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The combination of atezolizumab and bevacizumab (Atezo-Bev) has become the standard first-line therapy for patients with advanced hepatocellular carcinoma (HCC), but the prognosis and treatment pattern after its treatment failure are unclear.We reviewed the medical records of patients who failed first-line Atezo-Bev treatment for advanced HCC from January 2018 to May 2021 in four Taiwan medical centers. Post-first-line survival (PFLS) was defined as the date from the failure of Atezo-Bev treatment to the date of death or last follow-up.A total of 41 patients were included in the study. All patients had Child-Pugh A liver reserve before the initiation of Atezo-Bev treatment, but the liver reserve of 6 (15%) and 7 (17%) patients deteriorated to Child-Pugh B and C, respectively, after treatment failure. The median PFLS was 5.9 months. PFLS significantly differed among patients with various liver reserves after the failure of Atezo-Bev treatment (median 9.6 vs 3.8 vs 1.2 months, for Child-Pugh A, B, and C; p 0.001). In total, 30 (73%) patients received second-line systemic therapy, and they exhibited significantly longer PFLS (median 8.0 vs 1.8 months, p = 0.033) than patients who did not. Deteriorated liver function and not receiving second-line therapy remained associated with inferior PFLS in multivariate analysis. The most common second-line therapies were sorafenib (n = 19, 63%) and lenvatinib (n = 9, 30%), with no significant differences in efficacies.Receiving second-line therapy and good liver reserve were associated with favorable PFLS after the failure of first-line Atezo-Bev treatment.

Although anti-cancer therapy-induced cardiotoxicity is known, until now it lacks a reliable risk predictive model of the subsequent cardiotoxicity in breast cancer patients receiving anthracycline therapy. An artificial intelligence (AI) with a machine learning approach has yet to be applied in cardio-oncology. Herein, we aimed to establish a predictive model for differentiating patients at a high risk of developing cardiotoxicity, including cancer therapy-related cardiac dysfunction (CTRCD) and symptomatic heart failure with reduced ejection fraction. This prospective single-center study enrolled patients with newly diagnosed breast cancer who were preparing for anthracycline therapy from 2014 to 2018. We randomized the patients into a 70%/30% split group for ML model training and testing. We used 15 variables, including clinical, chemotherapy, and echocardiographic parameters, to construct a random forest model to predict CTRCD and heart failure with a reduced ejection fraction (HFrEF) during the 3-year follow-up period (median, 30 months). Comparisons of the predictive accuracies among the random forest, logistic regression, support-vector clustering (SVC), LightGBM, K-nearest neighbor (KNN), and multilayer perceptron (MLP) models were also performed. Notably, predicting CTRCD using the MLP model showed the best accuracy compared with the logistic regression, random forest, SVC, LightGBM, and KNN models. The areas under the curves (AUC) of MLP achieved 0.66 with the sensitivity and specificity as 0.86 and 0.53, respectively. Notably, among the features, the use of trastuzumab, hypertension, and anthracycline dose were the major determinants for the development of CTRCD in the logistic regression. Similarly, MLP, logistic regression, and SVM also showed higher AUCs for predicting the development of HFrEF. We also validated the AI prediction model with an additional set of patients developing HFrEF, and MLP presented an AUC of 0.81. Collectively, an AI prediction model is promising for facilitating physicians to predict CTRCD and HFrEF in breast cancer patients receiving anthracycline therapy. Further studies are warranted to evaluate its impact in clinical practice.

