Concurrent Chemoradiotherapy Treatment Research Articles

Efficacy of Shenglin decoction in preventing acute severe lymphocytopenia in patients with non-small cell lung cancer undergoing concurrent chemoradiotherapy: a study protocol for a randomized controlled trial

BackgroundDefinitive concurrent chemoradiotherapy (CCRT) followed by maintenance therapy with immune checkpoint inhibitors offers the best chance of cure for patients with stage III non-small cell lung cancer (NSCLC). A significant challenge in this regimen is the occurrence of acute severe lymphopenia (ASL), which can compromise treatment efficacy. Currently, there are no effective strategies for preventing and treating ASL. Shenglin decoction (SLD), a traditional Chinese herbal medicine formulation, has demonstrated preliminary efficacy in mitigating ASL. However, robust evidence from clinical trials and a clear understanding of its mechanism of action are still needed. This study aims to comprehensively assess the efficacy, safety, and underlying mechanisms of SLD in the prevention of ASL.MethodsThis prospective, dual-center, open-label, randomized controlled trial will enroll 140 stage III NSCLC patients. Participants will be randomly allocated in a 1:1 ratio to a control group or an experimental group. Both groups will undergo definitive CCRT. Alongside the commencement of CCRT, the experimental group will receive an additional oral SLD intervention for a duration of three months. The primary outcome is the incidence rate of ASL, defined as the proportion of patients who experience at least one instance of a total lymphocyte count falling below 0.5 × 10^9 cells/L within 3 months of initiating CCRT treatment. Additionally, 16S rRNA gene sequencing analysis of fecal samples to assess gut microbiota, as well as metabolomic analysis of fecal/blood samples, will be conducted to explore potential mechanisms.DiscussionThis study protocol aims to rigorously evaluate the efficacy and safety of SLD, as well as elucidate its mechanism of action in preventing ASL. Successful outcomes could establish SLD as an evidence-based intervention for ASL prevention in NSCLC patients undergoing CCRT.Trial RegistrationThe trial was registered at the Chinese Clinical Trials Registry (ChiCTR2300071788, https://www.chictr.org.cn/).

Chemoradiotherapy treatment with gemcitabine improves renal function in locally advanced cervical cancer patients with renal dysfunction

BackgroundCervical cancer (CC) in Mexico is diagnosed mainly in locally advanced (LACC) and advanced (ACC) stages, where ureteral obstruction is more frequent. The standard treatment for this population is concurrent chemoradiotherapy (CCRT) with cisplatin, which is nephrotoxic and could lead to further deterioration of renal function in LACC patients with renal function decline. We aimed to evaluate the effect of CCRT with Gemcitabine on renal function in LACC patients. MethodsThis retrospective study included LACC patients treated with CCRT with Gemcitabine as a radiosensitizer from February 2003 to December 2018. Data were collected from medical archives and electronic records. We assessed renal function before and after CCRT treatment and analyzed the patient's response to treatment and survival. Results351 LACC patients treated were included and stratified into two groups: 198 with Glomerular Filtration Rate (GFR) ≥60ml/min (group A) and 153 with GFR<60ml/min (group B). An improvement in GFR was observed after CCRT in patients in group B, from 33 ml/min to 57.5 ml/min (p<0.001). Complete response was observed in 64.1% of patients in Group A and 43.8% in Group B (p<0.0001). Factors associated with increased risk of death included having a GFR of 15-29 ml/min (HR: 2.17; 1.08-4.35), having GFR<15 ml/min (HR: 3.08; 1.63-5.79), and receiving Boost treatment (HR: 2.09; 1.18-3.69). On the other hand, receiving brachytherapy is a positive predictor for OS (HR:0.51; 0.31-0.84). ConclusionCCRT with gemcitabine is an appropriate treatment option for patients diagnosed with LACC who present impaired renal function due to the disease's obstructive nature or other comorbidities.

Polymorphism at codon 31 of CDKN1A (p21) as a predictive factor for bevacizumab therapy in glioblastoma multiforme

