[Safety and effectiveness of oxaliplatin combined with capecitabine or oxaliplatin combined with S-1 neoadjuvant chemotherapy in the treatment of advanced gastric cancer].

Objective: To explore the safety and efficacy of oxaliplatin plus capecitabine (CapeOX) or oxaliplatin plus S-1 (SOX) regimen neoadjuvant chemotherapy in the treatment of advanced gastric cancer. Methods: A retrospective cohort study was performed. Clinical data of patients diagnosed as advanced gastric cancer undergoing CapeOX/SOX neoadjuvant chemotherapy and standard laparoscopic radical operation for gastric cancer in Ruijin Hospital of Shanghai Jiaotong University School of Medicine from April 2016 to April 2019 were retrospectively collected. Inclusion criteria were as follows: (1) age≥18 years; (2) gastric adenocarcinoma was confirmed by histopathology and the clinical stage was T3-4aN+M0; (3) tumor could be resectable; (4) preoperative neoadjuvant chemotherapy was CapeOX or SOX regimen without radiotherapy or other regimen chemotherapy; (5) no other concurrent malignant tumor; (6) the Eastern Cooperative Oncology Group (ECOG) score ≤ 1; (7) no bone marrow suppression; (8) normal liver and kidney function. Exclusion criteria were as follows: (1) patients with recurrent gastric cancer; (2) patients receiving emergency surgery due to tumor perforation, bleeding, obstruction, etc.; (3) allergy to oxaliplatin, S-1, capecitabine or any drug excipients; (4) diagnosed with coronary heart disease, cardiomyopathy, or the New York Heart Association class III or IV; (5) pregnant or lactating women. A total of 118 patients were enrolled as the neoadjuvant chemotherapy group, and 379 patients with locally advanced gastric cancer who received surgery combined with postoperative adjuvant chemotherapy over the same period simultaneously were included as the adjuvant chemotherapy group. After propensity score matching was performed including gender, age, ECOG score, tumor site, clinical stage, chemotherapy regimen and other factors by 1:1 ratio, there were 40 cases in each group. The differences between the two groups in general conditions, efficacy of neoadjuvant chemotherapy, intraoperative conditions, postoperative conditions, histopathological results, chemotherapy-related adverse events, and survival status were compared and analyzed. Results: Comparison of baseline demographics between the two groups showed no statistically significant difference (all P>0.05). In the neoadjuvant chemotherapy group, 5.0% (2/40) of patients achieved clinical complete response, 57.5% (23/40) achieved partial response, 32.5% (13/40) remained stable disease, and 5.0% (2/40) had disease progression before surgery. Objective response rate was 62.5% (25/40), and disease control rate was 95.0% (38/40). There were no statistically significant differences between neoadjuvant chemotherapy group and adjuvant chemotherapy group in terms of operation time, intraoperative blood loss, number of lymph node harvested, length of postoperative hospital stay, and postoperative mortality and morbidity (all P>0.05). Postoperative complications were well managed with conservative treatment. No Clavien-Dindo IV or V complications were observed in both groups. Pathological results showed that the proportion of patients with pathological stage T1 in the neoadjuvant chemotherapy group was significantly higher than that in the adjuvant chemotherapy group [27.5% (11/40) vs. 5.0% (2/40)], while the proportion of patients with pathological stage T3 was significantly lower than that in the adjuvant chemotherapy group [20.0% (8/40) vs. 45.0% (18/40)], with statistically significant difference (χ(2)=15.432, P=0.001). In the neoadjuvant chemotherapy group, there were 4 cases of tumor regression grade 0, 8 cases of grade 1, 16 cases of grade 2, and 12 cases of grade 3. The pathological complete response rate was 10% (4/40), the overall pathological response rate was 70.0% (28/40). There was no statistically significant difference in the incidence of chemotherapy-related adverse events between neoadjuvant chemotherapy group and adjuvant chemotherapy group [40% (16/40) vs. 37.5% (15/40), P>0.05). There were no statistically significant differences in OS (43 months vs. 40 months) and 3-year OS rate (66.1% vs. 59.8%) between neoadjuvant chemotherapy group and adjuvant chemotherapy group (P=0.428). The disease-free survival (DFS) and 3-year DFS rates of the neoadjuvant chemotherapy group were significantly superior to those of the adjuvant chemotherapy group (36 months vs. 28 months, 51.4% vs. 35.8%, P=0.048). Conclusion: CapeOX or SOX regimen neoadjuvant chemotherapy is a safe, effective and feasible treatment mode for advanced gastric cancer without increasing surgical risk and can improve the DFS of patients.