Constitutive photomorphogenic 1 (COP1) is a p53-targeting E3 ubiquitin ligase that is downregulated by DNA damage through mechanisms that remain obscure. Here, we report that COP1 is not downregulated following DNA damage in 14-3-3σ null cells, implicating 14-3-3σ as a critical regulator in the response of COP1 to DNA damage. We also identified that 14-3-3σ, a p53 target gene product, interacted with COP1 and controlled COP1 protein stability after DNA damage. Mechanistic studies revealed that 14-3-3σ enhanced COP1 self-ubiquitination, thereby preventing COP1-mediated p53 ubiquitination, degradation, and transcriptional repression. In addition, we found that COP1 expression promoted cell proliferation, cell transformation, and tumor progression, manifesting its role in cancer promotion, whereas 14-3-3σ negatively regulated COP1 function and prevented tumor growth in a mouse xenograft model of human cancer. Immunohistochemical analysis of clinical breast and pancreatic cancer specimens demonstrated that COP1 protein levels were inversely correlated with 14-3-3σ protein levels. Together, our findings define a mechanism for posttranslational regulation of COP1 after DNA damage that can explain the correlation between COP1 overexpression and 14-3-3σ downregulation during tumorigenesis. Cancer Res; 71(3); 884–94. ©2010 AACR.

Supplementary Figures 1-3, Table 1 from 14-3-3σ Exerts Tumor-Suppressor Activity Mediated by Regulation of COP1 Stability

Background/Aim: The combination of bevacizumab and atezolizumab (Bev-Ate) has been established as a standard first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC) since 2020. This study examined the outcomes of HCC patients who received the combination in southern Taiwan. Patients and Methods: All patients were enrolled from four hospitals in Taiwan. They received Bev-Ate therapy for unresectable HCC. Results: Thirty-five patients were included; 28 (80%) had Barcelona Clinic Liver Cancer stage C disease. Hepatitis etiology was chronic hepatitis B and C in 63% and 17% of patients, respectively. Eleven (31%) patients had received prior systemic treatment for unresectable HCC. The response rate was 51%, and the disease control rate was 72% for all patients. The median progression-free survival (PFS) and overall survival (OS) was 5.2 and 22.2 months, respectively. For patients who received prior systemic treatment, the efficacy of Bev-Ate in terms of response rates was similar compared with those without prior systemic treatment. Patients who received lower doses of bevacizumab (

Background Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. Methods This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m2 . Results In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). Conclusions Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. Lay summary Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Dignity is a basic human right that is related to psychological distress factors in patients with cancer such as depression and demoralization. Hence, the dignity issue is of great importance to healthcare professionals. The present study aimed to advise healthcare professionals regarding the related distress factors of dignity in patients with cancer by investigating its relationship with patients' demographics, disease characteristics, and psychological distress.This was a cross-sectional study design. A convenience sample of 267 patients with cancer from a medical center were recruited into this study. Each patient completed demographics and disease characteristics questionnaires, the Patient Dignity Inventory Mandarin Version (PDI-MV), the Demoralization Scale Mandarin Version (DS-MV), and the Patient Health Questionnaire-9 (PHQ-9). Data were analyzed with SPSS 22.0 software.Dignity was significantly correlated with age, demoralization and depression. Cancer patients aged 65 or above were more likely to have a lower sense of dignity. In the present study, the sensitivity and specificity of the Patient Dignity Inventory Mandarin Version for demoralization (DS-MV≥30) were 84.8% and 79.1% and for depression (PHQ-9≥10) were 73.8% and 70.9% in cancer patients with an aggregate score of 35 or above.Dignity is significantly correlated with personal demographic characteristics and psychological distress in patients with cancer. The results provide reference data for healthcare professionals to understand and enable dignity in patients with cancer and aid in the development of methods that promote their dignity.

