Clinical implication of naive and memory T cells in locally advanced cervical cancer:A proxy for tumor biology and short-term response prediction

Background:This study was designed to investigate the feasibility of tumor-infiltrating immune cells with different phenotypic characteristics for predicting short-term clinical responses in patients with locally advanced cervical cancer(LACC).Methods:Thirty-four patients who received concurrent chemoradiotherapy and twenty-one patients who merely underwent radiotherapy were enrolled in this study.We retrospectively analyzed the T cell markers(i.e.,CD3,CD4,CD8),memory markers(i.e.,CD45,CCR7),and differentiation markers(i.e.,CD27)in the peripheral blood and tumor tissues of patients with LACC before treatment based on flow cytometry.We also analyzed the relationship of T cell subsets between peripheral blood and tumor tissues,and their correlation with complete response or partial response.Results:The percentage of central memory CD8^(+)TCM(CD8^(+)CD45RA^(−)CD27^(+)CCR7^(+))cells in LACC patients was significantly lower than that of the control group.The percentage of CD8^(+)TN in the peripheral blood of LACC patients was significantly higher than that of tumor tissues.CD8^(+)TEM in the peripheral blood was significantly lower than that of tumor tissues.The percentage of CD8^(+)TN and CD8^(+)TCM in human papillomavirus(HPV)positive samples was significantly higher than that of HPV-negative samples.Similarly,the percentage of CD8^(+)TCM in tumor tissues was significantly higher in cancer tissue samples with lymph nodes compared with those without.Conclusion:A higher proportion of CD4^(+)TCM and a lower proportion of CD8^(+)TN in the tumor microenvironment of LACC may contribute to the therapy response prediction.

Epidemiology and prognostic nomogram for locally advanced gastric signet ring cell carcinoma:A population-based study

BACKGROUND Gastric signet ring cell carcinoma(GSRC)represents a specific subtype of gastric cancer renowned for its contentious epidemiological features,treatment principles,and prognostic factors.AIM To investigate the epidemiology of GSRC and establish an improved model for predicting the prognosis of patients with locally advanced GSRC(LAGSRC)after surgery.METHODS The annual rates of GSRC incidence and mortality,covering the years 1975 to 2019,were extracted from the Surveillance,Epidemiology,and End Results(SEER)database to explore the temporal trends in both disease incidence and mortality rates using Joinpoint software.The clinical data of 3793 postoperative LAGSRC patients were collected from the SEER database for the analysis of survival rates.The Cox regression model was used to explore the independent prognostic factors for overall survival(OS).The risk factors extracted were used to establish a prognostic nomogram.RESULTS The overall incidence of GSRC increased dramatically between 1975 and 1998,followed by a significant downward trend in incidence after 1998.In recent years,there has been a similarly optimistic trend in GSRC mortality rates.The trend in GSRC showed discrepancies based on age and sex.Receiver operating characteristic curves,calibration curves,and decision curve analysis for 1-year,3-year,and 5-year OS demonstrated the high discriminative ability and clinical utility of this nomogram.The area under the curve indicated that the performance of the new model outperformed that of the pathological staging system.CONCLUSION The model we established can aid clinicians in the early prognostication of LAGSRC patients,resulting in improved clinical outcomes by modifying management strategies and patient health care.

Clinical analysis of concurrent chemoradiotherapy in 83 patients with locally advanced non-small cell lung cancer

