[The influence of two kinds of transnasal endoscopic surgery on the outcome status of sinus cavity in patients with eosinophilic chronic rhinosinusitis with nasal polyps].

Objective: To investigate the trend of postoperative cavity status in patients with eosinophilic chronic sinusitis with nasal polyps (eCRSwNP) who underwent total nasalization surgery and partial reboot surgery. And to discuss the relationship between tissue eosinophil counts and status of postoperative cavity. Methods: Patients with eCRSwNP in four tertiary medical centers (Longgang ENT Hospital, Xiamen Humanity Hospital, Guangdong Clifford Hospital and the First Affiliated Hospital of Sun Yat-Sen University) from March 2018 to October 2021 were divided into 2 groups. The group without previous surgery history was performed for the nasalization surgery, and another group with previous surgery history underwent the part-reboot surgery. The follow-up time after operation was defined as the following 5 stages: 6, 12, 20-24, 36 and more than 42 months. According to FESS-95 Guangzhou standard, status of sinus cavity was assessed and classified into 3 categories: good, better and bad. The association between the sinus cavity status and tissue eosinophil counts in the above 5 stages was analyzed by one-way ANOVA, and P<0.05 was considered statistically significant. Results: A total of 72 eCRSwNP patients finished the follow-up in this study. There were 47 males and 25 females in these patients, aged from 11 to 67 years. A total of 50 cases underwent nasalization surgery and 22 cases underwent partial reboot surgery. With the follow-up time from 6 to 48 months, there were 72 cases (100.0%) who completed 6 months and 12 months follow up, 46 cases (63.9%) for 20-24 months, 36 cases (50.0%) for 32-36 months and 16 cases (22.2%) with the follow-up time more than 42 months. No matter what kind of surgery, there was no "bad" situation of the surgical cavity status 6 months after the operation, and the differentiation gradually occurred more than 12 months after the surgery. Moreover, the rates of "good" cavity status for the 5 stages in the group of nasalization surgery were 78.0%, 66.0%, 56.7%, 47.6% and 42.9%, and were 63.6%, 45.5%, 25.0%, 20.0% and 11.1% in the partial reboot surgery group, respectively, suggesting that the status of nasal cavity in nasalization surgery group was always better than that in partial reboot surgery group in every period. In addition, the "bad" rate was 0, 8.0%, 10.0%, 14.3% and 28.6% in the group of nasalization surgery, and was 0, 27.3%, 18.8%, 33.3% and 55.6% in the partial reboot surgery group, respectively. The average percentage of tissue eosinophil counts in the 72 cases was 42.1%, which had no obvious effect on the status of the surgical cavity (P>0.05). Conclusions: For eCRSwNP patients, the operative cavity status in the patients without previous operation history treated with nasalization surgery is good. The time of 1-2 years after surgery is the main period for sinus lesions. The counts of tissue eosinophils has no significant influence on surgical sinus cavity status in the eCRSwNP patients.

Research on mechanism of MAPK signal pathway induced by BMSCs for the proteinuria of rat's kidney, glomerulosclerosis and activity of RAS.

OBJECTIVE: The aim of the article was to explore the mechanism of MAPK (Mitogen-activated protein kinase) signal pathway induced by BMSCs (Bone marrow mesenchymal stem cells) for the proteinuria of rat's kidney, glomerulosclerosis and activity of RAS (Renin angiotensin) system. MATERIALS AND METHODS: Thirty rats were divided into sham group, FSGS (Focal Segmental Glomerular Sclerosis) group and BMSCs group. The variation of biochemical criterion and protein of rats in the three groups was compared. The variation condition of rats' kidney and GSI (Glomerular sclerosis index), ECM/GA (Extracellular matrix/glomerular area) was compared. The activity of RAS was analyzed. Finally, the p38 MAPK and p-p38 MAPK protein was compared. RESULTS: Compared with sham group rats, the SCr, BUN and proteinuria after twenty-four hours in FSGS group was improved. The blood albumin was notably reduced. At the same time, there was evident deterioration in the pathology of nephridial tissue (p<0.05). The biochemical criterion in transplanted BMSCs group was significantly reduced. At the same time, the blood albumin and pathology of nephridial tissue was also improved (p<0.05). The glomerulus in sham group was normal. There was abundant induration for the glomerulus in FSGS group compared with sham group. The relative value of GSI and ECM/GA was higher than in sham group (p<0.05). The relative value of GSI and ECM/GA in BMSCs group was reduced notably compared with FSGS group (p<0.05). The activity of RAS in FSGS group was enhanced. But activity of RAS in BMSCs group was remarkably restrained. The p38 MAPK and p-p38 MAPK protein in FSGS group was significantly increased compared with the other groups (p<0.05). The protein expression in BMSCs group and inhibitor group was restrained (p<0.05). CONCLUSIONS: The BMSCs could restrain the proteinuria of rat's kidney and activity of RAS and they were related with the expression of MAPK signal pathway closely.

