Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

Comparative analysis of the therapeutic outcomes of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma patients aged 80 years and older: Multicenter study.

AIM: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older. METHODS: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first-line treatment, respectively, were retrospectively analyzed. RESULTS: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01-86.0) and 83.0 (82.0-86.0) years (p = 0.3), respectively. Men accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p = 0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p = 1.0). The median progression-free survival (PFS) in the LEN and Atez/Bev groups was 6.3 and 7.2 months, respectively, which were not significantly different (p = 0.2). The median overall survival (OS) was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p = 0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of postprogression treatment (59.0% vs. 35.7%, p = 0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p < 0.001) compared to the LEN group. CONCLUSIONS: Atezolizumab plus bevacizumab showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of postprogression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first-line treatment even for elderly HCC patients.

Comparing the impact of atezolizumab plus bevacizumab and lenvatinib on the liver function in hepatocellular carcinoma patients: A mixed-effects regression model approach.

AIM: This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma. METHODS: We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity-score-matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed-effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow-up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups. RESULTS: Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were -2.41 ± 0.40 and -2.44 ± 0.42 at baseline, and -2.17 ± 0.56 and -2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN-treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev. CONCLUSIONS: Using a nonlinear mixed-effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN-treated patients with BCLC advanced stage or those receiving the full dose of LEN.

Full genome-based characterization of an Asian G3P[6] human rotavirus strain found in a diarrheic child in Japan: Evidence for porcine-to-human zoonotic transmission.

Human rotavirus strains having the unconventional G3P[6] genotype have been sporadically detected in diarrheic patients in different parts of the world. However, the full genomes of only three human G3P[6] strains from Asian countries (China, Indonesia, and Vietnam) have been sequenced and characterized, and thus the exact origin and evolution of G3P[6] strains in Asia remain to be elucidated. Here, we sequenced and characterized the full genome of a G3P[6] strain (RVA/Human-wt/JPN/SO1199/2020/G3P[6]) found in a stool sample from a 3-month-old infant admitted with acute gastroenteritis in Japan. On full genomic analysis, strain SO1199 was revealed to have a unique Wa-like genogroup configuration: G3-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1. VP6 genotype I5 and NSP1 genotype A8 are commonly found in porcine rotavirus strains. Furthermore, phylogenetic analysis demonstrated that all 11 genes of strain SO1199 were closely related to those of porcine and/or porcine-like human rotaviruses and thus appeared to be of porcine origin. Thus, strain SO1199 was shown to possess a porcine-like genomic backbone and thus is likely to be the result of interspecies transmission of a porcine rotavirus strain. Of note is that all 11 genes of strain SO1199 were phylogenetically located in clusters, distinct from those of the previously identified porcine-like human G3P[6] strains from around the world including Asia, suggesting the occurrence of independent porcine-to-human zoonotic transmission events. To our knowledge, this is the first report on full genome-based characterization of a human G3P[6] strain that has emerged in Japan. Our findings revealed the diversity of unconventional human G3P[6] strains in Asia, and provide important insights into the origin and evolution of G3P[6] strains.

Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer: A Case Report.