Glioblastoma (GBM), a prevalent and malignant brain tumor, poses a challenge in surgical resection due to its invasive nature within the brain parenchyma. CDKN1A (p21, Waf-1), a cyclin-dependent kinase inhibitor, plays a pivotal role in regulating cell growth arrest, terminal differentiation, and apoptosis. The existence of natural variants of CDKN1A has been associated with specific cancer types. In this retrospective study, our objective was to identify polymorphic variants of CDKN1A, specifically c.93C > A (codon 31 Ser31Arg), and investigate its potential impact within the scope of bevacizumab therapy for glioblastoma multiforme. This study involved a cohort of 139 unrelated adult Chinese GBM patients in Taiwan. Genomic DNA extracted from tumor samples was utilized for genotyping using the polymerase chain reaction (PCR) restriction fragment length polymorphism method (PCR–RFLP analysis). Through unconditional logistic regression analysis, odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Our findings unveiled that among these GBM patients, the distribution of codon 31 polymorphisms was as follows: 23.02% were Serine homozygotes (Ser/Ser), 27.34% were Arginine homozygotes (Arg/Arg), and 49.64% were Serine/Arginine heterozygotes (Ser/Arg). While CDKN1A c.93C > A polymorphisms did not exhibit a direct association with overall survival in GBM patients, noteworthy survival benefits emerged among individuals with Arg/Arg and Arg/Ser genotypes who received combined concurrent chemoradiotherapy (CCRT) and bevacizumab treatment compared to those who underwent CCRT alone. Our findings indicate a significant involvement of the CDKN1A c.93C > A polymorphism in the development and onset of GBM, offering potential implications for the early prognostication of bevacizumab therapy outcomes.

CAN008 prolongs overall survival in patients with newly diagnosed GBM characterized by high tumor mutational burden

BackgroundA previous phase 1 dose-escalation study in Taiwan indicated CAN008 (asunercept) with standard concurrent chemoradiotherapy (CCRT) improved progression-free survival (PFS) in newly diagnosed glioblastoma (GBM) patients. This study evaluates the efficacy of CAN008 in promoting overall survival (OS) and identifies genetic alterations associated with treatment responses. MethodsWe compared OS of 5-year follow-ups from 9 evaluable CAN008 cohort patients (6 received high-dose and 3 received low-dose) to a historical Taiwanese GBM cohort with 164 newly diagnosed patients. CAN008 treatment response-associated genetic alterations were identified by whole-exome sequencing and comparing variant differences between response groups. Associations among patient survival, tumor mutational burden (TMB), and genetic alterations were analyzed using CAN008 cohort and TCGA-GBM dataset. ResultsOS for high-dose CAN008 patients at 2 and 5 years was 83% and 67%, respectively, and 40.1% and 8.8% for the historical GBM cohort, respectively. Better OS was observed in the high-dose CAN008 cohort (without reaching the median survival) than the historical GBM cohort (median OS: 20 months; p = 0.0103). Five high-dose CAN008 patients were divided into good and poor response groups based on their PFS. A higher variant count and TMB were observed in good response patients, whereas no significant association was observed between TMB and patient survival in the newly diagnosed TCGA-GBM dataset, suggesting TMB may modulate patient CAN008 response. ConclusionCAN008 combined with standard CCRT treatment prolonged the PFS and OS of newly diagnosed GBM patients compared to standard therapy alone. Higher treatment efficacy was associated with higher TMB.

High Thioredoxin Domain-Containing Protein 11 Expression Is Associated with Tumour Progression in Glioma.

Glioblastoma (GBM) is the most common primary brain malignancy in adults. Despite multimodal treatment that involves maximal safe resection, concurrent chemoradiotherapy, and tumour treatment for supratentorial lesions, the prognosis remains poor. The current median overall survival is only <2 years, and the 5-year survival is only 7.2%. Thioredoxin domain-containing protein 11 (TXNDC11), also known as EF-hand binding protein 1, was reported as an endoplasmic reticulum stress-induced protein. The present study aimed to elucidate the prognostic role of TXNDC11 in GBM. We evaluated the clinical parameters and TXNDC11 scores in gliomas from hospitals. Additionally, proliferation, invasion, migration assays, apoptosis, and temozolomide (TMZ)-sensitivity assays of GBM cells were conducted to evaluate the effects of short interfering RNA (siRNA) on these processes. In addition, these cells were subjected to Western blotting to detect the expression levels of N-cadherin, E-cadherin, and Cyclin D1. High levels of TXNDC11 protein expression were significantly associated with World Health Organization (WHO) high-grade tumour classification and poor prognosis. Multivariate analysis revealed that in addition to the WHO grade, TXNDC11 protein expression was also an independent prognostic factor of glioma. In addition, TXNDC11 silencing inhibited proliferation, migration, and invasion and led to apoptosis of GBM cells. However, over-expression of TXNDC11 enhanced proliferation, migration, and invasion. Further, TXNDC11 knockdown downregulated N-cadherin and cyclin D1 expression and upregulated E-cadherin expression in GBM cells. Knock-in TXNDC11 return these. Finally, in vivo, orthotopic xenotransplantation of TXNDC11-silenced GBM cells into nude rats promoted slower tumour growth and prolonged survival time. TXNDC11 is a potential oncogene in GBMs and may be an emerging therapeutic target.