Purpose: The aim of the study was to determine the effectiveness of dignity therapy for end-of-life patients with cancer. Methods: This study used a quasi-experimental study design with a nonrandomized controlled trial. Dignity therapy was used as an intervention in the experimental group, and general visit was used in the control group. Thirty end-of-life patients with cancer were recruited, with 16 in the experimental group and 14 in the control group. Outcome variables were the participants' dignity, demoralization, and depression. Measurements were taken at the following time points: pre-test (before intervention), post-test 1 (the 7th day), and post-test 2 (the 14th day). The effectiveness of the intervention in the two groups was analyzed using the generalized estimating equation, with the p value set to be less than .05. Results: After dignity therapy, the end-of-life patients with cancer reflected increased dignity significantly [β = −37.08, standard error (SE) = 7.43, Wald χ2 = 24.94, p

Anthracycline anticancer drugs such as epirubicin and doxorubicin may induce myocardial dysfunction, leading to poor prognosis. Early detection of minor left ventricular (LV) myocardial dysfunction is important for the prevention of anthracylcine-induced cardiotoxicity. Using layer-specific speckle tracking echocardiography (STE), we investigated the progressive distribution of myocardial dysfunction in both breast cancer patients and an animal toxicity model.Patients with preserved LV ejection fraction (LVEF) preparing for epirubicin chemotherapy (N = 125) were prospectively enrolled. Layer-specific STE, including LV longitudinal and circumferential strains on subepicardium and subendocardium, were evaluated at baseline and after the first cycle, third cycle and six months of epirubicin therapy. A decline of LVEF above 10% to55% at six months was defined as cardiotoxicity. These same strain measures were obtained in doxorubicin-treated rats and the distribution of myocardial fibrosis evaluated.In patients developing cardiotoxicity, LV longitudinal strain on subendocardium (LVLSendo) was significantly reduced after three cycles of therapy despite no significant changes in conventional LV systolic, diastolic parameters as well as LV circumferential strains at that moment. Compared to conventional echocardiographic parameters, LVLSendo was significantly predictive of cardiotoxicity. Declines in LVLSendo were also observed in doxorubicin-treated rats at an early stage. These reductions also predicted significant fibrosis in the subendocardial layer.LVLSendo is useful for the early detection of minor cardiac dysfunction during chemotherapy, thereby implicating endocardial involvement in the development of cardiotoxicity.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-08.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA 2 investigates tesetaxel plus a reduced dose of capecitabine as an all-oral regimen in taxane-naïve patients with HER2-, HR+ MBC. Trial design: CONTESSA 2 is a 125-patient, multinational, multicenter, single-arm, Phase 2 study of tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day for 14 days of each 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have not previously been treated with a taxane in any setting. Patients with CNS metastases are eligible. The primary endpoint is confirmed ORR assessed by an Independent Radiologic Review Committee (IRC). A sample size of 125 will allow the ORR to be estimated with a maximum standard error of < 5%. Secondary endpoints include duration of response, pharmacokinetics (PK) of tesetaxel and potential for a PK interaction between tesetaxel and capecitabine. Enrollment was initiated in January 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03858972). Citation Format: Lee Schwartzberg, Jamil Asselah, Igor Bondarenko, YeeSoo Chae, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Julie Lemieux, Mei-Ching Liu, Gavin Marx, Joyce O'Shaughnessy, Mafalda Oliveira, Hope Rugo, Andrew Seidman, Gail Wright, Joseph O'Connell, Thomas Wei, Sung-Bae Kim. CONTESSA 2: A multinational, multicenter, phase 2 study of tesetaxel plus a reduced dose of capecitabine in patients with HER2-, HR+ metastatic breast cancer (MBC) who have not previously received a taxane [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-07.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication after vaccination of Oxford-AstraZeneca coronavirus disease 2019 (COVID-19) vaccine (AZD1222) or Janssen COVID-19 vaccine. It makes a rare complication of thrombosis at common and/or uncommon organs with thrombocytopenia after COVID-19 vaccination four to 28 days later and most patients were younger than 60 years of age. We reported the case of a 75-year-old female with end-stage renal disease who received regular hemodialysis. She received Oxford-AstraZeneca COVID-19 vaccination eight days ago and then she suffered from intermittent chest tightness and epigastric pain with tarry stool passage for two days. Severe thrombocytopenia with elevated D-dimer value was noted and computed tomography of the chest showed azygos vein thrombosis. Elevated cardiac enzyme with ST-T change in 12-lead electrocardiogram was also noted. For positive anti-platelet factor 4 antibodies, VITT with myocardial infarction and azygos vein thrombosis was diagnosed.