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Importance: Immune checkpoint inhibitors (ICIs) are increasingly used in patients with advanced hepatocellular carcinoma (HCC). However, data on ICI therapy in patients with advanced HCC and impaired liver function are scarce. Objective: To conduct a systematic review and meta-analysis to determine the efficacy and safety of ICI treatment for advanced HCC with Child-Pugh B liver function. Data Sources: PubMed, Embase, Web of Science, and Cochrane Library were searched for relevant studies from inception through June 15, 2022. Study Selection: Randomized clinical trials, cohort studies, or single-group studies that investigated the efficacy or safety of ICI therapy for Child-Pugh B advanced HCC were included. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline was followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 > 50%); otherwise, a fixed-effect model was used. Main Outcomes and Measures: The objective response rate (ORR) and overall survival (OS) were considered to be the primary efficacy outcomes of ICI treatment for Child-Pugh B advanced HCC, and the incidence of treatment-related adverse events (trAEs) was set as the primary measure for the safety outcome. Results: A total of 22 studies including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC comprised the analytic sample (median age range, 53-73 years). Upon pooled analysis, patients treated with ICIs in the Child-Pugh B group had an ORR of 14% (95% CI, 11%-17%) and disease control rate (DCR) of 46% (95% CI, 36%-56%), with a median OS of 5.49 (95% CI, 3.57-7.42) months and median progression-free survival of 2.68 (95% CI, 1.85-3.52) months. The rate of any grade trAEs in the Child-Pugh B group was 40% (95% CI, 34%-47%) and of grade 3 or higher trAEs was 12% (95% CI, 6%-23%). Compared with the Child-Pugh A group, the ORR (odds ratio, 0.59; 95% CI, 0.43-0.81; P < .001) and DCR (odds ratio, 0.64; 95% CI, 0.50-0.81; P < .001) were lower in the Child-Pugh B group. Child-Pugh B was independently associated with worse OS in patients with advanced HCC treated with ICIs (hazard ratio, 2.72 [95% CI, 2.34-3.16]; adjusted hazard ratio, 2.33 [95% CI, 1.81-2.99]). However, ICIs were not associated with increased trAEs in the Child-Pugh B group. Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that although the safety of ICI treatment was comparable between patients with HCC with vs without advanced liver disease and the treatment resulted in a significant number of radiologic responses, survival outcomes are still inferior in patients with worse liver function. More study is needed to determine the effectiveness of ICI treatment in this population.

Relationship of Atezolizumab plus Bevacizumab Treatment with Muscle Volume Loss in Unresectable Hepatocellular Carcinoma Patients: Multicenter Analysis.

Background/Aim: There is no known report regarding the relationship of atezolizumab plus bevacizumab (Atez/Bev) treatment with muscle volume loss (MVL) in unresectable hepatocellular carcinoma (u-HCC) patients. This study aimed to elucidate the clinical relationship between MVL and Atez/Bev. Materials/Methods: From September 2020 to December 2021, 229 u-HCC patients treated with Atez/Bev and with muscle volume data obtained by computed tomography at the baseline available were analyzed (median age, 74 years; males, 186 (81.2%); ECOG PS 0/1, 221 (96.5%); HCV:HBV:alcohol:others = 81:33:40:75; Child-Pugh A, 212 (92.6%); modified albumin-bilirubin (mALBI) grade 1:2a:2b = 79:60:90; BCLC 0:A:B:C = 1:24:87:117; median observation period, 6.8 months). Japan Society of Hepatology criteria were used for definition of MVL and prognostic factors were retrospectively evaluated. Results: Multivariate Cox-hazard analysis of prognostic factors for progression-free survival (PFS) showed elevated alpha-fetoprotein (AFP) (≥100 ng/mL) (HR 1.848, 95% CI 1.264-2.702, p = 0.002), mALBI grade (≥2a) (HR 1.563, 95% CI 1.035-2.359, p = 0.034), and MVL (HR 1.479, 95% CI 1.020-2.144, p = 0.039) as significant factors. For overall survival (OS), significant factors included elevated AFP (≥100 ng/mL) (HR 3.564, 95% CI 1.856-6.844, p < 0.001), mALBI grade (≥2a) (HR 3.451, 95% CI 1.580-7.538, p = 0.002), and MVL (HR 2.119, 95% CI 1.150-3.904, p = 0.016). Patients with MVL (MVL group, n = 91) showed worse PFS than those without (non-MVL group, n = 138) (median PFS 5.3 vs. 7.6 months, p = 0.025), while the MVL group showed worse OS (p = 0.038), though neither reached the median survival time. Conclusion: MVL may be a clinical factor related to poor prognosis in patients receiving Atez/Bev treatment for u-HCC.

Guidelines for the Management of Respiratory Infectious Diseases in Children in Japan 2022.

