Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia.

IKZF1 deletion is a recurrent genomic alteration in B-cell acute lymphoblastic leukemia (B-ALL) and is divided into dominant-negative (DN) and loss of function (LOF) deletions. The prognostic impact of each deletion has not been fully elucidated. We retrospectively analyzed 117 patients with adult B-ALL including 60 patients with BCR::ABL1-positive B-ALL and 57 patients with BCR::ABL1-negative B-ALL by the fluorescence in situ hybridization (FISH) method for IKZF1 deletion and multiplex PCR for the 4 most common IKZF1 deletions (∆4-7, ∆2-7, ∆2-8, and ∆4-8). Samples, in which IKZF1 deletion was detected by FISH but a specific type of deletion was not identified by the PCR, were categorized as "other." Patients were classified into a DN group that had at least 1 allele of ∆4-7 (n = 23), LOF and other group (n = 40), and wildtype group (n = 54). DN type IKZF1 deletions were found in 33.3% of BCR::ABL1-positive cases and 5.2% of BCR::ABL1-negative cases. LOF and other type IKZF1 deletions were found in 43.4% of BCR::ABL1-positive cases and 24.6% of BCR::ABL1-negative cases. Patients with the DN group showed significantly higher overall survival (OS) than that of the LOF and other and WT groups (P = 0.011). Multivariate analysis including age, WBC counts, complex karyotype, and DN type IKZF1 deletion showed that the DN type of IKZF1 deletion (HR = 0.22, P = 0.013) had a positive impact and age ≥ 65 (HR = 1.92, P = 0.029) had a negative impact on OS. The prognostic impact of IKZF1 deletion depends on the type of deletion and DN type of IKZF1 deletion showed better prognosis in adult B-ALL patients.Clinical trial registration This study was part of a prospective observational study (Hokkaido Leukemia Net, UMIN000048611). It was conducted in compliance with ethical principles based on the Helsinki Declaration and was approved by the institutional review board of Hokkaido University Hospital (#015-0344).

Low Baseline CXCL9 Predicts Early Progressive Disease in Unresectable HCC with Atezolizumab Plus Bevacizumab Treatment.

Introduction: Atezolizumab plus bevacizumab treatment is highly effective in patients with unresectable hepatocellular carcinoma (HCC). However, progressive disease (PD) occurs in approximately 20% of HCC patients treated with atezolizumab plus bevacizumab, resulting in a poor prognosis. Thus, the prediction and early detection of HCC is crucial. Methods: Patients with unresectable HCC treated with atezolizumab plus bevacizumab and had baseline preserved serum (n = 68) were screened and classified according to their PD, 6 weeks after treatment initiation (early PD; n = 13). Of these, 4 patients each with and without early PD were selected for cytokine array and genetic analyses. The identified factors were validated in the validated cohort (n = 60) and evaluated in patients treated with lenvatinib. Results: No significant differences were observed in the genetic alterations in circulating tumor DNA. Cytokine array data revealed that baseline MIG (CXCL9), ENA-78, and RANTES differed substantially between patients with and without early PD. Subsequent analysis in the validation cohort revealed that baseline CXCL9 was significantly lower in patients with early PD than that in patients without early PD, and the best cut-off value of serum CXCL9 to predict early PD was 333 pg/mL (sensitivity: 0.600, specificity: 0.923, AUC = 0.75). In patients with lower serum CXCL9 (<333 pg/mL), 35.3% (12/34) experienced early PD with atezolizumab plus bevacizumab, while progression-free survival (PFS) was significantly shorter relative to that in patients without (median PFS, 126 days vs. 227 days; HR: 2.41, 95% CI: 1.22-4.80, p = 0.0084). While patients with objective response to lenvatinib had significantly lower CXCL9 levels compared with those of patients without. Conclusion: Baseline low serum CXCL9 (<333 pg/mL) levels may predict early PD in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Effects of activation of an alcohol metabolic gene, cigarette smoking, and alcohol intake on the incidence of metachronous gastric cancer in patients who underwent endoscopic resection for gastric cancer: A multicenter retrospective pilot study.

