Key clinical point: The use of immune checkpoint inhibitor (ICI)-based regimens after prior immunotherapy is safe and confers a treatment benefit in a clinically meaningful proportion of patients with hepatocellular carcinoma (HCC).

Major finding: The objective response and disease control rates were 22% and 59% with first-line ICI therapy (ICI-1) and 26% and 55% with second-line ICI therapy (ICI-2), respectively. The median times to progression with ICI-1 and ICI-2 were 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Grade 3-4 treatment-related adverse events with ICI-1 and ICI-2 occurred in 16% and 17% of patients, respectively.

Study details: This multicenter retrospective included 58 patients with HCC who received ≥2 lines of ICI-based therapies.

Disclosures: This study did not receive any specific funding. Some authors declared serving as investigators for or receiving advisory, consulting, or speaker fees or travel support from various sources.

Source: Scheiner B et al. Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma. JHEP Rep. 2022;100620 (Oct 26). Doi: 10.1016/j.jhepr.2022.100620

Key clinical point: The use of immune checkpoint inhibitor (ICI)-based regimens after prior immunotherapy is safe and confers a treatment benefit in a clinically meaningful proportion of patients with hepatocellular carcinoma (HCC).

Major finding: The objective response and disease control rates were 22% and 59% with first-line ICI therapy (ICI-1) and 26% and 55% with second-line ICI therapy (ICI-2), respectively. The median times to progression with ICI-1 and ICI-2 were 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Grade 3-4 treatment-related adverse events with ICI-1 and ICI-2 occurred in 16% and 17% of patients, respectively.

Study details: This multicenter retrospective included 58 patients with HCC who received ≥2 lines of ICI-based therapies.

Disclosures: This study did not receive any specific funding. Some authors declared serving as investigators for or receiving advisory, consulting, or speaker fees or travel support from various sources.

Source: Scheiner B et al. Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma. JHEP Rep. 2022;100620 (Oct 26). Doi: 10.1016/j.jhepr.2022.100620

Key clinical point: The use of immune checkpoint inhibitor (ICI)-based regimens after prior immunotherapy is safe and confers a treatment benefit in a clinically meaningful proportion of patients with hepatocellular carcinoma (HCC).

Major finding: The objective response and disease control rates were 22% and 59% with first-line ICI therapy (ICI-1) and 26% and 55% with second-line ICI therapy (ICI-2), respectively. The median times to progression with ICI-1 and ICI-2 were 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Grade 3-4 treatment-related adverse events with ICI-1 and ICI-2 occurred in 16% and 17% of patients, respectively.

Study details: This multicenter retrospective included 58 patients with HCC who received ≥2 lines of ICI-based therapies.

Disclosures: This study did not receive any specific funding. Some authors declared serving as investigators for or receiving advisory, consulting, or speaker fees or travel support from various sources.

Source: Scheiner B et al. Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma. JHEP Rep. 2022;100620 (Oct 26). Doi: 10.1016/j.jhepr.2022.100620

Key clinical point: Compared with sorafenib, atezolizumab-bevacizumab led to more frequent acute variceal bleeding (AVB) in patients with locally advanced hepatocellular carcinoma (HCC) and cirrhosis, with a history of AVB being associated with AVB during follow-up.

Major finding: At 1 year, patients who received atezolizumab-bevacizumab vs sorafenib had significantly higher AVB occurrence (21% vs 5%; P = .02). A previous history of AVB was independently associated with AVB during therapy (adjusted hazard ratio 10.58; P = .03).

Study details: This single-center prospective study included 43 patients with locally advanced HCC and cirrhosis who received atezolizumab-bevacizumab and a retrospective series of 122 control patients who received sorafenib.

Disclosures: This study did not receive any funding. No information on conflicts of interest was provided.

Source: Larrey E et al. A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC. Liver Int. 2022 (Oct 18). Doi: 10.1111/liv.15458

Key clinical point: Compared with sorafenib, atezolizumab-bevacizumab led to more frequent acute variceal bleeding (AVB) in patients with locally advanced hepatocellular carcinoma (HCC) and cirrhosis, with a history of AVB being associated with AVB during follow-up.

Major finding: At 1 year, patients who received atezolizumab-bevacizumab vs sorafenib had significantly higher AVB occurrence (21% vs 5%; P = .02). A previous history of AVB was independently associated with AVB during therapy (adjusted hazard ratio 10.58; P = .03).

Study details: This single-center prospective study included 43 patients with locally advanced HCC and cirrhosis who received atezolizumab-bevacizumab and a retrospective series of 122 control patients who received sorafenib.

Disclosures: This study did not receive any funding. No information on conflicts of interest was provided.

Source: Larrey E et al. A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC. Liver Int. 2022 (Oct 18). Doi: 10.1111/liv.15458

Key clinical point: Compared with sorafenib, atezolizumab-bevacizumab led to more frequent acute variceal bleeding (AVB) in patients with locally advanced hepatocellular carcinoma (HCC) and cirrhosis, with a history of AVB being associated with AVB during follow-up.

