[Comparison of the efficacy of carelizumab combined with chemotherapy and chemotherapy alone in the induction therapy of locally advanced hypopharyngeal carcinoma].

Objective: To compare the efficacy and safety of carrelizumab combined with the modified TPF regimen (docetaxel, cisplatinand capecitabine) and TPF regimen alone in larynx preservation strategy for locally advanced resectable hypopharyngeal squamous cell carcinoma. Methods: A cohort study was conducted. Patients with locally advanced resectable hypopharyngeal carcinoma (cT3-4aN0-3bM0) who were treated at the Eye & ENT Hospital of Fudan University from January 2017 to April 2023 were enrolled in the study. One group was treated with a modified TPF regimen (TPF group) for 2-3 cycles (retrospective data), and the other group was a prospective phase Ⅱ trial with a modified TPF regimen combined with carrelizumab (TPFC group) for three cycles. The patients with complete or partial remission of the primary focus were treated with sequential radical radiotherapy and/or drug therapy. The patients in the TPFC group were treated with carrelizumab at the end of radiotherapy with a maximum of up to 18 doses. The patients with stable or progressive disease were given radical surgery, and those who refused the surgery were given radical chemoradiotherapy. Objective response rate (ORR), overall survival rate, progression-free survival (PFS) rate, larynx preservation rate (LPR), and adverse reactions were compared between the two groups. Results: There were 51 male patients in the TPFC group, with an median age of 57 (35, 69) years. Meanwhile, 44 patients were in the TPF group, among which 43 were male and one was female, with an median age of 62 (46, 70) years. The ORR of the TPFC group was higher than that of the TPF group [82.4% (42/51) vs 63.6% (28/44), P=0.039]. During a median follow-up of 24.4 (18.5, 31.4) months, the TPFC group showed a higher 2-year survival rate (84.8% vs 64.6%, P=0.013) and 2-year LPR (66.6% vs 48.6%, P=0.045) than those in the TPF group. In patients with poor effect of induction therapy for hypopharyngeal carcinoma, surgical combination therapy significantly prolonged the 2-year PFS rate (77.9% vs 18.2%, P<0.001) and 2-year survival rate (76.9% vs 45.5%, P=0.005)than those of non-surgical combination therapy. The incidences of nausea and/or vomiting, reactive cutaneous capillary endothelial proliferation, thyroid dysfunction, and rash were increased in the TPFC group (all P<0.05). There was no treatment-related death. Conclusion: Carrelizumab combined with a modified TPF regimen has good efficacy and safety and can improve the LPR of locally advanced hypopharyngeal carcinoma.

Age distribution of human papillomavirus infection and neutralizing antibodies in healthy Chinese women aged 18-45 years enrolled in a clinical trial.

OBJECTIVES: Data from clinical trials of human papillomavirus (HPV) vaccines showed that women naïve (negative for both type-specific antibodies and DNA) to vaccine types would derive benefit from vaccination; therefore, an understanding of the proportion of naïve women in different age groups is important for developing HPV vaccination strategies. METHODS: From November 2012 to April 2013, a total of 7372 healthy women aged 18-45 years were recruited in five provinces in China. Cervical specimens and serum samples were collected for each woman at entry. Cervical specimens were first tested by the HPV DNA enzyme immunoassay method; if positive, the specimens were then tested by reverse hybridization line probe assay and HPV-16 and HPV-18 specific polymerase chain reactions. Neutralizing antibodies against HPV-16 or HPV-18 were tested with a pseudovirion-based neutralization assay. RESULTS: The overall prevalence of high-risk HPV DNA was 14.8% (1088/7367, 95% CI 14.0-15.6), and the seroprevalence of neutralizing antibodies against HPV-16 and HPV-18 was 12.6% (925/7367) and 4.9% (364/7367), respectively. In younger women (18-26 years) and middle-aged women (27-45 years), 83.8% (3116/3719) and 81.4% (2968/3648) were naïve to both HPV-16 and HPV-18 (both neutralizing antibodies and DNA were negative), respectively. In addition, 98.5% (3664/3719) and 98.0% (3575/3648) of the younger or middle-aged women were naïve to at least one HPV type (HPV-16 or HPV-18). DISCUSSION: This study revealed that the majority of Chinese women aged 18-26 years and 27-45 years were naïve to both HPV-16 and HPV-18 and would thus derive full benefit from bivalent HPV vaccination.