Survival after induction chemotherapy in locoregional advanced nasopharyngeal carcinoma: An updated systematic review and meta-analysis.

Induction chemotherapy (ICT) augmentation is a common strategy for standard concurrent chemoradiotherapy (CCRT) of locoregionally advanced nasopharyngeal carcinoma (NPC). The survival condition is a crucial issue for patients with locoregionally advanced NPC. The survival of ICT patients with CCRT treatment versus standard CCRT alone should be elucidated via a systemic review and meta-analysis of randomized clinical trials. We compared ICT with CCRT and CCRT alone treatment to determine if ICT with CCRT can be associated with a significant benefit of survival conditions versus CCRT. Different survival indicators were analyzed for the ICT with CCRT. Twelve studies with a total of 3711 patients with locoregionally advanced NPC were enrolled. The focused outcome was the overall survival, progression-free survival, distant metastasis-free survival, and locoregional recurrence-free survival. Our results showed that ICT with CCRT is associated with a significant benefit for the overall survival status versus CCRT treatment. Similar significant benefits in the survival condition were seen in progression-free survival, distant metastasis-free survival, and locoregional recurrence-free survival. The updated meta-analysis results suggest that the ICT with CCRT might be associated with significant benefits of survival in overall, progression-free, distant metastasis-free, as well as locoregional recurrence-free dimensions versus CCRT treatment. However, the bias of different kinds, doses, and regimens of chemotherapy agents and radiotherapy should not be ignored.

Initial analysis of the synergy of programmed cell death-1 (PD-1) inhibitor and concurrent chemoradiotherapy treatment for recurrent/metastatic head and neck squamous cell carcinoma patients

BackgroundProgrammed cell death-1 (PD-1) inhibitor was proven to be useful for the recurrent/metastatic head and neck squamous carcinoma (R/M HNSCC) patients. Though both PD-1 inhibitor alone and combination with chemotherapy showed some benefit for PFS and OS, the survival outcome was still not satisfactory. Some studies showed the possible benefit for PD-1 inhibitors combination with radiation for head and neck squamous carcinoma, however there was few studies concerned about synergy of concurrent PD-1 inhibitor combination with chemoradiotherapy for R/M HNSCC. So, we aimed to explore the potential effect and toxicity of the concurrent PD-1 inhibitor and chemoradiotherapy for R/M HNSCC.MethodsWe consecutively enrolled the R/M HNSCC patients treated with concurrent PD-1 inhibitor and chemoradiotherapy from August 2018 to April 2022 in Sichuan Cancer hospital. All the patients received the combination of PD-1 inhibitor and chemotherapy, and followed with synergy of concurrent PD-1 inhibitor and chemoradiotherapy, then maintenance PD-1 inhibitor. ORR and DCR was calculated by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST-1.1), and Common terminology criteria for adverse events (CTCAE-4.0) was used to evaluate the toxicity.The Kaplan–Meier method was used to analyze OS and PFS.Results40 R/M HNSCC patients were enrolled in our stuty. The median follow up time was 14 months. 22 patients had recurrent disease only, 16 patients had metastatic disease only, and 2 patients had both recurrence and metastasis disease. For the recurrent lesions, 23 patients received a median radiation dose of 64 Gy (range 50–70 Gy). 18 patients received a median dose of 45 Gy (range 30–66 Gy) for metastatic lesions. The median courses of PD-1 inhibitors and chemotherapy were 8 and 5 respectively. After the treatment, the ORR and DCR were 70.0% and 100%. The median OS was 19 months (range 6.3–31.7 months), with 1 and 2-years OS rates of 72.8% and 33.3%. The median PFS was 9 months (range 3.1–14.9 months), with 6 and 12 months PFS rates of 75.5% and 41.4% respectively. The PFS had no statistical significance in PD-L1 negative and positive group (7 vs 12 months, p = 0.059). The most common grade 3 or 4 adverse events(AE) were leucopenia (25.0%), neutropenia (17.5%), anemia (10.0%), thrombocytopenia (5.0%), hyponatremia (2.5%), and pneumonia(2.5%). No grade 5 AE was observed.ConclusionsThe synergy of concurrent PD-1 inhibitor treatment with chemoradiotherapy shows promise as a treatment strategy and an acceptable toxicity for the R/M HNSCC patients.

