Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1^st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1^st- and 2^nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.     

Cavotricuspid isthmus ablation guided by force‐time integral – A randomized study

BackgroundForce‐time integral (FTI) is an ablation marker of lesion quality and transmurality. A target FTI of 400 gram‐seconds (gs) has been shown to improve durability of pulmonary vein isolation, following atrial fibrillation ablation. However, relevant targets for cavotricuspid isthmus (CTI) ablation are lacking.HypothesisWe sought to investigate whether CTI ablation with 600 gs FTI lesions is associated with reduced rate of transisthmus conduction recovery compared to 400 gs lesions.MethodsFifty patients with CTI‐dependent flutter were randomized to ablation using 400 gs (FTI400 group, n = 26) or 600 gs FTI lesions (FTI600 group, n = 24). The study endpoint was spontaneous or adenosine‐mediated recovery of transisthmus conduction, after a 20‐min waiting period.ResultsThe study endpoint occurred in five patients (19.2%) in group FTI400 and in four patients (16.7%) in group FTI600, p = .81. First‐pass CTI block was similar in both groups (50% in FTI400 vs. 54.2% in FTI600, p = .77). There were no differences in the total number of lesions, total ablation time, procedure time and fluoroscopy duration between the two groups. There were no major complications in any group. In the total population, patients not achieving first‐pass CTI block had significantly higher rate of acute CTI conduction recovery, compared to those with first‐pass block (29.2% vs. 7.7% respectively, p = .048).ConclusionsCTI ablation using 600 gs FTI lesions is not associated with reduced spontaneous or adenosine‐mediated recurrence of transisthmus conduction, compared to 400 gs lesions.     

Serum Resistin as a Biomarker in Nonalcoholic Fatty Liver Disease: Is This a Road to be Taken?

Nonalcoholic fatty liver disease (NAFLD), which encompass-es a broad spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH...     

The role of central venous pressure and type of vascular control in blood loss during major liver resections

BACKGROUND: Blood loss during liver resection constitutes the primary determinant of the postoperative outcome. Various techniques of vascular control and maintenance of a low central vein pressure (CVP) have been used in order to prevent intraoperative blood loss and postoperative complications. Our study aims at assessing the effects of different levels of CVP in relation to type of vascular control on perioperative blood loss and patient outcome. METHODS: The records of 102 consecutive patients who underwent a major hepatectomy were retrospectively analyzed. Forty-two patients were operated on with a CVP of 6 mm Hg or more and 60 patients had a CVP of 5 mm Hg or less. The Pringle maneuver was used in 45 patients and selective hepatic vascular exclusion (SHVE) in 57 patients. Blood loss, complications, and mortality were analyzed comparing the two CVP groups in relation to type of vascular control. RESULTS: The Pringle maneuver is associated with more blood loss when CVP is 6 mm Hg or more compared with CVP 5 mm Hg or less (1,250 mL [250 to 2,850] versus 780 mL [150 to 3,100]; P <0.05). Conversely, blood loss during SHVE is independent of the CVP levels. A significant difference in blood loss between the Pringle maneuver and SHVE was observed, only when CVP was 6 mm Hg or more (1,250 mL [250 to 2,850] versus 680 mL [150 to 1,260]; P <0.05). Hospital stay was also significantly longer in patients operated on with CVP 6 mm Hg or more (15 days [4 to 38] than in patients with CVP 5 mm Hg or less (10 days [4 to 32]; P <0.05). CONCLUSIONS: Elevated CVP during major liver resections results in greater blood loss and a longer hospital stay. The Pringle maneuver with CVP 5 mm Hg or less is associated with blood loss not significantly different from that with SHVE. The latter, though, has been shown not to be affected by CVP levels and should be used whenever CVP remains high despite adequate anesthetic management.     

Chemoprevention of liver cancer by plant polyphenols

Primary liver cancer or hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer. Currently, the treatments for HCC are not so effective and new strategies are needed for its fight. Chemoprevention, the use of natural or synthetic chemical agents to reverse, suppress or prevent carcinogenesis is considered an important way for confronting HCC. Many of the chemopreventive agents are phytochemicals, namely non-nutritive plant chemicals with protective or disease preventive properties. In this review, we focus on plant polyphenols, one of the most important classes of phytochemicals, their chemopreventive properties against HCC and discuss the molecular mechanisms accounting for this activity.     

