Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Dacomitinib, a second-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) to treat non-small cell lung cancer.

Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4 tyrosine kinase. On September 27, 2018, the United States Food and Drug Administration (FDA) approved dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations. On January 8, 2019, the Ministry of Health, Labour and Welfare of Japan approved this second-generation EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR mutation-positive inoperable or recurrent NSCLC. The European Commission also approved dacomitinib on April 3, 2019, as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Approval of dacomitinib was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050; ClinicalTrials.gov Identifier NCT01774721) which demonstrated the safety and efficacy of dacomitinib compared to gefitinib in 452 patients with unresectable and metastatic NSCLC. Dacomitinib represents a powerful new treatment option compared with first-generation EGFR-TKIs. In this paper, we review the clinical and preclinical studies of dacomitinib and discuss the drug's clinical value.

Adenosarcoma of the uterine body initially presenting as an interstitial small tumor of the uterus: a case report.

Adenosarcoma of the uterine body is a rare mixed tumor in which a benign epithelial component is mixed with a malignant stromal element. It has been considered that this tumor originates from the endometrium and its most common finding of imaging is a polypoid tumor occupying the uterine cavity. The authors herein present a case of 37-year-old female with a complaint of abnormal vaginal bleeding. At the first visit, transvaginal ultrasound and magnetic resonance imaging (MRI) showed a round mass with a diameter of one cm in the uterine wall. No malignant pathological finding was detected. The patient visited the authors again one year later, because of continuous bleeding. At that time, they found a polypoid tumor in the uterine cavity, which turned out to be adenosarcoma with sarcomatous overgrowth. The round mass in the uterus detected at first time seems to have been incipience of adenosarcoma. Prodromal sign of adenosarcoma has not been reported previously.

Biochemical and hematologic effects of polyvinylpyrrolidone-wrapped fullerene C60 after oral administration.

The fullerene C60 is used in consumer products such as cosmetics owing to its antioxidative effects and is being developed for nanomedical applications. However, knowledge regarding the safety of fullerene C60, especially after oral administration, is sparse. Here, we examined the safety of fullerene C60 in mice after 7 d of exposure to orally administered polyvinylpyrrolidone (PVP)-wrapped fullerene C60 (PVP-fullerene C60). Mice treated with PVP-fullerene C60 showed few changes in the plasma levels of various markers of kidney and liver injury and experienced no significant hematologic effects. Furthermore, the histology of the colon of PVP-fullerene C60-treated mice was indistinguishable from that of control mice. These results suggest that PVP-fullerene C60 lacks toxicity after high-dose oral administration and indicate that PVP-fullerene C60 can be considered safe for oral medication. These data provide basic information that likely will facilitate the production of safe and effective forms of fullerene C60.

Preferential Fas-mediated apoptotic execution at G1 phase: the resistance of mitotic cells to the cell death.

Apoptosis is induced by various stresses generated from the extracellular and intracellular environments. The fidelity of the cell cycle is monitored by surveillance mechanisms that arrest its further progression if any crucial process has not been completed or damages are sustained, and then the cells with problems undergo apoptosis. Although the molecular mechanisms involved in the regulation of the cell cycle and that of apoptosis have been elucidated, the links between them are not clear, especially that between cell cycle and death receptor-mediated apoptosis. By using the HeLa.S-Fucci (fluorescent ubiquitination-based cell cycle indicator) cells, we investigated the relationship between the cell cycle progression and apoptotic execution. To monitor apoptotic execution during cell cycle progression, we observed the cells after induction of apoptosis with time-lapse fluorescent microscopy. About 70% of Fas-mediated apoptotic cells were present at G(1) phase and about 20% of cells died immediately after cytokinesis, whereas more than 60% of etoposide-induced apoptotic cells were at S/G(2) phases in random culture of the cells. These results were confirmed by using synchronized culture of the cells. Furthermore, mitotic cells showed the resistance to Fas-mediated apoptosis. In conclusion, these findings suggest that apoptotic execution is dependent on cell cycle phase and Fas-mediated apoptosis preferentially occurs at G(1) phase.

Reflux esophagitis after esophagectomy: impact of duodenogastroesophageal reflux.