Treatment patterns and outcomes among locally advanced cervical cancer patients receiving concurrent chemoradiotherapy.

e17511 Background: Concurrent chemoradiotherapy (CCRT) is standard treatment for patients with locally advanced cervical cancer (LACC). However, little is known on the real-world treatment patterns and outcomes among LACC patients. This study evaluated patient characteristics and treatment patterns of LACC patients, and real-world outcomes among patients receiving CCRT as the first treatment after diagnosis (CCRT-first) in US academic and community settings. Methods: Data were drawn from the ConcertAI Oncology Dataset, a US-based electronic medical record dataset. We included adult patients diagnosed between 2010-2018 with LACC, defined as stage IB2-IIB with node involvement or stage III-IVA cervical cancer, with squamous cell carcinoma (excl. verrucous), adenocarcinoma (excl. clear cell and endometroid), or adenosquamous carcinoma. Patients with prior immunotherapy or a second primary cancer (other than in situ or non-melanoma skin cancer) were excluded. Patients were followed from initial diagnosis through end of the second regimen of systemic anti-cancer therapy, end of record, or death, whichever occurred first. Patient characteristics and treatments were reported overall and in CCRT-first patients. Among CCRT-first patients, real-world time on CCRT treatment (rwTOT), recurrence-free survival (rwRFS), and progression-free survival (rwPFS) among patients with persistent disease were estimated using Kaplan-Meier methods. Results: Overall, 300 patients with LACC were included. At LACC diagnosis, median age of patients was 51 years, 53.7% were White, 30.0% were Black, 48.0% were peri/postmenopausal, 89.3% had squamous cell histology, 75.3% had stage III disease, 92.7% had no evidence of performance status impairment, 50.3% were treated in community settings, and 21.7% had only public insurance (11.0% Medicaid, 10.7% Medicare; 56.3% had no documentation of insurance). Distributions were similar among CCRT-first patients. First treatment after diagnosis included CCRT (N=229), surgery (N=28), systemic therapy (N=11), and radiation therapy alone (N=5). 27 were untreated, and 29 patients received CCRT after another therapy. Of the 229 CCRT-first patients, median (95% CI) rwTOT was 1.6 (1.4-1.7) months; 78.2% received cisplatin within CCRT, and median duration of cisplatin treatment was 35 days; 28.4% received a systemic therapy after CCRT, and 11.8% further initiated a second systemic therapy. 27 patients had recurrent disease after complete response (median rwRFS not reached). 179 patients had persistent disease after CCRT, among whom median (95% CI) rwPFS was 29.7 (16.9-59.3) months from CCRT start. Conclusions: In US clinical practice during 2010-2018, most LACC patients received CCRT as the first treatment after diagnosis. The high proportion of patients who develop persistent disease after CCRT indicates a need for improved first treatment options.

Support and information needs for patients with non-small cell lung cancer receiving concurrent chemo-radiotherapy treatment with curative intent: Findings from a qualitative study.

Concurrent chemotherapy and radiotherapy treatment (CCRT) is used to treat locally advanced Non-Small Cell Lung Cancer (NSCLC) in patients with suitable fitness. CCRT is associated with significant toxicity and time spent receiving treatment. Our aim was to identify the support and information needs of patients, and where possible their informal caregivers (IC), at key points along the CCRT pathway. Participants were NSCLC patients who were either about to undergo, currently receiving or had finished CCRT. Semi-structured interviews were conducted with participants, and their IC where applicable, at the treatment centre or participants' home. Interviews were audio recorded and transcribed prior to undergoing thematic analysis. Fifteen patients were interviewed; five were interviewed with their IC. Themes of physical, psychological, and practical support needs are identified with associated subthemes exploring specific needs, such as dealing with late treatment effects, and how patients seek support. Information needs prior to, during and following CCRT were also established as predominant themes with subthemes detailing the needs at these time points. Examples include differences in participant desire for toxicity information and life after treatment. The need for disease, treatment and symptom related information and support remains consistent throughout CCRT and beyond. Further information and support for other matters including engaging in regular activities may also be desired. Time allocated within consultations to establish changes in needs or desire for further information may benefit patient and IC experience and QOL.

Performance of Pretreatment MRI-Based Radiomics in Recombinant Human Endostatin Plus Concurrent Chemoradiotherapy Response Prediction in Nasopharyngeal Carcinoma: A Retrospective Study.