Major finding: At 1 year, patients who received atezolizumab-bevacizumab vs sorafenib had significantly higher AVB occurrence (21% vs 5%; P = .02). A previous history of AVB was independently associated with AVB during therapy (adjusted hazard ratio 10.58; P = .03).

Study details: This single-center prospective study included 43 patients with locally advanced HCC and cirrhosis who received atezolizumab-bevacizumab and a retrospective series of 122 control patients who received sorafenib.

Disclosures: This study did not receive any funding. No information on conflicts of interest was provided.

Source: Larrey E et al. A history of variceal bleeding is associated with further bleeding under atezolizumab-bevacizumab in patients with HCC. Liver Int. 2022 (Oct 18). Doi: 10.1111/liv.15458

Key clinical point: Highly elevated antidrug antibody (ADA) levels (≥1,000 ng/mL) at 3 weeks (cycle 2 day 1 [C2D1]) may be associated with poor clinical outcomes after atezolizumab/bevacizumab (Atezo/Bev) treatment in patients with advanced hepatocellular carcinoma (HCC).

Major finding: In both discovery cohort (DC) and validation cohort (VC), patients with high vs low ADA levels at C2D1 had worse progression-free survival (DC: hazard ratio [HR] 2.84; P = .005; VC: HR 2.52; P = .006) and overall survival (DC: HR 3.30; P = .003; VC: HR 5.81; P = .001).

Study details: This prospective cohort study included 132 patients with advanced HCC treated with first-line Atezo/Bev (DC n = 50; VC n = 82).

Disclosures: This study was sponsored by a National Research Foundation of Korea grant funded by the Korean government and others. Some authors reported serving as advisors for or receiving personal fees or grants from various sources. Two authors declared having a pending method patent for predicting therapeutic response to biologic drugs by quantifying blood ADA.

Source: Kim C et al. Association of high levels of antidrug antibodies against atezolizumab with clinical outcomes and T-cell responses in patients with hepatocellular carcinoma. JAMA Oncol. 2022 (Oct 20). Doi: 10.1001/jamaoncol.2022.4733

Key clinical point: Highly elevated antidrug antibody (ADA) levels (≥1,000 ng/mL) at 3 weeks (cycle 2 day 1 [C2D1]) may be associated with poor clinical outcomes after atezolizumab/bevacizumab (Atezo/Bev) treatment in patients with advanced hepatocellular carcinoma (HCC).

Major finding: In both discovery cohort (DC) and validation cohort (VC), patients with high vs low ADA levels at C2D1 had worse progression-free survival (DC: hazard ratio [HR] 2.84; P = .005; VC: HR 2.52; P = .006) and overall survival (DC: HR 3.30; P = .003; VC: HR 5.81; P = .001).

Study details: This prospective cohort study included 132 patients with advanced HCC treated with first-line Atezo/Bev (DC n = 50; VC n = 82).

Disclosures: This study was sponsored by a National Research Foundation of Korea grant funded by the Korean government and others. Some authors reported serving as advisors for or receiving personal fees or grants from various sources. Two authors declared having a pending method patent for predicting therapeutic response to biologic drugs by quantifying blood ADA.

Source: Kim C et al. Association of high levels of antidrug antibodies against atezolizumab with clinical outcomes and T-cell responses in patients with hepatocellular carcinoma. JAMA Oncol. 2022 (Oct 20). Doi: 10.1001/jamaoncol.2022.4733

Key clinical point: Highly elevated antidrug antibody (ADA) levels (≥1,000 ng/mL) at 3 weeks (cycle 2 day 1 [C2D1]) may be associated with poor clinical outcomes after atezolizumab/bevacizumab (Atezo/Bev) treatment in patients with advanced hepatocellular carcinoma (HCC).

Major finding: In both discovery cohort (DC) and validation cohort (VC), patients with high vs low ADA levels at C2D1 had worse progression-free survival (DC: hazard ratio [HR] 2.84; P = .005; VC: HR 2.52; P = .006) and overall survival (DC: HR 3.30; P = .003; VC: HR 5.81; P = .001).

Study details: This prospective cohort study included 132 patients with advanced HCC treated with first-line Atezo/Bev (DC n = 50; VC n = 82).

Disclosures: This study was sponsored by a National Research Foundation of Korea grant funded by the Korean government and others. Some authors reported serving as advisors for or receiving personal fees or grants from various sources. Two authors declared having a pending method patent for predicting therapeutic response to biologic drugs by quantifying blood ADA.

Source: Kim C et al. Association of high levels of antidrug antibodies against atezolizumab with clinical outcomes and T-cell responses in patients with hepatocellular carcinoma. JAMA Oncol. 2022 (Oct 20). Doi: 10.1001/jamaoncol.2022.4733

Key clinical point: The use of aspirin is independently associated with a reduced risk for hepatocellular carcinoma (HCC) incidence, recurrence, and mortality, but an increased risk for bleeding.

Major finding: Aspirin use was associated with a reduced incidence of HCC (hazard ratio [HR] 0.75; 95% CI 0.71-0.80), recurrence of HCC (HR 0.79; 95% CI 0.65-0.96), and HCC-related mortality (HR 0.64; 95% CI 0.44-0.94), but an increased risk for bleeding (HR 1.10; 95% CI 1.02-1.20).

