Myeloprotection with trilaciclib in Chinese patients with extensive-stage small cell lung cancer receiving chemotherapy: Results from a randomized, double-blind, placebo-controlled phase III study (TRACES).

INTRODUCTION: Trilaciclib is a transient cyclin-dependent kinase 4/6 inhibitor that decreases the incidence of chemotherapy-induced myelosuppression in extensive-stage small cell lung cancer (ES-SCLC). TRACES study was designed to assess the safety, efficacy and pharmacokinetics (PK) of trilaciclib before chemotherapy in Chinese patients with ES-SCLC. METHODS: The study included an open-label safety run-in part (Part 1) and double-blinded, placebo-controlled part (Part 2) where patients received trilaciclib or placebo before chemotherapy. Treatment-naïve or previously treated ES-SCLC patients received intravenous trilaciclib (240 mg/m2) or placebo before etoposide/carboplatin or topotecan, respectively. Primary endpoints were PK, safety and duration of severe neutropenia (DSN) in Cycle 1 in Part 1 and Part 2. Exploratory endpoints included the effect of trilaciclib on other myeloprotection endpoints, safety and antitumor efficacy. RESULTS: Overall, 95 Chinese patients were enrolled, of which 12 and 83 patients were in Part 1 and Part 2, respectively. In Part 1, trilaciclib was well tolerated. Non-compartmental analysis results revealed no substantial differences in the main exposure parameters. In Part 2, 41 patients received trilaciclib, and 42 received placebo. Patients in trilaciclib arm vs placebo arm had a clinically and statistically significant decrease in DSN (mean [SD]) in Cycle 1 (0 [1.7] vs 2 [3.0] days; P = 0.0003), with improvements in additional neutrophil, red blood cell, and platelet measures. After a median follow-up of 14.1 months, the median overall survival was 12.0 months in trilaciclib arm and 8.8 months in placebo arm (HR, 0.69; 95 % CI: 0.40-1.22). Median progression-free survival was 4.8 months and 4.3 months, respectively (HR, 0.86; 95 % CI: 0.53-1.39). Trilaciclib had a well-tolerated safety profile. CONCLUSIONS: Trilaciclib in the Chinese population demonstrated a similar PK and safety profile as seen in other global trials. There was significant reduction of DSN in Cycle 1, thereby substantiating the myeloprotective effects of trilaciclib in Chinese ES-SCLC patients.

Association between the ESR1 and ESR2 polymorphisms and osteoporosis risk: An updated meta-analysis.

BACKGROUND: Gene polymorphisms of estrogen receptor (ESR) 1 PvuII (rs2234693), XbaI (rs9340799), G2014A (rs2228480), ESR2 AluI (rs4986938), and RsaI (rs1256049) had been reported to be associated with the risk of osteoporosis. However, these conclusions were inconsistent, therefore, an updated meta-analysis was conducted to further explore these issues. OBJECTIVE: To evaluate the association between gene polymorphisms of ESR1 PvuII (rs2234693), XbaI (rs9340799), G2014A (rs2228480), ESR2 AluI (rs4986938), RsaI (rs1256049), and osteoporosis risk. MATERIALS AND METHODS: PubMed, Medline, Ovid, Embase, CNKI, and China Wanfang databases were searched. Association was assessed using odds ratio with 95% confidence interval. Moreover, the false-positive reporting probability, Bayesian false-finding probability, and Venetian criteria were used to assess the credibility of statistically significant associations. RESULTS: Overall, ESR1 PvuII (rs2234693) and XbaI (rs9340799) were associated with the risk of osteoporosis in Indians. Moreover, ESR1 G2014A (rs2228480) was associated with the decreased risk of osteoporosis in East Asians. Moreover, ESR2 Alul (rs4986938) was associated with the increased risk of osteoporosis in East Asians and Caucasians. There was a significant association between ESR2 Rsal (rs1256049) and osteoporosis risk in overall population. When only high-quality and Hardy-Weinberg equilibrium studies were included in the sensitivity analysis, all results did not change in the present study. When the credibility was evaluated applying false-positive reporting probability, Bayesian false-finding probability, and Venetian criteria, all significant associations were considered as false positive results. CONCLUSIONS: In summary, this study shows that all substantial associations between gene polymorphisms of ESR1 (PvuII, XbaI, and G2014A) and ESR 2 (AluI and RsaI) and osteoporosis risk are possibly false positive results instead of real associations or biological variables.

