Safety and effcacy of remimazolam tosilate for sedation during combined spinal-epidural anesthesia for orthopedic procedures: a randomized controlled trial.

OBJECTIVE: The objective of this study was to assess the efficacy and safety of Remimazolam in the context of combined spinal-epidural anesthesia for sedation during orthopedic surgery. METHODS: This randomized controlled trial enrolled patients scheduled for orthopedic surgery under combined spinal-epidural anesthesia (N = 80), who were randomly allocated to receive either dexmedetomidine (Group-D) or remimazolam (Group-R). The target sedation range aimed for a Ramsay score of 2-5 or a BIS value of 60-80 to evaluate the effectiveness and safety of remimazolam during sedation. RESULTS: The time taken to achieve the desired level of sedation was significantly shorter in the remimazolam group compared to the dexmedetomidine group (3.69 ± 0.75 vs. 9.59 ± 1.03; P < 0.0001). Patients in the remimazolam group exhibited quicker recovery, fewer intraoperative adverse events, more consistent vital signs, and greater satisfaction at various time points throughout the surgery. CONCLUSION: This preliminary study demonstrates that remimazolam tosilate serves as a safe and effective sedative for orthopedic surgery performed under combined spinal-epidural anesthesia, in comparison with dexmedetomidine.

Modulation of immune functions, inflammatory response, and cytokine production following long-term oral exposure to three food additives; thiabendazole, monosodium glutamate, and brilliant blue in rats.

The food additives thiabendazole (TBZ), monosodium glutamate (MSG), and brilliant blue (BB) are commonly used in many daily-consumed food products worldwide. They are widely used in major agricultural and industrial applications. Yet, many of its toxicological aspects are still unclear, especially immune modulation. This research was therefore intended to investigate the effects of male Wistar rats' daily oral exposure for 90 days to TBZ (10 mg/kg b.wt), MSG (20 mg/kg b.wt), or BB (1.2 mg/kg b.wt) on the blood cells, immunity, and inflammatory indicators. The three tested food additives showed varying degrees of hematological alterations. Initially, megaloblastic anemia and thrombocytopenia were evident with the three tested food additives. At the same time, TBZ showed no significant changes in the leukogram element except eosinopenia. MSG induced leukopenia, lymphocytopenia, neutrophilia, and eosinophilia. BB evoked neutrophilia and lymphopenia. The immunoglobins M (IgM) and IgG were significantly reduced with the three tested food additives. In contrast, lysozyme and nitric oxide levels were elevated. A reduced considerably lymphocyte proliferation was detected with TBZ and MSG exposure without affecting the phagocytic activity. Various pathologic disturbances in splenic tissues have been detected. An obvious increase in CD4+ but a lessening in CD8+ immunolabeling was evident in TBZ and MSG groups. The cytokines, including interferon-gamma, tumor necrosis factor-alpha, and interleukin 1ß, 6, 10, and 13, were significantly upregulated in the spleen of rats exposed to TBZ, MSG, and BB. These results concluded that TBZ, MSG, and BB negatively affect hematological parameters, innate and humoral immune functions together with inflammatory responses. TBZ achieved the maximal negative impacts followed by MSG and finally with BB. Given the prevalence of these food additives, TBZ and MSG should be limited to a minimal volume use, or natural food additives should be used instead.

Safety and Stability of Antibody-Dye Conjugate in Optical Molecular Imaging.

PURPOSE: The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients. PROCEDURES: Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis. RESULTS: Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria. CONCLUSIONS: Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.

Edible additive effects on zebrafish cardiovascular functionality with hydrodynamic assessment.

Food coloring is often used as a coloring agent in foods, medicines and cosmetics, and it was reported to have certain carcinogenic and mutagenic effects in living organisms. Investigation of physiological parameters using zebrafish is a promising methodology to understand disease biology and drug toxicity for various drug discovery on humans. Zebrafish (Danio rerio) is a well-acknowledged model organism with combining assets such as body transparency, small size, low cost of cultivation, and high genetic homology with humans and is used as a specimen tool for the in-vivo throughput screening approach. In addition, recent advances in microfluidics show a promising alternative for zebrafish manipulation in terms of drug administration and extensive imaging capability. This pilot work highlighted the design and development of a microfluidic detection platform for zebrafish larvae through investigating the effects of food coloring on cardiovascular functionality and pectoral fin swing ability. The zebrafish embryos were exposed to the Cochineal Red and Brilliant Blue FCF pigment solution in a concentration of (0.02‰, 0.2‰) cultured in the laboratory from the embryo stage to hatching and development until 9 days post fertilization (d.p.f.). In addition, zebrafish swimming behaviors in terms of pectoral fin beating towards the toxicity screening were further studied by visualizing the induced flow field. It was evidenced that Cochineal Red pigment at a concentration of 0.2‰ not only significantly affected the zebrafish pectoral fin swing behavior, but also significantly increased the heart rate of juvenile fish. The higher concentration of Brilliant Blue FCF pigment (0.2%) increased heart rate during early embryonic stages of zebrafish. However, zebrafish exposed to food coloring did not show any significant changes in cardiac output. The applications of this proposed platform can be further extended towards observing the neurobiological/hydrodynamic behaviors of zebrafish larvae for practical applications in drug tests.