[Effect of an oral nutritional supplementation on nutritional status and quality of life in patients with colorectal cancer and postoperative adjuvant chemotherapy: A multi-center prospective randomized control trial].

Objective: To evaluate the effect of oral nutritional supplementation (ONS) on the nutritional status and quality of life in patients with colorectal cancer and postoperative adjuvant chemotherapy. Methods: This study was registered in the Chinese Clinical Trial Registry (ChiCTR-TRC-13003798). A multi-center randomized controlled trial was conducted. Colorectal cancer patients who underwent radical surgery and postoperative adjuvant chemotherapy, and had nutritional risk (nutrition risk screening 2002 score ≥3) when discharge from hospital in six hospitals (Beijing Hospital, Peking University Third Hospital, Guangzhou Nanfang Hospital, Shanghai Xinhua Hospital, Shanghai Ruijin Hospital, and Shanghai The Sixth People's Hospital) from June 2013 to August 2015 were prospectively enrolled. These patients were randomly divided into the ONS group and control group. Patients in the ONS group received dietary guidance and oral nutritional supplements (2092 kJ/day, whole protein enteral nutrition) for 90 days after discharge from hospital, while patients in the control group only received dietary guidance. Anthropometric measurements (body weight, body mass index [BMI], upper arm circumference, gripping power of the dominant hand, triceps skin fold), nutrition-related laboratory tests (hemoglobin, albumin, prealbumin, total cholesterol, triglyceride), gastrointestinal function scores and quality of life (evaluated by EuroQol five dimensions questionnaire) were collected and compared at baseline (at discharge), and at 30-day, 60-day and 90-day after discharge. Results: A total of 90 patients were included into this multi-center study, of whom 5 patients dropped out, 43 patients were assigned to the ONS group and 42 patients to the control group. Compared with baseline, the body weight of patients in the ONS group increased by (1.523±0.525) kg at 60-day and (1.967±0.661) kg at 90-day, which were significantly higher than those of patients in the control group [60-day: (-0.325±0.518) kg, P=0.015; 90-day: (-0.224±0.705) kg, P=0.027, respectively]. A similar pattern was observed for BMI, the ONS group increased by (0.552±0.203) kg/m(2) at 60-day and (0.765±0.205) kg/m(2) at 90-day, which were significantly higher than those of patients in control group [60-day: (-0.067±0.202) kg/m(2), P=0.034; 90-day: (0.022±0.210) kg/m(2), P=0.013]. No significant differences of other anthropometric measurements and nutrition-related laboratory tests were found between the two groups (all P>0.05). Furthermore, there were no significant differences of improvement in gastrointestinal function and quality of life between two groups (all P>0.05). Conclusion: Oral nutritional supplements can improve the body weight and BMI of colorectal cancer patients with nutritional risk receiving postoperative adjuvant chemotherapy, though it does not improve the quality of life.

Recurrent fungal infections in a Chinese patient with CARD9 deficiency and a review of 48 cases.