The members of the Japanese Society for Pediatric Infectious Diseases and the Japanese Society of Pediatric Pulmonology have developed Guidelines for the Management of Respiratory Infectious Diseases in Children with the objective of facilitating appropriate diagnosis, treatment and prevention of respiratory infections in children. The first edition was published in 2004 and the fifth edition was published in 2022. The Guideline 2022 consists of 2 parts, clinical questions and commentary, and includes general respiratory infections and specific infections in children with underlying diseases and severe infections. This executive summary outlines the clinical questions in the Guidelines 2022, with reference to the Japanese Medical Information Distribution Service Manual. All recommendations are supported by a systematic search for relevant evidence and are followed by the strength of the recommendation and the quality of the evidence statements.

Severe cardiotoxicity induced by osimertinib in a patient with EGFR-mutated adenocarcinoma of the lung.

A man in his 70s was detected an infiltrative shadow on the right lung. A bronchoscopy confirmed the diagnosis of adenocarcinoma of the lung, classified as cT2bN2M0 stage IIIA, with a deletion mutation in EGFR exon 19. Weekly carboplatin plus paclitaxel was administered in combination with thoracic radiotherapy, followed by maintenance therapy with durvalumab for 1 year. Four months later, he was diagnosed with a recurrence of adenocarcinoma in the lung. He started treatment with osimertinib. Six months after initiating osimertinib, a chest CT revealed bilateral pleural effusion and expansion of the inferior vena cava. Eleven months later, he entered our emergency department with progressive dyspnoea. A chest CT showed bilateral massive pleural effusion and cardiac enlargement. He was diagnosed with osimertinib-induced cardiac failure. Osimertinib was discontinued, and echocardiology demonstrated a gradual improvement in cardiac function. It is necessary to take care of osimertinib-related cardiotoxicity.

Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissue: a Japanese Musculoskeletal Oncology Group (JMOG) multi-institutional study.

PURPOSE: Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissues are rare mesenchymal neoplasms, some of which are malignant. However, their clinical and pathological characteristics remain unclear. This study was performed to investigate the clinical and pathological characteristics of PEComas in bone and soft tissues by leveraging information from the Japanese Musculoskeletal Oncology Group. METHODS: Nine patients, including four male and five female patients with a median age of 50 years, were retrospectively reviewed. PEComas of the visceral organs, including the uterus and retroperitoneum, were excluded. RESULTS: Eight tumors arose in the soft tissue and one in the bone, with a mean size of 8.8 cm. Four patients showed local recurrence or distant metastasis. The 1-year survival rate was 78%. Pathologically, eight tumors were classified as malignant and one as having uncertain malignancy potential. Half of the tumors showed high MIB-1 index values of > 30%. Immunohistochemically, the melanocyte marker HMB45 was expressed in 89% of the cases, and muscle-specific markers were expressed only in 30-50% of the cases. Transcription factor binding to IGHM enhancer 3 (TFE3) expression was positive in 100% of the patients. Tumors with high expression of TFE3 were classified as PEComas with malignant potential according to Folpe's classification. CONCLUSIONS: Bone and soft tissue PEComas may have a higher malignancy potential than other visceral PEComas and are more likely to develop as TFE3-rearranged PEComas.

Association of proton pump inhibitor and antibiotic use with the clinical outcomes of hepatocellular carcinoma patients receiving atezolizumab and bevacizumab: A multicenter analysis.

AIM: This retrospective study aimed to investigate the impact of proton pump inhibitor treatment (PPI) and antibiotic treatment on the therapeutic outcomes of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). METHODS: The present study included a total of 441 HCC patients who were treated with Atez/Bev in 20 Japanese institutions from September 2020 to April 2022. We adopted the inverse probability of treatment weight to adjust for imbalance in the baseline characteristics of patients with and without PPI treatment as well as patients with and without antibiotic treatment. RESULTS: The progression-free survival (PFS) and overall survival (OS) of patients with and without PPI treatment did not differ to a statistically significant extent. In the weighted cohort, the difference in PFS and OS between the patients with and without PPI did not reach statistical significance (median PFS, 7.0 vs. 6.5 months, p = 0.07; 1-year survival rate 66.3% and 73.8%, p = 0.9). The PFS and OS in patients with antibiotic treatment were worse in comparison to patients without antibiotic treatment (median PFS, 3.8 vs. 7.0 months, p = 0.007; 1-year survival rate 58.8% and 70.3%, p = 0.01). In the weighted cohort, the PFS and OS of the two groups did not differ to a statistically significant extent (median PFS, 3.8 vs. 6.7 months, p = 0.2; 1-year survival rate, 61.8% and 71.0%, p = 0.6). CONCLUSIONS: The therapeutic outcomes of Atez/Bev in HCC patients did not differ between patients with and without PPI treatment or between patients with and without antibiotic treatment.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib.

BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.

Clinical role of radiofrequency ablation for early-stage hepatocellular carcinoma in an advanced aging society.

AIM: It is unclear whether prognosis differs by age for early-stage hepatocellular carcinoma (HCC). We aimed to examine prognosis and recurrence after radiofrequency ablation (RFA) for early-stage HCC and to determine its prognostic factors for different age groups. METHODS: This retrospective study enrolled 1079 patients with initial early-stage HCC treated with RFA at two institutions. All patients in this study were divided into four groups: <70 years old (group1, n = 483), 70-74 years old (group2, n = 198), 75-79 years old (group3, n = 201), and ≥80 years old (group4, n = 197). Prognostic factors were evaluated by comparing survival and recurrence rates between each group. RESULTS: The median survival time and 5-year survival rates for each group were 113 months and 70.8% in group1, 99.2 months and 71.5% in group2, 91.3 months and 66.5% in group3, and 71 months and 52.6% in group 4, respectively. Group4 had a significantly shorter survival than the other groups (p < 0.05). There were no significant differences in recurrence-free survival among the groups. In group4, the most common cause of death was nonliver-related disease (69.4%). In all groups, modified albumin-bilirubin index grade was a factor contributing to prolonged prognosis, but only in group4 performance status (PS) was a significant factor (hazard ratio, 2.46; 95% confidence interval, 1.16-3.00; p = 0.009). CONCLUSION: For early-stage HCC in the elderly, preoperative evaluation of PS and management of other diseases could contribute to a prolonged prognosis.

Does first-line treatment have prognostic impact for unresectable HCC?-Atezolizumab plus bevacizumab versus lenvatinib.

BACKGROUND/AIM: A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first-line therapy for unresectable hepatocellular carcinoma (u-HCC) in regard to progression-free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u-HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. MATERIALS/METHODS: From 2020 to January 2022, 251 u-HCC (Child-Pugh A, ECOG PS 0/1, BCLC-B/C) treated were enrolled (Atez/Bev-group, n = 194; lenvatinib-group, n = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). RESULTS: There was a greater number of patients with macro-vascular invasion in Atez/Bev-group (22.7% vs. 8.8%, p = 0.022). In lenvatinib-group, the frequencies of appetite loss (38.6% vs. 19.6%, p = 0.002), hypothyroidism (21.1% vs. 6.7%, p = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p < 0.001), and diarrhea (10.5% vs. 4.6%, p = 0.012) were greater, while that of general fatigue was lower (22.8% vs. 26.3%, p = 0.008). Comparisons of therapeutic best response using modified response evaluation criteria in solid tumors (mRECIST) did not show significant differences between the present groups (Atez/Bev vs. lenvatinib: CR/PR/SD/PD = 6.1%/39.1%/39.1%/15.6% vs. 0%/48.0%/38.0%/14.0%, p = 0.285). In patients of discontinuation of treatments, 48.2% switched to lenvatinib, 10.6% continued beyond PD, 8.2% received another systemic treatment, 5.9% underwent transcatheter arterial chemoembolization (TACE), 3.5% received hepatic arterial infusion chemotherapy (HAIC), and 1.2% underwent surgical resection in Atez/Bev-group, while 42.2% switched to Atez/Bev, 4.4% continued beyond PD, 4.4% received another systemic treatment, 2.2% nivolumab, 6.7% received TACE, and 2.2% received HAIC in lenvatinib-group. Following adjustment with inverse probability weighting (IPW), Atez/Bev-group showed better PFS (0.5-/1-/1.5-years: 56.6%/31.6%/non-estimable vs. 48.6%/20.4%/11.2%, p < 0.0001) and OS rates (0.5-/1-/1.5-years: 89.6%/67.2%/58.1% vs. 77.8%/66.2%/52.7%, p = 0.002). CONCLUSION: The present study showed that u-HCC patients who received Atez/Bev as a first-line treatment may have a better prognosis than those who received lenvatinib.

