Targeting Metabolic-Redox Nexus to Regulate Drug Resistance: From Mechanism to Tumor Therapy.

Drug resistance is currently one of the biggest challenges in cancer treatment. With the deepening understanding of drug resistance, various mechanisms have been revealed, including metabolic reprogramming and alterations of redox balance. Notably, metabolic reprogramming mediates the survival of tumor cells in harsh environments, thereby promoting the development of drug resistance. In addition, the changes during metabolic pattern shift trigger reactive oxygen species (ROS) production, which in turn regulates cellular metabolism, DNA repair, cell death, and drug metabolism in direct or indirect ways to influence the sensitivity of tumors to therapies. Therefore, the intersection of metabolism and ROS profoundly affects tumor drug resistance, and clarifying the entangled mechanisms may be beneficial for developing drugs and treatment methods to thwart drug resistance. In this review, we will summarize the regulatory mechanism of redox and metabolism on tumor drug resistance and highlight recent therapeutic strategies targeting metabolic-redox circuits, including dietary interventions, novel chemosynthetic drugs, drug combination regimens, and novel drug delivery systems.

Targeted degradation of NDUFS1 by agrimol B promotes mitochondrial ROS accumulation and cytotoxic autophagy arrest in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global public health problem with increased morbidity and mortality. Agrimol B, a natural polyphenol, has been proved to be a potential anticancer drug. Our recent report showed a favorable anticancer effect of agrimol B in HCC, however, the mechanism of action remains unclear. Here, we found agrimol B inhibits the growth and proliferation of HCC cells in vitro as well as in an HCC patient-derived xenograft (PDX) model. Notably, agrimol B drives autophagy initiation and blocks autophagosome-lysosome fusion, resulting in autophagosome accumulation and autophagy arrest in HCC cells. Mechanistically, agrimol B downregulates the protein level of NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1) through caspase 3-mediated degradation, leading to mitochondrial reactive oxygen species (mROS) accumulation and autophagy arrest. NDUFS1 overexpression partially restores mROS overproduction, autophagosome accumulation, and growth inhibition induced by agrimol B, suggesting a cytotoxic role of agrimol B-induced autophagy arrest in HCC cells. Notably, agrimol B significantly enhances the sensitivity of HCC cells to sorafenib in vitro and in vivo. In conclusion, our study uncovers the anticancer mechanism of agrimol B in HCC involving the regulation of oxidative stress and autophagy, and suggests agrimol B as a potential therapeutic drug for HCC treatment.

Healing of the Torn Anterior Horn of Rabbit Medial Meniscus to Bone after Transtibial Pull-Out Repair and Autologous Platelet-Rich Plasma Gel Injection.

OBJECTIVES: The transtibial pull-out repair (TP) is a relatively new method for treating meniscal root tear; however, the clinical evaluation of its healing effect remains controversial. Due to ethical constraints and limitations of imaging techniques in humans, here we dynamically observe the healing effects of TP and TP with platelet-rich plasma gel (PRG) at the histological level using an animal model. METHODS: Platelet-rich plasma (PRP) and PRG of rabbits were prepared. Platelet-derived growth factor (PDGF) and transforming growth factor-ß1 (TGF-ß1) levels in PRP and PRG were determined using an enzyme-linked immunosorbent assay. A rabbit model of anterior horn tear of the medial meniscus and TP surgery were created. PRG was injected between the anterior horn of the medial meniscus and the tibial tunnel. Rabbits were divided into three groups: the anterior horn tear group (Tear group), the anterior horn tear + TP group (TP group), and the anterior horn tear + TP + PRG group (TP + PRG group). The healing effect was observed dynamically using histopathological studies and biomechanical experiments. RESULTS: The platelet content in PRP significantly increased to approximately 4.57 times that of whole blood. PDGF and TGF-ß1 concentrations in PRG increased to 2.46 and 4.15 times those in PRP, respectively. Hematoxylin and eosin (H&E) and Masson staining showed that the number of inflammatory cells in healing tissue decreased and the collagen fibers significantly increased in TP and TP + PRG groups at 4, 8, and 12 weeks postoperatively compared to those in Tear group. Neatly arranged, interlaced, and dense collagen fibers were found between the anterior horn and bone at 12 weeks. H&E and toluidine blue staining showed that the injury to the femoral condyle cartilage was alleviated. The healing performance in TP + PRG group was better and faster than that in TP group. The maximum tensile fracture strength of the meniscus progressively increased at 8 and 12 weeks postoperatively. CONCLUSIONS: Anterior horn injury of the medial meniscus in rabbits can be repaired using the TP technique, and the addition of autologous PRG to the bone tunnel promotes early healing of the meniscus and bone postoperatively. Meanwhile, both treatments can reduce the secondary damage to the cartilage due to osteoarthritis.