Study details: This study meta-analyzed the data of 3,273,524 individuals from 30 studies on HCC incidence, HCC recurrence, or mortality.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Ma S, Qu G et al. Does aspirin reduce the incidence, recurrence, and mortality of hepatocellular carcinoma? A GRADE-assessed systematic review and dose-response meta-analysis. Eur J Clin Pharmacol. 2022 (Nov 5). Doi: 10.1007/s00228-022-03414-y

Key clinical point: The use of aspirin is independently associated with a reduced risk for hepatocellular carcinoma (HCC) incidence, recurrence, and mortality, but an increased risk for bleeding.

Major finding: Aspirin use was associated with a reduced incidence of HCC (hazard ratio [HR] 0.75; 95% CI 0.71-0.80), recurrence of HCC (HR 0.79; 95% CI 0.65-0.96), and HCC-related mortality (HR 0.64; 95% CI 0.44-0.94), but an increased risk for bleeding (HR 1.10; 95% CI 1.02-1.20).

Study details: This study meta-analyzed the data of 3,273,524 individuals from 30 studies on HCC incidence, HCC recurrence, or mortality.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Ma S, Qu G et al. Does aspirin reduce the incidence, recurrence, and mortality of hepatocellular carcinoma? A GRADE-assessed systematic review and dose-response meta-analysis. Eur J Clin Pharmacol. 2022 (Nov 5). Doi: 10.1007/s00228-022-03414-y

Key clinical point: The use of aspirin is independently associated with a reduced risk for hepatocellular carcinoma (HCC) incidence, recurrence, and mortality, but an increased risk for bleeding.

Major finding: Aspirin use was associated with a reduced incidence of HCC (hazard ratio [HR] 0.75; 95% CI 0.71-0.80), recurrence of HCC (HR 0.79; 95% CI 0.65-0.96), and HCC-related mortality (HR 0.64; 95% CI 0.44-0.94), but an increased risk for bleeding (HR 1.10; 95% CI 1.02-1.20).

Study details: This study meta-analyzed the data of 3,273,524 individuals from 30 studies on HCC incidence, HCC recurrence, or mortality.

Disclosures: This study did not report the source of funding. The authors declared no conflicts of interest.

Source: Ma S, Qu G et al. Does aspirin reduce the incidence, recurrence, and mortality of hepatocellular carcinoma? A GRADE-assessed systematic review and dose-response meta-analysis. Eur J Clin Pharmacol. 2022 (Nov 5). Doi: 10.1007/s00228-022-03414-y

Key clinical point: Among patients with hepatocellular carcinoma (HCC), an “ideal candidate for ablation” per the Barcelona Clinic Liver Cancer (BCLC) staging system may not be ideal for microwave ablation (MWA); however, patients with BCLC-0 disease may comprise the optimal population for MWA.

Major finding: Liver resection (LRE) vs MWA led to a significantly longer recurrence-free survival in the overall population (P = .025) and patients with BCLC-A disease (P = .003) but not in those with BCLC-0 disease (P = .270), in addition to similar overall survival (P = .976) and post-procedure-related complication rates (P = 1.00) in BCLC-0 patients.

Study details: This retrospective study included patients with HCC who met the criteria of “ideal candidates for ablation” per the BCLC staging system and propensity score-matched those receiving MWA and LRE (overall population 140 pairs; BCLC-0 disease 35 pairs; BCLC-A disease 99 pairs).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Tong Y, Cai R  et al. Liver resection versus microwave ablation for hepatocellular carcinoma in ideal candidates for ablation per Barcelona Clinic Liver Cancer staging: A propensity score matching and inverse probability of treatment weighting analysis. Aliment Pharmacol Ther. 2022;56(11-12):1602-1614 (Oct 26). Doi: 10.1111/apt.17263

Key clinical point: Among patients with hepatocellular carcinoma (HCC), an “ideal candidate for ablation” per the Barcelona Clinic Liver Cancer (BCLC) staging system may not be ideal for microwave ablation (MWA); however, patients with BCLC-0 disease may comprise the optimal population for MWA.

Major finding: Liver resection (LRE) vs MWA led to a significantly longer recurrence-free survival in the overall population (P = .025) and patients with BCLC-A disease (P = .003) but not in those with BCLC-0 disease (P = .270), in addition to similar overall survival (P = .976) and post-procedure-related complication rates (P = 1.00) in BCLC-0 patients.

Study details: This retrospective study included patients with HCC who met the criteria of “ideal candidates for ablation” per the BCLC staging system and propensity score-matched those receiving MWA and LRE (overall population 140 pairs; BCLC-0 disease 35 pairs; BCLC-A disease 99 pairs).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Tong Y, Cai R  et al. Liver resection versus microwave ablation for hepatocellular carcinoma in ideal candidates for ablation per Barcelona Clinic Liver Cancer staging: A propensity score matching and inverse probability of treatment weighting analysis. Aliment Pharmacol Ther. 2022;56(11-12):1602-1614 (Oct 26). Doi: 10.1111/apt.17263

Key clinical point: Among patients with hepatocellular carcinoma (HCC), an “ideal candidate for ablation” per the Barcelona Clinic Liver Cancer (BCLC) staging system may not be ideal for microwave ablation (MWA); however, patients with BCLC-0 disease may comprise the optimal population for MWA.