Objective:The purpose of this study was to evaluate the efficacy and safety of concurrent chemoradiotherapy (CCRT) in patients with locally advanced non-small cell lung cancer (LANSCLC). Methods:83 cases of patients who have been diagnosed for locally advanced NSCLC by determined cytology or pathology were divided into two groups randomly, 42 patients in NP group and 41 patients in EP group. All patients accepted thoracic three-dimensional conformal radiotherapy (3D-CRT) and concurrent either NP chemotherapy in NP group or EP chemotherapy in EP group. 3D-CRT were started on day 1 in the first cycle of chemotherapy. Chemotherapy were carried out for 4 cycles, every cycle was 21 days. Thoracic radiotherapy adopted conventional fractionated irradiation with 15 MeV-X ray, a total dose of 60 Gy. Results: In 83 patients were evaluable, there were 5 cases complete regression to be observed, 29 cases had partial regression (PR), 7 cases with stable disease (SD) and 1 case with progression disease (PD) in NP group. CR 3 cases, PR 27 cases, SD 9 cases and PD 2 cases in EP group. The overall response rate (RR) both NP group and EP group were 80.9%, 73.2%, respectively (P = 0.785).1-, 2-, 3-year survival rate were 90.5%, 69.0%, 28.6% and 82.9%, 51.2%, 21.9%, respectively (P = 0.393). The incidence of leukopenia and thrombocytopenia in NP group was higher than that in the EP group (P < 0.05). Conclusion:CCRT in patients with locally advanced non-small cell lung cancer, 3D-CRT with concurrent NP or EP chemotherapy. 1-, 2-, 3-year overall survival (OS) and average survival time (AST) were not statistically differences, a higher incidence of toxicities were observed in NP group but can be tolerable.

The expression and prognostic value of protein tyrosine kinase 6 in early-stage cervical squamous cell cancer

Background:Protein tyrosine kinase 6(PTK6) is overexpressed in many epithelial tumors and predicts poor prognosis.However,PTK6 expression status and its role in cervical squamous cell cancer are unknown.This study aimed to investigate the expression level and clinical significance of PTK6 in early-stage cervical squamous cell cancer.Methods:Quantitative reverse transcription-polymerase chain reaction(qRT-PCR) and western blotting analysis were performed to detect PTK6 mRNA and protein expression levels in 10 freshly frozen,early-stage cervical squamous cell cancer specimens and adjacent non-tumorous cervical tissues.The expression of PTK6 was detected using immunohistochemical staining in 150 formalin-fixed,paraffin-embedded,early-stage cervical squamous cell cancer sections and 10 normal cervical tissue sections.Results:The mRNA and protein levels of PTK6 in cancer tissues were higher than those in adjacent non-tumorous cervical tissues.Immunohistochemical analysis showed that PTK6 was not expressed in normal cervical tissues but was overexpressed in the cytoplasm of cervical squamous cell cancer cells.The level of PTK6 expression was significantly associated with tumor grade(P = 0.020).The 5-year overall survival rate of patients with high PTK6 expression was lower than that of patients with low PTK6 expression(81.3%vs.96.2%,P = 0.008).Multivariate Cox regression analysis showed that the expression level of PTK6 in cervical squamous cell cancer was an independent prognostic factor for patient survival(hazard ratio = 5.999,95%confidence interval 1.622-22.191,P< 0.05).Conclusions:PTK6 is overexpressed in cervical squamous ceil cancer.Increased PTK6 expression is associated with reduced 5-year overall survival.PTK6 expression is an independent prognostic predictor for cervical cancer.

Nimotuzumab with Concurrent Chemoradiation in Inoperable Locally Advanced Squamous Cell Carcinoma of Head and Neck: An Indian Experience

Background: The prognosis of patients with Epidermal Growth Factor Receptor (EGFR) overexpression in inoperable Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN) remains poor. Nimotuzumab is an Anti EGFR humanized monoclonal antibody approved for treatment of LASCCHN, with concurrent chemoradiation. Objective: To assess the efficacy and safety of nimotuzumab with concurrent chemoradiation in inoperable LASCCHN patients. Methodology: This is a single-centre, single arm, retrospective study evaluating 35 patients with histologically confirmed inoperable LASCCHN (stages III-IV). The patients were administered IV cisplatin 50 mg/m2 and IV nimotuzumab 200 mg for 6 - 7 weeks, along with radiotherapy of 6600 - 7000 cGy over 35 fractions. Patients were evaluated over response evaluation criteria in solid tumors (RECIST) criteria 12 weeks after the last cycle of chemotherapy. They were also followed up for overall survival and relapse free survival. Results: The median duration of follow-up was 20 months. The most common site of cancer was oropharynx (68.6%). One patient was lost to follow up. Objective Response Rate (ORR) was observed in 97% of the patients with 17 patients (48.6%) achieving complete response (CR) and 17 patients (48.6%) achieving partial response (PR). The median overall survival was 22.7 months (95% CI: 21.30, 34.27). The median relapse free survival was 16.7 months (95% CI: 9.80, 24.50). Nimotuzumab was safe and well tolerated with few mild, self-limiting adverse events. Conclusion: Nimotuzumab with chemoradiation is a safe and efficacious option in patients with LASCCHN. Larger studies are needed to verify the same.