Factors Related to Activation in Chinese Patients With Chronic Obstructive Pulmonary Disease: A Cross-Sectional Survey Study.

BACKGROUND: Improving patient activation can lead to better health outcomes among patients with chronic obstructive pulmonary disease (COPD). However, no studies have focused on the issue of activation in patients with COPD in China. PURPOSE: This study was designed to explore the status of activation in patients with COPD in China and explicate the significant influencing factors. METHODS: One hundred seventy patients with COPD were recruited using a convenience sampling method from eight tertiary and secondary hospitals in Nanjing, China. Sociodemographic, clinical, and patient-reported factor data were collected. Univariate analysis and multivariate linear regression were performed. RESULTS: Only 10.6% of the patients were identified as activated for self-management. Multivariate linear regression analysis revealed four explanatory elements as significantly associated with patient activation, including social support (ß = .463, p < .001), free medical insurance (ß = .173, p = .007), smoking status (ß = -.195, p = .002), and health status (ß = -.139, p = .04). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings of this study indicate that a minority of patients with COPD are activated for self-management in China. Having a higher level of patient activation was associated with having better social support, having free medical insurance, being a nonsmoker, and having a better health status. Creating a supportive environment, promoting smoking cessation, and improving medical security and health status may be considered as potential strategies to activate patients into better self-management.

Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.

Multimodality treatment provides modest survival benefits for patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC). Nevertheless, preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC.This phase 2 trial enrolled patients with AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC deemed surgically resectable. Patients received three cycles of neoadjuvant treatment with intravenous PD-1 inhibitor toripalimab (240 mg), carboplatin (area under the curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for other subtypes) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks afterward. The primary endpoint was major pathological response (MPR), defined as less than 10% residual tumor remaining at the time of surgery.Thirty-three patients were enrolled, of whom 13 (39.4%) had T3-4N2 stage IIIB disease. Thirty (90.9%) patients underwent resection and all except one (96.7%) achieved R0 resection. Twenty patients (60.6%) in the intention-to-treat population achieved an MPR, including 15 patients (45.5%) who achieved a pathological complete response (pCR). The MPR and pCR rates in the per-protocol population were 66.7% and 50.0%, respectively. The surgical complications included three cases of arrhythmias, one case of a prolonged air leak, and one case of chylothorax. The most common grade 3 treatment-related adverse event (TRAE) was anemia (2, [6.1%]). Severe TRAEs included one (3.0%) case of grade 3 peripheral neuropathy that resulted in surgical cancellation.Toripalimab plus platinum-based doublet chemotherapy yields a high MPR rate, manageable toxicity, and feasible resection in stage III NSCLC.Trial ClinicalTrials.gov (NCT04304248).

Impact of endoscopic sedation on gastric polyp detection: A one-center retrospective observational study.