Major finding: Liver resection (LRE) vs MWA led to a significantly longer recurrence-free survival in the overall population (P = .025) and patients with BCLC-A disease (P = .003) but not in those with BCLC-0 disease (P = .270), in addition to similar overall survival (P = .976) and post-procedure-related complication rates (P = 1.00) in BCLC-0 patients.

Study details: This retrospective study included patients with HCC who met the criteria of “ideal candidates for ablation” per the BCLC staging system and propensity score-matched those receiving MWA and LRE (overall population 140 pairs; BCLC-0 disease 35 pairs; BCLC-A disease 99 pairs).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Tong Y, Cai R  et al. Liver resection versus microwave ablation for hepatocellular carcinoma in ideal candidates for ablation per Barcelona Clinic Liver Cancer staging: A propensity score matching and inverse probability of treatment weighting analysis. Aliment Pharmacol Ther. 2022;56(11-12):1602-1614 (Oct 26). Doi: 10.1111/apt.17263

Key clinical point: Compared with transcatheter arterial chemoembolization (TACE) followed by radiotherapy (RT), administering RT before TACE leads to better survival outcomes in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).

Major finding: Patients who received RT+TACE vs TACE+RT had significantly longer median progression-free survival (6.6 vs 4.2 months; hazard ratio [HR] 0.66; P = .030), with the prolongation of median overall survival being marginally significant (15.4 vs 11.5 months; HR 0.68; P = .054).

Study details: Findings are from a randomized controlled study including 120 patients with unresectable HCC and PVTT who were randomly assigned (1:1) to receive RT+TACE or TACE+RT.

Disclosures: This study was supported by the Clinical Research Plan of Shanghai Shenkang Hospital Development Center, China, among others. The authors declared no conflicts of interest.

Source: Guo L et al. Radiotherapy prior to or after transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus: A randomized controlled trial. Hepatol Int. 2022 (Oct 21). Doi: 10.1007/s12072-022-10423-7

Key clinical point: Compared with transcatheter arterial chemoembolization (TACE) followed by radiotherapy (RT), administering RT before TACE leads to better survival outcomes in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).

Major finding: Patients who received RT+TACE vs TACE+RT had significantly longer median progression-free survival (6.6 vs 4.2 months; hazard ratio [HR] 0.66; P = .030), with the prolongation of median overall survival being marginally significant (15.4 vs 11.5 months; HR 0.68; P = .054).

Study details: Findings are from a randomized controlled study including 120 patients with unresectable HCC and PVTT who were randomly assigned (1:1) to receive RT+TACE or TACE+RT.

Disclosures: This study was supported by the Clinical Research Plan of Shanghai Shenkang Hospital Development Center, China, among others. The authors declared no conflicts of interest.

Source: Guo L et al. Radiotherapy prior to or after transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus: A randomized controlled trial. Hepatol Int. 2022 (Oct 21). Doi: 10.1007/s12072-022-10423-7

Key clinical point: Compared with transcatheter arterial chemoembolization (TACE) followed by radiotherapy (RT), administering RT before TACE leads to better survival outcomes in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT).

Major finding: Patients who received RT+TACE vs TACE+RT had significantly longer median progression-free survival (6.6 vs 4.2 months; hazard ratio [HR] 0.66; P = .030), with the prolongation of median overall survival being marginally significant (15.4 vs 11.5 months; HR 0.68; P = .054).

Study details: Findings are from a randomized controlled study including 120 patients with unresectable HCC and PVTT who were randomly assigned (1:1) to receive RT+TACE or TACE+RT.

Disclosures: This study was supported by the Clinical Research Plan of Shanghai Shenkang Hospital Development Center, China, among others. The authors declared no conflicts of interest.

Source: Guo L et al. Radiotherapy prior to or after transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma with portal vein tumor thrombus: A randomized controlled trial. Hepatol Int. 2022 (Oct 21). Doi: 10.1007/s12072-022-10423-7

Key clinical point: Atezolizumab plus bevacizumab (Atezo/Bev) is a more effective and safe first-line therapy than lenvatinib in patients with unresectable hepatocellular carcinoma (HCC).

Major finding: Patients who received Atezo/Bev vs lenvatinib had a significantly longer progression-free survival (8.3 vs 6.0 months; P = .005) and overall survival (median survival time not reached vs 20.2 months; P = .039) and lower prevalence of grade ≥3 adverse events, such as hypertension (P = .004) and proteinuria (P = .046).

Study details: This retrospective study propensity score-matched patients with unresectable HCC who received Atezo/Bev (n = 152) with those who received lenvatinib (n = 152) as first-line systemic therapies.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Niizeki T et al. Comparison of efficacy and safety of atezolizumab plus bevacizumab and lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: A propensity score matching analysis. Target Oncol. 2022 (Oct 22). Doi: 10.1007/s11523-022-00921-x

Key clinical point: Atezolizumab plus bevacizumab (Atezo/Bev) is a more effective and safe first-line therapy than lenvatinib in patients with unresectable hepatocellular carcinoma (HCC).