The prognostic value of 11th Japanese classification and 8th AJCC staging systems in Chinese patients with esophageal squamous cell carcinoma.

BACKGROUND: Two staging systems, the 8th staging system by the American Joint Committee on Cancer (AJCC) and the 11th Japanese classification by Japan Esophageal Society (JES), are currently applied in the clinic for predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC). The differences between the two staging systems have been widely researched. However, little studies focus on the differences in specific staging between the two systems. Therefore, we aimed to compare the performance of different staging in predicting overall survival (OS) of Chinese patients with ESCC. METHODS: This retrospective study included 268 patients who underwent radical esophagectomy and mediastinal lymph node dissection for ESCC between January 2008 and December 2013. Patients were staged by the 8th AJCC and 11th JES staging systems. OS was estimated using the Kaplan-Meier method and compared between N stages and between stage groupings using the log-rank test. Cox proportional hazards regression analysis was performed to identify factors independently related to outcome. Further, we compared the concordance indexes (C-indexes) of the two staging systems. RESULTS: The mean age was 61.25 ± 7.056 years, median follow-up was 44.82 months, and 5-year OS rate was 47%. The OS was well predicted by the 8th AJCC N staging (P < 0.001) and the 11th JES N staging (P < 0.001), with a c-index of 0.638 (95% CI: 0.592-0.683) for AJCC N staging and 0.627 (95% CI: 0.583-0.670) for JES N staging (P = 0.13). In addition, the OS was also well predicted by stage groupings of the 8th AJCC (P < 0.001) and the 11th JES systems (P < 0.001), with a c-index of 0.658 (95% CI: 0.616-0.699) for 8th AJCC stage grouping and 0.629 (95% CI: 0.589-0.668) for the11th JES stage grouping (P = 0.211). CONCLUSIONS: The prognostic effect of 11th JES staging system is comparable with that of AJCC 8th staging system for patients with ESCC. Therefore, both systems are applicable to clinical practice.

The Efficacy and Safety of Anlotinib Alone and in Combination with Other Drugs in Previously Treated Advanced Thymic Epithelia Tumors: A Retrospective Analysis.

BACKGROUND: Thymic epithelial tumors (TETs) are rare thoracic malignancies with no standard second-line treatment. Tumor angiogenesis is closely associated with the pathogenesis and invasiveness of TETs. Anlotinib is a small-molecule multitarget tyrosine kinase inhibitor (TKI) which inhibits tumor angiogenesis and tumor cell proliferation. Published studies have demonstrated the promising clinical effect of multitarget TKIs sunitinib and lenvatinib in previously treated TETs. However, TKIs have a high incidence of adverse events (AEs). OBJECTIVE: In this study, we investigated the clinical efficacy and safety of anlotinib in previously treated TET patients. METHODS: We collected clinical data of 22 patients from Shandong Cancer Hospital and Institute between October 2018 and March 2022. These patients were diagnosed with advanced TETs and received at least the first-line (1st-line) treatment. We analyzed the clinical effects between anlotinib monotherapy and anlotinib combination therapy in the second-line (2nd-line) or anlotinib treatment in different lines. RESULTS: These 22 patients included 18 cases of thymic carcinoma (TC) and 4 cases of thymoma (T). 68.2% of patients were males, and the median age was 53 years. Fourteen patients (63.6%) received anlotinib monotherapy and 8 patients (36.4%) received anlotinib combination therapy. The objective response rate (ORR) was 9.1% in the overall patients. The median progression-free survival (PFS) in the overall population was 12 months (14 months for T and 9 months for TC), and the median overall survival (OS) was 24 months (survival was not reached for T and was 24 months for TC). The incidence of AEs was 50%, most of them were grades I and II, and the incidence of grades III and IV AEs was 9%. CONCLUSION: This is the first study reporting the clinical effect of anlotinib in previously treated TETs patients. The survival data indicate that the efficacy of anlotinib is superior to sunitinib and lenvatinib. Our results suggest that anlotinib is a promising treatment option for previously treated TET patients and its toxicity is tolerable. More research and patents are needed in the future to explore better options for the diagnosis and treatment of TETs.

Efficacy and safety of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer: a prospective, single-arm, phase II study in China.