Nimotuzumab with Concurrent Chemo-Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of Head and Neck (LASCCHN)

Background: Head and neck cancers (HNCs) constitute 5% of all cancers globally and are the most common cancers in India. Chemotherapy and radiotherapy have not been proved to be effective in advanced cases and the prognosis remains dismal. This underscores the need for newer treatment options in these cases. Nimotuzumab, an anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody, was safer when combined with chemo- or radio-therapy. Aim: To evaluate the safety and efficacy of concurrently administered nimotuzumab with chemo-radiotherapy in patients with advanced inoperable squamous cell carcinomas of head and neck (LASCCHN). Methods:?This was an open-label, single arm study evaluating 57 patients with histologically confirmed inoperable LASCCHN (stages III and IV) and eastern co-operative oncology group (ECOG) performance status < 2. Informed consent was obtained from all patients. The patients were administered IV cisplatin 30 mg/m2?and IV nimotuzumab 200 mg weekly for 6 weeks, along with radiotherapy of 6600 cGy over 33 fractions. Patients were evaluated over response evaluation criteria in solid tumors (RECIST) criteria 24 weeks after the last cycle of chemotherapy. Results: Mean age of patient was 50 years old (29 - 79 years old). The most common site of cancer was oral cavity (56.1%). Forty six patients (80.7%) completed 6 cycles of therapy. Objective response rate (ORR) was 80.7%, with 34 patients (59.6%) achieving complete response (CR), and 12 (21%) achieving partial response (PR). Stable disease (SD) was noted in 8 (14%) patients and progressive disease in 3 (5.2%) patients. Conclusion: Addition of nimotuzumab is a safe and efficacious option in patients with inoperable LASCCHN. Our observations confirm the available Phase II data. The long term survival benefits based on this encouraging response rate need to be further evaluated in this subset of cancer patients.

Chemotherapy-free radiotherapy combined with immune checkpoint inhibitors:a new regimen for locally advanced non-small cell lung cancer?

Maintenance immunotherapy after concurrent chemoradiotherapy remains the standard therapeutic approach in patients with unresectable locally advanced non-small cell lung cancer(LA-NSCLC).The efficacy of pembrolizumab without chemotherapy in stage IV NSCLC has incited interest in similar approaches for LA-NSCLC.Several recent investigations involving the synergistic potential of immunotherapy combined with radiotherapy(i RT)have generated encouraging results.This review discusses the existing studies and prospective directions of chemotherapy-free i RT strategies in unresectable LA-NSCLC.Although the initial findings of chemotherapy-free i RT strategies have shown promising efficacy,we must consider the methodologic limitations of current studies and the myriad of challenges that accompany the implementation of chemotherapy-free i RT.These challenges include determining the optimal dose and fractionation,precise target volume delineation,and identification of additional suitable patient cohorts.Furthermore,the feasibility of chemotherapy-free i RT as a novel treatment modality for select patients with LA-NSCLC is contingent upon validation through randomized phase III trials.

Association between Pretreatment Levels of Serum Vascular Endothelial Growth Factor (VEGF) and Survival Outcomes in Locally Advanced Cervical Cancer Patients