Deficiency of CARD9 (caspase recruitment domain-containing protein 9) has been reported in individuals with recurrent and invasive fungal infections. We report on a patient who first had Trichosporon asahii affecting the skin then Candida albicans infections involving the digestive tract and knee joint, along with elevated serum IgE. After stimulation with C. albicans, peripheral blood mononuclear cells of this patient produced less tumour necrosis factor-α, interferon-γ and interleukin-17 than those of healthy controls. Furthermore, the serum IgE levels of this patient were positively correlated with the severity of fungal infection during the course of treatment. Sanger sequencing identified one homozygous frameshift mutation (p.D274fsX60) in CARD9. We further performed a review including 48 cases with CARD9 deficiency. According to the data published previously, CARD9-deficient patients demonstrated obviously elevated IgE in serum (median 1300 IU mL-1 ), which could distinguish them from otherwise healthy people with fungal infections (area under the curve 0·94, P < 0·001). Patients carrying the mutations Q289X and Q295X had a higher mortality rate (24% vs. 0%, P < 0·05). Patients with the mutations R18W, R35Q, R70W, G72S or Y91H in the CARD domain, and the nonsense mutation Q295X in the coiled-coil domain, seemed to be more prone to Candida infections (90% vs. 20%, P < 0·005) and central nervous system infections (60% vs. 12%, P < 0·005).

Lack of association between the hOGG1 gene Ser326Cys polymorphism and gastric cancer risk: evidence from a case-control study and a meta-analysis.

The association between the human 8-oxoguanine glycosylase 1 (hOGG1) gene Ser326Cys polymorphism (rs1052133) and gastric cancer has been widely evaluated, yet a definitive answer to whether this association exists is lacking. We first conducted a case-control study to assess this association in a large Han Chinese population, and then performed a meta-analysis to further address this issue. This case-control study involved 448 patients clinically diagnosed with gastric cancer and 372 cancer-free control individuals from China. Genotyping was conducted using the polymerase chain reaction-ligase detection reaction method. Meta-analysis was performed by the STATA software. Data and study quality were assessed in duplicate. Our case-control association study indicated that there were no significant differences in the genotype and allele distributions of the Ser326Cys polymorphism between gastric cancer patients and controls (P = 0.8026 for genotype, and P = 0.5857 for allele), consistent with the results of the subsequent meta-analysis involving 2745 patients and 4588 controls under both allelic [odds ratio (OR) = 1.02; 95% confidence interval (CI) = 0.91-1.14; P = 0.739] and dominant (OR = 0.97; 95%CI = 0.78-1.21; P = 0.803) models. Further subgroup analyses by ethnicity, source of controls, and sample size also did not detect any positive associations in this meta-analysis. Overall, our study in the Han Chinese population, along with the meta-analysis, failed to confirm the association of the hOGG1 gene Ser326Cys polymorphism with gastric cancer risk, even across different ethnic populations.

Potential impact of cardiac dose-volume on acute cardiac toxicity following concurrent trastuzumab and radiotherapy.

PURPOSE: To analyse the risk factors associated with acute cardiotoxicity in HER2-positive breast cancer patients receiving concurrent trastuzumab and radiotherapy. PATIENTS AND METHODS: Medical records of 45 breast cancer patients treated between 02/2009 and 02/2011 by concurrent trastuzumab and radiotherapy were collected. Radiation was delivered to the conserved breast or chest wall with or without regional nodes. Dose prescription was 50Gy in 25 fractions over five weeks with a tumor bed boost of 10Gy in 5 fractions in breast conservation. Acute cardiotoxicity (grade≥1) was defined using NCI-CTC v2.0. Doses to the heart and left ventricle were quantified. RESULTS: Median follow-up of left ventricular ejection fraction and clinical assessment from the completion of radiotherapy was 10 months (range: 3-27 months) and 25 months (range: 13-40 months), respectively. Ten (22.2%) and one (2.2%) of the 45 patients developed grade 1 and grade 2 cardiotoxicity, respectively. For 24 left-sided patients, the mean heart dose was significantly higher in those with cardiac events compared to those without (10.14 and 6.27Gy, respectively; P<0.05). A continuous increase of D17-D57 and V10-V15 of the heart and increase of D40-D80 and V5-V7 of the left ventricle were statistically significant in left-sided patients who developed cardiotoxicity compared with those who did not (P<0.05). No significant relationship of dosimetric parameters of cardiac structures and cardiac events was found in right-sided patients. CONCLUSIONS: Left-sided irradiation with increased low dose-volume and mean heart dose were associated with increased but reversible low-grade early cardiac toxicity after use of concurrent trastuzumab.