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.

BACKGROUND: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. PATIENTS AND METHODS: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH. RESULTS: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6-10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. CONCLUSIONS: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study.

BACKGROUND: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). PATIENTS AND METHODS: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. RESULTS: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32-0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46-0.98). The 5-year OS rate was 62.5% (95% CI 54.3-70.8) with alectinib and 45.5% (95% CI 33.6-57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34-1.00)] and those without [HR 0.76 (95% CI 0.45-1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. CONCLUSIONS: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. CLINICAL TRIALS NUMBER: NCT02075840.

Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.

BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001.

BACKGROUND: In the ongoing phase I PROFILE 1001 study, crizotinib showed antitumor activity in patients with ROS1-rearranged advanced non-small-cell lung cancer (NSCLC). Here, we present updated antitumor activity, overall survival (OS) and safety data (additional 46.2 months follow-up) for patients with ROS1-rearranged advanced NSCLC from PROFILE 1001. PATIENTS AND METHODS: ROS1 status was determined by FISH or reverse transcriptase-polymerase chain reaction. All patients received crizotinib at a starting dose of 250 mg twice daily. RESULTS: Fifty-three patients received crizotinib, with a median duration of treatment of 22.4 months. At data cut-off, treatment was ongoing in 12 patients (23%). The objective response rate (ORR) was 72% [95% confidence interval (CI), 58% to 83%], including six confirmed complete responses and 32 confirmed partial responses; 10 patients had stable disease. Responses were durable (median duration of response 24.7 months; 95% CI, 15.2-45.3). ORRs were consistent across different patient subgroups. Median progression-free survival was 19.3 months (95% CI, 15.2-39.1). A total of 26 deaths (49%) occurred (median follow-up period of 62.6 months), and of the remaining 27 patients (51%), 14 (26%) were in follow-up at data cut-off. Median OS was 51.4 months (95% CI, 29.3 to not reached) and survival probabilities at 12, 24, 36, and 48 months were 79%, 67%, 53%, and 51%, respectively. No correlation was observed between OS and specific ROS1 fusion partner. Treatment-related adverse events (TRAEs) were mainly grade 1 or 2, per CTCAE v3.0. There were no grade ≥4 TRAEs and no TRAEs associated with permanent discontinuation. No new safety signals were reported with long-term crizotinib treatment. CONCLUSIONS: These findings serve as a new benchmark for OS in ROS1-rearranged advanced NSCLC, and continue to show the clinically meaningful benefit and safety of crizotinib in this molecular subgroup. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT00585195.

Dexmedetomidine protects liver cell line L-02 from oxygen-glucose deprivation-induced injury by down-regulation of microRNA-711.

