Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma.

Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

Quality evaluation of Hawk tea from different months and regions based on quantitative analysis of multiple components with a single marker (QAMS) combined with HPLC fingerprint.

BACKGROUND: Hawk tea, a medicinal and edible plant, has been consumed for thousands of years in Southwest China. To date, no unified food safety standard for Hawk tea has been established, and systematic research on the quality of Hawk tea is lacking. OBJECTIVE: The aim of this study was to develop a comprehensive evaluation method for the quality of Hawk tea based on inclusions content, high-performance liquid chromatography (HPLC) fingerprinting combined with the quantitative analysis of multiple components with a single marker (QAMS) method. METHODS: The contents of total flavonoids, total phenols, total polysaccharides, and total protein were determined using the colorimetric method. An effective comprehensive evaluation method was established to classify the 16 batches of samples based on HPLC fingerprint analysis combined with similarity analysis (SA), hierarchical cluster analysis (HCA), principal component analysis (PCA), partial least-squares discrimination analysis (PLS-DA), and the QAMS method. RESULTS: Flavonoids were the main chemical components of Hawk tea. The accuracy of the QAMS method was verified by comparing the calculated results with those of the external standard method (ESM). No significant differences were found between the two methods. Additionally, the fingerprint of Hawk tea was also established. CONCLUSION: The method established in this study can be used for the comprehensive quality evaluation of Hawk tea and can also provide a reference for the quality evaluation of other herbal medicines.

Identification of patients with locally advanced rectal cancer eligible for neoadjuvant chemotherapy alone: Results of a retrospective study.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (nCT) appears in a few clinical studies as an alternative to neoadjuvant chemoradiation (nCRT) in selected patients with locally advanced rectal cancer (LARC). We aimed to compare the clinical outcomes of nCT with or without nCRT in patients with LARC and to identify patients who may be suitable for nCT alone. MATERIALS AND METHODS: A total of 155 patients with LARC who received neoadjuvant treatment (NT) were retrospectively analysed from January 2016 to June 2021. The patients were divided into two groups: nCRT (n = 101) and nCT (n = 54). More patients with locally advanced disease (cT4, cN+ and magnetic resonance imaging-detected mesorectal fascia [mrMRF] positive [+]) were found in the nCRT group. Patients in the nCRT group received a dose of 50 Gy/25 Fx irradiation with concurrent capecitabine, and the median number of nCT cycles was two. In the nCT group, the median number of cycles was four. RESULTS: The median follow-up duration was 30 months. The pathologic complete response (pCR) rate in the nCRT group was significantly higher than that in the nCT group (17.5% vs. 5.6%, p = 0.047). A significant difference was observed in the locoregional recurrence rate (LRR); 6.9% in the nCRT group and 16.7% in the nCT group (p = 0.011). Among patients with initial mrMRF (+) status, the LRR in the nCRT group was significantly lower than that in the nCT group (6.1% vs. 20%, p = 0.007), but not in patients with initial mrMRF negative (-) (10.5% in each group, p = 0.647). Compared with the nCT group, a lower LRR was observed in patients in the nCRT group with initial mrMRF (+) converted to mrMRF (-) after NT (5.3% vs. 23%, p = 0.009). No significant difference was observed between the two groups regarding acute toxicity and overall and progression-free survivals. Multivariate analysis showed that nCRT and ypN stage were independent prognostic factors for the development of LRR. CONCLUSION: Patients with initial mrMRF (-) may be suitable for nCT alone. However, patients with initial mrMRF (+) converted to mrMRF (-) after nCT are still at high risk of LRR, and radiotherapy is recommended. Prospective studies are required to confirm these findings.

Evaluation of systemic inflammatory and nutritional indexes in locally advanced gastric cancer treated with adjuvant chemoradiotherapy after D2 dissection.