Allopregnanolone (allo) is a physiological regulator of neuronal activity that treats multiple neurological disorders. Allo penetrates the blood-brain barrier with very high efficiency, implying that allo can treat CNS-related diseases, including glioblastoma (GBM), which always recurs after standard therapy. Hence, this study aimed to determine whether allo has a therapeutic effect on GBM. We found that allo enhanced temozolomide (TMZ)-suppressed cell survival and proliferation of TMZ-resistant cells. In particular, allo enhanced TMZ-inhibited cell migration and TMZ-induced apoptosis. Additionally, allo strongly induced DNA damage characterized by γH2Ax. Furthermore, quantitative proteomic analysis, iTRAQ, showed that allo significantly decreased the levels of DPYSL3, S100A11, and S100A4, reflecting the poor prognosis of patients with GBM confirmed by differential gene expression and survival analysis. Moreover, single-cell RNA-Seq revealed that S100A11, expressed in malignant cells, oligodendrocytes, and macrophages, was significantly associated with immune cell infiltration. Furthermore, overexpression of DPYSL3 or S100A11 prevented allo-induced cell death. In conclusion, allo suppresses GBM cell survival by decreasing DPYSL3/S100A11 expression and inducing DNA damage.

BACKGROUND: Despite the increasing prevalence of therapies utilizing immune checkpoint inhibitors (ICIs), the associated cardiovascular complications have been poorly reported. Given the fatality of ICI-related complications, especially myocarditis, optimal risk stratification to predict major adverse cardio- and cerebrovascular events (MACCEs) in patients receiving ICIs is mandatory. METHODS: We collected clinical data from patients receiving ICIs, and the primary outcomes were MACCEs, including myocarditis, heart failure, and ischemic stroke. Other systemic immune responses relating to ICIs were also recorded. The median follow-up duration was 3 years. RESULTS: Among 580 patients, the incidence of MACCEs was 3.9%. Older patients, male patients, and patients with lung cancer, liver cirrhosis, or diabetes had higher risks of MACCEs. There was no significant difference between the use of PD-1/PD-L1 inhibitors or CTLA inhibitors in terms of developing cardiovascular toxicities. The development of ICI-related MACCEs was associated with worse survival. Notably, after re-review by specialists, three patients eventually diagnosed with ICI-related myocarditis had not previously been identified. Only one was treated with pulse steroids, and none survived. The most common concomitant extracardiac immune-related adverse events were myositis/dermatitis, endocrine toxicity and hepatitis. CONCLUSIONS: Collectively, ICIs may lead to severe cardiovascular toxicities and require more attention. Early identification, proper diagnosis, and prompt treatment are pivotal for improving survival.

Background Roles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer. However, the role of Egr1 in the metastasis of lung cancer remains undetermined, especially in regard to stem cell-related pathways. Methods Egr1, osteopontin (OPN) and Oct4 expression in human lung cancer was determined by performing immunohistochemistry. Immunoblotting, ELISA, luciferase reporter assay, chromatin immunoprecipitation assay and RT-PCR were performed to validate the regulation of Oct4-Egr1-OPN axis. Moreover, the effect of Oct4-Egr1-OPN axis on lung cancer progression was evaluated by cell migration assay and mice study. Results We detected Oct4, Egr1, and OPN expression in clinical specimens from 79 lung cancer patients, including 72 adenocarcinomas and 7 squamous cell carcinomas. High expression of Oct4, Egr1, and OPN accounted for 53, 51, and 57% of the patients, respectively. All of the three biomarkers were positively correlated in clinical human lung cancer. Patients with high expression of OPN were significantly associated with shorter disease-free survivals than those with low expression of OPN (p