PURPOSE: Although immune checkpoint inhibitor monotherapy has been used as a second-line treatment in advanced non-small cell lung cancer (NSCLC), the improvement in progression-free survival (PFS) remains unsatisfactory. We investigated the feasibility of sintilimab plus chemotherapy as a second-line treatment in advanced NSCLC. METHODS: This was a phase II, single-arm, prospective study in advanced NSCLC patients who had failed standard platinum-based chemotherapy (ChiCTR1900027634, Registered 22 November 2019). Eligible patients received docetaxel 75 mg/m2 (day 1) plus sintilimab 200 mg (day 3) Q3W. Those did not progress after 4-6 cycles received sintilimab 200 mg Q3W as maintenance treatment. The primary endpoint was PFS. RESULTS: Forty patients were enrolled between October 2019 and October 2020. With a median follow-up of 12.2 months, the median PFS was 5.8 months, and the PFS rates at 6 and 12 months were 48% and 30%, respectively. The median overall survival (OS) was 12.6 months, with a 12-month OS rate of 62.0%. The overall response rate was 32.4%, and the disease control rate was 89.2%. The incidence of all and ≥ grade 3 treatment-related adverse events (TRAEs) were 65% (26/40) and 17.5% (7/40), respectively. No TRAEs-related permanent treatment discontinuation or death occurred. bTMB reduction at 6 weeks was associated with a longer PFS (NR vs 3.0 months, P < 0.0001). CONCLUSION: This prospective phase II study in China suggested that sintilimab plus docetaxel might improve PFS and tumor response with good tolerability for Chinese patients with previously treated advanced NSCLC. bTMB reduction at 6 weeks could serve as a potential predictive biomarker for this regimen.

Curcumin against gastrointestinal cancer: A review of the pharmacological mechanisms underlying its antitumor activity.

Gastrointestinal cancer (GIC) poses a serious threat to human health globally. Curcumin (CUR), a hydrophobic polyphenol extracted from the rhizome of Curcuma longa, has shown reliable anticancer function and low toxicity, thereby offering broad research prospects. Numerous studies have demonstrated the pharmacological mechanisms underlying the effectiveness of CUR against GIC, including the induction of apoptosis and autophagy, arrest of the cell cycle, inhibition of the epithelial-mesenchymal transition (EMT) processes, inhibition of cell invasion and migration, regulation of multiple signaling pathways, sensitization to chemotherapy and reversal of resistance to such treatments, and regulation of the tumor survival environment. It has been confirmed that CUR exerts its antitumor effects on GIC through these mechanisms in vitro and in vivo. Moreover, treatment with CUR is safe and tolerable. Newly discovered types of regulated cell death (RCD), such as pyroptosis, necroptosis, and ferroptosis, may provide a new direction for research on the efficacy of CUR against GIC. In this review, we discuss the recently found pharmacological mechanisms underlying the effects of CUR against GIC (gastric and colorectal cancers). The objective is to provide a reference for further research on treatments against GIC.

Short-term dynamics of circulating tumor DNA predicting efficacy of sintilimab plus docetaxel in second-line treatment of advanced NSCLC: biomarker analysis from a single-arm, phase 2 trial.

OBJECTIVE: Robust biomarker predicting efficacy of immunotherapy is limited. Circulating tumor DNA (ctDNA) sought to effectively monitor therapeutic response as well as disease progression. This study aims to investigate predictive role of ctDNA short-term dynamic change (6 weeks postimmunotherapy) in a single-arm, phase 2 trial of sintilimab plus docetaxel for previously treated advanced non-small cell lung cancer (NSCLC) patients. METHODS: A total of 33 patients with advanced NSCLC with disease progression during or after any first-line treatment were prospectively enrolled between 2019 and 2020. Patients received sintilimab (200 mg, day 1, every 3 weeks) plus docetaxel (75 mg/m2, day 3, every 3 weeks) for 4-6 cycles, followed by maintenance therapy with sintilimab (200 mg, day 1, every 3 weeks) until disease progression or unacceptable toxic effects. Blood samples were prospectively collected at baseline, and after 2 cycles of treatment (6 weeks post-treatment). All samples were subjected to targeted next-generation sequencing with a panel of 448 cancer-related genes. The landscape of high-frequency genomic profile of baseline and 6th week was described. Major molecular characteristics in preselected genes of interest associated with response to second-line chemoimmunotherapy were analyzed. The curative effects and prognosis of patients were evaluated. RESULTS: Patients with ctDNA clearance at 6th week had decreased tumor volume, while most patients with positive ctDNA at 6th-week experienced an increase in tumor volume. Positive 6th-week ctDNA was associated with significantly shorter progression-free survival (PFS) (91 vs NR days; p<0.0001) and overall survival (47 vs 467 days; p =0.0039). Clearance of clonal mutations and none new clonal formation at 6th week were associated with longer PFS (mPFS 89 vs 266 days, p =0.003). ctDNA clearance at 6th week was an independent risk factor for progression or death (HR=100 (95% CI 4.10 to 2503.00), p=0.005). CONCLUSION: ctDNA status and ctDNA mutation clearance putatively serve as predictive biomarkers for sintilimab combined with docetaxel chemotherapy in pretreated advanced NSCLC patients.