Major finding: Patients who received Atezo/Bev vs lenvatinib had a significantly longer progression-free survival (8.3 vs 6.0 months; P = .005) and overall survival (median survival time not reached vs 20.2 months; P = .039) and lower prevalence of grade ≥3 adverse events, such as hypertension (P = .004) and proteinuria (P = .046).

Study details: This retrospective study propensity score-matched patients with unresectable HCC who received Atezo/Bev (n = 152) with those who received lenvatinib (n = 152) as first-line systemic therapies.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Niizeki T et al. Comparison of efficacy and safety of atezolizumab plus bevacizumab and lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: A propensity score matching analysis. Target Oncol. 2022 (Oct 22). Doi: 10.1007/s11523-022-00921-x

Key clinical point: Atezolizumab plus bevacizumab (Atezo/Bev) is a more effective and safe first-line therapy than lenvatinib in patients with unresectable hepatocellular carcinoma (HCC).

Major finding: Patients who received Atezo/Bev vs lenvatinib had a significantly longer progression-free survival (8.3 vs 6.0 months; P = .005) and overall survival (median survival time not reached vs 20.2 months; P = .039) and lower prevalence of grade ≥3 adverse events, such as hypertension (P = .004) and proteinuria (P = .046).

Study details: This retrospective study propensity score-matched patients with unresectable HCC who received Atezo/Bev (n = 152) with those who received lenvatinib (n = 152) as first-line systemic therapies.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Niizeki T et al. Comparison of efficacy and safety of atezolizumab plus bevacizumab and lenvatinib as first-line therapy for unresectable hepatocellular carcinoma: A propensity score matching analysis. Target Oncol. 2022 (Oct 22). Doi: 10.1007/s11523-022-00921-x

PHILADELPHIA – A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Richard Mark Kirkner/MDedge News

Three members of the core planning group that wrote the update, jointly commissioned by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test results:

• Macrovascular – venous thromboembolism (VTE) with and without high VTE risk profile.
• Macrovascular – arterial thrombosis with and without a high cardiovascular disease risk profile.
• Microvascular – additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected and established APS.
• Obstetric – expanded definitions to account for the absence or presence of preeclampsia or premature birth with or without fetal death.
• Cardiac valve – accounts for thickening and vegetation.
• Hematologic – includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 10⁹/L).
• Antiphospholipid (aPL) test – coagulation-based functional assay, assigning greater weight to persistent over one-time positive test results.
• aPL test by solid-phase assay – includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive results depending on isotype, whether immunoglobulin G or M.

Changes from Sapporo criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All of these are included in the draft criteria under two domains.

“These novel clinical features will help us better stratify patients according to the risk factor profile,” Stéphane Zuily, MD, PhD, a vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated domains.

“We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify single, double, and triple aPL positivity based on different domains and weights,” said Dr. Zuily, professor of medicine at Lorraine University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. “And we were also able to identify different thresholds in terms of aPL positivity,” Dr. Zuily said.
 

Rationale and methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant professor at Weill Cornell Medicine in New York, explained the rationale for the update. “The existing criteria were drafted in 1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with antiphospholipid antibodies,” she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

“These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades there have been important advancements in the methodology of classification criteria development,” she said. ACR and EULAR both endorsed the new methodology for developing the classification criteria, Dr. Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international centers, dividing them into two validation cohorts of 284 cases each.
 

How classification criteria work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the classification system works. “If you have a patient that you are considering for APS classification, the story starts with entry criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of the clinical criteria,” he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Dr. Erkan explained that weighted point values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

“APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory domains,” he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation cohorts. “Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts with 99% specificity,” Dr. Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

“Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion,” he added, vs. 100% and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Dr. Erkan said. “When this work is completed, another chapter will start,” he said. “If a case doesn’t meet APS classification criteria, the case may still be uncertain or equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new criteria.”
 

Comment: Why these updates are needed

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS criteria, explained why these updated criteria are needed. “It’s very important to get the updated criteria because, as the speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications, and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they’re not part of the criteria.”

She added, “I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that future studies can be done in this population.”

Dr. Jorge called the 99% specificity described in the analysis “impressive” and “promising.”

Dr. Barbhaiya and Dr. Zuily have no relevant disclosures. Dr. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and GlaxoSmithKline. Dr. Jorge has no relevant disclosures.
 

PHILADELPHIA – A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Richard Mark Kirkner/MDedge News

Three members of the core planning group that wrote the update, jointly commissioned by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test results:

• Macrovascular – venous thromboembolism (VTE) with and without high VTE risk profile.
• Macrovascular – arterial thrombosis with and without a high cardiovascular disease risk profile.
• Microvascular – additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected and established APS.
• Obstetric – expanded definitions to account for the absence or presence of preeclampsia or premature birth with or without fetal death.
• Cardiac valve – accounts for thickening and vegetation.
• Hematologic – includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 10⁹/L).
• Antiphospholipid (aPL) test – coagulation-based functional assay, assigning greater weight to persistent over one-time positive test results.
• aPL test by solid-phase assay – includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive results depending on isotype, whether immunoglobulin G or M.