Background and Aim: Metachronous gastric cancer (GC) frequently occurs in patients who have undergone endoscopic resection (ER) for GC. We evaluated the risk for development of metachronous GC following ER for GC based on genetic polymorphisms for alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2), as well as alcohol consumption and smoking habits. Methods: We studied 77 patients who underwent ER for GC (median follow-up of 84 months). Genotyping of ADH1B/ALDH2 was performed using saliva sampling. Histories of alcohol consumption and smoking before and after ER and Helicobacter pylori eradication were documented. Results: Multivariate analyses revealed that homozygous slow-metabolizing ADH1B (hazard ratio [HR] = 2.38, P < 0.13), heavy smoking (HR = 2.36, P < 0.09), and cigarette smoking after ER (HR = 2.47, P < 0.10) were not independently associated with the risk of secondary GC development. We analyzed the cessation status of the 38 patients who were classified as heavy smokers before ER based on their smoking habits after the ER and divided them into a cessation group (n = 27, non-smokers after ER) and a non-cessation group (n = 11). Cumulative incidence curves of secondary GC in the cessation and non-cessation groups revealed 5-year incidence rates of 19.0% and 45.0%, respectively (P = 0.02). Conclusion: Continued cigarette smoking, at a high level, may be an important risk factor for the development of metachronous GC. Advice for smoking cessation should be given.

Infection with male and female Trichuris trichiura diagnosed in a non-endemic area.

Trichuris trichiura parasitizes only humans through fecal-oral transmission. In non-endemic areas, the frequency of endoscopic identification has been increasing due to the increasing number of immigrants from endemic countries. To prevent infection, it is important to pay attention to sanitary conditions such as soil and water sources.

Prognostic impact of FLT3-ITD, NPM1 mutation and CEBPA bZIP domain mutation in cytogenetically normal acute myeloid leukemia: a Hokkaido Leukemia Net study.

Mutation status of FLT3, NPM1, and CEBPA is used to classify the prognosis of acute myeloid leukemia, but its significance in patients with cytogenetically normal (CN) AML is unclear. We prospectively analyzed these genes in 295 patients with CN-AML and identified 76 (25.8%) FLT3-ITD, 113 (38.3%) NPM1 mutations, and 30 (10.2%) CEBPA biallelic mutations. We found that patients with FLT3-ITD had a poor prognosis at any age, while patients with CEBPA biallelic mutation were younger and had a better prognosis. FLT3-ITD and NPM1 mutations were correlated, and the favorable prognostic impact of being FLT3-ITD negative and NPM1 mutation positive was evident only in patients aged 65 years or more. For CEBPA, 86.7% of the patients with biallelic mutation and 9.1% of patients with the single allele mutation had in-frame mutations in the bZIP domain, which were strongly associated with a favorable prognosis. Multivariate analysis showed that age < 65 years, FLT3-ITD and CEBPA bZIP in-frame mutation were independent prognostic factors. The results suggest that analyzing these gene mutations at diagnosis can inform selection of the optimal intensity of therapy for patients with CN-AML.

Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia.

Venetoclax (VEN) is now widely used in the treatment of acute myelogenous leukemia (AML) in elderly patients who are not eligible for intensive remission induction therapy. Prolonged myelosuppression, increased incidence of infection, and long duration of hospital stay were major concerns for VEN treatment cases, and we thought that shortening the duration of VEN administration during induction therapy might solve these problems. Thirteen newly diagnosed AML patients who underwent VEN+azacitidine (AZA) induction therapy from March 2021 to June 2022 at Kushiro Rosai Hospital were analyzed retrospectively. The median age was 79 (range, 68-86) years, and 8 of the patients (61.5%) were classified as high risk according to the ELN 2017 risk stratification. Eight patients received VEN for 14 days (VEN14 group), and 5 patients received VEN for 28 days (VEN28 group). The composite complete remission (CRc) rate was 76.9% in total, and the CRc rates in the VEN14 and VEN28 groups were almost the same (75.0% and 80.0%, respectively). The median overall survival (OS) was not reached in the VEN14 group and was 254 days in the VEN28 group. The median event-free survival (EFS) was not reached in the VEN14 group and was 178 days in the VEN28 group. The VEN14 group might have a possibility to reduce febrile neutropenia (37.5% vs. 80%) and reduce the duration of hospital stay (median, 21.5 vs. 31 days) compared with the VEN28 group. VEN14 produced the same CRc rate and survival rate, safer profile, and shorter duration of hospital stay than VEN28.

Study protocol for HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer refractory to anti-EGFR antibodies.

Background: The first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies. Methods: FOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi. Discussion: There is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy. Clinical trial registration: Japan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.

Efficacy and Effect on Liver Functional Reserve of Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma in Patients Who Do Not Meet Eligibility Criteria of IMbrave150.