Reflux esophagitis (RE) is a known complication disturbing patients' quality of life after esophageal resection. It is generally recognized that bile reflux as well as acid reflux cause RE. However, the clinical influence of acid and bile reflux, and Helicobacter pylori (H. pylori) infection on RE in the cervical esophagus after esophagectomy is not yet clarified. Sixty patients who underwent cervical esophagogastrostomy following esophagectomy were enrolled in this study. They underwent examination for H. pylori infection, endoscopic examination, and continuous 24-hour pH and bilirubin monitoring, at 1 month after surgery. The influence of acid and/or bile reflux, H. pylori infection, and others on the development of RE were investigated. RE was observed in 19 patients (32%) at 1 month after esophagogastrostomy, mild RE in 16 (27%), and severe RE in 3 (5%). The percentage of time duration of both acid and bile reflux into the cervical esophagus was higher in patients with RE than in those without (P = 0.027, P < 0.001). A significant difference in %time pH < 4 acid reflux was found between mild RE and severe RE (P = 0.014), and a statistical difference in %time abs. > 0.14 between non-RE and mild RE (P = 0.017). Acid and/or bile reflux was observed in 31 patients (52%), acid-only reflux in 6 (10%), bile-only reflux in 15 (25%), and acid-and-bile reflux in 10 (17%). Severe RE was observed only in patients having acid-and-bile reflux. On the univariate analysis, no infection of H. pylori, acid reflux, and bile reflux were determined to be the influencing factors to RE among the clinical factors including age, gender, route of esophageal reconstruction, H. pylori infection, and acid-and-bile reflux. In the subanalysis using the logistic model, there were significant correlations between bile reflux and RE irrespective of the presence of H. pylori infection (P = 0.016, P = 0.007). On the other hand, there was a significant correlation between acid reflux and RE only in patients without H. pylori infection (P = 0.039). In the early period after esophagogastrostomy, bile reflux could cause RE irrespective of H. pylori infection, while acid reflex could cause RE only in patients without H. pylori infection. There is a possibility that bile reflux plays an important role in the development of RE after esophagectomy.

Thoracic endovascular aortic repair for aortic complications after esophagectomy for cancer: report of three cases.

Aortic complications after esophageal cancer surgery are rare and usually fatal. Here, we report three patients who underwent thoracic endovascular aortic repair (TEVAR) for aortic complications after esophagectomy for cancer. In the first case, aortic rupture was caused by pyothorax due to residual tumor after esophagectomy. In the second case, aortic rupture was caused by pyothorax due to anastomotic leakage. In the third case, a pseudoaneurysm was caused by surgical injury during esophagectomy. TEVAR was safe and effective for severe aortic complications when graft infection was avoided. The first case died of sepsis on the 84th postoperative day, and the other two cases have survived 4 years and 2 years to date.

Outcomes of multimodality therapy for stage IVB esophageal cancer with distant organ metastasis (M1-Org).

Esophageal cancer patients with distant organ metastasis have usually been treated only to palliate symptoms without multimodality therapy. The current study evaluates the role of multimodality therapy in esophageal squamous cell cancer patients with distant organ metastasis. Between February 1988 and January 2007, 80 esophageal squamous cell cancer patients with distant organ metastases were treated at our institution. Multimodality therapy was performed in 58 patients: 43 patients received chemoradiotherapy, 13 underwent surgery followed by chemotherapy and/or radiation therapy, and two received chemotherapy or chemoradiotherapy followed by surgery. Thirteen patients received single-modality therapy; chemotherapy, radiotherapy, or surgery alone. The remaining nine patients received best supportive care alone. The metastatic organ was the liver (n= 40), the lungs (n= 33), bone (n= 10), and other (n= 6). Nine patients had metastasis in two organs. There was no difference in the median survival among the sites of organ metastasis, lung, liver, or bone (P= 0.8786). The survival of patients treated with multimodality therapy was significantly better than that of the patients who received single-modality therapy or best supportive care alone (P < 0.0001). In patients treated with multimodallity therapy, there was no difference in survival for patients treated with surgery compared with patients treated without surgery (P= 0.1291). This retrospective study involves an inevitable issue of patient selection bias. However, these results suggested that multimodality therapy could improve survival of the esophageal squamous cell cancer patients with distant organ metastasis.

Surgical management for small cell carcinoma of the esophagus.

Esophageal small cell carcinoma (SmCC) has been regarded as a rare and aggressive tumor with early metastasis. The optimal treatment has not yet been established, and the role of surgery has remained controversial. In this retrospective study, we report seven cases studies of SmCC of the esophagus and analyze the clinical outcomes after surgery. Between 1986 and 2007, there were seven patients with esophageal SmCC treated surgically in our institution. All the patients with clinically limited disease underwent transthoracic esophagectomy with lymphadenectomy. Lymph node involvement was found in all cases irrespective of the depth of tumor invasion. Three of the seven patients were diagnosed as having an extensive disease on pathological examination after esophagectomy. Five patients received postoperative chemotherapy. Two patients are alive with no recurrence at 16 months and at 45 months after surgery. Another one without chemotherapy survived 93 months and died of another disease. The remaining four patients died of recurrent disease or another disease. The median overall survival to date of these patients was 16 months (range 12-93 months). Esophagectomy with lymphadenectomy resulted in a relatively better survival in some patients with esophageal SmCC. We concluded that surgery may be helpful as part of multimodality treatment in selected patients with esophageal SmCC.