Objective: To evaluate the association between pretreatment levels of serum vascular endothelial growth factor (VEGF) and long-term treatment outcomes in patients with locally advanced cervical cancer (LACC). Methods: Thirty-nine patients diagnosed with LACC (stage IIB-IVA) and obtaining blood for serum VEGF were identified. All patients received complete treatment as radical radiotherapy with or without concurrent chemotherapy. Surveillance for all patients was every 3 months during the first 2 years, and every 6 months later. Results: Mean age of 39 patients was 52.3 ± 10.8 years old. Twenty-three patients (59.0%) had stage IIB, and 16 patients (41.0%) had stage IIIB. Histological cell type was mostly squamous cell carcinoma (89.7%). The median and 75th percentile level of serum VEGF were 610.2 pg/ml (0.0 - 4067.2 pg/ml) and 825.6 pg/ml, respectively. At median follow-up of 37.0 months (range, 26.8 - 46.3 months), the 3-year OS rate was 78.6%. Clinical stage (p = 0.04) and 75th percentile of VEGF level (p = 0.04) were impacted on OS in univariable analysis. The 3-year OS of patients in stage IIB with serum VEGF of ≤825.6 pg/ml and of > 825.6 pg/ml was slightly different, 94.4% and 80.0% respectively (p = 0.34), whereas there were many differences in stage IIIB, 71.4% and 25.0% in patients with serum VEGF of ≤825.6 pg/ml and of >825.6 pg/ml respectively (p = 0.05). Conclusion: High pretreatment serum VEGF level has an influence on OS for LACC. It is potentially used as a predictive factor, especially in patients stage IIIB, in order to provide efficient treatment and improve survival outcomes in the future.

Neoadjuvant intra-arterial infusion chemotherapy followed by surgery in patients with locally advanced cervical cancer

Objective： The aim of this study was to investigate the role of preoperative neoadjuvant intra-arterial infusion chemotherapy （NAIC） in treating locally advanced cervical caner. Methods： Nineteen locally advanced cervical cancer （LACC） patients from November 2003 to November 2005 were analyzed retrospectively. NAIC was administrated 2 courses every 2 weeks using a combination of 30 mg/m^2 bleomycin and 50 mg/m^2 cisplatin via bilateral femur artedes. The response to NAIC was assessed by pelvic examination and imaging diagnostics and histological analysis. Two weeks after NAIC radical hysterectomy with pelvic lymphadenectomy was performed. Results： Radical hysterectomy with pelvic lymphadenectomy were performed in 18 patients successfully. The mean tumor reduction rate was 73.04%. The overall clinical response rate of NAIC was 84.2% with 2 complete responses and 16 partial responses. Only 1 nonresponder. Six of 7 cases who had parametrial infiltration had a absence after chemotherapy, no significant change was observed in 1 case who followed by radiotherapy. Multivariate logistic regression analysis indicated that tumor volume prior to treatment was determining factor affecting the efficacy of NAIC in LACC. Conclusion： pre-operative NAIC inhibited the growth of LACC, minimized the size, eliminate effectively the pathologic dsk factors in the pelvic cavity, to improve the operability in cervical cancer patients with stage lib or above, considered inoperable.

Effects of Yiqi Gu Ben Decoction combined with DC chemotherapy on serum tumor markers, inflammatory factors and immune function in patients with locally advanced non-small cell lung cancer

Objective: To investigate the effects of Yiqi Gu decoction combined with DC chemotherapy on serum tumor markers, inflammatory factors and immune function in patients with locally advanced non-small cell lung cancer. Methods: A total of 95 patients with locally advanced non-small cell lung cancer were selected as the research objects, according to the random data table they were divided into control group (n=48) and observation group (n=47), patients in the control group were given DC chemotherapy, On the basis of this treatment, the patients in the observation group were given Yiqi Gu decoction treatment, Comparison of the levels of serum tumor markers [antigen (CEA) and carbohydrate antigen 19-9 (CA19-9)], inflammatory factor [C reactive protein (CRP) and tumor necrosis factor-α (TNF-α)] and immune function (CD3+, CD4+, CD8+, CD4+/CD8+)Results: Before treatment, there were no significant difference in the levels of CEA, CA19-9, CRP, TNF-α, CD3+, CD4+, CD8+, CD4+/CD8+ between the two groups;After treatment, the CEA, CA19-9, CRP, TNF-α, CD8+ levels of two groups were significantly lower than those in the same group before treatment, and the decreased range in observation group was significantly higher than the control group, moreover the levels after treatment were obviously lower than control group;After treatment, the levels of CD3+, CD4+, CD4+/CD8+ in the observation group were (64.72±5.25)% , (39.51±5.14)% and (1.35±0.27), which were significantly higher than the same group before treatment, and significantly higher than the control group [(58.57±5.09)%, (31.34±5.06)%, (1.14±0.33)], differences were statistically significant. Conclusion: DC chemotherapy combined with Yiqi Guben Decoction in the treatment of locally advanced non-small cell lung cancer, can effectively reduce the serum tumor marker levels, decrease inflammatory stress, improve immune function, has an important clinical value.

