Patterns of Progression and Treatment Discontinuation in a Real Life Latin American Prospective Cohort Study of Intermediate-Advanced Hepatocellular Carcinoma: Second Interim Analysis

Introduction and Objectives: Previously published regional real-world results of overall survival (OS) in Barcelona Clinic Liver Cancer (BCLC) B and C patients demanded a prospective cohort study nested in a systematic and continuous medical educational networking group. This study aimed to describe and evaluate the treatment decisions in patients with hepatocellular carcinoma (HCC) within BCLC B and C stages. Material(s) and Method(s): A multicenter prospective cohort study, conducted in different Latin American centers from Argentina, Brazil and Colombia, started on 15th May 2018 (delayed recruitment during COVID locked-down period). Patients within BCLC B or C stages were included. Survival, tumor progression and patterns of treatment suspension were evaluated. Result(s): At this second interim analysis (projected final analysis March 2023), 390 HCC BCLC-B or C patients were included (n=15 excluded);mean age 65 years, 75.6% males and 89.5% cirrhotic. Median OS since HCC diagnosis was 27.2 months. Among BCLC-B patients, the most frequent therapy was transarterial chemoembolization (TACE, 42.3%);51.8% using drug-eluting beads and 47.4% conventional TACE;with a median OS since 1st TACE of 41.9 months. Similar radiological responses after 1st TACE were observed between both modalities. Overall, 48.2% of the cohort received systemic therapy for HCC (n=188), 23.7% still on BCLC-B stage. The most frequent systemic treatments were Sorafenib (74.5%), atezolizumab bevacizumab (17.5%), and lenvatinib (12.2%), with a median OS since systemic therapy of 15.7 months. Lenvatinib or atezolizumab bevacizumab was used as the second line following sorafenib in 5 and 3 patients, respectively. The most common causes of systemic treatment discontinuation were tumor progression and liver function deterioration (15% to 36.4%). Patterns of tumor progression were not specifically associated with prognosis or treatment discontinuation. Conclusion(s): Liver function deterioration occurs in a third of patients following systemic therapies. The complexity of treatment decisions underly the need for a multidisciplinary team and the role of hepatologists.Copyright © 2023

Alternative Management of Cushing's Syndrome During Covid-19 Pandemic

Cushing's syndrome results from prolonged exposure to glucocorticoids. Surgery is often the first-line treatment for this condition, regardless of etiology. However, the COVID-19 pandemic caused a decrease in surgical procedures due to the risk of infection transmission. There are still emergency cases of Cushing's syndrome that are admitted to the hospital and require urgent management. The current treatment should be focused on medical management and endovascular embolization in selective cases. Embolization can be performed in facilities where there aretrained personnel with experience in adrenal embolization. Surgery, which traditionally is a first-line therapy, can increase the risk of infection, therefore, it should be avoided. The current review provides a brief description of the possible options for the management of adrenal Cushing's syndrome during the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

Regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) in real-world practice in Asia: Final analysis of the prospective, observational REFINE study