Pharyngolaryngeal reflux in patients who underwent cervical esophago-gastrostomy following esophagectomy.

Pharyngolaryngeal reflux has been generally accepted as a cause for pharyngolaryngitis, hoarseness, aspiration pneumonia, chronic cough, and nocturnal asthma. Although patients who have undergone gastric conduit reconstruction after esophagectomy are at a high risk to pharyngolaryngeal reflux disease (PLRD), PLRD after esophagectomy is still unknown. The aim of this study is to investigate the correlation between reflux pharyngolaryngitis and acid reflux into the hypopharynx and into the cervical esophagus in patients who have undergone cervical esophagogastrostomy. We enrolled 62 patients who received follow-up endoscopy and 24-h pH monitoring after cervical esophagogastrostomy. These included 26 at 1 month after surgery and 36 at 1 year or more after surgery. We investigated: (i) the correlation between the extent of reflux pharyngolaryngitis and that of reflux esophagitis based on endoscopic findings; and (ii) the correlation between the extent of reflux pharyngolaryngitis and that of acid exposure -'% time pH < 4' measured by 24-h pH monitoring - in the hypopharynx and in the cervical esophagus, and of acidity in the gastric conduit. There was no difference in acid exposure between the hypopharynx and the cervical esophagus according to time after surgery. However, the acidity in the gastric conduit was significantly more at one year or more after surgery compared with acidity at 1 month after surgery (P= 0.001). There was a significant correlation between acid exposure in the hypopharynx and that in the cervical esophagus (P < 0.001), although acid exposure in the hypopharynx was significantly less than that in the cervical esophagus (P < 0.001). A significant correlation between reflux pharyngolaryngitis and reflux esophagitis was observed (P < 0.001). There was a significant correlation between reflux pharyngolaryngitis and acid exposure in the hypopharynx (P= 0.021), and also that in the proximal esophagus (P= 0.001). The correlation between the extent of reflux pharyngolaryngitis and the acidity in the gastric conduit was not observed. These findings are consistent with pharyngolaryngitis being caused by gastro-esophago-pharyngolaryngeal reflux in patients after cervical esophagogastrostomy, despite the upper esophageal sphincter strongly preventing acid reflux from the cervical esophagus into the hypopharynx.

Mmp-20 and Klk4 cleavage site preferences for amelogenin sequences.

Mmp-20 and Klk4 are the two key enamel proteases. Can both enzymes process amelogenin to generate the major cleavage products that accumulate during the secretory stage of amelogenesis? We isolated Mmp-20 and Klk4 from developing pig teeth and used them to digest the tyrosine-rich amelogenin polypeptide (TRAP), the leucine-rich amelogenin protein (LRAP), and 5 fluorescence peptides. We characterized the digestion products by LC-MSMS, SDS-PAGE, and C18 RP-HPLC monitored with fluorescence and UV detectors. Mmp-20 cleaves amelogenin sequences after Pro(162), Ser(148), His(62), Ala(63), and Trp(45). These cleavages generate all of the major cleavage products that accumulate in porcine secretory-stage enamel: the 23-kDa, 20-kDa, 13-kDa, 11-kDa, and 6-kDa (TRAP) amelogenins. Mmp-20 cleaves LRAP after Pro(45) and Pro(40), producing the two LRAP products previously identified in tooth extracts. Among these key cleavage sites, Klk4 was able to cleave only after His(62). We propose that Mmp-20 alone processes amelogenin during the secretory stage.

ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex.

Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex.

Expression and characterization of disulfide bond use of oligomerized A2-Pancortins: extracellular matrix constituents in the developing brain.

The region-specific characteristics of the extracellular matrix are crucial for diverse functions in the brain. Pancortins/neuron-specific olfactomedin-related glycoproteins are components of the extracellular matrix. They comprise four alternatively spliced variants, Pancortin-1 to -4, which share a common portion, the B part, in the middle of their structure, have two pairs of alternatively spliced 5' regions, A1 and A2, and 3' regions, C1 and C2. Here we demonstrate that in mice, Pancortin-3 (A2-B-C1) and Pancortin-4 (A2-B-C2), which we have grouped together the A2-Pancortins, were transcribed early during the development of the brain in a region specific manner and were expressed very stably in vivo. They are N-glycosylated and secreted. Furthermore, we examined their ontogenetical expression profiles in the developing thalamus using antiserum against the common B region, since transient expressions of their mRNAs were notable there. In the developing thalami, they lasted long in oligomerized form even after the transcription of their mRNAs decreased to an undetectable level. Further analyses revealed that cysteine residues that are located in the common B part are important for homo- and hetero-oligomer formation of A2-Pancortins. When we substituted cysteine residues 45 and 47 with serine residues in that common B part, oligomerization of the A2-Pancortins was highly disturbed.