Background: Many studies have shown that the peripheral blood inflammatory index and nutritional index, such as the platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), lymphocyte monocyte ratio (LMR), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI), are independent prognostic factors for tumors. The present study aimed to investigate the prognostic role of these peripheral blood indexes before treatment in locally advanced gastric cancer (LAGC) treated with adjuvant chemoradiotherapy after D2 dissection. Methods: A total of 89 patients with LAGC who underwent D2 gastrectomy and adjuvant chemoradiotherapy at our hospital from 2010-2018 were eligible. Systemic inflammatory indicators before treatment were evaluated. Receiver operating characteristic curve (ROC), Kaplan-Meier analysis, and Cox regression were utilized for prognosis evaluation. Results: The median follow-up time was 29.1 (4.1-115.8) months. The overall survival at 3 years (OS) and the disease-free survival (DFS) were 78.9% and 59.1%, respectively. According to the ROC curve for 3-year DFS, the best cut-off values of pre-treatment NLR, PLR, LMR, SII, SIRI, PIV and PNI were 1.7, 109.3, 2.9, 369.2, 0.58, 218.7, and 48, respectively. Multivariate Cox regression analysis showed that NLR was an independent prognostic factor for DFS (HR 2.991, 95%CI 1.085-8.248, P = 0.034). Kaplan-Meier analysis showed that a higher NLR (>1.70) was significantly associated with a poorer OS (3-year OS: 68.8% vs 92.9%, P = 0.045) and DFS (3-year DFS: 47.5% vs 80.9%, P = 0.005). In terms of the free locoregional recurrence rate (LRR), the prognosis of patients with high NLR was also significantly worse than those with low NLR (70.2% vs 96.0%, P = 0.017). Paraaortic lymph nodes were the most common site of LRR (7/14 patients). The seven cases of paraaortic lymph node metastasis occurred in patients with high NLR. Conclusions: In our retrospective analysis, we found that pretreatment NLR could serve as a prognostic factor for survival in LAGC treated with adjuvant chemoradiotherapy after D2 dissection, especially for the prediction of LRR and paraaortic lymph node metastasis. Prospective studies are needed to confirm our findings.

Bioactive phenolic components and antioxidant activities of water-based extracts and flavonoid-rich fractions from Salvadora persica L. leaves.

Salvadora persica L. (Sp) has been widely used as folk medicine. This study aimed to identify and assess the significant phenolics' antioxidant activities in young (S1) and old (S2) leaves of Sp. Six flavonoids; isoquercitrin, kaempferol-3-neohesperidoside, myricetin-3-galactoside, apigenin-O-hexoside, isorhamnetin and isorhamnetin-3-neohesperidoside, were identified for the first time in Sp leaves using LC-ESI-QTOF MS/MS analysis. The flavonoid-rich fraction obtained after purification of S1 (S1TF7) has the highest TFC (358.88 ± 0.12 mg rutin equivalent/g) and TPC (180.82 ± 0.82 mg gallic acid equivalent/g) and exhibits significant (p < 0.05) free-radical scavenging activity in DPPH(IC50% = 14.64 ± 0.29 µg/mL) and ABTS (IC50% = 200.41 ± 1.85 µg/mL) assays which was similar to Butylated hydroxytoluene (BHT) as a positive control (IC50% =12.94 ± 0.10 µg/mL and IC50% = 190.47 ± 8.93 µg/mL, respectively). Also, S1TF7 inhibits Lipopolysaccharide (LPS)-stimulated ROS production in raw-cell-264.7 with no significant toxicity at 200 µg/mL (p > 0.05). The study concludes that S1TF7 can serve as a mean to prevent oxidative diseases, and it merits further pharmacological investigations.

Identification of Patients With Locally Advanced Gastric Cancer Who May Benefit From Adjuvant Chemoradiotherapy After D2 dissection: A Propensity Score Matching Analysis.