Background: In an interim analysis of Asian pts with uHCC in the observational REFINE study of regorafenib (NCT03289273), treatment-emergent adverse events (TEAEs) were consistent with those reported in the global, phase 3 RESORCE trial. Here, we present the final analysis of Asian pts with uHCC in REFINE. Method(s): REFINE is an international, prospective, multicenter study that enrolled pts with uHCC for whom a decision to treat with regorafenib was made by the treating physician prior to enrollment, according to the local health authority approved label. The primary objective is safety, including the incidences of TEAEs and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints include overall survival, progression-free survival, and treatment duration. Result(s): Of the 1005 evaluable pts, 557 (55%) were from Asia (Korea [31%], Japan [26%], Taiwan [24%], China [18%], Thailand [1%]) and 82% were male. At baseline, median age was 65 years (range 21-94) and the most common HCC etiology in Asian pts was hepatitis B (60%) and in non-Asian pts was alcohol use (36%;Table). More Asian pts (71%) had received prior transarterial chemoembolization vs non-Asian pts (42%). The initial daily regorafenib dose was 160/120/80/40 mg in 51%/12%/35%/3% of Asian pts and 42%/9%/45%/4% of non-Asian pts. The median treatment duration was 3.7 months (range 0-34.4) in Asian pts and 3.6 months (range 0-38.9) in non-Asian pts. The most common TEAEs in Asian pts were hand-foot skin reaction (40%), diarrhea (27%), and decreased appetite (17%). TEAEs led to dose modification in 44% of Asian pts. [Formula presented]. Conclusion(s): These final data from REFINE confirm the safety and effectiveness of regorafenib in Asian pts with uHCC from a broad population in real-world practice. Final analyses from REFINE are ongoing and will be presented at the conference. Clinical trial identification: NCT03289273. Editorial acknowledgement: Editorial assistance in the preparation of this manuscript was provided by Matthew Reynolds of OPEN Health Communications (London, UK), with financial support from Bayer. Legal entity responsible for the study: Bayer. Funding(s): Bayer. Disclosure: Y.J. Kim: Financial Interests, Personal, Advisory Role: Bayer, Bristol Myers Squibb, Samil, PharmaKing, Celltrion, Bukwang;Financial Interests, Personal, Invited Speaker: Roche, AbbVie, Eisai, Ipsen, Boston Scientific, Bristol Myers Squibb, BTG, Bayer, MSD, Gilead Sciences, Novo Nordisk, Green Cross Cell, Boehringer Ingelheim, AstraZeneca;Financial Interests, Personal, Funding: BTG, Bayer, Boston Scientific, AstraZeneca, Gilead Sciences, Samjin, BL&H. M. Kurosaki: Financial Interests, Personal, Speaker's Bureau: Gilead Sciences, AbbVie, Eisai, Chugai, Lilly, Takeda. H.Y. Lim: Financial Interests, Personal, Advisory Role: Bayer, Eisai, Roche, Ipsen. M. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, Ono, Takeda, GlaxoSmithKline;Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eli Lilly Japan, Eisai, Nihon Servier, Novartis, Taiho, Yakult, Teijin Pharma, AbbVie, Abbott Japan, Fujifilm Toyama Chemical, Incyte Biosciences Japan, ASLAN, Chugai, Nihon Servier, Takeda;Financial Interests, Institutional, Invited Speaker: Bayer, Bristol Myers Squibb, Eisai, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Merck Serono, MSD, Ono, Yakult, Novartis, Takeda, J-Pharma, Pfizer, Chiome Bioscience, Nihon Servier, Delta-Fly Pharma, Syneos Health, Merus.N.V. M. Kudo: Financial Interests, Personal, Invited Speaker: Eisai, Chugai, Eli Liiy, Bayer, Takeda, MSD;Financial Interests, Institutional, Research Grant: Otsuka, Sumitomo Dainippon Pharma, EA Pharma, Taiho, Eisai, AbbVie, Gilead Sciences, Takeda, GE Healthcare, Chugai. Y. Huang: Financial Interests, Personal, Advisory Role: Eisai, Bayer, BMS, Ono, Gilead, Lilly, AbbVie, Roche;Financial Interests, Personal, Invited Speaker: Eisai, Bayer, BMS, Ono, Gilead, Lilly, AbbVie, Roche;Financial Inte ests, Personal, Speaker's Bureau: Eisai, Bayer, BMS, Ono, Gilead, Lilly, AbbVie, Roche;Financial Interests, Institutional, Funding: Gilead. N. Kato: Financial Interests, Personal, Invited Speaker: Gilead Sciences Inc., AbbVie G.K., Ohtsuka Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Olympus Corporation, Eisai Co., Ltd., Aska Pharmaceutical Co., Ltd., Tsumura & Co., Mochida Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Covidien Japan Inc., Eli Lilly Japan K.K., Nobelpharma Co., Ltd., Kowa Company, Ltd., Incyte Biosciences Japan GK, Yakult Honsha Co.,Ltd., Olympus Marketing, Inc., Taisho Pharmaceutical Co.,Ltd., Janssen Pharmaceutical K.K.;Financial Interests, Institutional, Research Grant: AbbVie G.K., Ohtsuka Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Tsumura & Co., Nippon Kayaku Co., Ltd., JIMRO Co., Ltd., Kowa Company, Ltd. C. Hsu: Financial Interests, Personal, Speaker's Bureau: Bristol Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme, Roche, Eisai;Financial Interests, Institutional, Funding: Ono Pharmaceutical, AstraZeneca, MSD, Merck Serono, Taiho Pharmaceutical, Bristol Myers Squibb, BeiGene, NuCana BioMed, Johnson & Johnson, Roche/Genentech, BeiGene;Financial Interests, Personal, Advisory Role: Ono Pharmaceutical, MSD, Bristol Myers Squibb, Merck Serono, Roche/Genentech. B. Chewaskulyong: Financial Interests, Personal, Advisory Role: Pfizer, STADA;Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, DKSH, Janssen, BMS, MSD, Roche, TAIHO;Financial Interests, Personal, Speaker's Bureau: AstraZeneca, Pfizer, DKSH, Janssen, BMS, MSD, Roche, TAIHO;Financial Interests, Institutional, Funding: Bayer. J. Khan: Financial Interests, Institutional, Full or part-time Employment: Bayer. K. Ozgurdal: Financial Interests, Institutional, Full or part-time Employment: Bayer;Financial Interests, Personal, Stocks/Shares: Bayer. All other authors have declared no conflicts of interest. Copyright © 2022

