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.

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.

Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study

Background:Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer(CLAP study;NCT03816553).We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival.The outcomes of patients who underwent immune checkpoint inhibitor(ICI)retreatment were also reported.Methods:In this phase II trial,eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years.Treatment was continued until disease progression,unacceptable toxicity,or withdrawal of consent.Results:Between January 21 and August 1,2019,a total of 45 patients were enrolled.Data were analyzed as of July 31,2023,representing>48 months since treatment initiation for all patients.Nine(20.0%)patients completed the 2-year study.The median duration of response(DOR)was 16.6 months,and 45.0%of patients achieved a DOR of≥24 months.The 12-month progression-free survival(PFS)rate was 40.7%(95%confidence interval[CI],25.2-55.6),with an 18-month PFS rate of 37.8%(95%CI,22.7-52.8).The median overall survival(OS)was 20.3 months(95%CI,9.3-36.9),and the 24-month OS rate was 47.8%(95%CI,31.7-62.3).Age>50 years,programmed death-ligand 1(PD-L1)combined positive score(CPS)≥1(versus[vs.]<1),CPS≥10(vs.<1),high tumor mutational burden,and PIK3CA mutations were associated with improved PFS(hazard ratio[HR]<1)and longer OS(HR<1).Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs.Among them,2(25.0%)achieved a partial response,while 5(62.5%)had stable disease.Notably,four patients who received retreatment with ICIs survived for more than 45months.No new safety signals were identified in the present study.Conclusion:Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust,sustained,and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy.No new safety signals were noted with long-term treatment.

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.

Specific Immunotherapy in Advanced Cervical-Uterine Cancer Using Humanized Monoclonal Antibody Nimotuzumab and CIMAvax-EGF^®Therapeutic Vaccine

Cervical uterine cancer represents the fourth most common malignant neoplasm worldwide in the female sex in terms of incidence, principally from epithelial origen. The high expression of EGFR in this tumor leads to the search for therapeutic alternatives. An Expanded Access Clinical Program was carried out in parallel groups, randomized, multicenter and prospective study, to evaluate the survival of patients with advanced cervical carcinoma, without therapeutic alternative, who would be treated with the therapeutic vaccine CIMAvax-EGF®, the humanized mAb nimotuzumab or the combination of both products, which targeted EGF and EGFR respectively. The patients were included between 2008 and 2010 with a more than five years follow-up. The results show that the serious adverse events related to the experimental treatments were 0.9%;1.1% and 2.6% and a median ITT survival of 9.1, 23.5, and 16.3 months for CIMAvax-EGF®, nimotuzumab and the combination of both, respectively. Thus fulfilling the hypothesis of safety and efficacy proposed in the investigation was achieved. The three therapeutic regimens achieved overall survival rates greater than 35% at 60 months, encouraging results for advanced uterine cervical cancer. A phase III clinical trial is proposed to consolidate these results in a greater number of patients with nimotuzumab as study drug.

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.

Evaluation of the Factors Associated with Delay in Initiation of Treatment of Advanced Stage Cervical Cancer Patients in Bangladesh

Research Background: Cervical cancer is the second most common cancer in women and the third leading cause of female cancer death in Bangladesh. Delay in initiation of treatment in advanced stage cervical cancer patients is an important modifiable risk factor for cancer-related mortality. Identifying elements associated with delay of diagnosis will help reduce barriers to timely treatment of cervical cancer. Research Objectives: The objective of this study was to analyze the factors leading to delay in diagnosis and treatment of women with advanced stage cervical cancer. Methods: A cross-sectional observational study analyzed the factors associated with delay in initiation of treatment for 138 patients with advanced-stage cervical cancer from November 2019 to October 2020 at the National Institute of Cancer Research and Hospital (NICRH) in Dhaka, Bangladesh. Advanced-stage cervical cancer patients between the ages of 30 to 70 years were included in this study. Face-to-face interviews with the participants used a predesigned data collection sheet. In this study, three components of delay were identified: primary delay due to patient factors, healthcare provider delay, and healthcare-system infrastructure delay. Factors associated with delay were the independent variables and durations of delay were the outcome variables. Descriptive statistics were expressed as mean + standard deviation, median, percentage, and frequency. Results: One hundred and thirty-eight patients with advanced stage cervical cancer were included in the study. The mean age of the patients was 48.74 (±9.57) years. Thirty-four percent of patients were illiterate. More than half (57.25%) of the patients were from lower middle-class families. Delays were categorized as patient-related, healthcare provider delay, and healthcare-system infrastructure related. Patient-related factors included low monthly income, residence in a rural area, embarrassment, fear, lack of knowledge regarding cervical cancer, delay in contacting a spouse, family member or friend prior to the first medical encounter. These elements predicted a primary delay of more than 60 days (P value Conclusion: Three broad categories of delay in diagnosis and treatment of cervical cancer: patient-related factors, healthcare provider-related factors, and healthcare-system infrastructure factors were analyzed. Illiteracy, lack of awareness regarding cervical cancer, lack of health-seeking behavior, and poor income status were associated with patient-related primary delay. Nonperformance of speculum examination in the initial consultation, misdiagnosis, inappropriate management, and delay in referral to the cancer treatment center by primary healthcare providers were the contributing factors for healthcare provider delay. Lack of availability and accessibility of health services and limitation of radiotherapy resources led to healthcare-system infrastructure delays. All three categories of delay must be addressed through the education of communities, the gynecologic training of community healthcare providers, the improvement of medical infrastructure, and the increase of medical resources.

Different strategies of treatment for uterine cervical carcinoma stage ⅠB2-ⅡB

Uterine cervical cancer is the second most common gynecological malignancy. It is estimated that over 35% of tumors are diagnosed at locally advanced disease, stage ⅠB2-ⅡB with an estimated 5-year overall survival of 60%. During the last decades, the initial treatment for these women has been debated and largely varies through different countries. Thus, radical concurrent chemoradiation is the standard of care in United Sated and Canada, and neoadjuvant chemotherapy followed by radical surgery is the first line of treatment in some institutions of Europe, Asia and Latin America. Until today, there is no evidence of which strategy is better over the other. This article describe the evidence as well as the advantages and disadvantages of the main strategies of treatment for women affected by uterine cervical cancer stage ⅠB2-ⅡB.