BACKGROUND: One of the most controversial areas in gastrointestinal oncology is the benefit of postoperative chemoradiotherapy (CRT) over chemotherapy (CT) alone after D2 dissection of locally advanced gastric cancer (LAGC). We aimed to identify the LAGC patients who may benefit from adjuvant CRT. METHODS: We analyzed retrospectively 188 patients receiving radical gastrectomy with D2 dissection for LAGC in our hospital. Patients were divided into two balanced groups by using propensity score matching: CRT group (n = 94) received adjuvant CRT, and CT group received adjuvant CT alone. RESULTS: At a median follow-up of 27.10 months, 188 patients developed 79 first recurrence events (36 in CRT group and 43 in CT group). Our results showed that adjuvant CRT significantly decreased the risk of developing local regional recurrence (LRR) when compared to CT alone (14.9% vs. 25.5%, p = 0.044), while the estimated 3-year disease-free survival (DFS) was comparable between the CRT and CT groups (59.3% vs. 50.9%, p = 0.239). In the subgroup analysis, a significantly decreased LRR rate was also observed in LAGC patients with N1-3a stage after adjuvant CRT (p = 0.046), but not for N3b. Para-aortic lymph nodes (station No. 16) were the most frequent sites of LRR. After receiving radiotherapy, recurrence of 16 a2 region and 16 b1 region were significantly deceased (p = 0.026 and p = 0.044, respectively). Patients who received irradiation more than 4 months after surgery showed an increased risk of LRR (p = 0.022). CONCLUSIONS: This study showed that adjuvant CRT significantly reduced LRR after D2 dissection of LAGC. Early initiation of adjuvant RT with clinical target volume encompassing a2 and b1 regions of para-aortic lymph nodes is recommended for pN1-3a patients after D2 dissection.

Competing risk nomogram predicting initial loco-regional recurrence in gastric cancer patients after D2 gastrectomy.

BACKGROUND: Lacking quantitative evaluations of clinicopathological features and the risk factors for loco-regional recurrence (LRR) in gastric cancer after D2 gastrectomy, we aimed to develop a competing risk nomogram to identify the risk predictors for initial LRR. METHODS: We retrospectively analysed 1105 patients who underwent radical gastrectomy with D2 resection for stage I-III gastric cancer. A nomogram predicting initial LRR of gastric cancer was conducted based on Fine and Grey's competing risk analysis. The predictive accuracy and discriminative ability of the model were determined using the concordance index (C-index) and calibration curve. Decision tree analysis was performed for patient grouping. RESULTS: At a median follow-up of 28.4 months, 274 patients developed 373 first recurrence events (local, regional, and distant disease). The median recurrence-free survival (RFS) was 16.7 months. Multivariate competing risk analysis showed that age (SHR, 1.72; 95% CI, 1.10-2.83, p = 0.031), CEA (SHR, 1.94; 95% CI, 1.09-3.46, p = 0.024), pT4 (SHR, 2.77; 95% CI, 1.01-7.57, p = 0.047), lymph node metastasis (SHR 1.92, 95% CI: 1.09-3.38, p = 0.024) and LVI (SHR, 1.84; 95% CI, 1.06-3.20, p = 0.028) were independent risk factors for LRR (all p < 0.05). The nomogram incorporating these factors achieved good agreement between prediction and actual observation with a concordance index of 0.738 (95% CI, 0.767 to 0.709). In a subgroup analysis of node-positive patients, pN3b was associated with increased peritoneal and distant metastasis (p = 0.048). The para-aortic lymph nodes were the most frequent sites (n = 71) of LRR, and among them, the 16a2 and 16b1 nodes exhibited even more prevalence (90.1 and 81.7%). CONCLUSIONS: Adjuvant radiotherapy might be recommended in gastric cancer patients ≥65 years old or those with pN+, pT4, LVI, or increased CEA levels, particularly in high-risk or pN1-3a patients. The competing risk nomograms may be considered as convenient and individualized predictive tools for LRR in gastric cancer after D2 gastrectomy. It is also recommended that the clinical target volume (CTV) include 16a2 and 16b1 regions of para-aortic lymph nodes.