Changes from Sapporo criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All of these are included in the draft criteria under two domains.

“These novel clinical features will help us better stratify patients according to the risk factor profile,” Stéphane Zuily, MD, PhD, a vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated domains.

“We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify single, double, and triple aPL positivity based on different domains and weights,” said Dr. Zuily, professor of medicine at Lorraine University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. “And we were also able to identify different thresholds in terms of aPL positivity,” Dr. Zuily said.
 

Rationale and methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant professor at Weill Cornell Medicine in New York, explained the rationale for the update. “The existing criteria were drafted in 1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with antiphospholipid antibodies,” she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

“These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades there have been important advancements in the methodology of classification criteria development,” she said. ACR and EULAR both endorsed the new methodology for developing the classification criteria, Dr. Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international centers, dividing them into two validation cohorts of 284 cases each.
 

How classification criteria work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the classification system works. “If you have a patient that you are considering for APS classification, the story starts with entry criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of the clinical criteria,” he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Dr. Erkan explained that weighted point values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

“APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory domains,” he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation cohorts. “Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts with 99% specificity,” Dr. Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

“Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion,” he added, vs. 100% and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Dr. Erkan said. “When this work is completed, another chapter will start,” he said. “If a case doesn’t meet APS classification criteria, the case may still be uncertain or equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new criteria.”
 

Comment: Why these updates are needed

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS criteria, explained why these updated criteria are needed. “It’s very important to get the updated criteria because, as the speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications, and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they’re not part of the criteria.”

She added, “I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that future studies can be done in this population.”

Dr. Jorge called the 99% specificity described in the analysis “impressive” and “promising.”

Dr. Barbhaiya and Dr. Zuily have no relevant disclosures. Dr. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and GlaxoSmithKline. Dr. Jorge has no relevant disclosures.
 

PHILADELPHIA – A draft update of criteria for classifying antiphospholipid syndrome (APS) incorporates a much broader spectrum of disease signs and symptoms, such as kidney disease and more variables for pregnancy, and meets a higher level of specificity than the existing Sapporo criteria, although at the expense of lower sensitivity.

Richard Mark Kirkner/MDedge News

Three members of the core planning group that wrote the update, jointly commissioned by the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR), reviewed the proposed criteria at the annual meeting of the ACR.

If ACR and EULAR adopt the new criteria, it would be an update to the Sapporo classification criteria for APS, which was last updated in 2006. The pending criteria consist of the following eight domains encompassing clinical findings and laboratory test results:

• Macrovascular – venous thromboembolism (VTE) with and without high VTE risk profile.
• Macrovascular – arterial thrombosis with and without a high cardiovascular disease risk profile.
• Microvascular – additional categories for kidney disease, pulmonary embolism, and other conditions for both suspected and established APS.
• Obstetric – expanded definitions to account for the absence or presence of preeclampsia or premature birth with or without fetal death.
• Cardiac valve – accounts for thickening and vegetation.
• Hematologic – includes thrombocytopenia (defined as the lowest platelet count, 20-130 x 10⁹/L).
• Antiphospholipid (aPL) test – coagulation-based functional assay, assigning greater weight to persistent over one-time positive test results.
• aPL test by solid-phase assay – includes anticardiolipin enzyme-linked immunosorbent assay (aCL ELISA), and aCL/anti-beta 2 glycoprotein-I (aCL/anti-beta 2 GPI) tests, with greater weight assigned for moderate-to-high positive results depending on isotype, whether immunoglobulin G or M.

Changes from Sapporo criteria

The existing Sapporo criteria include two clinical categories, vascular thrombosis and pregnancy morbidity; and three laboratory categories, positive lupus anticoagulant, medium or high antibody titers, and high aCL/anti-beta 2 GPI measured by ELISA. All of these are included in the draft criteria under two domains.

“These novel clinical features will help us better stratify patients according to the risk factor profile,” Stéphane Zuily, MD, PhD, a vascular specialist and European co-principal investigator of the planning group, said in explaining the proposed updated domains.

“We well-defined the microvascular domain items further than the aPL nephropathy; we redefined pregnancy morbidities; we added cardiac valve disease and thrombocytopenia; and, through gathering novel laboratory features, we were able to quantify single, double, and triple aPL positivity based on different domains and weights,” said Dr. Zuily, professor of medicine at Lorraine University in Nancy, France.

Also noteworthy is the separation of aCL/anti-beta 2 GPI testing by IgG and IgM isotypes. “And we were also able to identify different thresholds in terms of aPL positivity,” Dr. Zuily said.
 

Rationale and methodology

Planning group member Medha Barbhaiya, MD, MPH, an attending physician at the Hospital for Special Surgery and assistant professor at Weill Cornell Medicine in New York, explained the rationale for the update. “The existing criteria were drafted in 1999 and updated in 2006 and require one clinical criterion, either vascular thrombosis event or pregnancy morbidity along with antiphospholipid antibodies,” she said.