Enamel matrix derivative gel stimulates signal transduction of BMP and TGF-{beta}.

It has been shown that Emdogain Gel (Emd-Gel) containing enamel matrix proteins promotes biomineralization, such as osteogenesis and cementogenesis, during the regeneration of periodontal tissues. However, the growth factors involved in these activities of Emd-Gel remain unclear. In this study, Emd-Gel was fractionated into 22 sub-fractions by size exclusion chromatography. The osteoinductive factors, TGF-beta and BMP, were examined by a specific luciferase reporter gene assay. In the unfractionated Emd-Gel, TGF-beta-like activity was detected, while BMP activity was not. In contrast, in the fractionated Emd-Gel samples, TGF-beta-like activity was detected from fractions 8 to 13, and BMP-like activity was detected from fractions 4 to 6. Also, it was confirmed that the BMP-like activity in Emd-Gel was inhibited by authentic TGF-beta1 and TGF-beta-like activity. These results indicate that Emd-Gel contains both TGF-beta- and BMP-like growth factors that contribute to the induction of biomineralization during periodontal regeneration.

Amyloid beta induces neuronal cell death through ROS-mediated ASK1 activation.

Amyloid beta (Abeta) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress have been implicated in Abeta-induced neurotoxicity. We have reported that apoptosis signal-regulating kinase 1 (ASK1) is required for ROS- and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Abeta-induced neuronal cell death. Abeta activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1-/- neurons were defective in Abeta-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Abeta-induced neurotoxicity, which plays a central role in Alzheimer's disease.

[Spinal cord protection during thoracoabdominal aortic aneurysm repair; efficacy of distal aortic perfusion and segmental aortic clamping].

Despite improvement in adjuncts for thoracoabdominal aortic aneurysms (TAAA) repairs, many devastating complications remains after the surgery. Our experience with these aneurysms has been reviewed in order to identify those methods at risk of major morbidity, as well as which further improvements required. During last 16 years, 53 consecutive patients were operated on TAAA. The mean age was 58 years. Twenty patients had dissecting aneurysms and 13 patients had had prior aortic surgery. A femoro-femoral bypass was used to maintain distal aortic perfusion in most patients. Reimplantation of intercostal or lumbar arteries under the multi-segmental aortic clamping is consistent in our technique. Motor evoked potentials (MEP) were measured to monitor spinal cord protection since 2000. The hospital mortality was 9.4% (5/53), 22.2% (2/9) for emergency operation and 15.4% (2/13) for patients with prior aortic surgery. The mortality for the first and elective operations was 3.2% (1/31). No any neurologic dysfunction was observed in all patients including the hospital deaths. In view of clinical results, our adjuncts and techniques are useful for prevention of spinal cord ischemia during the TAAA surgery.

Inflammatory pseudotumor of the liver complicated with recurrent gouty arthritis.

Inflammatory pseudotumor (IPT) of the liver is a rare benign lesion of unknown etiology and is often accompanied by fever. Unexplained persistent fever unresponsive to antibiotics developed in a 70-year-old man suffering from intractable recurrent gouty arthritis. 67Ga-scintigraphy disclosed intense focal uptake in the upper abdomen. The lesion in the left lobe of the liver was an ill-defined hypodensity mass on computed tomographic scan and was enhanced on dynamic magnetic resonance imaging. The tumor was surgically removed and a diagnosis of IPT was made. Fever and arthritis resolved completely after surgery. Possible interaction between IPT of the liver and gouty arthritis was suggested.

Overexpression of mitochondrial manganese superoxide dismutase protects against radiation-induced cell death in the human hepatocellular carcinoma cell line HLE.

We investigated the potential role of mitochondrial manganese superoxide dismutase (Mn-SOD) in protective activity against irradiation by analyzing cell viability by a colony formation assay and by detecting apoptosis in stably human Mn-SOD gene-transfected HLE, a hepatocellular carcinoma cell line. We found that overexpression of Mn-SOD reduced the levels of reactive oxygen species in the mitochondria and intracellular phospholipid peroxidation product (4-hydroxy-2-nonenal) and prevented cell death. The production of intracellular nitric oxide after irradiation was not changed by Mn-SOD overexpression. The results suggested that Mn-SOD might play an important role in protecting cells against radiation-induced cell death by controlling the generation of mitochondrial reactive oxygen species and intracellular lipid peroxidation.