum cell-free DNA (cfDNA) is useful for the diagnosis of hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In this retrospective study, we analyzed the relationships between TERT C228T in serum cfDNA and levels of AFP and PIVKAII in 57 Japanese patients with histopathologically confirmed NAFLD background, consisting of 36 patients with HCC and 21 without HCC. We also examined the liver-related survival rate and HCC recurrence rate after the initial treatment for HCC. TERT C228T was detected using a highly sensitive method based on wild-type blocking PCR (detection limit in excess of 0.7% mutant-type DNA). RESULTS: In all of the 57 patients, multivariate analysis identified TERT C228T positive as significant determinant of primary HCC. In the 36 patients with HCC, the percentage of patients positive for TERT C228T was 63.9%. The percentage of patients positive for TERT C228T with normal AFP and PIVKAII was 35.3%. The positive predictive value and specificity for prediction of BCLC stage 0 or A were both high. In 6 patients, TERT C228T was repeatedly negative during follow-up but became positive at the time of HCC diagnosis. Four patients who underwent HCC surgical resection had well-differentiated solitary HCC measuring <30 mm, and all were TERT C228T positive with normal AFP and PIVKAII. TERT C228T status had no influence on the cumulative liver-related survival rate and HCC recurrence rate. CONCLUSIONS: Our results highlight the superiority of TERT C228T in serum cfDNA compared with AFP and PIVKAII in the early diagnosis of primary HCC in NAFLD patients.

Pretreatment Positron Emission Tomography with 18F-Fluorodeoxyglucose May Be a Useful New Predictor of Overall Prognosis Following Lenvatinib Treatment.

BACKGROUND AND AIM: The aim of this study was to identify the utility of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a predictor of overall prognosis in patients with hepatocellular carcinoma treated with lenvatinib. METHODS: Forty-eight consecutive patients who received lenvatinib treatment were reviewed. The oncological aggressiveness of tumors estimated using 18F-FDG-PET/CT was investigated by the analysis of progression-free survival (PFS), post-progression survival (PPS), and overall survival (OS). Multivariate analysis was used to identify potential confounders for OS during lenvatinib therapy. RESULTS: Using the Modified Response Evaluation Criteria in Solid Tumors, a tumor-to-normal liver ratio (TLR) ≥2, indicating higher oncological aggressiveness in HCCs, was associated with a better objective response to lenvatinib than a TLR <2 (78 vs. 62%), resulting in a similar PFS (p = 0.751). Because of a significantly worse PPS, OS with a TLR ≥2 was poor compared to a TLR < 2 (p = 0.012). Multivariate analysis confirmed that a TLR ≥ 2 was associated with poor OS (hazard ratio, 2.709; 95% CI, 1.140-6.436; p = 0.024). Analysis of 24 patients who received a repeat 18F-FDG-PET/CT showed that daily changes expressed as ΔTLR × 103/day over the treatment course tended to be different among the types of subsequent treatment. A R0 resection and lenvatinib-TACE sequential therapy provided good disease control (median, -4.593 and -0.024, respectively) compared with other treatments (median, 5.278) (p = 0.075). CONCLUSION: Lenvatinib has acceptable disease control regardless of estimated tumor differentiation. A high TLR (≥2) is a poor prognostic factor of OS following lenvatinib treatment, while ΔTLR × 103/day provides useful information of disease control status.

Potential and Clinical Significance of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Evaluating Liver Cancer Response to Lenvatinib Treatment.

BACKGROUND: The sensitivity of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in hepatocellular carcinoma (HCC) is low; however, clinical evidence demonstrating its prognostic value in patients with HCC has recently been reported. This study aimed to assess the value of 18F-FDG-PET/CT as a tool for evaluating the response of HCC to lenvatinib treatment. METHODS: We evaluated 11 consecutive patients with HCC diagnosed by dynamic CT or magnetic resonance imaging combined with 18F-FDG-PET/CT from April 2018 to December 2019. The tumor-to-normal liver ratio (TLR) of the target tumor was measured before and during the course of lenvatinib treatment with 18F-FDG-PET/CT (pre and post analysis, respectively), with a TLR ≥2 classified as PET-positive HCC. At the time of each evaluation, we also used the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the modified RECIST (mRECIST), and the tumor marker alfa-fetoprotein (AFP). RESULTS: Of 11 patients, 3 (27%) and 8 (73%) had an objective response to lenvatinib treatment at the time of post-analysis by RECIST 1.1 and mRECIST, respectively. There were 3 (27%) and 7 (64%) patients with PET-positive HCC at the time of pre- and post-analysis, respectively. There was a significant correlation between the rates of change in AFP and TLR during lenvatinib treatment (r = 0.69, p = 0.019). Based on these results, we were able to perform liver resection on 4 patients with PET-positive HCC as conversion therapy. Three samples from these patients showed poorly differentiated tumors. CONCLUSION: 18F-FDG-PET/CT has potential as an evaluation tool for describing biological tumor behavior and reflecting disease progression, location, and treatment response. This modality may provide useful information for considering prognosis and subsequent therapy.