Accuracy of multi-echo Dixon sequence in quantification of hepatic steatosis in Chinese children and adolescents.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is currently the outstanding cause of chronic liver disease in children and adolescents, especially in overweight and obese groups. Liver biopsy is the reference standard to diagnose NAFLD but invasive, thus it is not the best choice in clinical diagnosis and follow-up. Magnetic resonance (MR) is widely used in clinical trials to noninvasively quantify liver fat content in adults and children in foreign countries. While currently, it is rarely used in Chinese children and adolescents. We postulated that quantifying hepatic steatosis by MR could be extended to children and adolescents in China. AIM: To investigate the accuracy of MR imaging (MRI) in quantifying liver fat with MR spectroscopy (MRS) as a reference. A secondary goal was to assess the prevalence of NAFLD in overweight and obese Chinese children and adolescents. METHODS: There were 86 children and adolescents enrolled in this study, including 65 overweight and obese children and 21 healthy children. The participants underwent MRI and MRS. MRI and MRS were performed using multi-echo Dixon and HISTO sequences, respectively, to calculate hepatic proton density fat fraction (PDFF). Hepatic steatosis was diagnosed using MRS-PDFF > 5% as the threshold. Spearman's analysis was used to evaluate the correlation between MRI and MRS. The agreement between these two methods was assessed by Bland-Altman analysis. RESULTS: The MRI-PDFF in the MRS region of interest and the entire liver was 9.9% ± 10.3% with a range of 0.3%-39.9%, and 10.6% ± 9.4% with a range of 1.9%-38.9%, respectively. The MRS-PDFF was 9.1% ± 10.0%, with a range of 0.5%-37.8%. The incidence of hepatic steatosis detected by MRS-PDFF was 46.5% (40/86) of all participants, all of whom belonged to the overweight and obese group. Spearman's analysis indicated an excellent correlation between multi-echo Dixon and MRS (r > 0.9, P < 0.01). Bland-Altman analysis also demonstrated a good agreement between these two methods. CONCLUSION: Multi-echo Dixon shows an excellent correlation and agreement with MRS in quantifying liver fat content and could be a potential tool to detect hepatic steatosis in Chinese children and adolescents.

Active Components, Antioxidant, Inhibition on Metabolic Syndrome Related Enzymes, and Monthly Variations in Mature Leaf Hawk Tea.

Hawk tea is a rich and edible resource, traditionally used as a beverage in South China. This drink has many pharmacologic effects, such as acting as an antioxidant and reducing blood sugar and lipids. The objective of this work was to explore the active compound contents, bioactivities and their monthly changes, and optimize the harvest time. In the present study, Hawk tea from each month in 2017 was collected and extracted with 70% (v/v) ethanol. The contents of the total flavonoids and total phenols were determined using the colorimetric method. We determined the contents of seven characteristic active substances-hyperin, isoquercitrin, trifolin, quercitrin, astragalin, quercetin, and kaempferol-using high-performance liquid chromatography. The crude extract was tested for its antioxidant and inhibitory properties on enzymes involved in metabolic syndrome. Specifically, 2,2-diphenyl-1-picrylhydrazyl, 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid), ferric-reducing power assay, and the inhibition capacity test on α-glucosidase and lipase were conducted to determine the antioxidant effect in vitro, as well as the reduction of blood sugar and lipids. Monthly variations in activities and components were determined by numeric analysis and comparison. Correlation analysis revealed that antioxidant effects are significantly correlated with the total flavonoids. The hierarchical cluster analysis of bioactivities and their contents indicates that October and November are the best harvesting months, which differs with the habitual collection of Hawk tea.

Efficacy of salvage radiotherapy for relapsed/refractory diffuse large B-cell lymphoma.