Impact of the COVID-19 Pandemic on the Outcomes of Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma: A Single Center Experience from a Developing Country.

Background and Objectives: Treatment of cancer patients during the COVID-19 pandemic has been a challenge worldwide. In accordance with the current recommendations for hepatocellular carcinoma (HCC) management during the COVID-19 pandemic, loco-regional therapy such as transarterial chemoembolization (TACE) was proposed with the purpose of achieving local tumor control and improving overall survival. The aim of this prospective cohort study was to evaluate the outcomes of TACE treatment in patients with HCC during the COVID-19 pandemic in comparison with the outcomes of patients treated in the pre-pandemic period. Materials and Methods: Between September 2018 and December 2021, 154 patients were managed by serial TACE procedures for different liver tumors. Ninety-seven patients met the study criteria and were divided into two groups: the study group n = 49 (patients treated from May 2020 to December 2021); the control group n = 48 (patients treated from September 2018 to May 2020). Results: The mean waiting time for TACE was significantly longer in the study group compared to the control group (p < 0.001). No significant difference in survival between the groups is noted (log-rank test p = 0.823). In multivariate analysis, the MELD score (HR 1.329, 95% CI 1.140−1.548, p < 0.001) remained a significant predictor of mortality. Conclusions: COVID-19 pandemic did not affect the final outcome of TACE treatment.

A phase Ib study of pembrolizumab following trans-arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): PETAL