Associations of placental weight with maternal and cord blood hormones

PurposePlacental weight has been associated with mammographic pattern and coronary heart disease in the adult offspring, but the mechanisms are unknown. We evaluated the associations of maternal and cord blood hormones with placental weight in normal pregnancies.MethodsProspective study of 167 normal singleton pregnancies in Boston, USA and 256 in Shanghai, China. Maternal hormone levels at the 27th gestational week were available for all pregnancies. Cord blood measurements were available for 86 pregnancies in Boston and 104 in Shanghai. Pearson partial correlation coefficients of log-transformed hormone levels with placental weight were calculated.ResultsMaternal levels of estriol, testosterone, and progesterone (P < .05) were positively associated with placental weight. There was no such evidence for adiponectin, prolactin, and insulin-like growth factor (IGF)-I. Cord blood steroids tended to be inversely associated with placental weight, the results being statistically significant for testosterone (P < .05). There was a marginally significant positive association of cord blood IGF-I with placental weight. Reported results were adjusted for study center.ConclusionsPlacental weight appears to be positively correlated with maternal steroids. Its correlation with cord blood steroids, however, appears inverse, compatible with negative feedback mechanisms. There is also a suggestion for placental weight to be positively associated with cord blood IGF-I.     

Cutaneous perforators of the peroneal artery: Cadaveric study with implications in the design of the osteocutaneous free fibular flap

Bilateral dissection of 15 formalin embalmed cadaver legs was performed in order to study the anatomic pattern of the peroneal artery (PA) and its cutaneous perforating vessels (CB). The total number of CB from the PA was 125 or an average of 4.17 branches per leg. CB were distributed in the superoinferior axis between 18.25 and 84.25% of the length of the fibula and their average length was 5 ± 1.8 cm. 86/125 (68.8%) of the CB were classified as myocutaneous branches (MC) that penetrated muscle before reaching the skin, whereas 39/125 (31.2%) were septocutaneous branches (SC) that passed through the intermuscular septum. The mean distance between the posterior border of the fibula and the site where the perforators emerged was 1.88 ± 0.79 cm for the SC and 1.21 ± 0.87 cm for the MC. These anatomic findings should encourage the surgeon to design the skin paddle in the boundary between the middle and the distal third of the fibular length about 2 cm behind the posterior fibular border on the posterolateral leg, where the number of CB is maximal. Clin. Anat. 22:826–833, 2009. © 2009 Wiley‐Liss, Inc.     

Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus

This is a prospective evaluation of the effect of structured care of dyslipidemia with atorvastatin (strict implementation of guidelines) versus usual care (physician's standard of care) on morbidity and mortality of patients with coronary heart disease (CHD) and diabetes mellitus (DM). From 1600 consecutive CHD patients randomized to either form of care in the GREek Atorvastatin and CHD Evaluation Study (GREACE), 313 had DM: 161 in the structured care arm and 152 in the usual care arm. All patients were followed up for a mean of 3 years. In the structured care group, patients were treated with atorvastatin to achieve the National Cholesterol Education Program (NCEP) low-density lipoprotein cholesterol (LDL-C) treatment goal of <2.6 mmol/L (100 mg/dL). Primary endpoints were all-cause and coronary mortality, coronary morbidity, and stroke. In the structured care group, 156 patients (97%) were taking atorvastatin (10-80 mg/day; mean, 23.7 mg/day) throughout the study; the NCEP LDL-C treatment goal was reached by 150 patients (93%). Only 17% (n=26) of the usual care patients were on long-term hypolipidemic drug treatment and 4% (n=6) reached the NCEP LDL-C treatment goal. During the study, 46 of 152 (30.3%) CHD patients with DM on usual care experienced a major vascular event or died versus 20 of 161 (12.5%) patients on structured care; relative risk reduction (RRR) 58%, p<0.0001. RRR for all-cause mortality was 52%, p=0.049; coronary mortality 62%, p=0.042; coronary morbidity 59%, p<0.002; and stroke 68%, p=0.046. Event rate curves started deviating from the sixth treatment month and the RRR was almost 60% by the 12th month. RRRs remained at that level until the end of the study, when they became statistically significant. The cost/life-year gained with structured care was estimated at 6200 US dollars. In CHD patients with DM, structured care of dyslipidemia with atorvastatin to achieve the NCEP LDL-C treatment goal, reduces all-cause and coronary mortality, coronary morbidity, and stroke by more than one half within a 3-year period, in comparison to usual care. Clinical benefit is manifested as early as the sixth month of treatment.     

Coronary and peripheral blood flow changes following biventricular pacing and their relation to heart failure improvement.

AIMS: To study the effect of cardiac resynchronization therapy (CRT) on coronary and peripheral arterial circulation and to assess whether their changes are related to the improvement in patients' functional capacity and prognostically important biochemical markers. METHODS AND RESULTS: Twenty-five patients were studied (New York Heart Association classes III and IV, left ventricular ejection fraction <35%, QRS>120 ms, mean age 66 +/- 2.1 years). Coronary blood flow (CBF), forearm blood flow (FBF), and their reserve were measured by transoesophageal echocardiography (in cm/s) and venous occlusion plethysmography (in mL/100 mL/min) at baseline and following 3 months of CRT. N-terminal-pro-brain natriuretic peptide (Nt-pro-BNP) and serum adhesion molecules, sICAM-1 and sVCAM-1 levels were also assessed. CRT induced a non-significant increase in resting CBF (baseline vs. CRT: 52.1 +/- 5.5 vs. 58.2 +/- 3.6, P: NS), whereas hyperaemic CBF was increased by CRT (baseline vs. CRT: 67.8 +/- 6.8 vs. 79.8 +/- 6.2, P < 0.05). Significant increases were observed in resting FBF (baseline vs. CRT: 1.6 +/- 0.2 vs. 2.6 +/- 0.2, P < 0.05) and hyperaemic FBF (baseline vs. CRT: 2.1 +/- 0.2 vs. 3.2 +/- 0.3, P < 0.05). The per cent difference in hyperaemic FBF was related to the per cent change in Nt-pro-BNP (r = -0.71, P < 0.05) and the per cent improvement in exercise duration (r = 0.80, P < 0.05). CONCLUSION: CRT induces favourable changes in coronary and peripheral arterial function. Changes in peripheral blood flow are related to patients' improvement and may be prognostically significant.     