Those 16-year-old criteria also ignored heterogeneous manifestations such as heart valve disease or thrombocytopenia, failed to stratify thrombotic events as risk factors, and used an outdated definition of pregnancy morbidity related to APS, she said.

“These findings helped to support our rationale for new criteria development, along with the fact that over the last 1 to 2 decades there have been important advancements in the methodology of classification criteria development,” she said. ACR and EULAR both endorsed the new methodology for developing the classification criteria, Dr. Barbhaiya added.

That methodology involved multidisciplinary international panels of experts and data-driven efforts, with the goal of identifying patients with a high likelihood of APS for research purposes. The planning group collected 568 cases from 29 international centers, dividing them into two validation cohorts of 284 cases each.
 

How classification criteria work

Doruk Erkan, MD, MPH, coprincipal investigator representing the United States on the planning group, an attending physician at the Hospital for Special Surgery in New York, and a professor at Weill Cornell Medicine in New York, explained how the classification system works. “If you have a patient that you are considering for APS classification, the story starts with entry criteria, which are one documented clinical criterion plus a positive aPL [antiphospholipid] test within 3 years of observation of the clinical criteria,” he said.

Once the entry criteria for APS are met, there are the clinical and laboratory domains. Dr. Erkan explained that weighted point values are assigned to individual categories under each domain. For example, in the macrovascular VTE domain, VTE with a high VTE risk profile is worth 1 point, but VTE without a high VTE risk profile is worth 3 points.

“APS classification will be achieved with at least three points from clinical domains and at least three points from the laboratory domains,” he said.

The planning group conducted a sensitivity and specificity analysis of the draft classification system using the two validation cohorts. “Our goal was very high specificity to improve the homogeneity in APS research, and we achieved this in both cohorts with 99% specificity,” Dr. Erkan said. That compares to sensitivity of 91% and 86% of the Sapporo criteria in the validation cohorts.

“Our sensitivity was 83% and 84% capturing a broad spectrum of patients assessed with APS suspicion,” he added, vs. 100% and 99% with the Sapporo criteria.

These criteria are not absolute and are structured to permit future modifications, Dr. Erkan said. “When this work is completed, another chapter will start,” he said. “If a case doesn’t meet APS classification criteria, the case may still be uncertain or equivocal rather than not APS. Uncertain or controversial cases should be studied separately to guide future updates of the new criteria.”
 

Comment: Why these updates are needed

April Jorge, MD, a rheumatologist at Massachusetts General Hospital in Boston and moderator of the session on the draft APS criteria, explained why these updated criteria are needed. “It’s very important to get the updated criteria because, as the speakers mentioned, the prior Sapporo criteria were limited to just large-vessel venous thrombosis or pregnancy complications, and so that makes it difficult to study the disease in other manifestations, such as kidney manifestations, if they’re not part of the criteria.”

She added, “I think there was a need for clear classification criteria that was thought to be highly specific for the disease so that future studies can be done in this population.”

Dr. Jorge called the 99% specificity described in the analysis “impressive” and “promising.”

Dr. Barbhaiya and Dr. Zuily have no relevant disclosures. Dr. Erkan disclosed relationships with Aurinia, Eli Lilly, Exagen, and GlaxoSmithKline. Dr. Jorge has no relevant disclosures.
 

Key clinical point: The combination of alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) may effectively predict the prognosis of patients with hepatocellular carcinoma (HCC) after radical hepatectomy.

Major finding: The 5-year overall and recurrence-free survival rates were significantly lower among patients with high preoperative serum AFP and CA19-9 levels than among those with high serum AFP or CA19-9 levels (P = .022 and P = .004, respectively) and those with low serum AFP and CA19-9 levels (both P < .001).

Study details: This retrospective study included 711 patients with HCC who were categorized as having low (≤400 ng/mL; n = 381) or high (>400 ng/mL; n = 330) preoperative serum AFP levels and as having low (≤37 U/mL; n = 552) or high (>37 U/mL; n = 159) preoperative serum CA19-9 levels.

Disclosures: This study was sponsored by the Youth Program of Scientific Research Foundation of Guangxi Medical University Cancer Hospital, China, among others. The authors declared no conflicts of interest.

Source: Zhang J et al. Prognostic significance of combined α-fetoprotein and CA19-9 for hepatocellular carcinoma after hepatectomy. World J Surg Oncol. 2022;20:346 (Oct 19). Doi: 10.1186/s12957-022-02806-9

Key clinical point: The combination of alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) may effectively predict the prognosis of patients with hepatocellular carcinoma (HCC) after radical hepatectomy.

Major finding: The 5-year overall and recurrence-free survival rates were significantly lower among patients with high preoperative serum AFP and CA19-9 levels than among those with high serum AFP or CA19-9 levels (P = .022 and P = .004, respectively) and those with low serum AFP and CA19-9 levels (both P < .001).