OBJECTIVE: In liver transplantation, long-time portal vein blocking causes the occurrence of ischemic liver injury. Dexmedetomidine, a widely admired anesthetic, has been reported as a protective agent on organs under ischemic condition. The objective of this study was to reveal the role and underlying mechanism of dexmedetomidine in ischemic liver injury. MATERIALS AND METHODS: L-02 cells were treated with dexmedetomidine during 6 h of oxygen-glucose deprivation (OGD) exposure. The expression of microRNA-711 (miR-711) in cell was overexpressed by miRNA transfection. Then, the following parameters were observed: cell viability, apoptosis, the expression of apoptosis-related proteins, and the expression and the release of Interleukin 1 beta (IL-1ß) and Tumor necrosis factor alpha (TNF-α). RESULTS: Apoptosis and inflammation were induced following OGD exposure in L-02 cells, as cell viability was impaired, apoptotic cell rate was increased, caspase-3, and caspase-9 was cleaved, and the expression and release of TNF-α and IL-1ß were increased. Dexmedetomidine attenuated OGD-induced apoptosis and inflammation, and dexmedetomidine down-regulated the expression of miR-711. Also, dexmedetomidine blocked the activation of p38 mitogen-activated protein kinase (p38MAPK) and Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signaling upon OGD. Moreover, when miR-711 was overexpressed, dexmedetomidine did not protect L-02 cells against OGD, and did not block p38MAPK and JAK/STAT signaling pathways. CONCLUSIONS: Dexmedetomidine ameliorated OGD-induced cell apoptosis and inflammation in L-02 cells, exerting protective activities in ischemic liver injury. The anti-OGD effects of dexmedetomidine might be realized by down-regulation of miR-711 and suppression of p38MAPK and JAK/STAT signaling pathways.

Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study.

Background: The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods: Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results: In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration: ClinicalTrials.gov NCT02075840.

MACC1 silencing inhibits cell proliferation and induces cell apoptosis of lung adenocarcinoma cells through the ß-catenin pathway.

It has been documented that over-expression of metastasis-associated in colon cancer-1 (MACC1) is related to poor prognosis in non-small cell lung cancer (NSCLC). This study investigates the function and underlying molecular mechanisms of MACC1 in lung adenocarcinoma. Here, we firstly employed immunohistochemistry, western blotting, real-time PCR, and online database to demonstrate that MACC1 expression was elevated in tumor tissues compared with tumoradjacent or normal tissues. Real-time PCR, CCK-8, colony formation western blotting, Hoechst staining, and flow cytometry assays then evaluated the effects of MACC1 knockdown on the cell cycle, cell proliferation and apoptosis in A549  and H1299 adenocarcinoma cells. Result highlighted that MACC1 knockdown inhibited cell proliferation, induced G0/ G1 phase arrest and promoted cell apoptosis in vitro. Mechanistic analysis revealed it also up-regulated expression levels of bax, cleaved-caspase-3 and cleaved-PARP while down-regulating cyclin D1, c-myc, bcl-2, and ß-catenin expression in A549 cells. Intriguingly, up-regulation of ß-catenin suppressed G0/G1 phase arrest and apoptosis in MACC1-silenced A549 cells and this was accompanied by increased levels of cyclin D1, c-myc, and bcl-2. Collectively, our results indicate that MACC1 knockdown effectively inhibited cell proliferation and promoted apoptosis of lung adenocarcinoma cells by regulating the ß-catenin pathway.

Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib.

Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment. This study demonstrates the importance of both tissue and blood based hybrid-capture based genomic profiling at disease progression to identifying novel resistance mechanisms in the clinic.

Clinical diagnostic value of free body of reduced iron protoporphyrin in uterus epithelial cells on cervical carcinoma and precancerous lesion.

OBJECTIVE: Cervical cancer is a common malignant tumor in women with increased incidence and younger onset age. As a curable tumor, timely diagnosis and early intervention are critical. Based on the golden standard of cervical tissues pathology examination, we investigated the value of free body of reduced iron protoporphyrin (FH) in uterus epithelial cells for the diagnosis of cervical cancer and precancerous lesions, aiming to provide novel methods for early screening of cervical cancer. PATIENTS AND METHODS: A total of 574 women who were screened for cervical cancer according to golden standard of pathology as the reference, were recruited for the analysis of authenticity, reliability, and predictive values of FH. The diagnostic value of FH on cervical carcinoma and precancerous lesion diagnosis was further analyzed. RESULTS: 340 individuals had normal cervical or benign lesion by pathology examination, while 155 people had precancerous lesion, among which 79 cases presented early infiltration and infiltrative cancer. In FH screening, 361 and 213 people had negative and positive results, respectively. No significant differences in the results were observed between the two methods in screening cancer and precancerous lesion (p>0.05). FH showed 93.55% sensitivity and 81.94% specificity in diagnosing precancerous lesion, while the sensitivity and specificity for cervical cancer diagnosis were 93.53% and 81.01%, respectively. CONCLUSIONS: FH assay was demonstrated to have advantages of high diagnostic value for cervical cancer and precancerous lesion, and might be used for early screening.