The IMbrave150 trial demonstrated the high efficacy and safety of atezolizumab and bevacizumab for unresectable hepatocellular carcinoma (HCC). In this multicenter study, the efficacy of this combination and its effect on liver functional reserve were evaluated in patients not meeting the eligibility criteria of IMbrave150. Of 115 patients with unresectable HCC treated with atezolizumab and bevacizumab between October 2020 and January 2022, 72 did not meet the eligibility criteria of IMbrave150, most frequently due to a history of systemic therapy (60/72), platelet counts < 75 × 109/L (7/72), Child-Pugh B (9/72), and 2+ proteinuria (8/72). Atezolizumab and bevacizumab therapy was equally effective for patients who did or did not meet the eligibility criteria (PFS, 6.5 vs. 6.9 months, p = 0.765), consistent with subgroup analyses of histories of systemic therapy, platelet counts, Child-Pugh, and proteinuria. Baseline ALBI scores were worse in patients who did not meet the criteria than in those who did and significantly worsened after treatment initiation in patients not meeting the criteria (baseline vs. 12 weeks; 2.35 ± 0.43 vs. −2.18 ± 0.54; p = 0.007). Accordingly, atezolizumab plus bevacizumab was effective for patients not meeting the eligibility criteria of IMbrave150, although careful monitoring for changes in liver functional reserve is needed.

Study protocol of the HGCSG1803: a phase II multicentre, non-randomised, single-arm, prospective trial of combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) as first-line treatment for metastatic or relapsed pancreatic cancer.

INTRODUCTION: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) has become one of the standard treatments for metastatic pancreatic cancer. However, the use of FOLFIRINOX requires prolonged infusion. Therefore, we planned to develop a new combination chemotherapy regimen with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. In the phase Ⅰ study that was conducted previously, the safety and recommended dose of OX-IRIS were assessed. In this study, we will evaluate the efficacy and safety of OX-IRIS. METHODS AND ANALYSIS: The HGCSG1803 study started as a multicentre, non-randomised, single-arm, prospective, phase II study in December 2019. Eligible subjects were patients with untreated metastatic or relapsed pancreatic cancer. OX-IRIS is administered as follows: 30 min infusion of antiemetic; 2-hour infusion of oxaliplatin (65 mg/m2); 1.5-hour infusion of irinotecan (100 mg/m2) on day 1 and 15 of each 4-week cycle; and oral S-1 (40 mg/m2) twice daily from after dinner on day one to after breakfast on day 15, followed by a 14-day rest, to be repeated every 2 weeks until disease progression, unacceptable toxicity or patient refusal. The primary endpoint is response rate. The secondary endpoints are overall and progression-free survival, safety and dose for each drug. Using a binomial test, a sample size of 40 patients was set with a threshold value of 10% and expected value of 30%. Registration of 40 cases is planned from 18 institutions in Japan. ETHICS AND DISSEMINATION: All the procedures will be conducted in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1964 and its later versions. All the patients will receive written information about the trial and will provide informed consent before enrolment. This trial was approved by the Hokkaido University Certified Review Board (approval No: 018-037). TRIAL REGISTRATION NUMBER: jRCTs011190008.

High CRP-albumin ratio predicts poor prognosis in transplant ineligible elderly patients with newly diagnosed acute myeloid leukemia.

Acute myeloid leukemia (AML) patients older than 65 years have a poor prognosis. Recently, CAR (C-reactive-protein/albumin ratio) has been actively reported as a prognostic index reflecting the nutritional and inflammatory status of elderly patients with solid tumors, but the usefulness of this index as a prognostic indicator in transplant-ineligible elderly AML patients has not been investigated. We studied genetic alterations and CARs in 188 newly diagnosed AML patients aged 65 years or older who were treated in a multicenter setting and had treated without HSCT. Both NCCN 2017 risk group, reflecting the genetic component of the tumor, and CAR, reflecting the inflammatory and nutritional status of the patient, successfully stratified the overall survival (OS) of the patients (2-year OS; CAR low vs high, 42.3% vs 17.8%, P < 0.001). Furthermore, in multivariate analysis, NCCN 2017 poor group and high CAR were extracted as independent poor prognostic factors predicting 2-year OS in the current study. We found, for the first time, that CAR at diagnosis predicted the prognosis of elderly patients with newly diagnosed AML treated without HSCT.

Non-age-related neoplastic loss of sex chromosome correlated with prolonged survival in real-world CBF-AML patients.