A novel One-pot rapid diagnostic technology for COVID-19.

Novel coronavirus disease (COVID-19) caused by SARS-CoV-2 is an ongoing global pandemic associated with high rates of morbidity and mortality. RT-qPCR has become the diagnostic standard for the testing of SARS-CoV-2 in most countries. COVID-19 diagnosis generally relies upon RT-qPCR-mediated identification of SARS-CoV-2 viral RNA, which is costly, labor-extensive, and requires specialized training and equipment. Herein, we established a novel one-tube rapid diagnostic approach based upon formamide and colorimetric RT-LAMP (One-Pot RT-LAMP) that can be used to diagnose COVID-19 without the extraction of specific viral RNA. The technique could visually detect SARS-CoV-2 within 45 min with a limit of detection of 5 copies per reaction in extracted RNA, and about 7.66 virus copies per µL in viral transport medium. The One-Pot RT-LAMP test showed a high specificity without cross-reactivity with 12 viruses including SARS-CoV, MERS-CoV, and human infectious influenza virus (H1N1/H3N2 of influenza A and B virus, ect. We validated this One-Pot RT-LAMP approach by its successful use for the analysis of 45 clinical nasopharyngeal swab samples, yielding results identical to those of traditional RT-qPCR analyses, while achieving good selectivity and sensitivity relative to a commercial RT-qPCR approach. As such, this One-Pot RT-LAMP technology may be a valid means of conducting high-sensitivity, low-cost and rapid SARS-CoV-2 identification without the extraction of viral RNA.

Next Generation Sequencing in the Management of Leptomeningeal Metastases of Non-Small Cell Lung Cancer: A Case Report and Literature Review.

BACKGROUND: Diagnosis of Leptomeningeal Metastases (LM) from Non-Small Cell Lung Cancer (NSCLC) is usually based on clinical symptoms, Cerebral-Spinal Fluid (CSF) cytology, and neuro-imaging. However, early diagnosis of LM in NSCLC is challenging due to the low sensitivity of these approaches. The Next-Generation Sequencing (NGS) using CSF could help improve the diagnosis of LM and guide its treatment options. CASE PRESENTATION: We report a 39-year-old male NSCLC patient with negative molecular testing results in the lung cancer tissue sample. The patient developed symptoms of LM with the negative CSF cytology and MRI; however, the NGS analysis of CSF revealed an EGFR exon 19 del mutation. The patient attained 6 months of Progression-Free Survival (PFS) by treating with erlotinib and anlotinib before the neurological symptoms appeared again. EGFR Thr790Met was positive in the CSF but negative in his plasma. The patient was then treated with osimertinib therapy and the response was maintained for more than 1 year. RESULTS & DISCUSSION: This case is the first study reporting the clinical benefit of using the combination of erlotinib and anlotinib for the treatment of LM with the EGFR 19 del, osimertinib with EGFR T790M mutation in CSF, but negative gene mutation in the blood or lung tumor biopsy specimens. Our results support that genetic analysis should be performed with CSF samples in all cases of suspected LM when the results of testing for EGFR/ALK/ROS1 mutation in blood samples or tumor biopsy specimens are negative, as these patients could benefit from treatment of TKIs in a poor prognostic setting. CONCLUSION: In parallel to current patents, NGS could be applied as a novel strategy in the managing of NSCLC patients with LM.