BACKGROUND: Radiotherapy (RT) is a modality of salvage therapy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but its efficacy is currently not well defined. This paper reports a retrospective review of patients who received salvage RT for R/R DLBCL in our hospital. METHODS: We selected 32 patients who had relapsed and had progressive disease after chemotherapy or partial remission (PR) after chemotherapy. The patients had a median age of 47 years (range, 13-85 years) and were treated between January 1, 2009, and June 30, 2016. The histological type was DLBCL in all cases. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method; predictors for adverse factors were evaluated using a Cox proportional hazards regression model. RESULTS: Median age-adjusted International Prognostic Index (IPI) score was 3 (range, 0-4), and 20 (62.5%) patients had large tumors. Patients were irradiated with a median dose of 42.7 Gy (range, 30-54 Gy): 4 (12.5%) by conventional RT, 2 (6.3%) by conformal 3D technique and 26 (81.3%) by intensity-modulated RT (IMRT). Most toxicities were mild (CTCAE grade 1 or 2), including neutropenia, diarrhea, dermatitis, mucositis and dysphagia. With a median follow-up of 25.4 months (range, 0.4-98.9 months) after irradiation, the 5-year PFS and OS were 61.8% and 83.2%, respectively. In multivariate analysis, adverse factors associated with PFS in our cohort were multiple lesions. CONCLUSIONS: Due to its low toxicity and ease of use, RT should remain a salvage therapy option for patients with R/R DLBCL.

Chemical Components, Biological Activities, and Toxicological Evaluation of the Fruit (Aril) of Two Precious Plant Species from Genus Taxus.

The fruit (aril) of the endangered genus Taxus plants is an abandoned herbal resource. Traditionally, people enthusiastically focus on its bark, its renewable, tremendous arils fall into the soil with seeds after they are mature. The present research investigated the fruit of two species from the genus Taxus, Taxus chinensis var. mairei, and Taxus media, with regards to their antioxidant and antihyperglycaemic activities, safety, and bioactive constituents. Results showed that T. chinensis var. mairei and T. media both had certain biological activities with T. chinensis var. mairei better in antioxidant activity and T. media better in antihyperglycaemic activity. Correlation analysis revealed that the differences in bioactivities depended on content of their mainly chemical components. The mice acute oral toxicity test indicated that the methanol extracts of the two biotypes of Taxus were safe. And nineteen compounds were tentatively assigned from the two varieties, via tandem mass spectrometry using a LC-ESI-Q-TOF-MS instrument, which included phenols, flavonoids, and terpenes. These results indicate a possible application of Taxus fruit extracts in various fields like in food industry, however, this still needs further investigations.

Sulfolobus acidocaldarius UDG Can Remove dU from the RNA Backbone: Insight into the Specific Recognition of Uracil Linked with Deoxyribose.

Sulfolobus acidocaldarius encodes family 4 and 5 uracil-DNA glycosylase (UDG). Two recombinant S. acidocaldarius UDGs (SacUDG) were prepared and biochemically characterized using oligonucleotides carrying a deaminated base. Both SacUDGs can remove deoxyuracil (dU) base from both double-stranded DNA and single-stranded DNA. Interestingly, they can remove U linked with deoxyribose from single-stranded RNA backbone, suggesting that the riboses on the backbone have less effect on the recognition of dU and hydrolysis of the C-N glycosidic bond. However, the removal of rU from DNA backbone is inefficient, suggesting strong steric hindrance comes from the 2' hydroxyl of ribose linked to uracil. Both SacUDGs cannot remove 2,2'-anhydro uridine, hypoxanthine, and 7-deazaxanthine from single-stranded DNA and single-stranded DNA. Compared with the family 2 MUG, other family UDGs have an extra N-terminal structure consisting of about 50 residues. Removal of the 46 N-terminal residues of family 5 SacUDG resulted in only a 40% decrease in activity, indicating that the [4Fe-4S] cluster and truncated secondary structure are not the key elements in hydrolyzing the glycosidic bond. Combining our biochemical and structural results with those of other groups, we discussed the UDGs' catalytic mechanism and the possible repair reactions of deaminated bases in prokaryotes.

Analysis of aflatoxins in traditional Chinese medicines: Classification of analytical method on the basis of matrix variations.