To investigate the capability of an Magnetic resonance imaging (MRI) radiomics model based on pretreatment texture features in predicting the short-term efficacy of recombinant human endostatin (RHES) plus concurrent chemoradiotherapy (CCRT) for nasopharyngeal carcinoma (NPC). We retrospectively enrolled 65 patients newly diagnosed as having NPC and treated with RHES + CCRT. A total of 144 texture features were extracted from the MRI before RHES + CCRT treatment of all the NPC patients. The maximum relevance minimum redundancy (mRMR) method was used to remove redundant, irrelevant texture features, and calculate the Rad score of the primary tumor. Multivariable logistic regression was used to select the most predictive features subset, and prediction models were constructed. The performance of the 3 models in predicting the early response of RHES + CCRT for NPC was explored. The diagnostic efficiency of combined model and radiomics model in distinguishing between the effective and the ineffective groups of patients was found to be moderate. The area under the ROC curve (AUC) of the combined model and radiomics model was 0.74 (95% confidence interval [CI]: 0.62-0.86) and 0.71 (95% CI: 0.58-0.84), respectively, with both being higher than the AUC of the clinics model (0.63, 95% CI: 0.49-0.78). Compared with the radiomics model, the combined model showed marginally improved diagnostic performance in predicting RHES + CCRT treatment response. The accuracy of combined model and radiomics model for RHES + CCRT response assessment in NPC were higher than those of the clinics model (0.723, 0.723 vs 0.677). The pretreatment MRI-based radiomics may be a noninvasive and effective method for the prediction of RHES + CCRT early response in patients with NPC.

Comparison of dynamic changes in the peripheral CD8+ T cells function and differentiation in ESCC patients treated with radiotherapy combined with anti-PD-1 antibody or concurrent chemoradiotherapy.

The systematic immune status of cancer patients undergoing immunotherapy is little known. We prospectively identified the function and differentiation traits of peripheral CD8+ T cells based on our phase 1b clinical trial (NCT03222440) of radiotherapy combined with camrelizumab in patients with locally advanced esophageal squamous cell carcinoma (ESCC) and compared it with concurrent chemoradiotherapy (CCRT). 19 and 18 patients were included in the cohort of radiotherapy plus camrelizumab and cohort of CCRT treatment. By using flow cytometry, we evaluated the expression levels of PD-1, Eomes, T-bet and IFN-γ (function), CD38 and HLA-DR (activation), and differentiation subsets classified according to the expression levels of CD45RA and CD62L in peripheral CD8+ T cells before and during treatment. Effective binding of anti-PD-1 antibody camrelizumab with PD-1 on CD8+ T cells was detected during treatment. Both two treatments elevated the expression levels of activation molecules CD38 and HLA-DR on CD8+ T cells. PD-1+CD8+ T cells had more activation features than PD-1-CD8+ T cells in two groups and the treatments did not alter these differences. The two treatments activated both PD-1+ and PD-1- CD8+ T cells. PD-1+CD8+ T cells had less Naïve and TEMRA but more Tcm and Tem than PD-1-CD8+ T cells in two groups and both two treatments changed the ratio of memory T cells in PD-1+ and PD-1- cells. RT plus camrelizumab treatment reduced Naïve T cells and TEMRA subsets both in PD-1+ and PD-1- CD8+ T cells while elevated Tcm subset in PD-1+CD8+ T cells and Tem subset in PD-1-CD8+ T cells. CCRT elevated Tcm subset and reduced TEMRA subset in PD-1-CD8+ T cells while did not change any subset in PD-1+CD8+ T cells. Furthermore, patients undergoing radiotherapy plus immunotherapy were found to obtain better prognosis than those receiving CCRT. This study identified the dynamic changes of systematic immune status of patients undergoing treatment. The two treatments had similar activation effects on peripheral CD8+ T cells with different PD-1 properties but had different effects on their differentiation status. These results provided potential clues to the reasons underlying the difference in prognosis of the two treatments.

Response Prediction Using 18F-FAPI-04 PET/CT in Patients with Esophageal Squamous Cell Carcinoma Treated with Concurrent Chemoradiotherapy.