Background: Trans-arterial chemoembolization (TACE) is the gold-standard for intermediate stage HCC. We hypothesised the ischemic and cytotoxic effect of TACE to boost anti-cancer immunity and to synergise with the anti PD-1 pembrolizumab (pembro). We designed a phase Ib study to test the safety and preliminary efficacy of pembro after TACE in intermediate HCC. Methods: PETAL study will enroll up to 32 patients with intermediate HCC to receive pembro 200 mg every 3 weeks for up to 1 year or until disease progression or unacceptable toxicity. The first safety-run-in phase includes 6 patients: if no dose limiting toxicities (DLTs) emerge over a 21-day window after first pembro, the others are enrolled in the expansion phase. Pembro is given within 30 days after 1 or 2 TACEs. The first phase includes 1 patient scoring Child-Pugh (CP)-B7 and the remaining have to be CP-A. Safety is the primary endpoint and is measured as the incidence of treatment-related adverse events (TRAEs), graded according to NCI CTCAEv4. Efficacy is the secondary endpoint and is evaluated as progression free survival (PFS) from first TACE, according to mRECIST criteria. Survival is estimated using Kaplan-Meier method. All the patients who have received at least one dose of pembro are evaluable for safety. Results: At the time of data cut-off, on the 14th of January 2022, 14 patients had received at least one dose of pembro. The median age was 72 (IQR: 63.3-74.6), 79% were male, 71% were cirrhotic, 29% had viral hepatis and 43% ECOG PS 1. One patient had Child-Pugh (CP) class B7 and 13 had A. The median number of nodules was 1.5 (IQR:1-2.8), and 4.1 cm (IQR: 3.7-4.5) the median diameter. Overall, 5 patients received 2 TACEs and 9 had 1. Patients received a median of 4.5 cycles (IQR: 2.3-6.5) of pembro. No DLTs emerged in the first phase. Treatment-related adverse events (TRAE) of any grade (G) were reported in 86% of participants, 21% of participants experienced G3 TRAEs, and there were no G4 or G5 TRAEs. Specific skin-related toxicity was the most frequently reported (35%) TRAE. No patients had treatment-related liver toxicity. Causes of treatment discontinuation were PD (n=7), TRAEs (n=1), clinical deterioration in the CP B patient (n=1), COVID pandemic (n=2) and withdrawal of consent (n=1);at the time of data cut-off, mPFS from first TACE was 10.8 months (95%CI: 6.63-14.97). Conclusions: Adjuvant pembro following TACE is manageable and tolerable with signs of activity. These results prompt the investigation in larger trials.

TWO-TIERED LIVER FIBROSIS ASSESSMENT IN PRIMARY CARE ANNUAL DIABETIC SCREENING - 3 YEAR FOLLOW UP

Introduction We previously presented the outcome of a pathway incorporating 2-tiered fibrosis assessment into annual diabetic reviews in primary care. This 3 year follow up study looks at: 1. Outcomes in patients referred into secondary care with moderate-advanced fibrosis Ongoing service delivery requirements after the first year of case finding Effectiveness of the pathway in detecting patients with advanced disease, by looking at the number of patients missed in the pathway presenting with advanced disease. Methods All patients aged >35 years with Type 2 Diabetes Mellitus (T2DM) attending annual review at two primary care practices in North East England between April 2018 and September 2019 (n=467) had a Fib-4 requested, followed by transient elastography (TE) if the Fib-4 was above the high sensitivity threshold. Those with a liver stiffness measurement (LSM) >8kPa were reviewed in secondary care. This pathway was continued in both practices after the end of the initial study period. We reviewed the outcomes of all patients referred to secondary care;the number of patients referred in the subsequent years with ongoing case-finding;and any patients missed from initial screening presenting with decompensated/ symptomatic disease. Results From the 467 patients in the initial study, 58 were referred for TE, 25 had a LSM>8kPa and 20 had advanced disease (on imaging/biopsy/endoscopy). 6/20 (30%) patients with advanced disease have died- 2/20 liver related deaths (hepatocellular carcinoma (HCC) and decompensated cirrhosis);1 patient diagnosed with HCC was treated with curative transarterial chemoembolisation;3 patients had varices on OGD (2 started on carvedilol for primary prophylaxis);12 remain under follow up. In all patients with LSM >8kPa (n=25): 8/25 (32%) died (3/8 from COVID-19);24% (6) LSM improved, 8% (2) LSM deteriorated;32% (8/25) lost weight. No patients missed by the pathway presented with decompensated disease. Serial FIB- 4 at annual screening 2019-2021: 4 patients new raised Fib-4 scores - 1 DNA, 1 TE is awaited, 1 LSM <8kPa (discharged), 1 advanced disease (LSM 17.1kPa). Conclusion Incorporation of a two-tiered liver fibrosis assessment into primary care annual diabetic screening significantly improves identification of advanced liver disease and no patients have presented with advanced disease out-with the pathway. It allows for early detection and interventions against the complications associated with advanced liver disease. Mortality in patients with advanced liver disease remains high. Referrals for TE and into secondary care dramatically reduce after the initial year of case finding.