Development and Clinical Application of a Rapid and Sensitive Loop-Mediated Isothermal Amplification Test for SARS-CoV-2 Infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak urgently necessitates sensitive and convenient COVID-19 diagnostics for the containment and timely treatment of patients. We aimed to develop and validate a novel reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay to detect SARS-CoV-2. Patients with suspected COVID-19 and close contacts were recruited from two hospitals between 26 January and 8 April 2020. Respiratory samples were collected and tested using RT-LAMP, and the results were compared with those obtained by reverse transcription-quantitative PCR (RT-qPCR). Samples yielding inconsistent results between these two methods were subjected to next-generation sequencing for confirmation. RT-LAMP was also applied to an asymptomatic COVID-19 carrier and patients with other respiratory viral infections. Samples were collected from a cohort of 129 cases (329 nasopharyngeal swabs) and an independent cohort of 76 patients (152 nasopharyngeal swabs and sputum samples). The RT-LAMP assay was validated to be accurate (overall sensitivity and specificity of 88.89% and 99.00%, respectively) and diagnostically useful (positive and negative likelihood ratios of 88.89 and 0.11, respectively). RT-LAMP showed increased sensitivity (88.89% versus 81.48%) and high consistency (kappa, 0.92) compared to those of RT-qPCR for SARS-CoV-2 screening while requiring only constant-temperature heating and visual inspection. The time required for RT-LAMP was less than 1 h from sample preparation to the result. In addition, RT-LAMP was feasible for use with asymptomatic patients and did not cross-react with other respiratory pathogens. The developed RT-LAMP assay offers rapid, sensitive, and straightforward detection of SARS-CoV-2 infection and may aid the expansion of COVID-19 testing in the public domain and hospitals.IMPORTANCE We developed a visual and rapid reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay targeting the S gene for SARS-CoV-2 infection. The strength of our study was that we validated the RT-LAMP assay using 481 clinical respiratory samples from two prospective cohorts of suspected COVID-19 patients and on the serial samples from an asymptomatic carrier. The developed RT-LAMP approach showed an increased sensitivity (88.89%) and high consistency (kappa, 0.92) compared with those of reverse transcription-quantitative PCR (RT-qPCR) for SARS-CoV-2 screening while requiring only constant-temperature heating and visual inspection, facilitating SARS-CoV-2 screening in well-equipped labs as well as in the field. The time required for RT-LAMP was less than 1 h from sample preparation to the result (more than 2 h for RT-qPCR). This study showed that the RT-LAMP assay was a simple, rapid, and sensitive approach for SARS-CoV-2 infection and can facilitate COVID-19 diagnosis, especially in resource-poor settings.

Confined space self-propagating room temperature synthesis of carbon-encapsulated Fe3O4 nanocrystals and its lithium storage performance.

A self-propagating reaction between ferrocene and iron nitrate nonahydrate that is initiated at room temperature is discovered. Amorphous carbon-encapsulated Fe3O4 nanocrystals (Fe3O4@C) can be one-step prepared in an autoclave through this reaction. The equiaxed Fe3O4 nanocrystals have typical dimensions in the range of 5-60 nm with a median size of 24.1 nm, and their weight percent is up to 82.3%. The course of the reaction is recorded, and the formation mechanism of Fe3O4@C with the core-shell structure is proposed. The scaling-up synthesis is also achieved, and 52.1 g of the Fe3O4@C can be obtained in a single batch. The shock wave appeared in the fast gas release self-propagating reaction in confined space plays a decisive role in the preparation of homogeneous Fe3O4@C with a core-shell structure. The Fe3O4@C anode shows excellent capacity retention with a high specific capacity of 494 mAh g-1 at 1 A g-1 in the 200th cycle.

Involved-field irradiation in definitive chemoradiotherapy for locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Since there is high local failure and poor survival for unresectable esophageal squamous cell carcinoma (ESCC), the necessity of elective node irradiation is controversial. The purpose of this study was to investigate the failure patterns and survival in patients with locally advanced ESCC receiving involved-field irradiation (IFI). METHODS: A retrospective study was preformed on the clinical records of patients with locally advanced ESCC, who have received IFI with concurrent chemotherapy between January 2003 and January 2009. Comparing the target volume and first sites of failure, patterns of failure were defined as in-field, out-of-field regional lymph node and distant failure. The survivals were analyzed by different patterns of failure. RESULTS: Eighty patients were included in our study. With a median follow-up of 52.6 months, failures were observed in 76 patients. In-field recurrence, distant metastasis, and out-of-field regional failure were seen in 53.75%, 41.25%, 30% patients, respectively. There were significant differences in OS for patients with and without in-field (median OS 14.2 vs.17.4 m, P=0.01)or distant failure(13.2 vs.15.9 m, P ≤ 0.0001), but not for out-of-field regional lymph node failure(both 14.5 m, P=0.665). CONCLUSIONS: The solitary regional nodal failure of out-of-field was acceptable in advanced ESCC patients treated with IFI. In-field and distant failures remained the predominant patterns and negatively impacted survival more significantly. Further investigation is needed to establish the optimal radiotherapy field for these patients at advanced stage.