This prospective study examined whether imaging results obtained using the tracer 18F-AlF-NOTA-fibroblast activation protein inhibitor (FAPI)-04 (denoted as 18F-FAPI-04) in PET/CT can predict the short-term outcome in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) treated with concurrent chemoradiotherapy (CCRT). Methods: The 18 enrolled LA-ESCC patients underwent 18F-FAPI-04 PET/CT scanning before CCRT. The SUVmax, SUVmean, SUVpeak, metabolic tumor volume, and total lesion fibroblast activation protein expression of the primary tumor were recorded. Additionally, the SUVmax of the primary tumor and SUVmean of normal tissue (muscle and blood) were measured, and their ratios were denoted as target-to-background ratios (TBRmuscle and TBRblood). Patients were classified as responders or nonresponders according to RECIST (version 1.1), and variables were compared between the 2 groups. Results: The TBRblood, TBRmuscle, and SUVmean were significantly higher in nonresponders than in responders (all P < 0.05). Receiver-operating-characteristic curve analysis identified TBRblood (area under the curve [AUC], 0.883; P = 0.008), TBRmuscle (AUC, 0.896; P = 0.006) and SUVmean (AUC, 0.870; P = 0.010) as significant predictors of the response to CCRT, with cutoffs of 10.68, 10.95, and 6.88, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were also determined for TBRblood (100.0%, 72.7%, 66.7%, 88.9%, and 77.8%, respectively), TBRmuscle (100.0%, 72.7%, 66.7%, 88.9%, and 77.8%, respectively), and SUVmean (85.7%, 81.8%, 75.0%, 90.0%, and 83.3%, respectively). On univariate logistic regression analysis, TBRblood (P = 0.026), TBRmuscle (P = 0.036), SUVmean (P = 0.045), and tumor site (P = 0.032) were significantly correlated with the short-term outcome. On multivariable logistic regression analysis, TBRblood (P = 0.046) was an independent prognostic factor for short-term outcome. Conclusion: A higher baseline TBRblood on 18F-FAPI-04 PET/CT scans was associated with a poor response to CCRT in LA-ESCC patients, and thus, TBRblood may be useful for screening LA-ESCC patients before CCRT treatment.

HIF-1α Expression Increases Preoperative Concurrent Chemoradiotherapy Resistance in Hyperglycemic Rectal Cancer.

Simple SummaryPreoperative Concurrent Chemoradiotherapy (CCRT) is one of the standard treatments for patients with locally advanced rectal cancer. However, the efficacy of CCRT in hyperglycemic rectal cancer patients does not seem to be as expected. Therefore, we used clinical specimens, ectopic hyperglycemia animal models, and rectal cancer cells in a high-glucose environment to confirm how the high-glucose environment causes radiation resistance. The results confirmed that the high-glycemic environment could induce the overexpression of HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. In future, HIF-1α inhibitors might be used as sensitizers to improve the efficacy of hyperglycemic rectal cancer patients receiving CCRT.Purpose: Preoperative concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced rectal cancer patients. However, the poor therapeutic efficacy of CCRT was found in rectal cancer patients with hyperglycemia. This study investigated how hyperglycemia affects radiochemotherapy resistance in rectal cancer. Methods and Materials: We analyzed the correlation between prognosis indexes with hypoxia-inducible factor-1 alpha (HIF-1α) in rectal cancer patients with preoperative CCRT. In vitro, we investigated the effect of different concentrated glucose of environments on the radiation tolerance of rectal cancers. Further, we analyzed the combined HIF-1α inhibitor with radiation therapy in hyperglycemic rectal cancers. Results: The prognosis indexes of euglycemic or hyperglycemic rectal cancer patients after receiving CCRT treatment were investigated. The hyperglycemic rectal cancer patients (n = 13, glycosylated hemoglobin, HbA1c > 6.5%) had poorer prognosis indexes. In addition, a positive correlation was observed between HIF-1α expression and HbA1c levels (p = 0.046). Therefore, it is very important to clarify the relationship between HIF-1α and poor response in patients with hyperglycemia receiving pre-operative CCRT. Under a high glucose environment, rectal cancer cells express higher levels of glucose transport 1 (GLUT1), O-GlcNAc transferase (OGT), and HIF-1α, suggesting that the high glucose environment might stimulate HIF-1α expression through the GLUT1-OGT-HIF-1α pathway promoting tolerance to Fluorouracil (5-FU) and radiation. In the hyperglycemic rectal cancer animal model, rectal cancer cells confirmed that radiation exposure reduces apoptosis by overexpressing HIF-1α. Combining HIF-1α inhibitors was able to reverse radioresistance in a high glucose environment. Lower HIF-1α levels increased DNA damage in tumors leading to apoptosis. Conclusions: The findings here show that hyperglycemia induces the expression of GLUT1, OGT, and HIF-1α to cause CCRT tolerance in rectal cancer and suggest that combining HIF-1α inhibitors could reverse radioresistance in a high glucose environment. HIF-1α inhibitors may be useful for development as CCRT sensitizers in patients with hyperglycemic rectal cancer.

Predicting Chemo-Radiotherapy Sensitivity With Concordant Survival Benefit in Non-Small Cell Lung Cancer via Computed Tomography Derived Radiomic Features.