Delineation of the cardiac substructures based on PET-CT and contrast-enhanced CT in patients with left breast cancer treated with postoperative radiotherapy.

The aim of this study is to evaluate the volume differences between contrast-enhanced CT-based left ventricle (LV) and PET-CT-based LV and assess the impact of dose on the substructure volume differences in patients with left breast cancer treated with adjuvant radiotherapy. From October 2008 to February 2009, 14 patients with post-operatively confirmed left breast cancer were enrolled in the current study. The patients were scanned using contrast-enhanced CT for simulation, and (18)F-FDG PET-CT was employed to display the structure of the left ventricle of each before radiotherapy (RT). The LV was delineated based on both contrast-enhanced CT and PET-CT. And other substructures, such as the left anterior descending coronary artery (LAD), were contoured in each patient, with the six-field simple intensity modulated radiotherapy (sIMRT) technique created for all. The mean volumes of the left ventricle based on contrast-enhanced CT (LV-CT) and PET-CT (LV-PET) were found to be 107.296 cm(3) and 112.931 cm(3), respectively (p = 0.06). The volume of LV receiving ≥ 50% prescription dose was significantly correlated with the volume of the heart receiving the same dosage (γ = 0.869). There was less correlation between the volume of LAD and that of the heart under the same condition (γ = 0.22). As a conclusion, the left ventricle can be delineated effectively based on the image of PET-CT, the contrast-enhanced CT based LV can serve as an appropriate alternative. Moreover, the volume of LV receiving high dose in RT closely correlated with the volume of the heart using sIMRT technique, which may pave the way for further exploring radiation-induced cardiac injuries in patients with left breast cancer.

Vascular endothelial growth factors C and D represent novel prognostic markers in colorectal carcinoma using quantitative image analysis.

BACKGROUND/AIMS: Vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor D (VEGF-D) are potent lymphangiogenic and angiogenetic mediators in many kinds of tumors. However, the exact impacts of VEGF-C and VEGF-D on the prognosis of colorectal cancer (CRC) remain elusive. The aims of this study were to demonstrate the expression of VEGF-C and VEGF-D and to correlate their expression levels with clinicopathological factors and long-term survival in patients with CRC. PATIENTS AND METHODS: Between January 1996 and January 1998, 69 patients with pathologically confirmed CRC who received routine follow-up at the Ruijin Hospital were included in this study. VEGF-C and VEGF-D protein expression and microvessel density of 69 surgical specimens were assessed by immunohistochemistry, with 20 samples of normal colorectal tissues as controls. All patients were followed up for 108 months or until death. The Immunohistochemical stains were quantified and analyzed by means of a Zeiss Axioplan 2 imaging analysis system. RESULTS: The protein expression of VEGF-C and VEGF-D in tumor tissues was much higher than that in normal colorectal tissues (p < 0.01). The VEGF-C expression significantly correlated with lymph node metastasis (p = 0.011) and clinical stages of CRC (p < 0.01). The VEGF-D expression correlated with patient ages (p = 0.013), depth of tumor invasion (p = 0.013), and lymph node metastasis (p = 0.028). The expression of VEGF-C and VEGF-D was significantly correlated with the microvessel density. Both overall survival and disease-free survival at 108 months were significantly lower in the CRC patients with a high VEGF-C and/or a high VEGF-D expression, and the patients with a high expression of both VEGF-C and VEGF-D had the shortest overall survival and disease-free survival when compared with other patients. CONCLUSION: The VEGF-C or VEGF-D expression was significantly correlated with lymph node metastasis and long-term prognosis and could be applied as prognostic markers in CRC.