A phase I study of concurrent chemotherapy and thoracic radiotherapy with oral epigallocatechin-3-gallate protection in patients with locally advanced stage III non-small-cell lung cancer.

BACKGROUND AND PURPOSE: Patients with unresectable stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy often develop esophagitis that may lead to unplanned treatment interruptions, which may severely reduce rates of locoregional tumor control and survival. No effectivetreatment that would reduce the incidence and severity of this complication has been identified up to now. Although acceleration of normal tissue protection using epigallocatechin-3-gallate (EGCG) has been reported, its actual clinical practicability remains obscure. METHODS AND MATERIALS: This is a phase I study of EGCG in combination with standard chemoradiation in surgically unresectable stage III non-small-cell lung cancer. Chemotherapy (cisplatin and etoposide) was given concurrently with radiation. EGCG solution was swallowed three times a day after the occurrence of grade 2 esophagitis at six concentration levels and dose escalation followed a standard phase I design. Esophageal toxicity and patient-reported pain was recorded weekly. RESULTS: Twenty-four patients with AJCC stage IIIA (six) and IIIB (eighteen) completed the course of therapy. Twelve had squamous histology, ten adenocarcinoma, and two not specified. Patients were treated in six cohorts at six dose levels of EGCG. RT was not interrupted with a median dose of 64 Gy. There were no dose-limiting toxicities reported in all EGCG dosing tiers. Dramatic regression of esophagitis to grade 0/1 was observed in 22 of 24 patients, whereas grade 2 esophagitis persisted in 2 of 24 patients at the end of radiotherapy. The pain score was also reduced from a mean of 4.58 (N=24), 1.29 (N=24), 1.42 (N=24), 0.96 (N=23) to 1.13 (N=16) every week in turn. CONCLUSION: We conclude that the oral administration of EGCG is feasible, safe and effective. The phase II recommended concentration is 440 µmol/L.

[Investigation of SLC26A4 mutations associated with inner ear malformations].

OBJECTIVE: To study the molecular pathogenesis of SLC26A4 mutations associated with inner ear malformations including large vestibular aqueduct syndrome (LVAS), Mondini dysplasia and inner ear malformations but not accompanied with LVAS. METHOD: DNA sample and clinical material were obtained from 14 sporadic LVAS probands, six Mondini dysplasia probands and seven inner ear malformations excluding IVAS probands. SLC26A4 gene mutation was analyzed by direct sequencing for its 20 coding exons. GJB2 gene and also mt12SrRNA were analyzed by direct sequencing. RESULT: In 14 cases of LVAS, two mutations were detected in 12 patients (85.7%, either homozygous or compound heterozygous mutations), and one mutation was found in two patients (14.3%). In six cases of Mondini dysplasia, two mutations were detected in all of patients (100%). No mutation could be found in the seven cases of other inner ear abnormalities not accompanied with LVAS. No pathogenic mutation was detected in all of these 27 probands in GJB2 gene and mt12SrRNA 1555/1494T. CONCLUSION: We have shown that LVAS and Mondini dysplasia closely correlate with SLC26A4 gene. No mutation was detected in seven probands of inner ear malformations not accompanied with LVAS. We should study the molecular pathogenesis of this disease in depth.

Linear correlation between patient survival and decreased percentage of tumor [(18)F]fluorodeoxyglucose uptake for late-course accelerated hyperfractionated radiotherapy for esophageal cancer.