Comparison of trypan blue and Brilliant Blue G for staining of the anterior lens capsule during cataract surgery: short-term results.

PURPOSE: The present study aimed to evaluate the potential corneal endothelial cell toxicity of trypan blue (TB) and Brilliant Blue G (BBG), two dyes used to stain the anterior capsule in cataract surgery. METHODS: We conducted a single-center, prospective, randomized study in which 150 eyes of 117 patients were randomly divided into control (CT), TB, and BBG groups. Preoperative and postoperative (1, 3, and 6 months) values for corrected distance visual acuity (CDVA), corneal endothelial cell count, and central corneal thickness were compared among the three groups. RESULTS: A total of 111 eyes from 88 patients were completely analyzed. The CDVA (logarithm of the minimal angle of resolution) values in the CT, TB, and BBG groups 1 month after surgery were 0.001, 0.023, and 0.019, respectively. The corneal endothelial cell counts 6 months after surgery were 2711 ± 225, 2748 ± 251, and 2680 ± 284 cells/mm2, respectively. The central corneal thicknesses 6 months after surgery were 524.3 ± 35.5, 532.2 ± 36.1, and 531.4 ± 33.0 µm, respectively. There were no significant differences in CDVA, endothelial cell count, or central corneal thickness among the three groups during the follow-up period. CONCLUSIONS: Our findings indicate that neither TB nor BBG was associated with detectable toxicity to corneal endothelial cells during cataract surgery, even when injected directly into the anterior chamber. Additionally, BBG exhibited equivalent staining efficiency to TB.

Dyeing but not dying: Colourful dyes as a non-lethal method of food labelling for in vitro-reared honey bee (Apis mellifera) larvae.

Several environmental factors (e.g. food source, pesticides, toxins, parasites and pathogens) influence development and maturation of honey bees (Apis mellifera). Therefore, controlled experimental conditions are mandatory when studying the impact of environmental factors: particularly food quality and nutrient consumption. In vitro larval rearing is a standard approach for monitoring food intake of larvae and the labelling of food is necessary to quantify intake in controlled feeding experiments. Here, we tested the suitability of two food dyes, Allura Red and Brilliant Blue, in an experimental set up using in vitro reared honey bee larvae and freshly hatched adult workers. Absorbance of both dyes was measured, in food and dye-fed larvae, to determine the optimal dye concentrations for accurate detection and quantification. By quantifying relative dye concentrations in dye mixtures, relative concentrations of mixed dyes can be estimated independent of the total food consumed by the larvae. Survival assays were conducted to test the impact of both dyes on larval and worker bee survival. Worker bees showed no increase in adult mortality, when fed with dyed honey. Larval survival was not significantly different until the late pupal stage. The physiological impact of dye feeding was tested by measuring larval immune response. No changes in innate immune gene expression were detectable for larvae fed with dyed and non-dyed food. In conclusion, we established a non-invasive food labelling protocol for food intake quantification in in vitro reared honey bee larvae, using non-toxic, inexpensive, and easy to apply food dyes.

Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers.

Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m2, cohort 2 received 25 mg/m2, and cohort 3 received 62.5 mg/m2. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab-IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data.

Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.

Purpose: To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730-41. ©2016 AACR.

[Efficacy and Safety of A0001 (Brilliant Blue G250) for Internal Limiting Membrane Staining and Peeling: Phase III Investigator-initiated Multicenter Clinical Trial].