A classification system for analytical methods was developed for the first time to determine the presence of aflatoxins B1, B2, G1 and G2 in traditional Chinese medicines (TCMs) based on different matrix types using ultra-performance liquid chromatography-tandem mass spectrometry. A useful characteristic of the approach was that the TCMs could be systematically divided into four categories (i.e., volatile oils, proteins, polysaccharides and fatty oils) depending on the matrix types. The approach concluded that different types of TCMs required different optimal sample preparation procedures. Based on the optimized analytical conditions, the limits of detection and quantification, average recoveries and linearity of four aflatoxins were determined and conformed to research limits. Of 22 TCMs samples, 14 samples were contaminated with at least one type aflatoxin at concentrations ranging from 0.2 to 7.5 µg/kg, and the average contents of aflatoxins were significantly different for the different matrix types. Moreover, we found a potential link between the contamination levels of aflatoxins and matrix types. TCMs containing fatty oils were the most susceptible to contamination by aflatoxins and followed by TCMs containing polysaccharides and proteins; TCMs containing abundant amounts of volatile oils were less prone to contamination.

Comparative Evaluation of the Chemical Composition, Antioxidant and Antimicrobial Activities of the Volatile Oils of Hawk Tea from Six Botanical Origins.

In this study, volatile oils of six Hawk tea varieties were studied for their chemical composition, antioxidant and antimicrobial activities to screen the most suitable botanical origins of Hawk tea. A total of 72 components were separated and identified from the six oils. The major constituents of the volatile oils were: α-pinene, camphene, limonene, 1,8-cineole, linalool, cis-nerolidol, and germacrene B. Moreover, the volatile oils were evaluated for antioxidant potential and antimicrobial activities. The results showed that all volatile oils exhibited acceptable antioxidant and antimicrobial activities, which suggested that these volatile oils may serve as natural alternatives to synthetic antioxidants and preservatives to be applied in food and pharmaceutical industries. Principal component analysis results denoted that some major compounds may be closely related to the antioxidant and antimicrobial activities. It also showed that the volatile oils from Litsea coreana var. lanuginosa and Litsea pungens Hemsl. were characterized by positive values of first two principal components, indicating higher active chemical compounds and antioxidant and antimicrobial activities compared with other species. Thus, they were temporarily considered as good sources of Hawk tea.

Antioxidant activity and optimization of extraction of polysaccharide from the roots of Dipsacus asperoides.

Polysaccharide extraction from Dipsacus asperoides roots (DAP) was proved to possess strong antioxidant activities, including 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-Azobis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical scavenging activities, inhibiting ß-carotene bleaching and strong reducing power. Cell assay demonstrated that the crude DAP possessed antioxidant activity and were effective against H2O2-induced L02 cells injury. Then, response surface methodology (RSM) was applied to optimize the ultrasonic extraction of DAP. The optimum variables given by central composite design (CCD) were as follows: ratio of water to raw material, 38.61mL/g; ultrasonic power, 308.68W; extraction time, 38.61min; and extraction temperature, 89°C. Under these conditions, the maximum yield of DAP obtained was 7.12±0.45%. Moreover, high performance liquid chromatography (HPLC) analysis suggested that the monosaccharide compositions of DAP contained primarily mannose, ribose, glucose, galactose, xylose and arabinose, with a molar ratio of 0.22:0.48:2.29:0.34:1.39:1.41. The results of the present study showed that DAP could be considered as potential sources of natural antioxidants.

Combination chemotherapy with paclitaxel, cisplatin and fluorouracil for patients with advanced and metastatic gastric or esophagogastric junction adenocarcinoma: a multicenter prospective study.