Safety of alectinib for the treatment of metastatic ALK-rearranged non-small cell lung cancer.

INTRODUCTION: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) may derive significant clinical benefit from targeted therapies against this driver mutation, but progression is virtually inevitable. Alectinib is a next-generation ALK inhibitor that provides a novel treatment option for this group of patients. Areas covered: In this review, we summarize the overall safety and tolerability of alectinib. Specifically, we cover cardiovascular, gastrointestinal, hepatic, musculoskeletal, and respiratory adverse events. The safety profile of alectinib is also described in special populations and in comparison with other ALK inhibitors. Expert opinion: Alectinib is a well-tolerated tyrosine kinase inhibitor and should be considered for patients with ALK-rearranged NSCLC. The question then arises as to how to choose a next-generation ALK inhibitor in the second-line setting. Understanding acquired resistant mechanisms has become essential. Whether or not to use alectinib in the first-line setting is extremely controversial, but we anticipate its approval for this indication and availability in more countries in the near future.

Plasma pharmacokinetics and tissue depletion of cyromazine and its metabolite melamine following oral administration in laying chickens.

The study was designed to characterize the plasma pharmacokinetics and tissue depletion profiles (including eggs) of cyromazine (CYR) in chickens following oral administration alone or in combination with melamine (MEL). In order to assess the pharmacokinetic profile of CYR, chickens were administered 1 or 10 mg/kg (single oral doses), whereas residue studies were conducted in chickens fed CYR alone (5 or 10 mg/kg) or CYR (5 mg/kg) and MEL (5 mg/kg) for a period of 14 days. Estimates for the apparent volume of distribution (1.66 L/kg), clearance (7.17 mL/kg/min), and elimination half-life (2.82 h) were derived by noncompartmental analyses. The highest concentration of CYR occurred in liver but fell below detectable limits within 3 days following drug withdrawal from feed. Combined feeding of MEL with CYR did not significantly alter CYR tissue levels. CYR residues were detected only in egg white and were undetectable at the 2nd day postadministration. No MEL was found in eggs unless it had been added to the feed, and when present, it almost exclusively restricted to the egg white. Based upon the results of this initial study of CYR pharmacokinetics and residue depletion, it appears that use of CYR as a feed additive either alone (5 or 10 mg/kg) or in combination with MEL (both agents at 5 mg/kg) does not produce unsafe residue levels in edible products as long as appropriate withdrawal periods are followed for tissues (3 days) and eggs (2 days). However, our results indicate that adoption of a zero-day withdrawal period should be reconsidered in light of these results.

What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).

BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion. PATIENTS AND METHODS: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions. RESULTS: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays. CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).

Zhi-Long-Huo-Xue-Tong-Yu modulates mitochondrial fission through the ROCK1 pathway in mitochondrial dysfunction caused by streptozotocin-induced diabetic kidney injury.

Zhi-Long-Huo-Xue-Tong-Yu (ZLHXTY) is a defined mixture of 5 herbs developed by Professor S.J. Yang according to the Buyang Huanwu decoction method, which has been recorded in the Yilingaicuo. This study investigated the renoprotective effects of ZLHXTY on mitochondrial dysfunction induced by diabetic kidney injury in a diabetic rat model. Diabetes was induced by a single intravenous injection of streptozotocin. Rats were daily fed either ZLHXTY or vehicle beginning in the 1st week after injection. Levels of mitofusin 2 (mfn2), dynamin-related protein 1 (Drp1), caspase-9, and rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) were detected using Western blotting. Levels of intracellular calcium and adenosine triphosphate (ATP) were examined using an enzyme-linked immunosorbent assay. An electron microscopic examination of kidney tissue was performed. The levels of mfn2 and ATP in the diabetes and ZLHXTY groups decreased from the 4th week after modeling. The expression levels of Drp1, ROCK1, and caspase-9 increased in the diabetes group but decreased in the ZLHXTY group from the 4th week after modeling. Compared with the diabetes group, ZLHXTY treatment decreased the mesangial expansion index and proteinuria levels, and improved the pathological changes typical of diabetic kidney injury. Furthermore, ZLHXTY treatment inhibited the activation of ROCK1 and expression of Drp1 and caspase-9, but did not affect the expression of mfn2. This study indicates that ZLHXTY treatment could protect kidney tissue from diabetic injury through the ROCK1 pathway response to mitochondrial dysfunction induced by diabetes.