Intratumoral IL17-producing cells infiltration correlate with antitumor immune contexture and improved response to adjuvant chemotherapy in gastric cancer.

BACKGROUND: Tumor IL17-producing (IL17A+) cells infiltration has different prognostic values among various cancers. The objective of this study was to assess the effect of IL17A+ cells in gastric cancer. PATIENTS AND METHODS: The study included two patient cohorts, the Cancer Genome Atlas cohort (TCGA, n = 351) and the Zhongshan Hospital cohort (ZSHC, n = 458). The TCGA and ZSHC were used for mRNA-related and cells infiltration-related analyses, respectively. The roles of IL17A mRNA and IL17A+ cells in overall survival (OS), response to adjuvant chemotherapy (ACT), and immune contexture were evaluated. Another independent cohort was included to identify the correlation between mRNA of IL17A and IL17A+ cells infiltration (the preliminary Zhongshan Hospital cohort, PZSHC, n = 21). RESULTS: The infiltration of IL17A+ cells was positively correlated with the expression of IL17A mRNA (Spearman's ρ = 0.811; P < 0.001). High IL17A mRNA expression and intratumoral IL17A+ cells were correlated with improved OS and remained to be significant after adjusted for confounders. Patients with TNM II/III disease whose tumor present higher intratumoral IL17A+ cells or lower peritumoral IL17A+ cells can benefit more from ACT. Elevated IL17A mRNA expression and increased intratumoral IL17A+ cells infiltration was associated with more antitumor mast cells and nature killer cells infiltration and less pro-tumor M2 macrophages infiltration. High IL17A mRNA expression represented a Th17 cells signature and immune response process and was correlated with increased cytotoxic GZMA, GZMB, IFNG, PRF1, and TNFSF11 expression. CONCLUSIONS: IL17A mRNA expression and intratumoral IL17A+ cells infiltration were correlated with antitumor immune contexture. IL17A+ cells infiltration could be used as an independent prognostic biomarker for OS and predictive biomarker for superior response to ACT, and further prospective validation needs to be conducted.

[Prevalence of type-specific human papillomavirus infection among 18-45 year-old women from the general population in Liuzhou, Guangxi Zhuang Autonomous Region: a cross-sectional study].

Objective: To analyze the type-specific prevalence of human papillomavirus (HPV) among women aged 18-45 years from the general population in Liuzhou, Guangxi Zhuang Autonomous Region. Methods: Totally, 2 300 women aged 18-45 years old were enrolled in Liuzhou,from March to July, 2013. Cervical exfoliated cells were collected for liquid based cytological and HPV DNA tests. Women were referred to colposcopy exam, based on the clinical practice guideline. Results: Overall, the prevalence rates of any HPV or oncogenic HPV appeared as 22.7% (95% CI: 21.0%-24.4%) and 17.3% (95% CI: 16.0%-19.1%), respectively in this population under study. The high-risk HPV prevalence peaked at the age groups of 18-25 and 41-45, increasing along with the severity through cytological and histological tests. Statistically significant differences between the prevalence of CIN2+ (Cervical intraepithelial neoplasia 2+) in women older than 26 years (1.7%, 95% CI: 1.0%-2.4%) and 18-25 years (1.2%, 95% CI: 0.5%-1.9%) of age, were not observed. Among samples diagnosed as CIN2+, positivity of HPV bivalent (16/18) and nine-valent (6/11/16/18/31/33/45/52/58) vaccine, related high risks on the types of HPV types appeared as 44.1% and 97.1%. Conclusions: The age-specific HPV prevalence rates in the general women aged 18-45 in Liuzhou presented as having bimodal distribution, suggesting that the disease burden of cervical diseases in women aged 26-45 years should not be ignored. Nine-valent HPV vaccine might provide more effective prevention outcomes on cervical cancer in China.