Functional characteristics of a protective monoclonal antibody against serotype A and C lipooligosaccharides from Moraxella catarrhalis.

A monoclonal antibody (MAb), designated MAb 8E7 (immunoglobulin G3), specific for Moraxella catarrhalis lipooligosaccharide (LOS) was evaluated for its functional activity in vitro and in a mouse model of colonization. Enzyme-linked immunosorbent assay (ELISA) demonstrated that the MAb 8E7 could be prepared to a high titer against LOS of the homologous strain 035E, and that it had bactericidal activity. MAb 8E7 reacted with M. catarrhalis serotype A and C LOSs but not serotype B LOS, as measured by ELISA and Western blotting. On the basis of published structures of LOSs, this suggests that the epitope recognized by MAb 8E7 is directed to a common sequence of either alpha-GlcNAc-(1-->2)-beta-Glc-(1--> at the branch substituting position 4 of the trisubstituted Glc residue or a terminal tetrasaccharide alpha-Gal-(1-->4)-beta-Gal-(1-->4)-alpha-Glc-(1-->2)-beta-Glc-(1--> at the branch substituting position 6 of the trisubstituted Glc residue. In a whole-cell ELISA, MAb 8E7 reacted with 70% of the 30 wild-type strains and clinical isolates tested. Immuno-electron microscopy demonstrated that MAb 8E7 reacted with a cell surface-exposed epitope of LOS on strain O35E. MAb 8E7 inhibited the adherence of strain O35E to Chang conjunctival epithelial cells by 90%. Passive immunization with MAb 8E7 could significantly enhance the clearance of strain O35E from mouse lungs in an aerosol challenge mouse model. This enhanced bacterial clearance was inhibited when MAb 8E7 was absorbed by M. catarrhalis serotype A LOS, indicating that the M. catarrhalis LOS-directed antibody may play a major role in the enhancement of M. catarrhalis clearance from lungs. These data suggest that MAb 8E7, which recognizes surface-exposed LOS of M. catarrhalis, is a protective antibody against M. catarrhalis.

Enhancement of clearance of bacteria from murine lungs by immunization with detoxified lipooligosaccharide from Moraxella catarrhalis conjugated to proteins.

Moraxella catarrhalis strain 25238 detoxified lipooligosaccharide (dLOS)-protein conjugates induced a significant rise of bactericidal anti-LOS antibodies in animals. This study reports the effect of active or passive immunization with the conjugates or their antiserum on pulmonary clearance of M. catarrhalis in an aerosol challenge mouse model. Mice were injected subcutaneously with dLOS-tetanus toxoid (dLOS-TT), dLOS-high-molecular-weight proteins (dLOS-HMP) from nontypeable Haemophilus influenzae (NTHi), or nonconjugated materials in Ribi adjuvant and then challenged with M. catarrhalis strain 25238 or O35E or NTHi strain 12. Immunization with dLOS-TT or dLOS-HMP generated a significant rise of serum anti-LOS immunoglobulin G and 68% and 35 to 41% reductions of bacteria in lungs compared with the control (P<0.01) following challenge with homologous strain 25238 and heterologous strain O35E, respectively. Serum anti-LOS antibody levels correlated with its bactericidal titers against M. catarrhalis and bacterial CFU in lungs. Additionally, immunization with dLOS-HMP generated a 54% reduction of NTHi strain 12 compared with the control (P<0.01). Passive immunization with a rabbit antiserum against dLOS-TT conferred a significant reduction of strain 25238 CFU in lungs in a dose- and time-dependent pattern compared with preimmune serum-treated mice. Kinetic examination of lung tissue sections demonstrated that antiserum-treated mice initiated and offset inflammatory responses more rapidly than preimmune serum-treated mice. These data indicate that LOS antibodies (whether active or passive) play a major role in the enhancement of pulmonary clearance of different test strains of M. catarrhalis in mice. In addition, dLOS-HMP is a potential candidate for a bivalent vaccine against M. catarrhalis and NTHi infections.