Innovative personalized medicine in gastric cancer: time to move forward.

Globally, gastric cancer (GC) is the second leading cancer cause of death. To date, only one targeted therapy trial generated positive survival outcomes in a selected population among many targeted therapy trials. This trial showed the addition of trastuzumab to fluoropyrimidine/platinum chemotherapy as first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive GC that resulted in an overall survival (OS) benefit. The increasing use of next generation sequencing approach to genomically profile GC patients allows the identification of many more GC patients who could benefit from specific targeted agents. Here we provide a comprehensive review of targeted therapy trials in GC and discuss future potential actionable driver mutations in GC.

The acoustic radiation force impulse elastography evaluation of liver fibrosis in posttransplantation dysfunction of living donor liver transplantation.

BACKGROUND: The acoustic radiation force impulse elastography (ARFI) is a new technology of elastography integrated into B-mode ultrasonography. It has been a reliable method to evaluate liver fibrosis of chronic liver disease in recent years, but less applied in the posttransplantation liver. The aim of the study was to evaluate liver fibrosis by the ARFI with correlation of pathological stages in living donor liver transplantation (LDLT). MATERIALS AND METHODS: From August 2010 to August 2012, there were 57 LDLT patients with liver biopsy (LB) due to posttransplantation dysfunction; all patients also received posttransplantation ARFI liver stiffness measurement (LSM) after transplantation for liver fibrosis staging. The ARFI elastography was performed using a Siemens Acuson S2000 ultrasound system with 4V1 transducers (Acusion, Siemens Medical Systems Co. Ltd. Erlangen, Germany). The ARFI LSM value was presented by shear wave velocity (SWV, m/s). The fibrosis staging as F0 to F4 was in accordance with the Metavir scoring system. RESULTS: A total of 57 patients had both posttransplantation LB and effective ARFI fibrosis staging for correlation. The ARFI LSM value increased with severity of liver fibrosis and had significant linear correlation with the results of histological fibrosis staging. The ARFI LSM sensitivities (Se), specificities (Sp), and cutoff values based on receiver-operator characteristic curve were F0: 0.75 m/s (Se: 93.8%, Sp: 4%), F1: 1.06 m/s (Se: 95.5%, Sp: 25.7%), F2: 1.81 m/s (Se: 50%, Sp: 83.6%) and F3: 2.33 m/s (Se: 100%, Sp: 92.9%). Predictive value of ARFI LSM reported a significant difference between early fibrosis stage (F0-F1) and advanced fibrosis stage (F ≧ 2) (P < .05). CONCLUSION: In this study, ARFI demonstrated a strong linear correlation and severity of liver fibrosis with LB pathologic staging. ARFI can be an alternative and compensatory method for frequent LB in the posttransplantation liver.

Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC.

BACKGROUND: Crizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit. PATIENTS AND METHODS: Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as >3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and post-progression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed. RESULTS: Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P=0.02). CBPD patients had significantly longer OS from the time of PD [median 16.4 versus 3.9 months; hazards ratio (HR) 0.27, 95% confidence interval (CI): 0.17-0.42; P<0.0001] and from the time of initial crizotinib treatment (median 29.6 versus 10.8 months; HR 0.30, 95% CI: 0.19-0.46; P<0.0001). The multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS after adjusting for relevant factors. CONCLUSIONS: Patients who continued CBPD were more likely to have good ECOG PS (0/1) at the time of PD. Continuing ALK inhibition with crizotinib after PD may provide survival benefit to patients with advanced ALK-positive NSCLC.