Sedation esophagogastroduodenoscopy (EGD) has become more prevalent in many countries. However, owing to the limitation of health insurance payment for sedation EGD in Taiwan, non-sedation EGD still accounts for the majority of cases. This study was aimed to explore the differences between the sedation and non-sedation groups in terms of endoscopic findings, such as detection rate of gastric polyp of any size, number of detected gastric polyps, and location of the gastric polyps detected.We enrolled 10,940 patients who underwent EGD between January 1, 2016 and December 31, 2016 at the Tri-Service General Hospital; among the patients, 1900 received intravenous sedation (IVS) and 9040 did not. The data reviewed included demographics, parameters of the polyp (number, size, and location), and pathology.Compared with the non-sedation group, the sedation group had a higher overall polyp detection rate (P < .001); a greater number of detected polyps (Odds ratio 1.50, P = .007); and a higher detection rate of smaller polyps, such as fundic gland polyp, and hyperplastic polyp (P < .001). Among the pathological findings, gastric neuroendocrine tumor (NET) was detected using EGD in 2 cases and manifested as small polyps (<0.05 cm), and it showed significantly better detection rates in the sedation EGD group than in the non-sedation EGD group (P = .002).Sedation EGD could enhance a patients willingness and cooperation during EGD. Furthermore, sedation EGD increased the detection rates of small gastric polyps and was more likely to enable identification of unusual findings, such as gastric NET.

TRAIL inhibits HBV replication and expression by down-regulating liver-enriched transcription factors.

BACKGROUND AND STUDY AIMS: To investigate the role of low-concentration TRAIL on HBV replication and expression. MATERIAL AND METHODS: MTT assay was performed to determine the minimum concentrations of TRAIL protein in HepG2 cell apoptosis. HepG2 cells were transfected by HBV replication plasmid pHBV4.1. After the treatment with low concentration of TRAIL, the culture supernatant was collected to detect HBsAg and HBeAg by ELISA. Proteins were extracted from the resulted cells, followed by total RNA and HBV DNA intermediate replication. Southern Blot and Northern Blot were carried out to detect HBV RNA and HBV DNA replication intermediates, respectively. RT-PCR and Western Blot were carried out to detect gene and protein expressions for HNF4α, PPARα, and RXRα, respectively. RESULTS: 50 ng/ml of TRAIL protein led to significant decline on the secretions of HBsAg and HBeAg. Expression levels of HBV RNA and HBV DNA replication intermediates were significantly decreased too. In addition, gene and protein expressions of HNF4α, PPARα and RXRα also dropped, especially for PPARα whose expressions significantly decreased. CONCLUSION: TRAIL could inhibit HBV replication and expression by downregulating the expressions of liver-enriched transcription factors HNF4α, PPARα, and RXRα.

The utility of EBUS-TBNA in the diagnosis of suspected intrathoracic recurrence after esophageal cancer surgery.

OBJECTIVES: Postoperative recurrences, especially anastomotic recurrence and regional lymph node recurrence were common in patients even with curative esophageal cancer surgery. Endobronchial ultrasound-guided transbronchial needle aspiration is an alternative to mediastinoscopy in patients with lung cancer and mediastinal lymphadenopathy. The aim of our study is to evaluate the utility of endobronchial ultrasound-guided transbronchial needle aspiration in postoperative patients suffered from esophageal malignancy. METHODS: All endobronchial ultrasound-guided transbronchial needle aspiration cases performed between August 2015 and December 2018 in our center were all retrospective reviewed. The patients with enlarged mediastinal lymph node and/or unknown intrathoracic mass after esophageal cancer surgery were enrolled. Final diagnoses were determined by the result of endobronchial ultrasound-guided transbronchial needle aspiration, second surgery and/or clinical follow-up for at least 6 months. RESULTS: Overall 29 patients were included in the analysis with 30 lesions sampled. No endobronchial ultrasound-guided transbronchial needle aspiration related complications were observed. In total, 22 of these (73.3%) had a diagnosis of tumor recurrence, whereas eight (26.7%) had a different diagnosis: two (6.7%) had a second primary malignancy and three (10.0%) had non-neoplastic diagnosis. Cases were false-negative in 3 (10.0%) out of 30 lesions. The overall sensitivity, negative predicted value and diagnostic accuracy were 88.9, 50.0 and 90.0%, respectively. CONCLUSIONS: Given its safety, low invasiveness, high sensitivity and diagnostic accuracy, endobronchial ultrasound-guided transbronchial needle aspiration could be considered for mediastinal lymphadenopathy and intrathoracic masses of unknown origin in patients after radical esophageal cancer resection, and its strategic role in the management of these patients was confirmed.

Design, synthesis and biological evaluation of novel amide-linked 18ß-glycyrrhetinic acid derivatives as novel ALK inhibitors.