Liver fibrosis staging using T1 mapping on gadoxetic acid-enhanced MRI compared with DW imaging.

AIM: To evaluate the utility of T1 mapping on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for staging liver fibrosis. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and included 145 patients (mean age: 54 years old; 115 men and 30 women). Necro-inflammatory activity grade (G) and liver fibrosis stage (S) were histopathologically determined. T1 relaxation time and apparent diffusion coefficient (ADC) of the liver were measured and the reduction rate of the T1 relaxation time (Δ%) was calculated. T1 relaxation time measurements were compared with ADC values according to S/G scores. RESULTS: Unenhanced hepatobiliary phase (HBP) and Δ% of T1 relaxation times showed significant correlations with S/G scores (rho: 0.28, 0.51, -0.35 for the S score, 0.26, 0.39, -0.26 for the G score, respectively, p<0.05). ADC values showed significant correlation with the S score (rho: -0.17, p = 0.04) and did not correlate significantly with the G score (rho: -0.07, p = 0.39). The areas under receiver operator characteristics (AUC) curve of unenhanced HBP, Δ% T1 relaxation time, and the ADC value were 0.68, 0.82, 0.71, 0.61 for the identification of S ≥ 3, and 0.63, 0.68, 0.62, 0.52 for the identification of G ≥ 3, respectively. The HBP T1 relaxation time was better than that of ADC for identification of S ≥ 3 (p = 0.0005) and G ≥ 3 (p = 0.014). CONCLUSIONS: The HBP T1 relaxation time measurement on gadoxetic acid-enhanced MRI images might be a potential biomarker in the staging of hepatic fibrosis, and was more accurate than the ADC measurement.

Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats.

Sleep disordered breathing (SDB), which is characterized by intermittent hypoxia (IH) during sleep, causes substantial cardiovascular and neurocognitive complications and has become a growing public health problem. SDB is associated with suppression of growth hormone (GH) secretion, the latter being integrally involved in the growth, development, and function of the CNS. Since GH treatment is able to attenuate neurocognitive deficits in a hypoxic-ischemic stroke model, GH, GH receptor (GHR) mRNA expression, and GH protein expression were assessed in rat hippocampus after exposures to chronic sustained hypoxia (CH, 10% O(2)) or IH (10% O(2) alternating with 21% O(2) every 90 s). In addition, the effect of GH treatment (50 µg/kg daily s.c. injection) on erythropoietin (EPO), vascular endothelial growth factor (VEGF), heme oxygenase-1 (HO-1), and GLUT-1 mRNA expression and neurobehavioral function was assessed. CH significantly increased GH mRNA and protein expression, as well as insulin-like growth factor-1 (IGF-1). In contrast, IH only induced a moderate increase in GH mRNA and a slight elevation in GH protein at day 1, but no increases in IGF-1. CH, but not IH, up-regulated GHR mRNA in the hippocampus. IH induced marked neurocognitive deficits compared with CH or room air (RA). Furthermore, exogenous GH administration increased hippocampal mRNA expression of IGF-1, EPO, and VEGF, and not only reduced IH-induced hippocampal injury, but also attenuated IH-induced cognitive deficits. Thus, exogenous GH may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from SDB-associated neuronal loss and associated neurocognitive dysfunction.

Efficacy and mechanisms of action of rmB7.2-Ig as an antitumor agent in combination with Adriamycin and Cytoxan chemotherapy.

