Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins.

Certain species of pathogenic bacteria damage tissues by secreting cholesterol-dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed step of cholesterol biosynthesis is catalyzed by squalene synthase, we explored whether inhibiting this enzyme protected cells against cholesterol-dependent cytolysins. We first synthesized 22 different nitrogen-containing bisphosphonate molecules that were designed to inhibit squalene synthase. Squalene synthase inhibition was quantified using a cell-free enzyme assay, and validated by computer modeling of bisphosphonate molecules binding to squalene synthase. The bisphosphonates were then screened for their ability to protect HeLa cells against the damage caused by the cholesterol-dependent cytolysin, pyolysin. The most effective bisphosphonate reduced pyolysin-induced leakage of lactate dehydrogenase into cell supernatants by >80%, and reduced pyolysin-induced cytolysis from >75% to <25%. In addition, this bisphosphonate reduced pyolysin-induced leakage of potassium from cells, limited changes in the cytoskeleton, prevented mitogen-activated protein kinases cell stress responses, and reduced cellular cholesterol. The bisphosphonate also protected cells against another cholesterol-dependent cytolysin, streptolysin O, and protected lung epithelial cells and primary dermal fibroblasts against cytolysis. Our findings imply that treatment with bisphosphonates that inhibit squalene synthase might help protect tissues against pathogenic bacteria that secrete cholesterol-dependent cytolysins.

Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses.

The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIRα in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIRα overexpression enhanced ER stress markers ATF4, ATF6, IRE1α, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIRα concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIRα-induced ER stress responses. Altogether, these findings suggested that IGF-IIRα contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.

[Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer].

As a newly emerged class of anticancer bioagents in the most precise and selectively targeted way, antibody-drug conjugate (ADC) combines the cancer-targeting abilities of monoclonal antibodies with the cytotoxicity potency of payload, delivering highly cytotoxic drug into tumors via 'targeted chemotherapy'. ADC has revolutionized the treatment landscape of human epidermal growth factor receptor 2 positive and triple negative subtypes in breast cancer. Three ADCs have been approved by U. S. Food and Drug Administration with breast cancer indications, including trastuzumab emtansine (T-DM1; also approved in China), trastuzumab deruxtecan (T-DXd, DS-8201) and sacituzumab govitecan (IMMU-132; also approved in China). Antibodies, cytotoxic drug, linker, and conjugation process are implicated in ADC profile, resulting in unique adverse drug reactions and toxicity heterogeneity within ADC class. For example, more attention should be paid to the management of thrombocytopenia, hepatotoxicity, and reductions in left ventricular ejection fraction (LVEF) in patients treated with trastuzumab emtansine; clinical physicians should pay attention to the risk of neutropenia, interstitial lung disease/pneumonitis, and reductions in LVEF when treated with trastuzumab deruxtecan; sacituzumab govitecan most frequently caused neutropenia, anemia and diarrhea requiring close monitor. ADC has generally favorable safety profiles, and dose modifications and/or symptomatic supporting treatment are effective in terms of toxicity management. This consensus aims at providing guidance for clinical oncologists of early detection, regular assessment, timely management and follow-up monitor of ADC-associated adverse reactions/events.

Human lung cDC1 drive increased perforin-mediated NK cytotoxicity in chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD), lung natural killer cells (NKs) lyse autologous lung epithelial cells in vitro, but underlying mechanisms and their relationship to epithelial cell apoptosis in vivo are undefined. Although this cytolytic capacity of lung NKs depends on priming by dendritic cells (DCs), whether priming correlates with DC maturation or is limited to a specific DC subset is also unknown. We recruited ever-smokers (≥10 pack-years; n = 96) undergoing clinically indicated lung resections. We analyzed lung NKs for cytotoxic molecule transcripts and for cytotoxicity, which we correlated with in situ detection of activated Caspase-3/7+ airway epithelial cells. To investigate DC priming, we measured lung DC expression of CCR2, CCR7, and CX3CR1 and cocultured peripheral blood NKs with autologous lung DCs, either matured using lipopolysaccharide (LPS) (nonobstructed smokers) or separated into conventional dendritic cell type-1 (cDC1) versus cDC type-2 (cDC2) (COPD). Lung NKs in COPD expressed more perforin (P < 0.02) and granzyme B (P < 0.03) transcripts; inhibiting perforin blocked in vitro killing by lung NKs. Cytotoxicity in vitro correlated significantly (Sr = 0.68, P = 0.0043) with numbers of apoptotic epithelial cells per airway. In nonobstructed smokers, LPS-induced maturation enhanced DC-mediated priming of blood NKs, reflected by greater epithelial cell death. Although CCR7 expression was greater in COPD in both cDC1 (P < 0.03) and cDC2 (P = 0.009), only lung cDC1 primed NK killing. Thus, rather than being intrinsic to those with COPD, NK priming is a capacity of human lung DCs that is inducible by recognition of bacterial (and possibly other) danger signals and restricted to the cDC1 subset.