A series of novel amide-linked 18ß-glycyrrhetinic acid derivatives were developed by incorporating substituted piperazine amide fragments into the C30-COOH of 18ß-glycyrrhetinic acid scaffold. The synthesized compounds were evaluated for their anticancer activity against Karpas299, A549, HepG2, MCF-7, and PC-3 cell lines by MTT assay. Besides, some compounds with electron-withdrawing groups on phenyl moieties exhibited noticeable antiproliferative activity. The most potent compound 4a was also found to be non-toxic to normal human hepatocytes LO2 cells. The compound 4a exhibited moderate inhibitory activity against wild-type ALK with an IC50 value of 203.56 nM and relatively weak potent activity to c-Met (IC50 > 1000 nM). Molecular docking studies were performed to explore the diversification in bonding patterns between the compound 4a and Crizotinib.

Radiofrequency Ablation Following Downstaging of Hepatocellular Carcinoma by Using Transarterial Chemoembolization: Long-term Outcomes.

Background Transarterial chemoembolization (TACE) is an effective downstaging procedure for hepatocellular carcinoma (HCC). However, knowledge of the effectiveness of radiofrequency ablation (RFA) after downstaging of HCC is currently lacking. Purpose To evaluate the clinical outcomes of RFA after downstaging of HCC by using TACE. Materials and Methods This retrospective study investigated a cohort of patients who underwent RFA with curative intent after downstaging with TACE to meet Milan criteria (one lesion up to 5 cm or no more than three lesions ≤3 cm without vascular invasion or extrahepatic metastasis) from January 2012 to July 2017. A control group of patients initially meeting the Milan criteria also underwent RFA as first-line treatment in the same period. Overall survival (OS), disease-free survival (DFS), and major complication rates were compared by using the log-rank test. To reduce potential bias, a propensity score analysis was also performed. Results There were 72 patients (median age, 56.5 years; range, 30-78 years; 67 men) in the downstaging group and 357 patients meeting the Milan criteria (median age, 58.0 years; range, 25-87 years; 313 men) included in this study. After propensity score matching, the 1-, 3-, and 5-year OS rates were 99%, 80%, and 66%, respectively, for the patients in the downstaging group and 94%, 84%, and 69%, respectively, for the patients in the Milan criteria group. The 1-, 3-, and 5-year DFS rate were 73%, 34%, and 24% for the downstaging group and 74%, 43%, and 37% for the Milan criteria group. There were no differences in the OS, DFS, or major complication rates between the two groups (P = .74, P = .39, P = .73, respectively). Conclusion The long-term patient survival and major complication rates of radiofrequency ablation following transarterial chemoembolization downstaging for hepatocellular carcinoma were similar to that of patients initially meeting the Milan criteria. © RSNA, 2019 See also the editorial by vanSonnenberg and Mueller in this issue.

The primary lesion apparent diffusion coefficient is a prognostic factor for locoregionally advanced nasopharyngeal carcinoma: a retrospective study.

BACKGROUND: To explore prognostic value of the pre-treatment primary lesion apparent diffusion coefficient (ADC) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: A total of 843 patients with newly diagnosed LA-NPC were enrolled from January 2011 to April 2014 and divided into two groups based on ADC values: the low-ADC group and high-ADC group. The 3-year local relapse-free survival (LRFS), distant metastasis free survival (DMFS), disease-free survival (DFS) and overall survival (OS) rates between two groups were compared using Kaplan-Meier curve, and Cox regression analyses were performed to test prognostic value of the pretreatment ADC in LA-NPC. RESULTS: The cut-off value of the pretreatment ADC for predicting local relapse was 784.5 × 10- 6 mm2/s (AUC [area under curve] = 0.604; sensitivity = 0.640; specificity = 0.574), thus patients were divided into low-ADC (< 784.5 × 10- 6; n = 473) group and high-ADC (≥784.5 × 10- 6; n = 370) group. The low-ADC group had significantly higher 3-year LRFS rate and DFS rate than the high-ADC group (LRFS: 96.2% vs. 91.4%, P = 0.003; DFS: 81.4% vs. 73.0%, P = 0.0056). Multivariate analysis showed that the pretreatment ADC is an independent prognostic factor for LRFS (HR, 2.04; 95% CI, 1.13-3.66; P = 0.017) and DFS (HR, 1.41; 95% CI, 1.04-1.89; P = 0.024). CONCLUSIONS: The pretreatment ADC of the primary lesion is an independent prognostic factor for LRFS and DFS in LA-NPC patients.

SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models.

Emerging evidence demonstrates that a c-Met antibody-drug conjugate (ADC) has superior efficacy and safety profiles compared with those of currently available small molecules or antibody inhibitors for the treatment of c-Met-overexpressing cancers. Here we described both the in vitro and in vivo efficacies of SHR-A1403, a novel c-Met ADC composed of a humanized IgG2 monoclonal antibody against c-Met conjugated to a novel cytotoxic microtubule inhibitor. SHR-A1403 showed high affinity to c-Met proteins derived from human or monkey and potent inhibitory effects in cancer cell lines with high c-Met protein expression. In mice bearing tumors derived from cancer cell lines or patient HCC tissues with confirmed c-Met overexpression, SHR-A1403 showed excellent anti-tumor efficacy. Antibody binding with c-Met contributed to SHR-A1403 endocytosis; the subsequent translocation to lysosomes and cytotoxicity of the released toxin are speculated to be predominant mechanisms underlying the anti-tumor activity of SHR-A1403. In conclusion, SHR-A1403 showed significant anti-tumor activity in cancer cell lines, xenograft mouse models and an HCC PDX model, which all have high c-Met levels. These data provide references for SHR-A1403 as a potential therapy for the treatment of cancers with c-Met overexpression.

A sensitive HPLC-MS/MS method for the simultaneous determination of anemoside B4, anemoside A3 and 23-hydroxybetulinic acid: Application to the pharmacokinetics and liver distribution of Pulsatilla chinensis saponins.

Pulsatilla chinensis saponins, the major active components in the herb, have drawn great attention as potential hepatitis B virus infection and hepatoma treatments. Here, a sensitive and accurate HPLC-MS/MS method was established for simultaneous determination of three saponins - anemoside B4, anemoside A3 and 23-hydroxybetulinic acid - in rat plasma and liver, and fully validated. The method was successfully applied to a pharmacokinetics and liver distribution study of P. chinensis saponins. Consequently, 23-hydroxybetulinic acid, with an extremely low content in the P. chinensis saponins, exhibited the highest exposure in the liver and in sites before and after hepatic disposition, namely, in the portal vein plasma and systemic plasma, followed by anemoside B4, which showed the highest content in the herb, whereas anemoside A3 displayed quite limited exposure. The hepatic first-pass effects were 71% for 23-hydroxybetulinic acid, 27% for anemoside B4 and 37% for anemoside A3, corresponding to their different extents of liver distribution. To our knowledge, this is the first investigation on the liver first-pass effect and distribution of P. chinensis saponins to date. These results also provide valuable information for the understanding of the pharmacological effect of P. chinensis saponins on liver diseases.

Clinical outcomes of endoscopic and open resection of recurrent sinonasal inverted papilloma.

PURPOSE: The aim of this study was to investigate the effectiveness of endoscopic surgery for recurrent sinonasal inverted papilloma and evaluate the recurrence rates of endoscopic and open resection at a single institution. METHODS: This retrospective study was performed on 21 patients with histopathologically confirmed recurrent sinonasal inverted papilloma who underwent an operation in our department from January 1990 to January 2005. The 21 recurrent cases were categorized according to the Krouse staging system into 1 case of stage 1 (5%), 18 cases of stage 2 (85%), 2 cases of stage 3 (10%), and 0 cases of stage 4 (0%). There were 7 patients (33%) who underwent endoscopic resection and 14 patients (67%) who underwent open resection. RESULTS: Of the 21 recurrent patients who underwent resection, 4 patients (19%) were found to have recurrence. The mean time to recurrence was 28 months. The recurrence rates of the patients with stage 1, stage 2, and stage 3 were 0%, 17%, and 50%, respectively (P < 0.05). Recurrence was observed in 1 patient (14%) in the endoscopic group and 3 patients (21%) in the open group (P > 0.05). There was statistical difference in recurrence rates between stage 1 and stage 2 in the endoscopic group (P < 0.05) and between stage 2 and stage 3 in the open group (P < 0.05). There was no significant difference in recurrence rates between the endoscopic and the open group in stage 2 (P > 0.05). CONCLUSIONS: Endoscopic and open approaches are both available to achieve radical excision of the recurrent sinonasal inverted papilloma, with similar rates of recurrence. The risk for recurrence is likely related to the Krouse stage of the tumor, with more aggressive tumors having a higher propensity for recurrence. Endoscopic surgery is an effective treatment of recurrent sinonasal inverted papilloma.