PURPOSE: To investigate the efficacy and safety of A0001 (brilliant blue G250) for visualization of the internal limiting membrane (ILM) during and after vitrectomy. METHODS: Patients (n = 31) requiring ILM peeling during vitrectomy were enrolled in this clinical trial. After injection of A0001 (range: 0.0625 to 0. 125 mg), the staining grade and the peeling ease of the ILM were evaluated in five steps (levels 0 to 4). The safety of A0001 was investigated for 7 days after surgery. RESULTS: From the evaluation of a primary endpoint by the Independent Data Monitoring Committee (IDMC) and a secondary endpoint by each surgeon, A0001 was effective in all cases at three or more levels ( ≥ level 2 was defined as effective) for evaluation of the grade of visualization and operating ease. Adverse events occurring in two or more cases included elevated intraocular pressure, eye pain, eye discharges, and retinal bleeding. One serious adverse event was a case of unclosed macular hole after vitrectomy, but the patient recovered after reoperation. CONCLUSIONS: A0001 was effective and safe for visualization of the ILM during vitrectomy, and there was an improvement in ease of operation.

Involvement of the P2X7 purinergic receptor in colonic motor dysfunction associated with bowel inflammation in rats.

BACKGROUND AND PURPOSE: Recent evidence indicates an involvement of P2X7 purinergic receptor (P2X7R) in the fine tuning of immune functions, as well as in driving enteric neuron apoptosis under intestinal inflammation. However, the participation of this receptor in the regulation of enteric neuromuscular functions remains undetermined. This study was aimed at investigating the role of P2X7Rs in the control of colonic motility in experimental colitis. EXPERIMENTAL APPROACH: Colitis was induced in rats by 2,4-dinitrobenzenesulfonic acid. P2X7R distribution was examined by immunofluorescence analysis. The effects of A804598 (selective P2X7R antagonist) and BzATP (P2X7R agonist) were tested on contractions of longitudinal smooth muscle evoked by electrical stimulation or by carbachol in the presence of tetrodotoxin. KEY RESULTS: P2X7Rs were predominantly located in myenteric neurons, but, in the presence of colitis, their expression increased in the neuromuscular layer. In normal preparations, A804598 elicited a negligible increase in electrically induced contractions, while a significant enhancement was recorded in inflamed tissues. In the presence of Nω-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor) the A804598 effects were lost. P2X7R stimulation with BzATP did not significantly affect electrical-induced contractions in normal colon, while a marked reduction was recorded under inflammation. The inhibitory effect of BzATP was antagonized by A804598, and it was also markedly blunted by NPA. Both P2X7R ligands did not affect carbachol-induced contractions. CONCLUSIONS AND IMPLICATIONS: The purinergic system contributes to functional neuromuscular changes associated with bowel inflammation via P2X7Rs, which modulate the activity of excitatory cholinergic nerves through a facilitatory control on inhibitory nitrergic pathways.

Safety testing of blue vital dyes using cell culture models.

PURPOSE: To investigate the safety of trypan blue, brilliant blue G (BBG), Evans blue (EB), patent blue, Chicago blue (CB), and bromophenol blue (BB), with and without halogen and xenon light exposure. METHODS: All dyes were diluted in a balanced saline solution at a concentration of 0.5%. Cells of the human RPE line ARPE-19 and rat RGC5 were exposed to vital dyes for 5 min. Experiments with and without xenon or halogen illumination were performed. The viability of ARPE-19 and RGC5 cells was determined at 12, 24, or 120 h by a cell proliferation assay using WST-1 reagent. The apoptotic events as well as cell numbers were registered for 72 h and counted by time-lapse videomicroscopy. RESULTS: There was no evidence of ARPE-19 or RGC5 toxicity, immediate (0 and 24 h) or delayed (120 h), following exclusive exposure to each single dye. After halogen light exposure, ARPE-19 cell lines did not show any significant toxicity, except for when they were exposed to EB. After xenon illumination, ARPE-19 cells showed a marked decrease in cell viability when exposed to EB or CB and a moderate decrease when exposed to BBG and BB. After xenon illumination, RGC5 cells showed the highest decrease in cell viability when exposed to EB and CB; BB caused the same decrease in cell viability as in ARPE-19 cells. CONCLUSION: Interaction of light from endo-illumination source and blue vital dyes may increase the risk of retinal toxicity.

Chromovitrectomy and the vitreoretinal interface.

It still remains unclear to which extent the presence and the amount of retinal debris seen in internal limiting membrane (ILM) specimens harvested during macular surgery for macular holes or epiretinal membranes are related to the procedure of ILM peeling itself or to modifications of the surgical technique, such as application of vital dyes for visualization of the ILM, or to pathological conditions with epiretinal membrane formation at the vitreoretinal interface. The presence of cellular fragments on the retinal side of the removed ILM appears to be of multifactorial origin, and additional causes besides dye application need to be considered. However, morphological studies with evaluation of vital dyes are still of relevance and provide additional insights into the ultrastructure of the vitreoretinal interface and its interaction with adjuvants used during macular surgery. Chromovitrectomy is an emerging field in vitreoretinal surgery. It is of importance to better understand the tissue-dye interactions, which not only alter the mechanical properties of the tissue being stained, but may also have an impact on the functional result postoperatively.