The efficacy of chemotherapy for cancer is often limited by toxicity. Immune approaches to cancer immunotherapy, while promising for specificity and long-term protection, have not typically proven potent enough to generate significant therapeutic responses. We have shown therapeutic benefit using recombinant murine B7.2-Ig (rmB7.2-Ig) in murine tumor models. Efficacy was dependent on immune activity and was not associated with toxicity. Recently, the efficacy of rmB7.2-Ig was demonstrated in leukemia tumor models in combination with chemotherapeutic agents. To further explore the potential of this approach, we evaluated the efficacy in solid tumor models of rmB7.2-Ig given in combination with chemotherapeutics commonly used in clinical practice, testing the effects of dose and schedule. RmB7.2-Ig in combination with some chemotherapeutics enhances the activity and efficacy of reduced chemotherapeutic doses. However, the relative timing of chemotherapy and rmB7.2-Ig dosing can be important. Investigation of mechanisms of action based on histological studies suggests that inflammatory as well as T cell mechanisms comprise the response. Additional studies of mice deleted of B7.1, B7.2, and CTLA-4 suggest that the enhanced response induced by rmB7.2-Ig may not be mediated through CD28 ligation alone. The efficacy suggests potential for recombinant human B7.2-Ig as an adjuvant to chemotherapy in promoting immune-mediated mechanisms to augment the activity of chemotherapy.

PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes.

We have previously shown that protein kinase C (PKC)-epsilon, nuclear factor (NF)-kappaB, and mitogen-activated protein kinases (MAPKs) are essential signaling elements in ischemic preconditioning. In the present study, we examined whether activation of PKCepsilon affects the activation of NF-kappaB in cardiac myocytes and whether MAPKs are mediators of this signaling event. Activation of PKCepsilon (+108% above control) in adult rabbit cardiomyocytes to a degree that has been previously shown to protect myocytes against hypoxic injury increased the DNA-binding activity of NF-kappaB (+164%) and activator protein (AP)-1 (+127%) but not that of Elk-1. Activation of PKCeta did not have an effect on these transcription factors. Activation of PKCepsilon also enhanced the phosphorylation activities of the p44/p42 MAPKs and the p54/p46 c-Jun NH(2)-terminal kinases (JNKs). PKCepsilon-induced activation of NF-kappaB and AP-1 was completely abolished by inhibition of the p44/p42 MAPK pathway with PD98059 and by inhibition of the p54/p46 JNK pathway with a dominant negative mutant of MAPK kinase-4, indicating that both signaling pathways are necessary. Taken together, these data identify NF-kappaB and AP-1 as downstream targets of PKCepsilon, thereby establishing a molecular link between activation of PKCepsilon and activation of NF-kappaB and AP-1 in cardiomyocytes. The results further demonstrate that both the p44/p42 MAPK and the p54/p46 JNK signaling pathways are essential mediators of this event.

Demonstration of selective protein kinase C-dependent activation of Src and Lck tyrosine kinases during ischemic preconditioning in conscious rabbits.

Src tyrosine kinases have been shown to mediate cellular responses to stress in noncardiac cells. However, the effect of myocardial ischemia on Src tyrosine kinases is unknown. Furthermore, the identity of the tyrosine kinase(s) involved in the genesis of ischemic preconditioning (PC) remains obscure. Here, we present the first evidence that ischemic PC (6 cycles of 4-minute coronary occlusion and 4-minute reperfusion) induces selective activation of 2 members of the Src family of tyrosine kinases, Src and Lck, in the heart of conscious rabbits. The activation of Src in the particulate fraction was not evident at 5 minutes after ischemic PC but became apparent at 30 minutes (+119% versus control), whereas the activation of Lck in the particulate fraction was apparent both at 5 minutes (+103% versus control) and at 30 minutes (+89%) after ischemic PC. The activity of the other 5 members of the Src tyrosine kinases expressed in the rabbit heart (Fyn, Fgr, Yes, Lyn, and Blk) was not affected by ischemic PC. Ischemic PC had no effect on the activity of epidermal growth factor receptor kinases, either at 5 or at 30 minutes. The activation of Src and Lck was completely abrogated by the tyrosine kinase inhibitor lavendustin A, given at doses that have previously been shown to block the protective effect of ischemic PC in this same conscious rabbit model, suggesting that Src and Lck kinases are essential for the development of ischemic PC. The activity of the epsilon isoform of protein kinase C (PKC) in the particulate fraction increased at 5 minutes (+72%) and at 30 minutes (+67%) after ischemic PC. Pretreatment with lavendustin A had no effect on the activation of PKCepsilon, whereas pretreatment with the PKC inhibitor chelerythrine (given at doses that have previously been shown to block ischemic PC) blocked not only the activation of PKCepsilon but also that of Src and Lck, indicating that Src and Lck are downstream of PKCepsilon in the signaling cascade of ischemic PC. This study identifies a new component of the signaling mechanism of ischemic PC. The results support the concept that, in conscious rabbits, 2 specific members of the Src family of tyrosine kinases, Src and Lck, play an important role in the genesis of late PC by serving as downstream elements of PKC-mediated signal transduction.