In this real-world clinical study, in which we determined eligibility for allogenic hematopoietic stem cell transplantation by prognostic factors and minimal residual disease status, we retrospectively evaluated cytogenetic, genetic, and clinical features in 96 patients with core-binding factor acute myeloid leukemia (CBF-AML) including 62 patients with RUNX1/RUNX1T1 and 34 patients with CBFß/MYH11. Multivariate analyses for 5-year overall survival (OS) in CBF-AML patients revealed that age of 50 years or older (HR: 3.46, 95% CI 1.47-8.11, P = 0.004) and receiving 2 or more induction cycles (HR: 3.55, 95% CI 1.57-8.05, P = 0.002) were independently associated with worse OS and that loss of sex chromosome (LOS) was independently associated with better OS (HR: 0.09, 95% CI 0.01-0.71, P = 0.022). At the time of complete remission, all 21 karyotyped patients with LOS had a normal karyotype. Furthermore, in all 9 patients with LOS who had a mosaic of metaphase cells with and without t(8;21) or inv(16), the metaphase cells without t(8;21)/inv(16) showed a normal karyotype. These results proved that LOS was not age-related and physiological, but rather a neoplastic chromosomal abnormality.

Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria.

AIM: A clinical trial (IMbrave150) indicated the efficacy and safety of atezolizumab plus bevacizumab for patients with unresectable hepatocellular carcinoma (HCC). In this study, we evaluated this therapeutic combination in a real-world setting, with a focus on patients who did not meet the IMbrave150 eligibility criteria. METHODS: In this multicenter study, patients with unresectable HCC treated with atezolizumab plus bevacizumab between October 2020 and May 2021 were screened. In patients who did not meet IMbrave150 eligibility criteria, treatment responses and safety at 6 and 12 weeks were evaluated. RESULTS: Atezolizumab plus bevacizumab was initiated in 64 patients, including 46 patients (71.9%) who did not meet IMbrave150 eligibility criteria. Most of these patients had a history of systemic therapy (44/46). The objective response rate and disease control rate observed using Response Evaluation Criteria in Solid Tumors 1.1 were 5.2% and 82.8% at 6 weeks and 10.0% and 84.0% at 12 weeks, respectively; these rates were similar between patients who met and did not meet the IMbrave150 criteria. Ten patients experienced progressive disease (PD) at 6 weeks. Portal vein tumor thrombosis was significantly associated with PD (p = 0.039); none of the 15 patients with hepatitis B virus-related HCC experienced PD (p = 0.050). The most common adverse events of grade 3 or higher were aspartate aminotransferase elevation (n = 8, 13.8%) and the safety profile was similar between patients who met and did not meet the IMbrave150 criteria. CONCLUSION: Most patients treated with atezolizumab plus bevacizumab did not meet the IMbrave150 criteria; however, the combination therapy showed good safety and efficacy at the early treatment phase.

Feasibility of a modified search, coagulation, and clipping method with and without the use of polyglycolic acid sheets and fibrin glue for preventing delayed bleeding after gastric endoscopic submucosal dissection.

BACKGROUND: Methods have been developed for preventing delayed bleeding (DB) after gastric endoscopic submucosal dissection (GESD). However, none of the methods can completely prevent DB. We hypothesized that DB could be prevented by a modified search, coagulation, and clipping (MSCC) method for patients at low risk for DB and by combining the use of polyglycolic acid sheets and fibrin glue with the MSCC method (PMSCC method) for patients at high risk for DB (antibleeding [ABI] strategy). This study assessed the technical feasibility of this novel strategy. METHOD: We investigated 123 lesions in 121 consecutive patients who underwent GESD in Kushiro Rosai Hospital between April 2018 and January 2020. The decision for continuation or cessation of antithrombotic agents was based on the Guidelines for Gastroenterological Endoscopy in Patients Undergoing Antithrombotic Treatment. RESULTS: Oral antithrombotic agents were administered to 28 patients (22.8%). The en bloc R0 resection rate was 98.4%. The MSCC method and the PMSCC method for preventing DB were performed in 114 and 9 lesions, respectively. The median time of the MSCC method was 16 min, and the median speed (the resection area divided by the time of method used) was 3.6 cm2/10 min. The median time of the PMSCC method was 59 min, and the median speed was 1.3 cm2/10 min. The only delayed procedural adverse event was DB in 1 (0.8%) of the 123 lesions. CONCLUSIONS: The ABI strategy is feasible for preventing DB both in patients at low risk and in those at high risk for DB after GESD, whereas the PMSCC method may be necessary for reduction of time.