PNPLA3 genotype and fibrosis-4 index predict cardiovascular diseases of Japanese patients with histopathologically-confirmed NAFLD.

BACKGROUND: Reliable noninvasive predictors of the top three causes of death [cardiovascular diseases (CVDs), malignancies, and liver-related events in patients with non-alcoholic fatty liver disease (NAFLD)] have not yet been determined. METHODS: We retrospectively investigated the incidence of three complications [CVDs, malignancy (except for liver cancer), and liver-related events] in 477 Japanese patients with histo-pathologically confirmed NAFLD for a median follow-up of 5.9 years. In addition to histological findings, we also investigated noninvasive predictors. RESULTS: A score of ≥ 2.67 for the noninvasive diagnosis of stage 4 fibrosis based on the Fibrosis-4 (FIB-4) index indicated a high level area under the receiver operating characteristic (AUROC) curve (0.90), sensitivity (82.9%), specificity (86.4%), and negative predictive value [(NPV) of 98.5%]. The yearly incidence rates of CVDs, malignancies, and liver-related events were found to be 1.04%, 0.83%, and 0.30%, respectively. Multivariate analysis identified a FIB-4 index ≥ 2.67 score as a significant and independent, noninvasive predictor of these three complications. Furthermore, the cumulative incidence rates of CVDs were significantly different among the three genotypes of PNPLA3. PNPLA3 genotype CC, chronic kidney disease (CKD), and FIB-4 index ≥ 2.67 was could be attributed to these three significant CVD risk factors. The rates of CVDs were significantly different among the three subgroups based on the combination of risk factors. In malignancy (except for liver cancer), the incidence rate of colon cancer was 25.0%; in particular, the rate in females was 53.8%. CONCLUSIONS: Our results highlighted the importance of the PNPLA3 genotype and FIB-4 index ≥ 2.67 on the incidence of complications in Japanese patients with NAFLD, especially the incidence of CVDs. Early diagnosis, based on the presence of one or more risk factors, and early treatment might improve the prognosis for NAFLD patients.

Mortality rates and risk factors in 1412 Japanese patients with decompensated hepatitis C virus-related cirrhosis: a retrospective long-term cohort study.

BACKGROUND: Hepatitis C virus is the leading cause of liver cirrhosis and hepatocellular carcinoma in Japan. We aimed to examine the long-term (> 20 years) mortality and hepatocellular carcinoma rates and associated risk factors in 1412 Japanese patients with decompensated hepatitis C virus-related cirrhosis (Child-Pugh B or C). METHODS: Cumulative survival and hepatocellular carcinoma rates were determined using Kaplan-Meier analysis. Independent risk factors were identified by multivariate analysis. A two-tailed P-value of < 0.05 was considered significant. RESULTS: The patients were followed up for a median of 2 years (range 0.5-24.2 years). In total, 62.3%, 41.7%, 4.7%, and 68.3% of the patients had a history of hepatocellular carcinoma, ascites, hepatic encephalopathy, and esophageal varices, respectively. The 1-, 5-, 10-, and 20-year cumulative overall survival rates in the total cohort was 74.9%, 29.0%, 9.1%, and 1.4%, respectively. The 1-, 3-, 5-, and 10-year cumulative survival rates for patients without hepatocellular carcinoma were 93.1%, 54.4%, 18.2%, and 4.0%, respectively, and the corresponding cumulative post-decompensation hepatocellular carcinoma rates were 14.0%, 31.6%, 46.1%, and 66.2%, respectively. The independent risk factors for mortality were older age, Child-Pugh C cirrhosis, the presence of hepatocellular carcinoma, low estimated glomerular filtration rate, low serum sodium level, low platelet count, and high γ-glutamyl transferase and α-fetoprotein levels for all patients and older age, Child-Pugh C cirrhosis, and low estimated glomerular filtration rate for patients without hepatocellular carcinoma. Overall, 1035 patients (73.3%) died; the causes of death were liver failure with/without hepatocellular carcinoma, pneumonia, sepsis, cardiovascular disease, and non-hepatocellular carcinoma malignancies. The corresponding morality rates per person-year were 133.4, 59.9, 10.9, 10.6, 9.0, and 5.2, respectively. CONCLUSIONS: Among Japanese patients with decompensated hepatitis C virus-related cirrhosis, hepatocellular carcinoma is associated with poor prognosis. Our results highlight the importance of managing liver-related events, including hepatocellular carcinoma, in these patients.