OBJECTIVE: To evaluate the efficacy and toxicity of the combination regimen of paclitaxel, cisplatin and 5-FU (PCF) as first-line or second-line therapy in patients with advanced gastric and esophagogastric junction (EGJ) adenocarcinoma in China. METHODS: The patients were treated with paclitaxel 150 mg/m(2) on d1; fractionated cisplatin 15 mg/m(2) and continuous infusion 5-FU 600 mg/(m(2)·d) intravenously on d1-d5 of a 21-d cycle until disease progression or unacceptable toxicities. RESULTS: Seventy-five patients have been enrolled, among which, 41 received PCF regimen as the first-line therapy (group A) and 34 received the regimen as the second-line therapy (group B) with the median age of 59 years old and Karnofsky performance status (KPS) score ≥80. Toxicities were analyzed in all 75 patients. Seventy-one patients were evaluable for efficacy. The median overall survival (mOS) was 12.0 months (95% CI: 7.9-16.2 months) in group A and 7.3 months (95% CI: 4.3-10.3 months) in group B, respectively. The median progression-free survival (mPFS) was 5.7 months (95% CI: 4.1-7.2 months) and 5.0 months (95% CI: 3.1-6.9 months), respectively. The response rate (CR+PR) was 40% (16/40; 95% CI: 24.9-56.7%) in group A and 22.6% (7/31; 95% CI: 9.6-41.1%) in group B. Major grade 3 or 4 adverse events include neutropenia (41.3%), febrile neutropenia (9.3%), nausea/anorexia (10.7%), and vomiting (5.3%). There was no treatment-related death. CONCLUSIONS: The combination chemotherapy with PCF is active and tolerable as first-line and second-line therapy in Chinese patients with advanced gastric and EGJ adenocarcinoma. The response and survival of PCF are same as those of DCF, but the tolerance is much better.

Prognostic impact of vascular endothelial growth factor-A expression in resected gallbladder carcinoma.

The purpose of this study was to evaluate the value of vascular endothelial growth factor-A (VEGF-A) expression and other confirmed prognostic factors in predicting clinical outcomes after the resection of gallbladder carcinoma (GBC). Between January 1999 and January 2006, a total of 84 consecutive and non-selected patients who underwent resection for GBC were retrospectively reviewed. Of the 84 patients studied, 45 cases (53.6%) exhibited high expression of VEGF-A and were placed into the high expression group. The 14 cases (16.7%) that showed no VEGF expression and the 25 cases (29.7%) that had lower VEGF-A levels were pooled into the low expression group (46.4%). There was a relationship between VEGF-A status and pM stage (P = 0.027) as well as histologic differentiation (P < 0.001). In univariate analysis by log-rank test, ECOG performance status, CA 19-9, pN stage, pM stage, histologic differentiation, and VEGF-A expression were significant prognostic factors (P = 0.015, 0.001, 0.020, <0.001, 0.040, and <0.001, respectively). Multivariate analysis revealed that pN status and VEGF-A expression maintained independent prognostic influence on overall survival (P < 0.001 and P = 0.013, respectively). VEGF-A expression has a positive correlation with pM stage and histologic differentiation. pN status and VEGF-A expression were independent prognostic factors of overall survival in patients with resected GBC.

FRET quenching of photosensitizer singlet oxygen generation.

The development of activatable photodynamic therapy (PDT) has demonstrated a utility for effective photosensitizer quenchers. However, little is known quantitatively about Forster resonance energy transfer (FRET) quenching of photosensitizers, even though these quenchers are versatile and readily available. To characterize FRET deactivation of singlet oxygen generation, we attached various quenchers to the photosensitizer pyropheophorbide-alpha (Pyro) using a lysine linker. The linker did not induce major changes in the properties of the photosensitizer. Absorbance and emission wavelength maxima of the quenched constructs remained constant, suggesting that quenching by ground-state complex formation was minimal. All quenchers sharing moderate spectral overlap with the fluorescence emission of Pyro (J > or = 5.1 x 10(13) M(-1) cm(-1) nm4) quenched over 90% of the singlet oxygen, and quenchers with weaker spectral overlap displayed minimal quenching. A self-quenched double Pyro construct exhibited intermediate quenching. Consistent with a FRET deactivation mechanism, extension of the linker to a 10 residue polyproline peptide resulted in only the quenchers with spectral overlap almost 2 orders of magnitude higher (J > or = 3.7 x 10(15) M(-1) cm(-1) nm4) maintaining high quenching efficiency. Overall, there was good correlation (0.98) between fluorescence quenching and singlet oxygen quenching, implying that fluorescence intensity can be a convenient indicator for the singlet oxygen production status of activatable photosensitizers. Uniform singlet oxygen luminescence lifetimes of the compounds, along with minimal triplet state transient absorption were consistent with quenchers primarily deactivating the photosensitizer excited singlet state. In vitro, cells treated with well-quenched constructs demonstrated greatly reduced PDT induced toxicity, indicating that FRET-based quenchers can provide a level of quenching useful for future biological applications. The presented findings show that FRET-based quenchers can potently decrease singlet oxygen production and therefore be used to facilitate the rational design of activatable photosensitizers.