Post-inflammatory glomerular remodeling is influenced by transformed mesangial cells.

To identify the role of transformed mesangial cells (MC) during glomerular remodeling, anti-thymocyte-1 (Thy1) nephritis; modified Thy1 nephritis (injections of anti-Thy1 antibody four times, weekly); and Thy1 nephritis treated with signal transduction inhibitor 571 (Thy1 + STI); were analyzed. At week 1 the index of MC proliferation in modified Thy1 nephritis and in mesangiolysis in Thy1 + STI nephritis was highest among the three models. From week 4, the index of alpha-smooth muscle actin (alpha-SMA) was significantly higher in modified Thy1 nephritis than the other two models. Production of the mesangial matrix including type IV collagen was increased in modified Thy1 but inhibited in Thy1 + STI nephritis. In contrast to modified Thy1 nephritis, the capillary numbers in glomeruli recovered to normal at week 4 in Thy1, and at week 8 in Thy1 + STI nephritis. At week 12, both the adhesive and sclerotic index was significantly higher in modified Thy1 than in the other two models. Data suggest that a moderate amount of mesangial matrix results in a complete repair of capillary loops. Overproduction of the mesangial matrix retards capillary remodeling and finally induces glomerulosclerosis. Insufficient mesangial matrix delays the repair of capillary loops. In conclusion, transformed MC may influence glomerular remodeling by changing the amount of mesangial matrix.

Lamivudine prophylaxis of liver allograft HBV reinfection in HBV related cirrhotic patients after liver transplantation.

BACKGROUND: Liver allograft hepatitis B virus (HBV) reinfection and hepatitis B (HB) recurrence jeopardize the long-term survival of recipient and liver allograft. Lamivudine has been referred as a novel antiviral agent against HBV in HBV cirrhotic patients even in liver transplantation setting. We assessed the prophylatic effect of lamivudine on liver allograft HBV reinfection and clarified the dynamic changes of HBV markers in HBV related decompensated liver cirrhosis after liver transplantation. METHODS: Twenty-five recipients were divided into three groups: HBV active replication group (15 recipients), HBV inactive replication group (7), and control group (3). 100 mg/d lamivudine was administered preoperatively except in the control group. The HBV markers of serial sera and liver biopsy samples of the 25 recipients were evaluated regularly with enzyme-linked radioimmunoassay, HBV DNA fluorescent quantitative assay, immunohistochemical staining, labelled streptavidin biotin (LSAB) and digoxin labelled HBV DNA hybridization in situ. The dynamic alternation of HBV markers under lamivudine prophylaxis was observed. RESULTS: In the HBV active replication group who had received lamivudine 2 weeks before liver transplantation, serum HBV DNA positive converted to negative by 80%. HBsAg of all recipients disappeared after liver transplantation, but corresponding antibodies of HBV appeared within one week after the operation. HBsAb 9/15, HBcAb 13/15 and HBeAb 11/15 appeared and subsided gradually within 24 weeks. HBV DNA in sera was kept negative; HBsAg, HBcAg and HBV DNA hybridization in situ of liver biopsy samples remained negative after use of lamivudine. Ten of the 15 recipients showed clearance of HBV, and per se HBV markers were undetectable both in serum and liver biopsy samples between 12 to 44 weeks (24 weeks on average). The 1-, 2-year survival rates were 83% in this group. Two of the 15 recipients developed HBV allograft reinfection or recurrence of hepatitis 2 years after lamivudine monoprophylaxis (2/15, 13.3%). In the HBV inactive replication group, the outcome was similar to that of the HBV active group. The HBV antibody frequency was HBsAb 4/7, HBcAb 6/7, and HBeAb 2/7. Three of 7 recipients showed HBV clearance both in sera and liver biopsy samples, whereas in the control group all 3 recipients developed HBV allograft reinfection and recurrent hepatitis 8, 10, 12 months postoperatively; one of them died of fibrosing cholestatic hepatitis, and the remaining 2 recovered after additional lamivudine therapy. The overall allograft reinfection rate was 9.1% (2/22) and the overall 1-, 2-year survival rates were 87% in the lamivudine prophylaxis group. CONCLUSIONS: Lamivudine prophylaxis can prevent effectively liver allograft from HBV reinfection in patients with HBV-related decompensated liver cirrhosis even in HBV active replication recipient after liver transplantation. Its long-term outcome remains to be studied.