Netilmicin pharmacokinetics in Hong Kong Chinese cancer patients.

OBJECTIVES: To study the pharmacokinetics of netilmicin in Chinese haematology-oncology patients and to determine the pharmacokinetic differences, if any, between this patient subpopulation of Chinese and Caucasians. METHODS: A prospective study was carried out in the adult oncology unit of a major hospital in Hong Kong. During a 6 week period in 1997, all patients commencing on netilmicin therapy were monitored; the patients' demographics, clinical status, netilmicin dose and regimen, and drug administration/blood sampling time were collected. Pharmacokinetic parameters were generated using the USC*PACK package based on specifics of the patients themselves and Caucasians matched for the same patients' parameters using the Bayesian alogrithms. RESULTS: A total of 22 patients were enrolled into the study. Twenty-nine sets of levels were drawn, but only 25 sets from 18 patients (86%) were interpretable. The predicted peak (7.47+/-1.46 microg ml-1 ) and trough levels (1.39+/-0.96 microg ml-1 ) generated by USC*PACK were found to be significantly higher than the levels observed (6.01+/-1.14 microg ml-1 and 0.93+/-0.71 microg ml-1, respectively). Netilmicin clearance, volume of distribution and rate of elimination were all significantly higher in this Chinese subpopulation than those predicted for matched Caucasians. Conclusion Alterations in the netilmicin pharmacokinetics observed in our study population might be related to the disease state and/or ethics of the study patient population. Direct application of Caucasian based population pharmacokinetic parameters to this subgroup of Chinese patients may not be appropriate and may result in underdose.

Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits.

Although it is recognized that late preconditioning (PC) results from upregulation of cardioprotective genes, the specific transcription factor(s) that govern this genetic adaptation remains unknown. The aim of this study was to test the hypothesis that the development of late PC is mediated by nuclear factor-kappaB (NF-kappaB) and to elucidate the mechanisms that control the activation of NF-kappaB after an ischemic stimulus in vivo. A total of 152 chronically instrumented, conscious rabbits were used. A sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles, which elicits late PC, induced rapid activation of NF-kappaB, as evidenced by a marked increase in p65 content (+164%; Western immunoblotting) and NF-kappaB DNA binding activity (+306%; electrophoretic mobility shift assay) in nuclear extracts isolated 30 minutes after the last reperfusion. These changes were attenuated 2 hours after ischemic PC and resolved by 4 hours. Competition and supershift assays confirmed the specificity of the NF-kappaB DNA complex signals. The mobility of the NF-kappaB DNA complex was shifted by anti-p65 and anti-p50 antibodies but not by anti-c-Rel antibodies, indicating that the subunits of NF-kappaB involved in gene activation after ischemic PC consist of p65-p50 heterodimers. Pretreatment with the NF-kappaB inhibitor diethyldithiocarbamate (DDTC; 150 mg/kg IP 15 minutes before ischemic PC) completely blocked the nuclear translocation and increased DNA binding activity of NF-kappaB. The same dose of DDTC completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that NF-kappaB activation is essential for the development of this phenomenon in vivo. The ischemic PC-induced activation of NF-kappaB was also blocked by pretreatment with Nomega-nitro-L-arginine (L-NA), a nitric oxide synthase (NOS) inhibitor, N-2-mercaptopropionyl glycine (MPG), a reactive oxygen species (ROS) scavenger, chelerythrine, a protein kinase C (PKC) inhibitor, and lavendustin A, a tyrosine kinase inhibitor (all given at doses previously shown to block late PC), indicating that ischemic PC activates NF-kappaB via formation of NO and ROS and activation of PKC- and tyrosine kinase-dependent signaling pathways. A subcellular redistribution and increased DNA binding activity of NF-kappaB quantitatively similar to those induced by ischemic PC could be reproduced pharmacologically by giving the NO donor diethylenetriamine/NO (DETA/NO) (at a dose previously shown to elicit late PC), demonstrating that NO in itself can activate NF-kappaB in the heart. Taken together, these results provide direct evidence that activation of NF-kappaB is a critical step in the signal transduction pathway that underlies the development of the late phase of ischemic PC in conscious rabbits. The finding that four different pharmacological manipulations (L-NA, MPG, chelerythrine, and lavendustin A) produced similar inhibition of NF-kappaB suggests that this transcription factor is a common downstream pathway through which multiple signals elicited by ischemic stress (NO, ROS, PKC, tyrosine kinases) act to induce gene expression. To our knowledge, this is the first demonstration that NO can promote NF-kappaB activation in the heart, a finding that identifies a new biological function of NO and may have important implications for various pathophysiological conditions in which NO is involved and for nitrate therapy.