Effects of combined treatment of bronchial arterial chemoembolization and radioactive particle implantation on tumor markers and T lymphocyte subsets in locally advanced non-small cell lung cancer

Objective: To investigate the effects of bronchial arterial chemoembolization combined with radioactive particle implantation on the level of serum tumor markers and T lymphocyte subsets in patients with locally advanced non-small cell lung cancer. Methods: A total of 91 cases of locally advanced non-small cell lung cancer patients according to the random data table were divided into the control group (n=45) and observation group (n=46) according to the random data table. Patients in the control group was treated with bronchial arterial chemoembolization, on the basis of the control group, patients in the observation group were treated with radioactive particle implantation, the serum tumor markers and T lymphocyte subsets of the two groups were compared before and after treatment. Results: The levels of CEA, NSE, CA125, CD4+, CD8+, CD4+/CD8+ and NK in the two groups before the treatment were not statistically significant. Compared with the group before treatment, levels of CEA, NSE, CA125and CD8+ of the two groups after treatment were significantly decreased, and after treatment the level of CEA, NSE, CA125and CD8+ in the observation group was significantly lower than those of the control group;The levels of CD4+, CD4+/CD8+ and NK in the two groups after treatment were significantly higher than those in the group before treatment, and the observation group levels were significantly higher than those of the control group. Conclusion: Bronchial artery embolization combined with radioactive particle implantation for locally advanced non-small cell lung cancer, can effectively reduce the serum tumor markers level, improve the level of T cell subsets of patients, has important clinical value.

The time-series behavior of systemic inflammation-immune status in predicting survival of locally advanced non-small cell lung cancer treated with chemoradiotherapy

Background:Systematic inflammation is believed to play a crucial role in tumorigenesis and metastasis.This study aims at evaluating the prognostic value of time-series behavior of systematic inflammation-immune status before and after definitive chemoradiotherapy(dCRT)in patients with locally advanced non-small cell lung cancer(LA-NSCLC).Methods:The relationship between systematic inflammation-immune score(SIS,defined as pretreatment periph-eral platelet count×neutrophil count/lymphocyte count)and the prognosis was tested in a retrospective study of 386 consecutive LA-NSCLC patients(Group A)with pretreatment SIS and 161 patients(Group B)with SIS before and one month after the dCRT.Results:SIS of 1400×10^(9)was found to be an optimal cutoffpoint to stratify the patients into high(>1400×10^(9))and low(≤1400×10^(9))SIS groups.Univariate and multivariate analyses revealed that the SIS,whether before or after dCRT,was an independent predictor for overall survival(OS),progress-free survival(PFS),and distant metastasis-free survival(DMFS).High SIS(>1400×10^(9))was shown to predict poor 3-year OS(P=0.006,hazard ratio[HR]=2.427),PFS(P=0.001,HR=2.442)and DMFS(P=0.015,HR=2.119).However,SIS was not related to local regional recurrence-free survival in either Group A(P=0.346)or Group B(P=0.486).Further,the area under the receiver operating characteristic curve of the SIS for OS was higher than the neutrophil count/lymphocyte count ratio,platelet count/lymphocyte count ratio,and other conventional clinic-pathological indices.Conclusions:The SIS is a stable and more sensitive survival predictor than other inflammation-based factors and conventional clinical indices,which may aid in more accurately stratifying patients for risk assessment and treatment decisions.