[Effect of gefitinib on radiosensitivity of gastric cancer cell lines].

BACKGROUND & OBJECTIVE: Epidermal growth factor receptor (EGFR) is expressed in most human epithelial cancers and is involved in the development of cancer cell resistance to irradiation. We used gefitinib, a selective EGFR tyrosine kinase inhibitor (EGFR-TKI), to investigate its effects and mechanisms in enhancing the radiosensitivity of human gastric cancer cell lines in vitro. METHODS: The expression of EGFR protein in 7 human gastric cell lines (MKN45, SGC7901, SNU-1, N87, AGS, SNU-16, and KATO-III) was determined by Western blot, in which 2 cell lines with high expression of EGFR were selected for additional test. The inhibitory effect of gefitinib on cell proliferation was measured by MTT assay. Cell survival was determined by clonogenic assay, and then the radiosensitivity parameters were calculated. The effects of gefitinib in combination with radiation on cell apoptosis and cell cycle distribution were analyzed by flow cytometry. RESULTS: Of the 7 gastric cancer cell lines, the expression of EGFR in MKN45 and SGC7901 cells were the highest. The 50% inhibition concentrations (IC(50)) of gefitinib were 0.4 mmol/L for MKN45 cells and 0.8 mmol/L for SGC7901 cells. Cell survival was significantly decreased with the elevation of gefitinib concentration or radiation dose (P<0.05). When treated with 0.1x and 0.2 x IC(50) of gefitinib, the radiosensitization enhancement ratios (SER) of MKN45 cells were 1.102 and 1.154, and those of SGC7901 cells were 1.092 and 1.176, respectively. Either gefitinib or radiation induced cell apoptosis, reduced the percentage of cells at S phase and increased the percentage of cells at G(2)/M phase (P<0.01). CONCLUSIONS: Gefitinib followed by radiation could increase the radiosensitivity of MKN45 and SGC7901 cells with high expression of EGFR and inhibit cell proliferation, induce apoptosis, and alter cell phase distribution. Gefitinib could be a radiation sensitizer for gastric tumors with high expression of EGFR.

[Evaluation of preoperative radiotherapy or chemoradiotherapy in sphincter preservation for locally advanced middle-low rectal cancer].

OBJECTIVE: To investigate the effect of preoperative radiotherapy or chemoradiotherapy on the sphincter preservation and local tumor control as well as survival for the patient with locally advanced middle-low rectal cancer. METHODS: 121 locally advanced middle-low rectal cancer patients were treated with preoperative radiotherapy or chemoradiotherapy followed by surgery after rest of 4 to 6 weeks. 103 of these patients who underwent radical surgery were finally included in this study. The irradiation regimen was: 40 Gy/4 - 5 weeks, whereas 57 of these 103 patients received concurrent chemotherapy of 5-Fu or Xeloda. Sphincter-preserving surgery was performed in 59 patients and abdominoperineal resection in 44 patients. The survival was estimated by Kaplan-Meier model, and the differences between groups were compared using Log rank test. Multivariate analysis was performed by Cox's model. RESULTS: Ten patients (9.7%) achieved a complete pathological response (pCR) to preoperative radiotherapy or chemoradiotherapy. The sphincter preservation rate was 57.3%. The 3-year overall survival (OS) and disease free survival (DFS) was 66.3% and 59.5%, respectively. Univariate analysis showed that pCR and postoperative pTNM stage were prognostic factors affecting survival, whereas, only pTNM stage was an independent prognostic factor (P = 0.003) by multivariate analysis. CONCLUSION: Neoadjuvant preoperative radiotherapy and chemoradiotherapy is effective in local tumor control and improving survival for locally advanced middle-low rectal cancer, which can raise the rate of sphincter-preserving surgery, and achieve comparable result to abdominoperineal resection.