Expression and prognostic value of proliferating cell nuclear antigen in transitional cell carcinoma of the urinary bladder.

Forty-eight patients with transitional cell carcinima (TCC) of the bladder were investigated. Routine paraffin-embedded sections were stained with proliferating cell nuclear antigen (PCNA) monoclonal antibody in order to determine the growth fraction of the bladder tumors and to correlate this with tumor grade, stage, development of recurrence and survival rate during follow-up. PCNA positive staining was detected in 95.8% (46/48) of the tumors. The mean labeling index (LI) of superficial tumors (Ta-1, n = 28) was 12.58 +/- 12.33%, and 34.55 +/- 21.89% in invasive tumors (T2-4, n = 18). A similar correlation was found in association with tumor grade. The patients were followed up for a mean of 4.9 years (range 1-14 years). The mean PCNA LI in nonrecurrent (n = 21) and simple recurrent (n = 7) superficial tumors was 11.29 +/- 11.79% and 16.44 +/- 14.05%, respectively, the difference not being statistically significant. To access survival, tumors with a PCNA LI above and below the median level (21%) were compared. Those patients (n = 19) with an index of > 21% (the mean of all the PCNA values) had a worse prognosis than those (n = 27) with an index of < 21%, a difference which is statistically significant. These results suggest that PCNA LI in bladder cancer may prove to be an objective and quantitative assay of biological aggressiveness and provide significant prognostic information, although it does not help the selection of patients at risk of simple recurrence in superficial tumors.

Pharmacodynamic modeling of bacterial kinetics: beta-lactam antibiotics against Escherichia coli.

A simple pharmacodynamic model has been developed to describe the bacterial kinetics exhibited by beta-lactam antibiotics. In contrast with previous models that only characterized the early killing phase of a time-kill curve, the present model is capable of simultaneously describing both the killing and regrowth phases. The model relied on the use of both first-order bactericidal and resistance formation rate constants to accurately define the time-dependent changes in the bacterial populations of an antibiotic-treated culture. The concentration dependency of the bactericidal rate constant was further delineated using a saturable-receptor model. Furthermore, an exponential decrease in the resistance formation rate with increasing antibiotic concentrations was demonstrated. The evolving pharmacodynamic model was also explored via computer simulations by perturbing the two governing rate constants. The model was subsequently applied to the description of time-kill data for amoxicillin, penicillin G, and cephalexin against Escherichia coli. The description of amdinocillin's action against E. coli was not as comprehensive because of the existence of a second killing phase. However, this model can be applicable to many classes of antibiotics that display the usual killing and regrowth phases in time-kill studies. The pharmacodynamic model can potentially improve the prediction of bacterial killing and regrowth and foster an improved understanding of complex antimicrobial pharmacodynamics.