The hepatocellular carcinoma modified Gustave Roussy Immune score (HCC-GRIm score) as a novel prognostic score for patients treated with atezolizumab and bevacizumab: A multicenter retrospective analysis.

AIM: This study investigated whether or not the hepatocellular carcinoma modified Gustave Roussy Immune Score (HCC-GRIm-Score) serves as a prognostic indicator for HCC patients treated with atezolizumab and bevacizumab (Atez/Bev). METHODS: A total of 405 HCC patients who received Atez/Bev from September 2020 to January 2022 at 22 different institutions were included in this retrospective study. The HCC-GRIm score was based on the combination of the albumin level (<3.5 g/L = 1 point), lactate dehydrogenase (≥245 U/L = 1 point), neutrophil-to-lymphocyte ratio (≥4.8 = 1 point), aspartate aminotransferase-to-alanine aminotransferase ratio (≥1.44 = 1 point), and total bilirubin level (≥1.3 mg/dl = 1 point). Patients were divided into the low-score group (0, 1, or 2 points) and the high-score group (3, 4, or 5 points). RESULTS: There were 89 (22.0%), 141 (34.8%), 106 (26.2%), 49 (12.1%), 16 (4.0%), and 4 (1.0%) patients with scores of 0, 1, 2, 3, 4, 5, respectively. The progression-free survival (PFS) in the low-score group was significantly longer than that in the high-score group (median 7.8 vs. 3.5 months, p < 0.001). The median overall survival (OS) of the low-score group was not reached at the time cutoff, with a 1-year survival rate of 75.5%, whereas the median OS of the high-score group was 8.5 months, showing a significant difference (p < 0.001). A high HCC-GRIm score was a significant unfavorable factor associated with the PFS and OS in multivariate analyses (p = 0.002 and p < 0.001, respectively). CONCLUSIONS: The HCC-GRIm score serves as a novel prognostic score for HCC patients treated with Atez/Bev.

Comparative efficacy and safety of atezolizumab and bevacizumab between hepatocellular carcinoma patients with viral and non-viral infection: A Japanese multicenter observational study.

AIM: This study compared the efficacy and safety of atezolizumab and bevacizumab (Atez/Bev) in patients with viral and non-viral infection in clinical settings. METHODS: We conducted the retrospective cohort study of 323 BCLC stage B or C hepatocellular carcinoma (HCC) patients with Child-Pugh class A, and a performance status of 0 or 1 who started Atez/Bev from September 2020 to December 2021 at 22 institutions in Japan. Patients with viral infection was defined as those who were either serum anti-HCV- Ab or HBs-Ag-positive, while patients with non-viral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. We constructed a propensity-score-matched cohort to minimize the risk of observable potential confounders. RESULTS: Propensity score matching produced 126 matched pairs for patients with viral versus non-viral infection. After matching, the significant differences in baseline demographic features did not exist between the two groups. The objective response rate was 20.6% and 24.6% in viral- and non-viral-related HCC patients, respectively, without a significant difference (p = 0.55). The disease control rate was not also significantly different (68.3% vs 69.0%, p = 1.00). The median progression-free survival was 7.0 months (95% confidence interval [CI] 6.0-9.6) and 6.2 months (95% CI 5.1-7.8) in patients with viral and non-viral infection, and the 12-month survival rates were 65.5% (95% CI 50.8-76.8) and 71.7% (95% CI 57.3-81.9) in those with viral and non-viral infection, respectively, which were not significantly different (p = 0.33, p = 0.38). No significant difference in treatment-related adverse events was found between the two groups. CONCLUSIONS: Our etiology-based study demonstrated that Atez/Bev showed good efficacy and safety for HCC patient with non-viral infection as well as those with viral infection.