Toll-like receptor 2 regulates intestinal inflammation by controlling integrity of the enteric nervous system.

BACKGROUND & AIMS: In the intestines, Toll-like receptor 2 (TLR2) mediates immune responses to pathogens and regulates epithelial barrier function; polymorphisms in TLR2 have been associated with inflammatory bowel disease phenotype. We assessed the effects of TLR2 signaling on the enteric nervous system (ENS) in mice. METHODS: TLR2 distribution and function in the ileal neuromuscular layer of mice were determined by immunofluorescence, cytofluorimetric analysis, immunoprecipitation, and immunoblot analyses. We assessed morphology and function of the ENS in Tlr2(-/-) mice and in mice with wild-type Tlr2 (wild-type mice) depleted of intestinal microbiota, using immunofluorescence, immunoblot, and gastrointestinal motility assays. Levels and signaling of glial cell line-derived neurotrophic factor (GDNF) were determined using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and immunoprecipitation analyses. Colitis was induced by administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid to Tlr2(-/-) mice after termination of GDNF administration. RESULTS: TLR2 was expressed in enteric neurons, glia, and smooth muscle cells of the intestinal wall. Tlr2(-/-) mice had alterations in ENS architecture and neurochemical profile, intestinal dysmotility, abnormal mucosal secretion, reduced levels of GDNF in smooth muscle cells, and impaired signaling via Ret-GFRα1. ENS structural and functional anomalies were completely corrected by administration of GDNF to Tlr2(-/-) mice. Wild-type mice depleted of intestinal microbiota had ENS defects and GDNF deficiency, similar to Tlr2(-/-) mice; these defects were partially restored by administration of a TLR2 agonist. Tlr2(-/-) mice developed more severe colitis than wild-type mice after administration of dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid; colitis was not more severe if Tlr2(-/-) mice were given GDNF before dextran sulfate sodium or 2,4 dinitrobenzensulfonic acid. CONCLUSIONS: In mice, TLR2 signaling regulates intestinal inflammation by controlling ENS structure and neurochemical coding, along with intestinal neuromuscular function. These findings provide information as to how defective TLR2 signaling in the ENS affects inflammatory bowel disease phenotype in humans.

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma.

BACKGROUND: Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand-foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib-induced HFSR and genetic polymorphisms in Korean patients with HCC. METHODS: For this prospective cohort study, the authors enrolled 59 consecutive patients with intermediate stage HCC from 5 centers in Korea. All patients received sorafenib 400 mg twice daily in combination with transarterial chemoembolization (TACE). Genotyping was performed on a total of 49 single nucleotide polymorphisms (SNPs) in 8 candidate genes (minor allelic frequency ≥5%). Serum levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were measured using enzyme-linked immunosorbent assays before therapy and 1 month after therapy. RESULTS: During a median treatment period of 18 months, 55 patients (93%) developed sorafenib-induced HFSR, including grade 1 reactions in 15 patients, grade 2 reactions in 27 patients, and grade 3 reaction in 13 patients. The SNPs TNF-α -308GG, VEGF -94GG, VEGF 1991CC, VEGF IVS3-28CC, and uridine diphosphate glucuronosyltransferase 1 family-polypeptide A9 (UGT1A9) IVS1-37431AA were associated significantly with the development of high-grade (grade 2 or 3) HFSR in univariate analysis (P < .05). In multivariate analysis, the SNPs VEGF 1991CC (odds ratio, 45.7), TNF-α -308GG (odds ratio, 44.1), and UGT1A9 IVS1-37431AA (odds ratio, 18.7) were identified as independent risk factors for the development of high-grade HFSR (P = .01, P = .02, and P = .02, respectively). He serum TNF-α level measured 1 month after sorafenib therapy was correlated significantly with the development of high-grade HFSR (odds ratio, 3.56; P = .026). CONCLUSIONS: Differences in the incidence of HFSR may have been caused by ethnic differences in genetic polymorphisms of the TNF-α, VEGF, and UGT1A9 genes, especially in relation to the expression of serum TNF-α after sorafenib therapy.

[Serum pancreatic enzyme elevation under treatment with sorafenib].