Influence of Asiatic acid on cell proliferation and DNA damage in vitro and in vivo systems.

Asiatic acid (AA) is a triterpene with promising pharmacological activity. In the present study, in vitro and in vivo assays were conducted to understand the effect of AA on cell proliferation and genomic instability. AA was cytotoxic to human tumor cell lines (M059J, HeLa, and MCF-7), with IC50 values ranging from 13.91 to 111.72 µM. In the case of M059J, AA exhibited selective cytotoxicity after 48 h of treatment (IC50 = 24 µM), decreasing the percentage of cells in the G0/G1 phase, increasing the percentage of cells in the S phase, and inducing apoptosis. A significant increase in chromosomal damage was observed in V79 cell cultures treated with AA (40 µM), revealing genotoxic activity. In contrast, low concentrations (5, 10, and 20 µM) of AA significantly reduced the frequencies of micronuclei induced by the mutagens doxorubicin (DXR), methyl methanesulfonate, and hydrogen peroxide. A reduction of DXR-induced intracellular free radicals was found in V79 cells treated with AA (10 µM). The antigenotoxic effect of AA (30 mg/kg) was also observed against DXR-induced chromosomal damage in Swiss mice. Significant reductions in p53 levels were verified in the liver tissue of these animals. Taken together, the data indicate that AA exerted antiproliferative activity in M059J tumor cells, which is probably related to the induction of DNA damage, leading to cell cycle arrest and apoptosis. Additionally, low concentrations of AA exhibited antigenotoxic effects and its antioxidant activity may be responsible, at least in part, for chemoprevention.

Differences in susceptibility of HT-29 and A549 cells to statin-induced toxicity: An investigation using high content screening.

Statins are a group of hydroxymethylglutaryl coenzyme A reductase inhibitors that are used in the treatment of cardiovascular diseases. However, statins have been found to be cytotoxic, and many unexpected side effects have been reported in clinical applications. The susceptibilities of different cell lines toward statins are diverse, and the mechanisms of cytotoxicity remain unknown. Therefore, the present study aimed to investigate differences in the susceptibility to and mechanisms of statin-induced cytotoxicity in two cell lines, HT-29 and A549, using a high content screening-based multiparametric toxicity assay panel. We found that the two cell types exhibited differing susceptibilities to the cytotoxic effects of the different statins. Additionally, the cytotoxicity was inconsistent between different statins in the two cell lines. Four statins with strong cytotoxicity decreased the viability of HT-29 cells via the mitochondrial pathway, as evidenced by decreased mitochondrial membrane potential, and elevated mitochondrial mass, calcium release and cell apoptosis, and reactive oxygen species. In contrast, these four statins only induced a decrease in the mitochondrial membrane potential in A549 cells. The above results provide an objective reason for future evaluations of cytotoxic differences in cell types and the underlying mechanisms of cytotoxicity in different statins, and provide a good scientific basis for further research on countermeasures against statin-induced cell injuries.

Natural compounds against cytotoxic drug-induced cardiotoxicity: A review on the involvement of PI3K/Akt signaling pathway.

Cardiotoxicity is a critical concern in the use of several cytotoxic drugs. Induction of apoptosis, inflammation, and autophagy following dysregulation of the PI3K/Akt signaling pathway contributes to the cardiac damage induced by these drugs. Several natural compounds (NCs), including ferulic acid, gingerol, salvianolic acid B, paeonol, apigenin, calycosin, rutin, neferine, higenamine, vincristine, micheliolide, astragaloside IV, and astragalus polysaccharide, have been reported to suppress cytotoxic drug-induced cardiac injury. This article reviews these NCs that have been reported to have a protective effect against cytotoxic drug-induced cardiotoxicity through regulation of the PI3K/Akt signaling pathway.

Cytotoxic and immunological responses of fish leukocytes to nodularin exposure in vitro.