Purpose: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+ breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib + capecitabine (N+C) against lapatinib + capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.Methods: 621 centrally-assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240mg qd) + C (750mg/m2 bid, day 1-14) with loperamide prophylaxis, or to L (1250mg qd) + C (1000mg/m2 bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally-assessed progression free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.Results: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P=0.0014), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P=0.039). Both median OS (23.8 versus 18.7 months; P=0.185) and DoR (11.1 versus 4.2 months; PConclusion: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. Clinical Trial Registration: NCT01808573

Purpose Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. Methods 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1–14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1–14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. Results 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P Conclusion Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. Clinical trial registration NCT01808573

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25–0.76) and for PFS was 0.60 (95% CI, 0.40–0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2–8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6–4.8) with sorafenib. Grade 3–4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3–4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Background Expression of Oct4 maintains cancer stem cell (CSC)-like properties in lung cancer cells and is correlated with poor prognosis of lung adenocarcinoma. M2-type tumor-associated macrophages (TAMs) promote cancer cell migration and metastasis. Tumor microenvironments promote monocyte differentiation into M2 TAMs via a complex cytokine-based connection. We explored the role of Oct4 in cytokine secretion in lung cancer and its impact on M2 TAM polarization. Methods Monocytes co-cultured with the conditioned medium from Oct4-overexpressing lung cancer cells were used to investigate M2 TAM differentiation. The inflammatory factors in the conditioned medium of Oct4-overexpressing A549 cells were examined using human inflammation antibody arrays. The correlations of Oct4, macrophage colony-stimulating factor (M-CSF), and M2 TAMs were validated in lung cancer cells, syngeneic mouse lung tumor models, and clinical samples of non-small cell lung cancer (NSCLC). Results Oct4-overexpressing A549 cells expressed elevated levels of M-CSF, which contributed to increased M2 macrophages and enhanced tumor migration. Overexpression of Oct4 enhanced tumor growth and reduced the survival of lung tumor-bearing mice, which was correlated with increased number of M2 macrophages in lung cancer. Notably, NSCLC patients with high expression levels of Oct4, M-CSF, and M2 TAMs had the poorest recurrence-free survival. A positive correlation between Oct4, M-CSF, and M2 TAMs was observed in the tumor tissue of NSCLC patient. Treatment with all-trans retinoic acid exerted anti-tumor effects and reduced M2 TAMs in tumor-bearing mice. Conclusions Our results indicate that Oct4 expressed by lung cancer cells promotes M2 macrophage polarization through upregulation of M-CSF secretion, leading to cancer growth and metastasis. Our findings also implicate that the Oct4/M-CSF axis in M2 macrophage polarization may be potential therapeutic targets for lung cancer.

Objective Bone marrow fluid (BMF) consists of various components that establishes a microenvironment for cell differentiation and remodeling. MicroRNA-21 (miR-21) levels have recently emerged as novel biomarkers for different diseases. However, the conventional RNU6B (U6), used as the reference for intracellular miRNA, may not be appropriate for the normalization of circulating miRNAs. Methods We measured the levels of U6, spiked-in RNA, and miR-21 in the BMF of 13 healthy controls and 37 patients with hematological disorders to investigate the reliability of either U6 or spike-in RNA as an endogenous reference and also to study the correlation between miR-21, hematological disorders and mortality. Results Notably, the levels of U6 demonstrated a high variability in BMF of healthy controls and patients. In contrast, the levels of spiked-in RNA displayed a significantly higher stability in both cohorts. Compared with controls, the levels of miR-21 were significantly upregulated in BMF of patients with leukemia but not lymphoma. Also, using 21 as the cut-off value of miR-21, it differentiated the mortality of patients with hematologic disorders. Conclusions Collectively, using spiked-in RNA as a reference the upregulated miR-21 levels in BMF could be an indicator of the diagnosis of leukemia and a predictor of mortality.