OBJECTIVE: Sorafenib is an oral multi-kinase inhibitor of Raf-1, VEGF and PDGF receptors and others, resulting in tumor regression and anti-angiogenesis. We studied serum pancreatic enzyme increase associated with sorafenib treatment. PATIENTS AND METHODS: In a phase II study of Japanese patients with metastatic renal cell carcinoma, a total of 131 patients received sorafenib 400 mg twice per day. Serum levels of lipase and amylase were measured on day 7 and every 3-4 weeks thereafter during treatment period. When grade 3 or 4 enzyme abnormalities were observed, ultrasound or computed tomography scan was performed to detect pancreatitis. RESULTS: The incidence of all-grades lipase and amylase increases were 55. 7% and 38. 2%, respectively, while those of grade 3 or 4 were 30. 5% and 5. 3%, respectively. The majority of these events were observed in the first 3 weeks of sorafenib treatment. Grade 3 or 4 lipase increase was detected in 32 patients (24. 4%)on day 7 measurement. These abnormal elevations spontaneously resolved in all patients. Regarding grade 3 lipase increase, the median time to recovery to grade 2 and 1 were 7 and 14 days, respectively. Three patients required interruption of the treatment. No patient showed any clinical manifestation or abnormal imaging finding suggesting pancreatitis. CONCLUSION: Pancreatic enzyme increases observed frequently under sorafenib treatment were transient and asymptomatic. They were not related to symptomatic pancreatitis.

Sunitinib- and sorafenib-induced nephrotic syndrome in a patient with gastrointestinal stromal tumor.

OBJECTIVE: To report a case of nephrotic syndrome (NS) induced by both sunitinib and sorafenib therapy. CASE SUMMARY: A 61-year-old woman with metastatic gastrointestinal stromal tumor (GIST) presented with NS and hypertension following therapy with sunitinib 400 mg/day. Because of grade 3 toxicity, the drug was discontinued. After sunitinib discontinuation, NS and hypertension resolved. However, NS recurred on rechallenge. A similar picture developed following therapy with sorafenib 800 mg/day. A renal biopsy revealed a focal segmental glomerulosclerosis (FSGS). A few months after sorafenib cessation, resolution of NS and hypertension was again achieved. DISCUSSION: Several cases of NS have been reported among patients receiving sunitinib and sorafenib. However, renal histopathologic data were obtained in only a few patients. Although biopsy-proven cases of FSGS associated with sunitinib have been reported, this is, to our knowledge, the first reported case of biopsy-proven FSGS associated with sorafenib. The Naranjo probability scale indicated probable causality for NS developing with sorafenib, and definite causality with sunitinib. The clinical and histopathologic findings have led us to agree with the class effect proposal that all antiangiogenic drugs share a similar toxicity profile. Evidence supporting this hypothesis includes worsening of hypertension and proteinuria by both drugs, with full recovery occurring within a few months after cessation of the drugs, which favors the role of vascular endothelial growth factor receptor inhibition in FSGS development. CONCLUSIONS: The clinical adverse spectrum of antiangiogenic drugs may be broader than initially observed because of a lack of renal biopsy data and routine screening for proteinuria. It can be speculated that proteinuria, as well as hypertension, is a class effect of all antiangiogenic drugs.

[A case of fatal clinical course with reversible acute cardiac failure and glucose intolerance during sorafenib therapy for metastatic renal cell carcinoma].

A 72-year-old man was diagnosed with right renal cell carcinoma (RCC) with multiple brain and lung metastases (cT3aN0M1). He underwent γ-knife treatment for brain metastases, palliative right renal artery embolization for primary RCC, and interferon- alpha treatment for residual lung metastases. Although the interferon-alpha treatment was effective, it was discontinued because of side effects. He received sorafenib (800 mg/daily) therapy for 2 months. Suddenly, he developed left cardiac failure, and he died 6 days later through a rapid clinical course that included circulatory failure, abnormal glucose tolerance, disseminated intravascular coagulation, and multiple organ failure. A pathological examination could not explain the cause of death. It is important to carefully observe metastatic RCC patients receiving a tyrosine kinase inhibitor, especially sorafenib, because critical side effects may appear.

Hepatic arterial thrombosis: a critical complication during combination therapy of arterial chemoinfusion and sorafenib.

Hepatic arterial infusion chemotherapy (HAIC) combined with sorafenib is considered to be a promising therapeutic strategy for patients with advanced hepatocellular carcinoma. However, this combination therapy carries the risk of hepatic arterial thrombosis (HAT), which interrupts the continuation of HAIC, due to the side-effects of sorafenib. This case demonstrates a complication of HAT which occurred during HAIC combined with sorafenib. HAT was detected early by angiography via an implantable port-catheter system and was successfully treated with catheter-directed thrombolysis.