Effect of intensity-modulated radiotherapy combined with local hyperthermia on Mortalin expression in advanced liver cancer lesions and its relationship with cell proliferation and EMT

Objective:To investigate the effect of intensity-modulated radiotherapy combined with local hyperthermia on Mortalin expression in advanced liver cancer lesions and its relationship with cell proliferation and EMT.Methods: A total of 82 patients with advanced liver cancer who were treated in this hospital between February 2016 and September 2017 were chosen as the research subjects, and the therapeutic regimens were reviewed and used to divide these patients into the control group (n=43) who received intensity-modulated radiotherapy and the combined treatment group (n=39) who received intensity-modulated radiotherapy combined with local hyperthermia. Abdominal puncture was done after treatment to obtain liver cancer tissue samples, and the differences in Mortalin gene, cell proliferation gene and EMT gene expression in tissues were compared.Results: After treatment, Mortalin mRNA expression in liver cancer tissues of combined treatment group was lower than that of control group;Fbxw7 mRNA expression in liver cancer tissues was higher than that of control group whereas NCX1, PRMT5 and XBP1S mRNA expression were lower than those of control group;Twist, ZEB-1, ZEB-2, Snail and HOXB7 mRNA expression in liver cancer tissues were lower than those of control group. Pearson test showed that the Mortalin gene expression in liver cancer tissues was directly correlated with cell proliferation genes and EMT genes.Conclusion:Intensity-modulated radiotherapy combined with local hyperthermia can effectively reduce Mortalin gene expression, and further optimize patients'condition by inhibiting hepatic cell proliferation, EMT activity and other pathways.

Concurrent chemoradiotherapy for cervical cancer： background including evidence-based data, pitfalls of the data, limitation of treatment in certain groups

Concurrent chemoradiotherapy （CCRT） is regarded as the standard treatment for locally advanced uterine cervical cancer （LACC）, including stage Ib2-IVa disease [International Federation of Gynecology and Obstetrics （FIGO） staging]. However, approximately a third of eligible patients in previous studies died of LACC despite receiving CCRT. The therapeutic significance of CCRT alone in stage Ⅲ-IVa disease has not yet been confirmed. Effective treatment of some LACC is beyond the scope of CCRT. The objective of the present review is to highlight some challenging work aimed at overcoming this seemingly intractable disease. CCRT with increased peak concentrations of cisplatin （CDDP）, surgery following CCRT, adjuvant chemotherapy （CT） following CCRT, and neoadjuvant CT followed by CCRT are strategies expected to enhance the therapeutic efficacy of CCRT. If patients with LACC were divided into those with low-risk or high-risk systemic disease or prognoses, novel strategies should be assessed in the group with high-risk disease.

CLINICAL SIGNIFICANCES OF THE EXPRESSION OF METALLO- THIONEIN IN FIVE TYPES EPITHELIUM CELL CANCER

Objective： To study the expressions of （CSC）, bladder transitional cell cancer metallothionein and the significances in cervical squamous cell cancer （BTC）, esophageal squamous cell cancer （ESC）, gastral tubular adenocarcinoma （GC） and large intestinal tubular adenocarcinoma （LIC）. Methods： lmmunohistochemical method was used to examine the expression rates of MT in five types of cancer tissue. Results： The expression rates of MT were 75.00% （24/32） in ESC, 52.27% （46/88） in GTC, 59.46% （44/74） in LIC, 64.86% （48/74） in BTC and 58.57% （41/70） in CSC respectively. The positive rates of MT expression were higher in low differentiation and deep muscular group than those in medium or high differentiation and superficial muscular invasion group （P〈0.05）. Conclusion： The expression of MT is related to differentiation degree and invasion degree.

Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage Ⅲ non-small cell lung cancer:a preliminary report

Objective： In recent years, the combination of cetuximab and chemoradiotherapy （CRT） has been used to treat stage III non-small cell lung cancer （NSCLC）; however, limited data are available for Chinese patients. Herein, we report preliminary data from a phase I/II study testing the combination of cetuximab with inductive chemotherapy, followed by concurrent CRT （CCRT） in Chinese patients with stage III NSCLC. Methods： Eligibility criteria were Zubrod performance status （PS） 0-1, forced expiratory volume in 1 second （FEV1） 〉_1.2 L and adequate organ function. Enrolled patients received weekly cetuximab （initial dose of 400 mg/m2 on day 1 of week 1 and a maintenance dose of 250 mg/m2 on week 2 to the end of CCRT） with cisplatin/vinorelbine （NP） chemotherapy （every 3 weeks for 2 cycles from week 2, followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy （TRT） （60-66 Gy/2 Gy）. The primary endpoints were toxicity and feasibility. All patients received positron emission tomography- computerized tomography （PET-CT） scans within the 2 weeks prior to enrollment. Univariate analyses were used to assess the correlation between SUV-T, SUV-N, SUV-TOTAL, gender, age, histology, tumor-node- metastasis （TNM） stage, PS and smoking status and survival. Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test. Results： Seventeen patients were enrolled and 16 completed the full regime. The overall response rate （ORR） was 58.8% and 82.3% after the induction and CCRT phases, respectively. With a median follow-up duration of 27.6 months, the median survival was 27.6 months [95% confidence interval （CI）： 11.3-43.9 months] with 1- and 2-year survival rates of 88.2% （95% CI, 60.6-96.9%） and 58.8% （95% CI, 60.6-77.8%）, respectively. Three patients remain progression-free to date, and the median progression-free survival （PFS） was 13.5 months （95% CI, 6.8-20.2 months）. No treatment-related death occurred; however, 76% of the patients experienced grade 3＋ adverse events （AEs）, including nansea/vomiting, intestinal obstruction, and esophagitis （〈6%）, while other AEs were mostly of hematological nature （71%）. The cut-off values for SUV-T and SUV-TOTAL were 11 and 20, respectively. Univariate analyses revealed SUV-TOTAL （P=0.027）, SUV-T （P=0.025）, and PS （P=0.006） as potential survival predictors, with a hazard ratio （HR） of 3.4, 3.7, and 9.9, respectively. Conclusions： The combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising. Local and locoregional maximal SUVs, defined by 18F-FDG PET-CT scanning, may represent a prognostic indicator for long-term survival for these patients, which warrants further study.

Management of locally advanced non-small cell lung cancer: State of the art and future directions

Lung cancer is the second most common and the deadliest type of cancer worldwide.Clinically,non-small cell lung cancer(NSCLC)is the most com-mon pathological type of lung cancer;approximately one-third of affected patients have locally advanced NSCLC(LA-NSCLC,stage III NSCLC)at diag-nosis.Because of its heterogeneity,LA-NSCLC often requires multidisciplinary assessment.Moreover,the prognosis of affected patients is much below satisfac-tion,and the efficacy of traditional therapeutic strategies has reached a plateau.With the emergence of targeted therapies and immunotherapies,as well as the continuous development of novel radiotherapies,we have entered an era of novel treatment paradigm for LA-NSCLC.Here,we reviewed the landscape of relevant therapeutic modalities,including adjuvant,neoadjuvant,and periop-erative targeted and immune strategies in patients with resectable LA-NSCLC with/without oncogenic alterations;as well as novel combinations of chemora-diation and immunotherapy/targeted therapy in unresectable LA-NSCLC.We addressed the unresolved challenges that remain in the field,and examined future directions to optimize clinical management and increase the cure rate of LA-NSCLC.

Immune checkpoint inhibitors in head and neck squamous cell carcinoma:A systematic review of phase-3 clinical trials