BackgroundTo identify a computed tomography (CT) derived radiomic signature for the options of concurrent chemo-radiotherapy (CCR) in patients with non-small cell lung cancer (NSCLC).MethodsA total of 226 patients with NSCLC receiving CCR were enrolled from public dataset, and allocated to discovery and validation sets based on patient identification number. Using CT images of 153 patients in the discovery dataset, we pre-selected a list of radiomic features significantly associated with 5-year survival rate and adopted the least absolute shrinkage and selection operator regression to establish a predictive radiomic signature for CCR treatment. We performed transcriptomic analyzes of the signature, and evaluated its association with molecular lesions and immune landscapes in a dataset with matched CT images and transcriptome data. Furthermore, we identified CCR resistant genes positively correlated with resistant scores of radiomic signature and screened essential resistant genes for NSCLC using genome-scale CRIPSR data. Finally, we combined DrugBank and Genomics of Drug Sensitivity in Cancer databases to excavate candidate therapeutic agents for patients with CCR resistance, and validated them using the Connectivity Map dataset.ResultsThe radiomic signature consisting of nine features was established, and then validated in the dataset of 73 patients receiving CCR log-rank P = 0.0005, which could distinguish patients into resistance and sensitivity groups, respectively, with significantly different 5-year survival rate. Furthermore, the novel proposed radiomic nomogram significantly improved the predictive performance (concordance indexes) of clinicopathological factors. Transcriptomic analyzes linked our signature with important tumor biological processes (e.g. glycolysis/glucoseogenesis, ribosome). Then, we identified 36 essential resistant genes, and constructed a gene-agent network including 10 essential resistant genes and 35 candidate therapeutic agents, and excavated AT-7519 as the therapeutic agent for patients with CCR resistance. The therapeutic efficacy of AT-7519 was validated that significantly more resistant genes were down-regulated induced by AT-7519, and the degree gradually increased with the enhanced doses.ConclusionsThis study illustrated that radiomic signature could non-invasively predict therapeutic efficacy of patients with NSCLC receiving CCR, and indicated that patients with CCR resistance might benefit from AT-7519 or CCR treatment combined with AT-7519.

P-140 Simple endoscopic scoring of patients with rectal cancer after concurrent chemoradiation therapy

Neoadjuvant concurrent chemoradiotherapy (CCRT) is an effective treatment option for patients with rectal cancer. In this study, we investigated the clinical efficacy of simple endoscopic scoring of patients with rectal cancer after CCRT. Between July 2008 and October 2015, medical records including endoscopic imaging from 41 patients with rectal cancer who received CCRT were retrospectively reviewed. Two expert gastroenterologists reviewed the endoscopic images and assigned scores from 0–3 according to post-CCRT findings. The scoring criteria were as follows: 0=no ulcer; 1=clean-based ulcer without marginal elevation; 2=clean-based ulcer with marginal elevation; 3=non-clean-based ulcer. We evaluated image scores to predict long-term outcomes using Kaplan-Meier curves and Cox regression models. The median follow-up duration was 55 months (interquartile range: 35–76). Patients with a low score (≤2) had a 17.2% recurrence rate, whereas patients with a high score (3) had a 50.0% recurrence rate. Patients with a low score had longer disease-free survival (DFS) than those with a high score in log-rank test (p=0.026). In multivariate Cox regression analysis, a high score was a significant predictor of poor DFS in patients with rectal cancer after CCRT treatment (hazard ratio=4.89, 95% confidence interval: 1.11–21.50, p=0.036). This simple endoscopic scoring approach is helpful for predicting prognosis of patients with rectal cancer after treatment with CCRT.

Concurrent Chemoradiotherapy-Driven Cell Plasticity by miR-200 Family Implicates the Therapeutic Response of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common and fatal malignancy with an increasing incidence worldwide. Over the past decade, concurrent chemoradiotherapy (CCRT) with or without surgery is an emerging therapeutic approach for locally advanced ESCC. Unfortunately, many patients exhibit poor response or develop acquired resistance to CCRT. Once resistance occurs, the overall survival rate drops down rapidly and without proper further treatment options, poses a critical clinical challenge for ESCC therapy. Here, we utilized lab-created CCRT-resistant cells as a preclinical study model to investigate the association of chemoradioresistantresistance with miRNA-mediated cell plasticity alteration, and to determine whether reversing EMT status can re-sensitize refractory cancer cells to CCRT response. During the CCRT treatment course, refractory cancer cells adopted the conversion of epithelial to mesenchymal phenotype; additionally, miR-200 family members were found significantly down-regulated in CCRT resistance cells by miRNA microarray screening. Down-regulated miR-200 family in CCRT resistance cells suppressed E-cadherin expression through snail and slug, and accompany with an increase in N-cadherin. Rescuing expressions of miR-200 family members in CCRT resistance cells, particularly in miR-200b and miR-200c, could convert cells to epithelial phenotype by increasing E-cadherin expression and sensitize cells to CCRT treatment. Conversely, the suppression of miR-200b and miR-200c in ESCC cells attenuated E-cadherin, and that converted cells to mesenchymal type by elevating N-cadherin expression, and impaired cell sensitivity to CCRT treatment. Moreover, the results of ESCC specimens staining established the clinical relevance that higher N-cadherin expression levels associate with the poor CCRT response outcome in ESCC patients. Conclusively, miR-200b and miR-200c can modulate the conversion of epithelial–mesenchymal phenotype in ESCC, and thereby altering the response of cells to CCRT treatment. Targeting epithelial–mesenchymal conversion in acquired CCRT resistance may be a potential therapeutic option for ESCC patients.