An aerosol challenge mouse model for Moraxella catarrhalis.

A simple, reproducible, and non-invasive mouse pulmonary clearance model for Moraxella catarrhalis via aerosol challenge was established. All of eight tested strains could be inoculated into mice at more than 10(5) colony-forming units (CFU)/lung with a challenge concentration of 1x10(9)-6x10(9) CFU/ml in a nebulizer. The number of bacteria retained at 6 h postchallenge was more than 10(4) CFU/lung while at 24 h postchallenge, approximate 10(3) CFU/ml or less remained in the lungs. A maximum of 100 mice could be challenged per aerosol exposure. The number of bacteria inoculated in the lungs could be adjusted by the bacterial challenge concentration, the exposure time, and the negative pressure. Lung tissue sections revealed that bacteria were evenly distributed in the lungs. Passive immunization significantly enhanced pulmonary clearance of the homologous strain in this model. These data indicate that this model will be useful for evaluating M. catarrhalis vaccine candidates and studying roles of immunity against M. catarrhalis.

Localization of a T-cell epitope of superantigen toxic shock syndrome toxin 1 to residues 125 to 158.

Toxic shock syndrome toxin 1 (TSST-1) is a member of the staphylococcal enterotoxin superantigen family. So far, little is known about T-cell epitopes on superantigens. In this study, we developed an improved method for localizing T-cell epitopes on superantigens that involved synthetic peptides plus costimulation by CD28 or phorbol myristate acetate. Using this method, we localized a T-cell epitope to a 34-residue region, TSST-1 (residues 125 to 158), which possessed only two of four TSST-1-targeted beta-chain variable element (Vbeta) specificities of T-cell receptors in humans and mice, human Vbeta2 and murine Vbeta15.

V beta specificity of superantigen TSST-1 plus CD28 costimulation without APCs.

Little has so far been known about the role of antigen-presenting cells (APCs) in the activation of T cells by superantigens. Recently several studies showed that superantigens could directly activate purified T cells in the presence of CD28 costimulation. Here we investigate V beta expression of T cells activated by the superantigen toxic shock syndrome toxin-1 (TSST-1), plus CD28 costimulation, in the absence of APCs. The aim of this study was to ask if TSST-1 activated purified T cells in the presence of CD28 costimulation with the same specificity as in the presence of APCs. We provide evidence that the specificity of TSST-1 to human V beta, in the presence of CD28 costimulation, is identical to that in the presence of APCs, with V beta 2 being significantly expanded. The results indicate that the main role of APCs in the superantigen-mediated T cell activation may be to provide T cells with CD28 costimulation.

[Changes in the concentration of plasma cardionatrin and morphological changes of atrial cardiocytes after severe burn].

The purpose of this experiment is to investigate the changes in plasma concentration cardionatrin of and morphological changes in atrial cardiocytes in rats after severe burn by means of radioimmunoassay, immunocytochemistry, electron microscopy and morphometry. The results showed that: (1) At 1, 2 h postburn the plasma cardionatrin concentrations were significantly increased, at 6-48 h significantly decreased and at 72, 168 h returned to normal. (2) The changes in plasma cardionatrin concentration were related to the alterations of secretory function in atrial cardiocytes. (3) The pathological changes in atrial cardiocytes were characterized by appearing early. The pathological changes and alterations of secretory function of atrial cardiocytes ran a dynamic course, which could be roughly divided into three phases, the phase of stress, the phase of secretory inhibition and injury, and the phase of recovery. (4) It might be one of the forms of atrial cardiocytes secreting cardionatrin that the atrial specific granules with intact limiting membrane were excreted from the defect of plasmalemma.