Light-chain amyloid myopathy isolated to skeletal muscles: A case report.

Isolated amyloidosis, especially of amyloid light-chain type, is an infrequent disease. Systemic chemotherapy for light-chain amyloidosis isolated to skeletal muscles plays a key role to reduce clonal plasma cells producing aberrant immunoglobulin.

A novel nutritional index "simplified CONUT" and the disease risk index independently stratify prognosis of elderly patients with acute myeloid leukemia.

Elderly patients aged 65 or older with acute myeloid leukemia (AML) have poor prognosis. The risk stratification based on genetic alteration has been proposed in national comprehensive cancer network (NCCN) guideline but its efficacy was not well verified especially in real world elderly patients. The nutritional status assessment using controlling nutritional status (CONUT) score is a prognostic biomarker in elderly patients with solid tumors but was not examined in elderly AML patients. We performed prospective analysis of genetic alterations of 174 patients aged 65 or older with newly diagnosed AML treated without hematopoietic stem cell transplantation (HSCT) and developed simplified CONUT (sCONUT) score by eliminating total lymphocyte count from the items to adapt AML patients. In this cohort, both the NCCN 2017 risk group and sCONUT score successfully stratified the overall survival (OS) of the elderly patients. A multivariable analysis demonstrated that adverse group in NCCN 2017 and high sCONUT score were independently associated with poor 2-year OS. Both risk stratification based on NCCN 2017 and sCONUT score predict prognosis in the elderly patients with newly diagnosed AML.

Validation and comparison of prognostic values of GNRI, PNI, and CONUT in newly diagnosed diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma. Emerging evidence indicates that poor nutritional status determined with nutritional indices such as geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI), and controlling nutritional status score (CONUT) was associated with poor prognosis of DLBCL. We conducted this multicenter retrospective study to validate and compare prognostic values of the three indices in 615 newly diagnosed DLBCL patients. The overall survival (OS) in patients with poor nutritional status determined with each of these nutritional indices were significantly inferior compared with that in those without nutritional risks (5-year OS in patients with GNRI < 95.7 and GNRI ≥ 95.7 were 56.4% and 83.5%, P < 0.001; PNI < 42.4 and PNI ≥ 42.4 were 56.1% and 81.0%, P < 0.001; CONUT > 4 and CONUT ≤ 4 were 53.1% and 77.1%, P < 0.001). GNRI and CONUT were independent prognostic predictors for OS (GNRI < 95.7, hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.22-2.74, P = 0.0032; CONUT > 4, HR 1.53, 95% CI 1.05-2.23, P = 0.028) after multivariate analyses. Nutritional status determined with GNRI affected OS more strongly in the patients with nongerminal center B cell-like (nonGCB) DLBCL compared with that in those with GCB-type DLBCL. In conclusion, baseline poor nutritional status determined based on GNRI or CONUT was an independent risk factor of newly diagnosed DLBCL, and GNRI was also useful as an independent prognostic factor for patients with nonGCB-type DLBCL.

Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria.

AIM: This study aimed to determine the efficacy and safety of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC) who did not meet REFLECT eligibility criteria (phase 3 clinical trial). METHODS: In this multicenter retrospective study, patients with unresectable HCC treated with lenvatinib between 2018 and 2019 and had adequate clinical data were included. Objective response rate, progression-free-survival (PFS) and safety were evaluated according to meeting or not meeting the REFLECT eligibility criteria and according to the criteria of the REFLECT trial. RESULTS: Of the 105 patients included, 61% (64 of 105) did not meet the REFLECT eligibility criteria. Safety and median PFS of lenvatinib were similar between the patients who did and those who did not meet the criteria. Among the patients who did not meet the criteria, 28, 27, 14, six, seven and five had a history of tyrosine kinase inhibitor (TKI) treatment, Child-Pugh score B, HCC in ≥50% of the liver, reduced platelet count, bile duct invasion and main portal vein invasion, respectively. The efficacy and safety of lenvatinib for patients with or without Child-Pugh-score B or HCC in ≥50% of the liver were similar. Although treatment outcome was not significantly different, patients with TKI treatment history tended to have longer median PFS, whereas those with main portal vein invasion tended to have shorter median PFS. CONCLUSION: Lenvatinib was effective for patients who did not meet the REFLECT inclusion criteria. However, the treatment outcome may vary according to several factors, such as a history of TKI treatment and tumor invasion.