Nodularin (NOD) is a cyclic peptide released by bloom-forming toxic cyanobacteria Nodularia spumigena commonly occurring in brackish waters throughout the world. Although its hepatotoxic effects are well known, other negative effects of NOD have not yet been completely elucidated. The present study aims were to evaluate and compare the cytotoxic and immunotoxic effects of the toxin on primary leukocytes (from head kidney [HK]) and stable fish leukocytes (carp leucocyte cell line [CLC] cells). The cells were incubated with the cyanotoxin at concentrations of 0.001, 0.01, 0.05, or 0.1 µg/ml. After 24 h of exposure, the concentrations ≥0.05 µg/ml of toxin resulted in cytotoxicity in the primary cells, while in CLC cells, the toxic effect was obtained only with the highest concentration. Similarly, depending on the concentration, exposure to NOD causes a significant inhibition of chemotaxis of the phagocytic abilities of primary leukocytes and a significant reduction in the proliferation of lymphocytes isolated from the HKs. Moreover, CLC cells and HK leukocytes incubated with this toxin at all the mentioned concentrations showed an increased production of reactive oxygen and nitrogen species. NOD also evidently influenced the expression of genes of cytokine TNF-α and IL-10 and, to a minor extent, IL-1ß and TGF-ß. Notably, the observed changes in the mRNA levels of cytokines in NOD-exposed cells were evident, but not clearly dose-dependent. Interestingly, NOD did not affect the production and release of IL-1ß of the CLC cells. This study provides evidence that NOD may exert cytotoxicity and immune-toxicity effects depending on cell type and toxin concentration.

Assessment of cytotoxicity and sensitization potential of intradermally injected tattoo inks in reconstructed human skin.

BACKGROUND: The number of people within the European population having at least one tattoo has increased notably, and with it the number of tattoo-associated clinical complications. Despite this, safety information and testing regarding tattoo inks remain limited. OBJECTIVE: To assess cytotoxicity and sensitization potential of 16 tattoo inks after intradermal injection into reconstructed human skin (RHS). METHODS: Commercially available tattoo inks were injected intradermally into RHS (reconstructed epidermis on a fibroblast-populated collagen hydrogel) using a permanent makeup device. RHS biopsies, tissue sections, and culture medium were assessed for cytotoxicity (thiazolyl blue tetrazolium bromide assay [MTT assay]), detrimental histological changes (haematoxylin and eosin staining), and the presence of inflammatory and sensitization cytokines (interleukin [IL]-1α, IL-8, IL-18; enzyme-linked immunosorbent assay). RESULTS: Varying degrees of reduced metabolic activity and histopathological cytotoxic effects were observed in RHS after ink injection. Five inks showed significantly reduced metabolic activity and enhanced sensitization potential compared with negative controls. DISCUSSION: Using the RHS model system, four tattoo inks were identified as highly cytotoxic and classified as potential sensitizers, suggesting that allergic contact dermatitis could emerge in individuals carrying these inks. These results indicate that an RHS-based assessment of cytotoxicity and sensitization potential by intradermal tattoo ink injection is a useful analytical tool to determine ink-induced deleterious effects.

Platinum nanoparticles inhibit intracellular ROS generation and protect against cold atmospheric plasma-induced cytotoxicity.

Platinum nanoparticles (PtNPs) have been investigated for their antioxidant abilities in a range of biological and other applications. The ability to reduce off-target cold atmospheric plasma (CAP) cytotoxicity would be useful in Plasma Medicine; however, little has been published to date about the ability of PtNPs to reduce or inhibit the effects of CAP. Here we investigate whether PtNPs can protect against CAP-induced cytotoxicity in cancerous and non-cancerous cell lines. PtNPs were shown to dramatically reduce intracellular reactive species (RONS) production in U-251 MG cells. However, RONS generation was unaffected by PtNPs in medium without cells. PtNPs protect against CAP induced mitochondrial membrane depolarization, but not cell membrane permeabilization which is a CAP-induced RONS-independent event. PtNPs act as potent intracellular scavengers of reactive species and can protect against CAP induced cytotoxicity. PtNPs, showing no significant biocorrosion, may be useful as a catalytic antioxidant for healthy tissue and for protecting against CAP-induced tissue damage.

Individual and combined hepatocytotoxicity of DDT and cadmium in vitro.