Dynamic alteration of HBV markers on active HBV replicative recipients after liver transplantation: a preliminary report.

OBJECTIVE: To investigate the dynamic alternations of HBV markers of active HBV replication recipients receiving lamivudine prophylaxis after liver transplantation. METHODS: Serial liver biopsy samples and sera were obtained from 15 recipients and examined with enzyme-linked radioimmunoassay for HBsAg, HBeAg, HBsAb, HBcAb and HBeAb, and fluorescent quantitative assay for quantitation of HBV DNA in serum. Immunohistochemical staining of HBsAg, HBcAg and HBV DNA hybridization in situ were used to detect HBV markers in liver biopsy samples. RESULTS: 100 mg lamivudine taken orally every day for 2 weeks before transplantation enabled 12 (80%) of 15 active viral replication recipients (HBV DNA positive) to converse to HBV DNA negative. HBsAb, HBcAb and HBeAb in serum emerged in 1-2 weeks after liver transplantation, and disappeared gradually within 6 months; HBV DNA fluorescent quantitative assay showed constant negativity in serum. Immunohistochemical staining of HBsAg, HBcAg and HBV DNA hybridization in situ in liver biopsy samples showed negative results synchorously. Eight of the 15 HBV active replication recipients lost HBV markers thoroughly both in serology and tissue staining as well as HBV DNA hybridization in situ of serial liver biopsy samples from 12 to 44 weeks after liver transplantation. Should any of HBsAg, HBeAg in serology and HBsAg, HBcAg in immunohistochemical staining was positive, or HBV DNA detectable in serum, or HBV DNA hybridization in situ in liver tissue positive, allograft HBV reinfection or De novo liver allograft infection could be diagnosed. Furthermore, if associated with elevation of ALT and bilirubin, the diagnosis of HBV hepatitis recurrence could be established. CONCLUSION: Allograft HBV reinfection or De novo liver allograft infection in active viral replication recipients could be prevented with lamivudine regimen, and further clearance of HBV may be possible if proper measures are taken.

[Pharyagoesophageal sphinoter myotomy for voice rehabilitation after total laryngectomy].

OBJECTIVE: In those patients received total laryngectomy, Blom-Singer prosthesis speech appears to be the more effective form of rehabilitation. To reduce the effect of pharyngoesophageal sphincter on the Blom-Singer prosthesis voice restoration following total laryngectomy, the pharyagoesphageal sphincter myotomy was designed and carried out. METHODS: After total laryngectomy, the cricopharyngeus muscle stricture or spasm appears to inhibit the air flowing and prevent the speech. The pharyngoesophageal sphincter is now defined as the area including the cricopharyngeus with a portion of inferior constrictor, as well as some of the upper cervical esophagus. The pharyngoesophageal sphincter were incised intra- and post- operation of total laryngectomy, the dissection was approximately 5 cm in vertical length and 1 cm in width. RESULTS: Among the 33 patients who received pharyngoesophageal sphincter myotomy following total laryngectomy, voice restoration was achieved in 32 cases, the success rate was 97%. 25 patients had survived for 3 years, 18 patients survived for 5 years. CONCLUSION: Pharyagoesophageal sphincter myotomy can raise the success rate of rehabilitation of the voice by Blom-Singer prosthesis.