The prognosis of elderly patients with hepatocellular carcinoma: A multi-center 19-year experience in Japan.

AIMS: This retrospective study compared the survival between elderly and non-elderly patients. METHODS: A total of 5545 treatment-naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively. RESULTS: There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p < 0.001). In both elderly and non-elderly patients, the median albumin-bilirubin score significantly improved over time and the diagnosis of HCC was made slightly earlier over time. The median overall survival (OS) in elderly patients was 52.8, 42.0, and 45.6 months in the early, middle, and late period, respectively, without a significant improvement (p = 0.17) whereas the OS in non-elderly patients was significantly improved (p < 0.001). The percentage of elderly patients receiving curative treatments did not significantly increase (p = 0.43), while that of non-elderly patients did (p = 0.017). Non-liver-related death in elderly patients significantly differed among periods (p = 0.023), while liver-related death did not (p = 0.050). Liver- and non-liver-related death in non-elderly patients significantly differed among periods (p < 0.001, p = 0.005). CONCLUSIONS: Survival in elderly patients was not improved despite an improvement in their liver function. Curative treatments should be conducted when appropriate after evaluating each elderly patient.

Preparation of composite monoliths of quaternized chitosan and diatom earth for protein separation.

In this study, composite monoliths with porous structures were prepared using quaternized chitosan and diatom earth for protein separation. Quaternized chitosan (N-[(2-hydroxy-3-trimethylammonium)propyl] chitosan chloride) dissolved in water was mixed with diatom earth and crosslinked with glutaraldehyde under low-temperature conditions to form a cryogel. Interconnected porous monoliths were obtained after removing ice crystals from the cryogel. The monoliths adsorbed bovine serum albumin selectively from the solution mixture of bovine serum albumin and bovine ɤ-globulin, and bovine ɤ-globulin was recovered in the flow-through fraction. The adsorption selectivity was enhanced by changing the solution pH from 6.8 to 5.5. The adsorption of bovine serum albumin by the monolith was replicated at least five times following its washing with a buffer containing 400 mM NaCl and subsequent regeneration with a 10 mM acetate buffer. The composited monolith is a promising adsorbent for the removal of acidic proteins, such as serum albumin contamination in neutral proteins, for example, ɤ-globulins, in bioproduction processes.

Development and validation of a modified albumin-bilirubin grade and α-fetoprotein score (mALF score) for hepatocellular carcinoma patients receiving atezolizumab and bevacizumab.

AIM: Predicting the survival of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/bev) remains a challenge. This study aims to validate the modified albumin-bilirubin grade and α-fetoprotein score (mALF score). METHODS: This retrospective, multicenter study included 426 HCC patients receiving Atez/Bev. Each patient was randomized 3:2 to a training set (n = 255) and a validation set (n = 171). We investigated prognostic factors in the training set and developed an easily applicable mALF score, which was evaluated in the validation set. RESULTS: We built the mALF score using baseline mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37-4.05, p = 0.002) and α-fetoprotein ≥ 100 ng/ml (HR 2.61, 95% CI 1.49-4.55, p < 0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9-90.8) in patients who meet neither of the criteria (mALF 0 points, n = 101), 61.7% (95% CI 44.5-74.9) in patients who meet either of the two criteria (mALF 1 point, n = 109), and 24.6% (95% CI 9.0-44.3) in patients who meet both criteria (mALF 2 points, n = 45); the difference was statistically significant (p < 0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0-8.0), and 3.8 months (95% CI 3.0-5.2), respectively, which amounted to a significant difference (p < 0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points = 94.2%/62.1%/46.3%, p < 0.001; median PFS, 0/1/2 points = 9.3/6.7/4.7 months, p = 0.018). CONCLUSION: The mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.