PURPOSE: The aims of this trial were to study whether a decreased percentage of tumor fluorodeoxyglucose (FDG) uptake (%DeltaSUVmax) correlated with overall survival and local control times for patients with esophageal cancer and which patients would benefit from a late-course accelerated hyperfractionated (LCHF) radiation scheme. METHODS AND MATERIALS: A total of 50 eligible patients with squamous esophageal cancer received positron-emission tomography examinations three times and were treated with the LCHF radiation scheme, with a dose of 68.4 Gy/41 fractions in 6.5 weeks. A %DeltaSUVmax value was calculated, and patients were stratified as highly radiosensitive (HR), moderately radiosensitive (MR), and low radiosensitivity (LR) according to %DeltaSUVmax values in the conventional fraction (CF) scheme. Then, a linear correlation was calculated between patients' survival time and %DeltaSUVmax. Local control and overall survival rates were compared after stratification. RESULTS: In the MR subgroup, there was no linear correlation between %DeltaSUVmax and the CF and LCHF schemes (correlation coefficient, R < 0.4; p > 0.05). In the other subgroups (HR and LR), %DeltaSUVmax values between the CF and LCHF schemes were correlated. Also, in the HR and LR subgroups, %DeltaSUVmax after radiation correlated with overall survival or local control rates (correlation coefficient, R ＞0.5, and p < 0.05). Three-year local control rates in the HR, MR, and LR subgroups were 100%, 81.5%, and 0%, respectively (p < 0.001). Also, 3-year overall survival rates were 92.4%, 58.8%, and 0% for HR, MR, and LR subgroups, respectively (p < 0.001). CONCLUSIONS: Postradiation %DeltaSUVmax was positively correlated with survival time for patients' with esophageal cancer. Patients who benefited from LCHF schedules were those with a decrease of 30% to 60% in tumor FDG uptake after the completion of CF radiation.

Feasibility of involved-field conformal radiotherapy for cervical and upper-thoracic esophageal cancer.

BACKGROUND: The aim of this study was to investigate the feasibility of involved-field irradiation (IFI) for the treatment of cervical and upper-thoracic esophageal cancer with concurrent chemoradiation. PATIENTS AND METHODS: 102 eligible patients with cervical or upper-thoracic esophageal cancer were treated with concurrent chemoradiation and randomized to either an IFI or elective nodal irradiation (ENI) group. RESULTS: Adverse events included infection (27.4 vs. 64.7%) and nausea (25.4 vs. 54.9%), with a statistically significant difference between the IFI and the ENI group (p = 0.008 and 0.028, respectively). No difference was seen for late radiation reaction. The cumulative incidence of local/regional failure (13.7 vs. 17.6%) and regional lymph failure (7.8 vs. 9.8%) showed no statistically significant difference between the IFI versus the ENI group (p = 0.837 and 0.837, respectively). A nodal out-field relapse rate of only 2% was seen in the IFI group. 3-year survival rates for the ENI and IFI group were 41.3 and 32.0%, respectively (p = 0.58), and 3-year local control rates were 85.7 and 80.1%, respectively (p = 0.34). CONCLUSION: IFI was acceptable for cervical and upper-thoracic esophageal cancer with a decrease in acute toxicities and no increase in lymph node failure.

[Low dose-intensity docetaxel monotherapy for patients with anthracycline-resistant metastatic breast cancer in poor physical status].

OBJECTIVE: To evaluate the efficacy and safety of a weekly schedule of low dose-intensity docetaxel monochemotherapy for patients with anthracycline-resistant metastatic breast cancer (MBC) in poor physical status. METHODS: Thirty MBC patients who were previously exposed to anthracycline treatment received docetaxel alone at a dose of 30 mg/m2 on D1, D8 and D15, repeated every 4 weeks for a maximum of 6 cycles. RESULTS: Of the 30 evaluable patients, 2 (6.7%) achieved a complete response, and 9 (30.0%) a partial response, with an overall objective response rate of 36.7% (95% CI: 20.5%-53.9%). The most common adverse event was hematologic toxicity. After an average follow-up of 15.0 months, the median time to progression (TTP) was 8. 5 months and the median overall survival (OS) had not reached yet at the end of follow-up. CONCLUSION: The weekly low dose-intensity docetaxel monochemotherapy is effective and well-tolerated in patients with anthracycline-resistant metastatic breast cancer in poor physical status.

[Enhancing effect of antisense oligonucleotide targeting bFGF on apoptosis in hepatoma cells in vitro].