[Synchronous Double Primary Non-B, and Non-C Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma-A Case Report]

A 78-year-old man without hepatitis virus B or C underwent right hemi-hepatectomy and lymph node dissection for a tumor 5 cm in diameter located in the hepatic hilum of the posterior segment of the liver with portal vein thrombi extending into the main portal trunk and a tumor 1.5 cm in diameter in the peripheral side of segment 5 of the liver. Histopathologically, the former was diagnosed as intrahepatic cholangiocarcinoma and the latter as hepatocellular carcinoma(HCC). Five months after the surgery, intrahepatic and lymph node metastases were diagnosed based on computed tomography(CT);therefore, chemotherapy with S-1 for 3 months and gemcitabine and cisplatin(GC)for 5 months was administered, after which the metastatic lesions were not detected. Nineteen months after the surgery, partial resection of segment 2 of the liver was performed for a tumor 3 cm in diameter, which was diagnosed as HCC histopathologically. Two years after the second surgery, 2 recurrent nodules in the liver in segments 3 and 4 were detected on CT. Platinum-based hepatic arterial infusion chemotherapy(HAIC)and transcatheter arterial chemoembolization(TACE)were performed, and chemotherapy with GC was then administered for 7 months. For a new tumor detected in segment 1 in the liver, TACE was performed 17 months after initial HAIC. Seventy-four months after the initial surgery, 5 new nodules less than 1 cm in diameter were detected, and chemotherapy with sorafenib was administered for 5 months, after which the patient died of coronavirus disease 2019.

Invasive Pulmonary Aspergillosis and Tuberculosis Complicated by Hemophagocytic Lymphohistiocytosis - Sequelae of COVID-19 in a Liver Transplant Recipient.

Liver transplant recipients are at an increased risk of opportunistic infections due to the use of immunosuppression. Coronavirus disease of 2019 (COVID-19) increases the risk of these infections further due to associated immune dysfunction and the use of high-dose steroids. We present a case of a liver transplant recipient who developed disseminated tuberculosis and invasive pulmonary aspergillosis complicated by acquired hemophagocytic lymphohistiocytosis after recovering from severe COVID-19.

Hyperthermia ablation combined with transarterial chemoembolization versus monotherapy for hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The existing evidence has indicated that hyperthermia ablation (HA) and HA combined with transarterial chemoembolization (HATACE) are the optimal alternative to surgical resection for patients with hepatocellular carcinoma (HCC) in the COVID-19 crisis. However, the evidence for decision-making is lacking in terms of comparison between HA and HATACE. Herein, a comprehensive evaluation was performed to compare the efficacy and safety of HATACE with monotherapy. MATERIALS AND METHODS: Worldwide studies were collected to evaluate the HATACE regimen for HCC due to the practical need for global extrapolation of applicative population. Meta-analyses were performed using the RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). RESULTS: Thirty-six studies involving a large sample of 5036 patients were included finally. Compared with HA alone, HATACE produced the advantage of 5-year overall survival (OS) rate (OR:1.90; 95%CI:1.46,2.46; p < 0.05) without increasing toxicity (p ≥ 0.05). Compared with TACE alone, HATACE was associated with superior 5-year OS rate (OR:3.54; 95%CI:1.96,6.37; p < 0.05) and significantly reduced the incidences of severe liver damage (OR:0.32; 95%CI:0.11,0.96; p < 0.05) and ascites (OR:0.42; 95%CI:0.20,0.88; p < 0.05). Subgroup analysis results of small (≤3 cm) HCC revealed that there were no significant differences between the HATACE group and HA monotherapy group in regard to the OS rates (p ≥ 0.05). CONCLUSIONS: Compared with TACE alone, HATACE was more effective and safe for HCC. Compared with HA alone, HATACE was more effective for non-small-sized (>3 cm) HCC with comparable safety. However, the survival benefit of adjuvant TACE in HATACE regimen was not found for the patients with small (≤3 cm) HCC.