Study details: This retrospective study included 711 patients with HCC who were categorized as having low (≤400 ng/mL; n = 381) or high (>400 ng/mL; n = 330) preoperative serum AFP levels and as having low (≤37 U/mL; n = 552) or high (>37 U/mL; n = 159) preoperative serum CA19-9 levels.

Disclosures: This study was sponsored by the Youth Program of Scientific Research Foundation of Guangxi Medical University Cancer Hospital, China, among others. The authors declared no conflicts of interest.

Source: Zhang J et al. Prognostic significance of combined α-fetoprotein and CA19-9 for hepatocellular carcinoma after hepatectomy. World J Surg Oncol. 2022;20:346 (Oct 19). Doi: 10.1186/s12957-022-02806-9

Key clinical point: The combination of alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) may effectively predict the prognosis of patients with hepatocellular carcinoma (HCC) after radical hepatectomy.

Major finding: The 5-year overall and recurrence-free survival rates were significantly lower among patients with high preoperative serum AFP and CA19-9 levels than among those with high serum AFP or CA19-9 levels (P = .022 and P = .004, respectively) and those with low serum AFP and CA19-9 levels (both P < .001).

Study details: This retrospective study included 711 patients with HCC who were categorized as having low (≤400 ng/mL; n = 381) or high (>400 ng/mL; n = 330) preoperative serum AFP levels and as having low (≤37 U/mL; n = 552) or high (>37 U/mL; n = 159) preoperative serum CA19-9 levels.

Disclosures: This study was sponsored by the Youth Program of Scientific Research Foundation of Guangxi Medical University Cancer Hospital, China, among others. The authors declared no conflicts of interest.

Source: Zhang J et al. Prognostic significance of combined α-fetoprotein and CA19-9 for hepatocellular carcinoma after hepatectomy. World J Surg Oncol. 2022;20:346 (Oct 19). Doi: 10.1186/s12957-022-02806-9

Key clinical point: Compared with hepatic arterial infusion chemotherapy (HAIC)+lenvatinib, the triple therapeutic regimen HAIC+lenvatinib+sequential ablation significantly improved the survival of patients with advanced hepatocellular carcinoma (HCC) without compromising safety.

Major finding: Patients who received HAIC+lenvatinib+sequential ablation vs HAIC+lenvatinib had a significantly longer median overall survival (>30 vs 13.6 months; P = .010), progression-free survival (PFS; 12.8 vs 5.6 months; P = .001), and intrahepatic PFS (14.6 vs 6.4 months; P = .002) and similar incidence of grade 1-2 (P = .404) and 3-4 (P = .333) adverse events.

Study details: This multicenter retrospective study included 150 patients with advanced HCC who received HAIC+lenvatinib (n = 97) or HAIC+lenvatinib+sequential ablation (n = 53).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Liu Y et al. Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and sequential ablation in the treatment of advanced hepatocellular carcinoma. Cancer Med. 2022 (Oct 17). Doi: 10.1002/cam4.5366

Key clinical point: Compared with hepatic arterial infusion chemotherapy (HAIC)+lenvatinib, the triple therapeutic regimen HAIC+lenvatinib+sequential ablation significantly improved the survival of patients with advanced hepatocellular carcinoma (HCC) without compromising safety.

Major finding: Patients who received HAIC+lenvatinib+sequential ablation vs HAIC+lenvatinib had a significantly longer median overall survival (>30 vs 13.6 months; P = .010), progression-free survival (PFS; 12.8 vs 5.6 months; P = .001), and intrahepatic PFS (14.6 vs 6.4 months; P = .002) and similar incidence of grade 1-2 (P = .404) and 3-4 (P = .333) adverse events.

Study details: This multicenter retrospective study included 150 patients with advanced HCC who received HAIC+lenvatinib (n = 97) or HAIC+lenvatinib+sequential ablation (n = 53).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Liu Y et al. Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and sequential ablation in the treatment of advanced hepatocellular carcinoma. Cancer Med. 2022 (Oct 17). Doi: 10.1002/cam4.5366

Key clinical point: Compared with hepatic arterial infusion chemotherapy (HAIC)+lenvatinib, the triple therapeutic regimen HAIC+lenvatinib+sequential ablation significantly improved the survival of patients with advanced hepatocellular carcinoma (HCC) without compromising safety.

Major finding: Patients who received HAIC+lenvatinib+sequential ablation vs HAIC+lenvatinib had a significantly longer median overall survival (>30 vs 13.6 months; P = .010), progression-free survival (PFS; 12.8 vs 5.6 months; P = .001), and intrahepatic PFS (14.6 vs 6.4 months; P = .002) and similar incidence of grade 1-2 (P = .404) and 3-4 (P = .333) adverse events.

Study details: This multicenter retrospective study included 150 patients with advanced HCC who received HAIC+lenvatinib (n = 97) or HAIC+lenvatinib+sequential ablation (n = 53).

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Liu Y et al. Efficacy and safety of hepatic arterial infusion chemotherapy combined with lenvatinib and sequential ablation in the treatment of advanced hepatocellular carcinoma. Cancer Med. 2022 (Oct 17). Doi: 10.1002/cam4.5366