OBJECTIVE: To investigate the cell cycle changes of hepatoma cells and the effect of antisense oligonucleotide targeting bFGF on apoptosis in the hepatoma cells. METHODS: The oligodeoxynucleotides were transfected with Lipofectin into hepatoma HepG2 cells. Inhibition of bFGF protein expression was assessed by confocal laser scanning microscopy and Western blot under the best condition of transfection of antisense oligonucleotide targeting bFGF, and the apoptosis in those cells was determined by flow cytometry. HepG2 cells were cultured in 24-well culture dish. The cultured cells were divided into 3 groups: group 1, the normal control group without any treatment; group 2, transfected with antisense oligonucleotide targeting bFGF; group 3, transfected with scrambled sequence targeting bFGF. RESULTS: The results from confocal microscopy and Western blot showed an inhibition of expression of bFGF at different levels under the best condition of transfection with antisense oligonucleotide targeting bFGF. The treatment with antisense oligonucleotide of bFGF not only reduced the expression of bFGF revealed by confocal microscopy and Western blotting, but also increased the apoptosis in HepG 2 cells (P < 0. 01). CONCLUSION: Treatment with antisense oligonucleotide of bFGF inhibits expression of bFGF protein and increase apoptosis. bFGF may take part in apoptosis regulation of hepatoma cells and may be used as a target in the treatment of hepatocellular carcinoma.

Biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX-4 regimen) as first-line chemotherapy for elderly patients with advanced gastric cancer.

OBJECTIVE: The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin (OXA) in combination with continuous infusional 5-fluorouracil (5-FU) and leucovorin (LV) administered every 2 weeks (modified FOLFOX-4 regimen) in elderly patients with advanced gastric cancer (AGC). PATIENTS AND METHODS: A total of 44 previously untreated AGC patients aged 65 or older were treated with OXA 85 mg m-2 on day 1, LV 200 mg m-2 as a 2-hour infusion followed by a 22-hour infusion of 5-FU 1000 mg m using a multichannel programmable pump, repeated for 2 consecutive days every 2 weeks. RESULTS: All patients were assessable for toxicity and 40 patients for response. Median age was 69 years (65-83). The response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 52.5% (95% confidence interval: 44.6%-68.0%) with 3 complete responses, 18 partial responses, 11 stable diseases, and 8 progressions. Median time to progression was 6.5 months and median overall survival was 10.0 months. Toxicity was generally mild. Grade 3 hematologic toxicities of neutropenia, anemia, and thrombocytopenia were in 6.8%, 2.3%, and 4.5% of the patients, respectively. No grade 4 hematologic toxicities occurred. Grade 1 peripheral neuropathy was a common event (34.1%), whereas grade 3 peripheral neuropathy was recorded in only 1 (2.3%) patient. An acute hypersensitivity reaction was observed in 1 patient during administration. CONCLUSION: The modified FOLFOX-4 regimen is an active and well-tolerated chemotherapy for elderly patients aged > or =65 years with AGC. OXA may occasionally cause mild hypersensitivity.

[Antisense oligonucleotide targeting endostatin enhances hematopoiesis reconstitution in BMT mice].

OBJECTIVE: To explore the effect of antisense oligonucleotide targeting endostatin (endostatin-ASON) transfecting bone marrow stromal cells ( BMSC) on hematopoiesis reconstitution in BMT mice. METHODS: Inhibition of endostatin / VCAM-1 protein and mRNA expression was investigated by transfection of antisense oligonucleotide targeting endostatin with confocal microscopy, Western blot and RT-PCR. Bone marrow stromal cells were cultured and divided into 4 groups: group (1) without any treatment; group (2) BMT only; group (3) BMT + endostatin-ASON transfection; group (4) BMT + endostatin scrambled sequence transfection. RESULTS: (1) Endostatin-ASON was successfully introduced into BMSC in vitro, and the transfecting rate was 86% ;(2) After Endostatin-ASON transfected into BMSC, the expression of Endostatin mRNA and its protein on the BMSC was signficantly inhibited at different time point after BMT [the grey value of Endostatin was (0.09 +/- 0.03) - (1.44 +/- 1.19) and (0.02 + 0.02) - (0.14 +/- 0.05), respectively] (P < 0.01 and P < 0.05); (3) Transfecting with Endostatin-ASON effectively promoted the expression of VCAM-1 mRNA and its protein on the BMSC [the gray value of VCAM-1 was (1.60 +/- 0. 92) - (8.05 +/- 0.87) and (0.07 +/- 0.02) - (0.67 +/- 0.09) , respectively] (P <0.01 and P <0.05) ; (4) There was no effects of transfecting Endostatin scrambled sequence on the expression of Endostatin and VCAM-1 on the BMSC (P > 0.05). CONCLUSION: Endostatin-ASON could inhibit Endostatin expression and enhance VCAM-1 expression in BMSC after syngeneic-BMT in mice, which might be one of the mechanisms underlying the endostatin-ASON accelerating hematopoiesis reconstitution after allogeneic-BMT.