The organochlorine insecticide dichlorodiphenyltrichloroethane (DDT) and heavy metal cadmium (Cd) are widespread environmental pollutants. They are persistent in the environment and can accumulate in organisms. Although the individual toxicity of DDT and Cd has been well documented, their combined toxicity is still not clear. Since liver is their common target, in this study, the individual and combined toxicity of DDT and Cd in human liver carcinoma HepG2 and human normal liver THLE-3 cell lines were investigated. The results showed that DDT and Cd inhibited the viability of HepG2 and THLE-3 cells dose-dependently and altered lysosomal morphology and function. Intracellular reactive oxygen species and lipid peroxidation levels were induced by DDT and Cd treatment. The combined cytotoxicity of DDT and Cd was greater than their individual cytotoxicity, and the interaction between Cd and DDT was additive on the inhibition of cell viability and lysosomal function of HepG2 cells. The interaction was antagonistic on the inhibition of cell viability of THLE-3 cells. These results may facilitate the evaluation of the cumulative risk of pesticides and heavy metal residues in the environment.

Association of PARP1 polymorphisms with response to chemotherapy in patients with high-risk neuroblastoma.

The genetic aetiology and the molecular mechanisms that characterize high-risk neuroblastoma are still little understood. The majority of high-risk neuroblastoma patients do not take advantage of current induction therapy. So far, one of the main reasons liable for cancer therapeutic failure is the acquisition of resistance to cytotoxic anticancer drugs, because of the DNA repair system of tumour cells. PARP1 is one of the main DNA damage sensors involved in the DNA repair system and genomic stability. We observed that high PARP1 mRNA level is associated with unfavourable prognosis in 3 public gene expression NB patients' datasets and in 20 neuroblastomas analysed by qRT-PCR. Among 4983 SNPs in PARP1, we selected two potential functional SNPs. We investigated the association of rs907187, in PARP1 promoter, and rs2048426 in non-coding region with response chemotherapy in 121 Italian patients with high-risk NB. Results showed that minor G allele of rs907187 associated with induction response of patients (P = .02) and with decrease PARP1 mRNA levels in NB cell line (P = .003). Furthermore, rs907187 was predicted to alter the binding site of E2F1 transcription factor. Specifically, allele G had low binding affinity with E2F1 whose expression positively correlates with PARP1 expression and associated with poor prognosis of patients with NB. By contrast, we did not find genetic association for the SNP rs2048426. These data reveal rs907187 as a novel potential risk variant associated with the failure of induction therapy for high-risk NB.

Regional outcomes of severe acute respiratory syndrome coronavirus 2 infection in hospitalised patients with haematological malignancy.

OBJECTIVES: We sought to characterise the outcomes of patients with haematological malignancy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospital in our regional network of 7 hospitals. METHODS: Consecutive hospitalised patients with haematological malignancy and SARS-CoV-2 infection were identified from 01/03/2020 to 06/05/2020. Outcomes were categorised as death, resolved or ongoing. The primary outcome was preliminary case fatality rate (pCFR), defined as the number of cases resulting in death as a proportion of all diagnosed cases. Analysis was primarily descriptive. RESULTS: 66 Patients were included, overall pCFR was 51.5%. Patients ≥ 70 years accounted for the majority of hospitalised cases (42, 63%) and fatalities (25, 74%). Mortality was similar between females (52%) and males (51%). Immunosuppressive or cytotoxic treatment within 3 months of the diagnosis of SARS-CoV-2 infection was associated with a significantly higher pCFR of 70%, compared with 28% in those not on active treatment (P = .0013, 2 proportions z test). CONCLUSIONS: Mortality rates in patients with haematological malignancy and SARS-CoV-2 infection in hospital are high supporting measures to minimise the risk of infection in this population.

Autophagic blockage by bismuth sulfide nanoparticles inhibits migration and invasion of HepG2 cells.