Additional file 3: Figure S2. M1 cytokines enhance Oct4 expression in A549 cells.

Additional file 2: Figure S1. Inflammatory factors secreted by Oct4-expressing cancer cells.

Additional file 1: Table S1. Clinicopathological parameter of the present study population.

Additional file 4: Figure S3. Flow cytometric analysis of M1 and M2 macrophage in the tumors at day 15 in mice after inoculation of LL2-Oct4 or control LL2 tumor cells.

430 Background: Pts with CCA progressing after first-line therapy have limited treatment options. We report an updated analysis of the ongoing LUC2001 open-label, multicenter, phase 2a study (NCT02699606) investigating the efficacy and safety of erdafitinib in Asian pts with advanced CCA and FGFR alterations who progressed after ≥1 prior systemic treatment. Methods: Eligible adults (aged ≥18 years) received erdafitinib 8 mg once daily (QD) with pharmacodynamically guided up-titration to 9 mg QD. The primary endpoint was objective response rate (ORR; RECIST 1.1); secondary endpoints included best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Survival estimates were determined by the Kaplan–Meier method. Results: Of 232 patients with CCA who underwent molecular screening, 39 (16.8%) had FGFR alterations (21 [9.1%] fusions and 19 [8.2%] mutations). Overall, 22 (9.5%) eligible pts (median age, 52 [range, 29–69] years) were enrolled and received treatment. Median follow-up was 22.4 (range, 2.3–47.0) months; median treatment duration was 6.2 (range, 1.5–35.6) months. All 22 pts received ≥1 line of prior systemic therapy and 12 (55.0%) pts had ≥2 prior lines of therapy. The ORR was 40.9% (95% CI, 20.7%–63.6%) and median time to response was 1.8 (range, 1.5–5.6) months. Median DOR was 7.3 (95% CI, 3.7–17.5) months, median PFS was 5.6 (95% CI, 3.6–12.7) months, and median OS was 40.2 (95% CI: 9.9–not estimable) months (Table). Responses were observed in 8/14 pts with FGFR fusions and 1/8 pts with FGFR mutations and in pts who received 1 or ≥2 prior lines of therapy. All 22 pts had ≥1 treatment-emergent adverse event (TEAE), the most common being dry mouth (15/22 [68.2%]) and stomatitis (14/22 [63.6%]). Grade ≥3 TEAEs occurred in 15/22 (68.2%) pts (11/22 [50.0%] were treatment related), of which the most common were stomatitis (3/22 [13.6%]) and alanine aminotransferase (ALT) increased (3/22 [13.6%]); 11/22 (50.0%) pts had ≥1 serious TEAE (1/22 [4.5%] pts had a serious treatment-related TEAE). A TEAE leading to death occurred in 1 patient (sepsis; not treatment-related). Conclusions: Asian pts with advanced CCA and FGFR alterations treated with erdafitinib had durable efficacy and a manageable safety profile, supporting the earlier findings of erdafitinib benefit in this population. Clinical trial information: NCT02699606. [Table: see text]

Primary hepatic lymphoma (PHL) is a tumor confined to the liver without involvement of the spleen, lymph nodes, or bone marrow. It is an extremely rare malignancy, accounting for only 0.0016% of non-Hodgkin lymphoma worldwide. Generally, a liver biopsy is required to make a diagnosis of PHL due to the lack of specific clinical manifestations, biochemical indicators, and image features. However, there is currently a lack of consensus on the standard treatment of PHL. Chemotherapy can be an effective treatment due to the tumor's chemosensitivity. Herein, we report a 78-year-old male with a confirmed diagnosis of primary hepatic diffuse large B-cell lymphoma via liver biopsy. We treated the patient with immunochemotherapy using Rituximab-COP combination. The tumor had a favorable response, without recurrence for over a three-year period of follow-up. Even though the reported median survival of PHL is 15 months, appropriate treatment can provide a chance for sustained remission.