BACKGROUND The outcomes of patients diagnosed with head and neck squamous cell carcinoma(HNSCC)who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal.A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors(ICIs).The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AIM To evaluate the evidence on the effectiveness of ICIs in HNSCC,based on published phase-3 clinical trials.METHODS We searched PubMed,Cochrane Library,Embase,and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC(R/M HNSCC)and locally advanced head and neck squamous cell carcinoma(LAHNSCC).We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma,recurrent,metastatic,locally advanced,immunotherapy,immune checkpoint inhibitors,monoclonal antibodies,programmed cell death protein-1(PD-1),programmed death-ligand 1(PD-L1),cytotoxic T-lymphocyte associated protein-4(CTLA-4),and phase-3 clinical trial.A sensitive search filter was used to limit our results to randomized controlled trials.RESULTS Five phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far:Four in R/M HNSCC and one in LAHNSCC.In patients with R/M HNSCC,anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care(standard singleagent systemic therapy).While the net gain in overall survival(OS)with nivolumab was 2.4 mo[hazard ratio(HR)=0.69,P=0.01],that with pembrolizumab was 1.5 mo(HR=0.80 nominal P=0.0161).The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T-lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes.In the first-line setting,in R/M HNSCC,pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo(HR=0.77,P=0.0034)in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive(combined positive score>20)population compared to standard of care(EXTREME regime).In patients with PD-L1 positive R/M HNSCC,monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.In LAHNSCC,immunotherapy using avelumab(an anti-PD-L1 agent)along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.CONCLUSION Anti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings,with acceptable toxicity profiles compared to standard therapy.There is no proven efficacy in the curative setting to date.

The impact of artificial intelligence-assisted intensity-modulated radiotherapy plan optimization on the radiation doses received by the rectum and bladder as well as radiation-induced injuries in patients with locally advanced cervical cancer

This study aimed to investigate the impact of artificial intelligence-assisted intensity-modulated radiotherapy(IMRT)plan optimization on the radiation doses received by the rectum and bladder as well as radiation-induced injuries in patients with locally advanced cervical cancer.A total of 100 patients with locally advanced cervical cancer were enrolled and divided into a conventional IMRT group and an artificial intelligence-assisted IMRT group.The results showed that in terms of the radiation doses to the rectum and bladder,all dosimetric parameters(such as mean dose,maximum dose,and volume-dose parameters,etc.)in the artificial intelligence-assisted group were significantly lower than those in the conventional group(p<0.05).Regarding radiation-induced injuries,the incidences and severities of both acute and late radiation-induced proctitis and cystitis in the artificial intelligence-assisted group were lower than those in the conventional group(p<0.05).These findings suggest that artificial intelligence-assisted IMRT plan optimization can effectively reduce the radiation doses to the rectum and bladder and decrease radiation-induced injuries in patients with locally advanced cervical cancer,which is expected to provide a more precise and safer treatment strategy for radiotherapy of locally advanced cervical cancer.However,this study has limitations such as a limited sample size and being a single-center study.Future research with multi-center,large-sample,and more in-depth investigations is needed.

Correlations between alterations of T-helper 17 cells and treatment efficacy after concurrent radiochemotherapy in locally advanced cervical cancer (stage IIB-IIIB): a 3-year prospective study

Background::Recently,T-helper 17(Th17)cells have been proved to play an important role in promoting cervical cancer.But,till now,few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments.This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer(LACC)patients before and after concurrent chemoradiotherapy(cCRT)and to analyze the correlations between the alterations in Th17 cells and treatment efficacy.Methods::A prospective study with 49 LACC(International federation of gynecology and obstetrics[FIGO]stage IIB-IIIB)patients and 23 controls was conducted.Patients received the same cCRT schedule and were followed up for 3 years.Circulating Th17 cells(CD3+CD8-interleukin[IL]-17+T cells)and related cytokines IL-17,transforming growth factor-β(TGF-β),IL-10,IL-23,IL-6,and IL-22 were detected before and after cCRT.Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed.Kaplan-Meier analysis was used for overall survival(OS)and progression-free survival(PFS).Results::We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study.The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls,and it significantly decreased after cCRT(P<0.05).After cCRT,patients were divided into two groups based on the average of the Th17 cells declined.The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times.Compared with the control patients,LACC patients had higher IL-6,IL-10,IL-22,TGF-βlevels and a lower IL-23 level(P<0.05).After cCRT,IL-6,IL-10,IL-17,IL-23 level significantly increased and TGF-βlevel significantly decreased compared with the levels before cCRT(P<0.05).Conclusion::Circulating Th17 cells in the LACC patients(FIGO stage IIB-IIIB)were higher than those in the controls,but they generally decreased after cCRT.A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.