Rapid dark aging of biomass burning as an overlooked source of oxidized organic aerosol

Oxidized organic aerosol (OOA) is a major component of ambient particulate matter, substantially impacting climate, human health, and ecosystems. OOA is readily produced in the presence of sunlight, and requires days of photooxidation to reach the levels observed in the atmosphere. High concentrations of OOA are thus expected in the summer; however, our current mechanistic understanding fails to explain elevated OOA during wintertime periods of low photochemical activity that coincide with periods of intense biomass burning. As a result, atmospheric models underpredict OOA concentrations by a factor of 3 to 5. Here we show that fresh emissions from biomass burning exposed to NO₂ and O₃ (precursors to the NO₃ radical) rapidly form OOA in the laboratory over a few hours and without any sunlight. The extent of oxidation is sensitive to relative humidity. The resulting OOA chemical composition is consistent with the observed OOA in field studies in major urban areas. Additionally, this dark chemical processing leads to significant enhancements in secondary nitrate aerosol, of which 50 to 60% is estimated to be organic. Simulations that include this understanding of dark chemical processing show that over 70% of organic aerosol from biomass burning is substantially influenced by dark oxidation. This rapid and extensive dark oxidation elevates the importance of nocturnal chemistry and biomass burning as a global source of OOA.

Highly oxidized organic aerosol (OOA) is a dominant component of particulate matter air pollution globally (1–3); however, sources of OOA remain uncertain, limiting the ability of models to accurately represent OOA and thus predict the associated climate, ecosystem, and health implications (4, 5). The current conceptual model of OOA formation suggests that anthropogenic OOA predominantly originates from the oxidation of volatile (VOCs), intermediate volatility (IVOCs), and semivolatile (SVOCs) organic compounds by the OH radical, resulting in lower-volatility products that condense to the particle phase (6). As the OH radical is formed through photolysis and has a very short atmospheric lifetime [less than a second (7)], this oxidation mechanism only occurs in the presence of sunlight. Further, the time scale for OOA formation through oxidation with OH in models is on the order of a few days (8). While this understanding is sufficient in explaining OOA concentrations in summer or periods with high solar radiation, atmospheric models fail to reproduce the observed concentration of OOA in the ambient atmosphere during winter and low-light conditions (9, 10). Fountoukis et al. (9) found simulated OOA concentrations significantly underestimated in wintertime Paris. Tsimpidi et al. (10) also reported an underprediction of simulated OOA globally in winter, suggesting missing sources of both primary OA (POA) and secondary formation pathways. This underproduction suggests a possible overlooked conversion pathway of organic vapors or particles to OOA that is not accounted for in current chemical transport and climate models.As stricter controls on fossil fuel combustion are implemented, residential biomass burning (BB) as a source of heating or cooking is becoming an increasingly important source of OA in urban environments (1, 11, 12). Further, increasing rates of wildfires from climate change are increasing the frequency of smoke-impacted days in urban areas (12–14). BB emissions include high concentrations of POA, SVOCs, IVOCs, and VOCs (15, 16), thus making BB a key source of OOA. Previous research has focused on quantifying the concentration of OOA formed through photochemical oxidation reactions (i.e., OH) with BB emissions (17, 18). However, oxidation of BB emissions in low or no sunlight is less well understood and is not included in chemical transport models. As opposed to OH, the NO₃ radical is formed through reactions with NO₂ and O₃ and is rapidly lost in the presence of sunlight (19). Thus, the NO₃ radical is only available in significant concentrations at night or other low-light conditions (20, 21). Previous research has established that biogenic VOCs may undergo oxidation at night when mixed with anthropogenic emissions containing NO₂ and O₃ (19, 22–27). There have been only a few studies that consider that nighttime oxidation of residential wood combustion may proceed through similar pathways (28–31); however, the magnitude and relevance to observed OOA in the ambient atmosphere has not yet been established. By combining laboratory experiments and ambient observations to inform a chemical transport model, we present strong evidence that nighttime oxidation of BB plumes (proceeding through reactions with O₃ and the NO₃ radical) is an important source of OOA.