The biological effects of nanoparticles are of great importance for the in-depth understanding of safety issues in biomedical applications. Induction of autophagy is a cellular response after nanoparticle exposure. Bismuth sulfide nanoparticles (Bi2S3 NPs) are often used as a CT contrast agent because of their excellent photoelectric conversion ability. Yet there has been no previous detailed study other than a cell toxicity assessment. In this study, three types of Bi2S3 NPs with different shapes (Bi2S3 nano rods (BSNR), hollow microsphere Bi2S3 NPs (BSHS) and urchin-like hollow microsphere Bi2S3 NPs (ULBSHS)) were used to evaluatecytotoxicity, autophagy induction, cell migration and invasion in human hepatocellular carcinoma cells (HepG2). Results showed that all three Bi2S3 NPs lead to blockage in autophagic flux, causing p62 protein accumulation. The cell death caused by these Bi2S3 NPs is proved to be autophagy related, rather than related to apoptosis. Moreover, Bi2S3 NPs can reduce the migration and invasion in HepG2 cells in an autophagy-dependent manner. ULBSHS is the most cytotoxic among three Bi2S3 NPs and has the best tumor metastasis suppression. These results demonstrated that, even with relatively low toxicity of Bi2S3 NPs, autophagy blockage may still substantially influence cell fate and thus significantly impact their biomedical applications, and that surface topography is a key factor regulating their biological response.

Cytotoxicity, cellular uptake and apoptotic responses in human coronary artery endothelial cells exposed to ultrasmall superparamagnetic iron oxide nanoparticles.

Ultrasmall superparamagnetic iron oxide nanoparticles (USPION) possess reactive surfaces, are metabolized and exhibit unique magnetic properties. These properties are desirable for designing novel theranostic biomedical products; however, toxicity mechanisms of USPION are not completely elucidated. The goal of this study was to investigate cell interactions (uptake and cytotoxicity) of USPION using human coronary artery endothelial cells as a vascular cell model. Polyvinylpirrolidone-coated USPION were characterized: average diameter 17 nm (transmission electron microscopy [TEM]), average hydrodynamic diameter 44 nm (dynamic light scattering) and zeta potential -38.75 mV. Cells were exposed to 0 (control), 25, 50, 100 or 200 µg/mL USPION. Concentration- and time-dependent cytotoxicity were observed after 3-6 hours through 24 hours of exposure using Alamar Blue and Real-Time Cell Electronic Sensing assays. Cell uptake was evaluated by imaging using live-dead confocal microscopy, actin and nuclear fluorescent staining, and TEM. Phase-contrast, confocal microscopy, and TEM imaging showed significant USPION internalization as early as 3 hours after exposure to 25 µg/mL. TEM imaging demonstrated particle internalization in secondary lysosomes with perinuclear localization. Three orthogonal assays were conducted to assess apoptosis. TUNEL staining demonstrated a marked increase in fragmented DNA, a response pathognomonic of apoptosis, after a 4-hour exposure. Cells subjected to agarose gel electrophoresis exhibited degraded DNA 3 hours after exposure. Caspase-3/7 activity increased after a 3-hour exposure. USPION uptake resulted in cytotoxicity involving apoptosis and these results contribute to further mechanistic understanding of the USPION toxicity in vitro in cardiovascular endothelial cells.

Hydrogen sulfide alleviates uranium-induced rat hepatocyte cytotoxicity via inhibiting Nox4/ROS/p38 MAPK pathway.

As a gasotransmitter, hydrogen sulfide (H2 S) plays a crucial role in regulating the signaling pathway mediated by oxidative stress. The purpose of this study was to investigate the protective effects of H 2 S on uranium-induced rat hepatocyte cytotoxicity. Primary hepatocytes were isolated and cultured from Sprague Dawley rat liver tissues. After pretreating with sodium hydrosulfide (an H 2 S donor) for 1 hour (or GKT-136901 for 30 minutes), hepatocytes were treated by uranyl acetate for 24 hours. Cell viability, reactive oxygen species (ROS), malondialdehyde (MDA), NADPH oxidase 4 (Nox4), and p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation were respectively determined. The effects of direct inhibition of Nox4 expression by GKT-136901 (a Nox4 inhibitor) on ROS and phospho-p38 MAPK levels were examined in uranium-treated hepatocytes. The results implicate that H 2 S can afford protection of rat hepatocytes against uranium-induced adverse effects through attenuating oxidative stress via prohibiting Nox4/ROS/p38 MAPK signaling.

Drug-Induced Alterations of Mitochondrial DNA Homeostasis in Steatotic and Nonsteatotic HepaRG Cells.