Thermal ablation alone vs thermal ablation combined with transarterial chemoembolization for patients with small (<3 cm) hepatocellular carcinoma.

PURPOSE: Thermal ablation (TA) and transarterial chemoembolization (TACE) may be used alone or in combination (TACE+TA) for the treatment of hepatocellular carcinoma (HCC). The aim of our study was to compare the time to tumor progression (TTP) and overall survival (OS) for patients who received TA alone or TACE+TA for HCC tumors under 3 cm. MATERIALS AND METHODS: This HIPAA-compliant IRB-approved retrospective analysis included 85 therapy-naïve patients from 2010 to 2018 (63 males, 22 females, mean age 62.4 ± 8.5 years) who underwent either TA alone (n = 64) or TA in combination with drug-eluting beads (DEB)-TACE (n = 18) or Lipiodol-TACE (n = 3) for locoregional therapy of early stage HCC with maximum tumor diameter under 3 cm. Kaplan-Meier analysis was performed using the log-rank test to assess TTP and OS. RESULTS: All TA and TACE+TA treatments included were technically successful. TTP was 23.0 months in the TA group and 22.0 months in the TACE+TA group. There was no statistically significant difference in TTP (p = 0.64). Median OS was 69.7 months in the TA group and 64.6 months in the TACE+TA group. There was no statistically significant difference in OS (p = 0.14). The treatment cohorts had differences in AFP levels (p = 0.03) and BCLC stage (p = 0.047). Complication rates between patient groups were similar (p = 0.61). CONCLUSION: For patients with HCC under 3 cm, TA alone and TACE+TA have similar outcomes in terms of TTP and OS, suggesting that TACE+TA may not be needed for these tumors unless warranted by tumor location or other technical consideration.

Impact of COVID-19 Pandemic on Intervals and Outcomes of Repeated Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma.

PURPOSE: Given that the novel coronavirus disease (COVID-19) pandemic has disrupted operations globally, an institution's ability to repeat transarterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC) has also been affected. The aim of this study was to evaluate the impact of the COVID-19 on the intervals and outcomes of TACE in HCC patients. MATERIALS AND METHODS: This retrospective study included 154 HCC patients who underwent follow-up after TACE treatment from January 2020 to March 2020 (n = 71, study group) and January 2019 to March 2019 (n = 83, control group) at two institutions in China. The endpoints included the follow-up interval and overall response rate (ORR). Multivariate logistic regression analyses were performed to identify independent risk factors for a worse ORR. The cut-off point was determined to divide follow-up durations into long- and short-intervals. RESULTS: The median follow-up interval was 82.0 days (IQR, 61-109) in the study group, which was significantly longer than 66.0 days (IQR, 51-94) in the control group (P = 0.004). The ORR was 23.9 and 39.8% in the study and control group, respectively (P = 0.037). The cut-off value was 95 days. The grouping (OR, 2.402; 95% CI, 1.040-5.546; P = 0.040), long interval (OR, 2.573; 95% CI, 1.022-6.478; P = 0.045), and China liver cancer staging system (OR, 2.500; 95% CI, 1.797-3.480; P <0.001) were independent predictors for the efficacy of TACE treatment. CONCLUSIONS: The COVID-19 pandemic causes a longer follow-up interval in general, which may further lead to a lower ORR in HCC patients. Those with a follow-up interval of >95 days tend to have a worse prognosis.