Although mitochondriotoxicity plays a major role in drug-induced hepatotoxicity, alteration of mitochondrial DNA (mtDNA) homeostasis has been described only with a few drugs. Because it requires long drug exposure, this mechanism of toxicity cannot be detected with investigations performed in isolated liver mitochondria or cultured cells exposed to drugs for several hours or a few days. Thus, a first aim of this study was to determine whether a 2-week treatment with nine hepatotoxic drugs could affect mtDNA homeostasis in HepaRG cells. Previous investigations with these drugs showed rapid toxicity on oxidative phosphorylation but did not address the possibility of delayed toxicity secondary to mtDNA homeostasis impairment. The maximal concentration used for each drug induced about 10% cytotoxicity. Two other drugs, zalcitabine and linezolid, were used as positive controls for their respective effects on mtDNA replication and translation. Another goal was to determine whether drug-induced mitochondriotoxicity could be modulated by lipid overload mimicking nonalcoholic fatty liver. Among the nine drugs, imipramine and ritonavir induced mitochondrial effects suggesting alteration of mtDNA translation. Ritonavir toxicity was stronger in nonsteatotic cells. None of the nine drugs decreased mtDNA levels. However, increased mtDNA was observed with five drugs, especially in nonsteatotic cells. The mtDNA levels could not be correlated with the expression of key factors involved in mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), PGC1ß, and AMP-activated protein kinase α-subunit. Hence, drug-induced impairment of mtDNA translation might not be rare, and increased mtDNA levels could be a frequent adaptive response to slight energy shortage. Nevertheless, this adaptation could be impaired by lipid overload.

Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib.

BACKGROUND: Before the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib. METHODS: A database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model. RESULTS: Forty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 - 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3-4 in 44.4% of the patients. CONCLUSION: In accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.

Cutaneous toxicity as a predictive biomarker for clinical outcome in patients receiving anticancer therapy.

The relationship between treatment outcome and cutaneous toxicity induced by anticancer therapy has gained attention in the past decade. In this article, we have provided an overview of the 3 main classes of anticancer agents-specifically, molecularly targeted kinase inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapeutics-and described the data evaluating the association between cutaneous toxicity induced by these agents and survival benefit. Although preliminary studies are promising with regard to the potential role of cutaneous toxicities as a surrogate biomarker of efficacy of treatment, larger prospective studies are needed to confirm this relationship. Dermatologists have a unique opportunity to collaborate with oncologists in the multidisciplinary treatment paradigm by helping to identify and manage these dermatologic events in patients with cancer. A heightened awareness of these toxicities is critical, as it can potentially allow recognition of the efficacy of anticancer therapy and may influence treatment decisions and patient outcomes.

High-Frequency Distortion-Product Otoacoustic Emission Repeatability in a Patient Population.

OBJECTIVES: Distortion-product otoacoustic emissions (DPOAEs) are repeatable over time at lower frequencies (≤8 kHz) and higher frequencies (>8 kHz) in healthy, normal-hearing subjects. The purpose of this study was to examine the repeatability of DPOAEs measured with high-frequency (HF) stimuli in a patient population. It was hypothesized that HF DPOAEs would be repeatable over four trials. DESIGN: DPOAEs were measured in 40 cystic fibrosis (CF) patients (17 females and 23 males) with measurable behavioral thresholds and present DPOAEs for at least 2 of the high frequencies tested (8 to 16 kHz). A depth-compensated simulator sound pressure level (SPL) method of calibration was utilized. Each patient attended four trials, in which a complete set of data were collected. At each trial, three different DPOAE paradigms were completed. First, a discrete frequency sweep was measured between 8 and 16 kHz with a ratio (f2/f1) of 1.2 and levels of 65/50 dB SPL for L1/L2. Next, ratio and level sweeps were obtained at the two highest frequencies with a present DPOAE determined from the discrete frequency sweep, and the results were used to calculate DPOAE group delay and DPOAE detection thresholds, respectively. Ratio sweeps were collected with f2/f1 varied from 1.1 to 1.3 and stimulus levels of 60/45 dB SPL (L1/L2). Level sweeps were collected with an f2/f1 of 1.22 and L2 = 50 and L1 varied between 20 and 70 dB SPL. Differences and correlations between trials, SE of the measurement, and confidence intervals were calculated, as well as a repeated-measures analysis of variance. RESULTS: DPOAE response and behavioral threshold variability in CF patients were not significantly different across four trials. It can be expected in 95% of CF patients that differences between trials of DPOAE levels, group delay, and detection thresholds and behavioral thresholds are less than 6.26 dB, 0.87 msec, 9.34 dB, and 9.60 dB, respectively. CONCLUSIONS: HF DPOAEs were repeatable across four test trials for all three paradigms measured in a group of CF patients. These results are encouraging for the measurement of HF DPOAEs to be monitored in those exposed to ototoxic agents.