The best postoperative adjuvant therapy for patients with early stage cervical adenosquamous carcinoma

BackgroundCervical adenosquamous carcinoma (ASC) was previously thought to be a subtype of cervical adenocarcinoma, but recent studies have found that the clinical features of the two diseases are different. Moreover, the pathological characteristics, survival, prognosis, and optimal ASC therapy remain unknown. This study aims to retrospectively analyze the postoperative survival of patients with early-stage ASC and to evaluate their condition after treatment with postoperative concurrent chemoradiotherapy (CCRT) and prophylactic irradiation of the para-aortic lymphatic drainage area.MethodsThis study enrolled 131 patients with pathologically confirmed ASC screened from 3502 patients with confirmed stage I–II cervical cancer diagnosis who had completed surgical treatments in our hospital. Among the 131 enrolled patients, 75 patients received CCRT, 33 patients received chemotherapy (CT), and 23 patients did not receive adjuvant treatment (named surgery alone (S alone). Of the 75 patients CCRT, 43 patients received prophylactic irradiation of the para-aortic lymphatic drainage area. The efficacy of the postoperative treatments of patients among groups (CCRT, CT, and S alone) was compared.ResultsThe median follow-up time, age, and overall survival (OS) were 76 months, 43 years, and 74 months, respectively. The 3- and 5-year survival rates were 82% and 71.4%, respectively. The median disease-free survival (DFS) was 64 months. Cox regression analysis showed that postoperative adjuvant treatment modalities and positive lymph node metastases were associated with OS and DFS. Patients who received CCRT treatment had higher OS and DFS than those with CT and S alone. Prophylactic irradiation of the para-aortic lymphatic drainage area did not improve the OS and DFS of patients with CCRT treatment. However, further subgroup analysis suggested that it might improve survival rates in patients who had positive pelvic lymph nodes as confirmed by postoperative pathology.ConclusionPostoperative CCRT improved the survival rates in patients with early-stage ASC. The value of prophylactic irradiation of the para-aortic lymphatic drainage area remains debatable, but it may benefit patients with pelvic lymph node involvement.

Isaacs\u2019 syndrome as the initial presentation of malignant thymoma and associated with double-positive voltage-gated potassium channel complex antibodies, a case report

BackgroundIsaacs’ syndrome is a peripheral nerve hyperexcitability (PNH) syndrome due to peripheral motor nerve instability. Acquired Isaacs’ syndrome is recognized as a paraneoplastic autoimmune disease with possible pathogenic voltage-gated potassium channel (VGKC) complex antibodies. However, the longitudinal correlation between clinical symptoms, VGKC antibodies level, and drug response is still unclear.Case presentationA 45-year-old man had progressive four limbs soreness, muscle twitching, cramps, and pain 4 months before admission. Electromyography (EMG) studies showed myokymic discharges, neuromyotonia, and an incremental response in the high-rate (50 Hz) repetitive nerve stimulation (RNS) test. Isaacs’ syndrome was diagnosed based on clinical presentations and EMG reports. Serum studies showed positive VGKC complex antibodies, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. The acetylcholine receptor antibody was negative. Whole-body computed tomography (CT) and positron emission tomography revealed a mediastinal tumor with the great vessels encasement, right pleura, and diaphragm seeding. Biopsy confirmed a World Health Organization type B2 thymoma, with Masaoka stage IVa. His symptoms gradually improved and both LGI1 and CASPR2 antibodies titer became undetectable after concurrent chemoradiotherapy (CCRT) and high dose steroid treatment. However, his Isaacs’ syndrome recurred after the steroid was reduced 5 months later. Follow-up chest CT showed probable thymoma progression. LGI1 antibody turned positive again while CASPR2 antibody remained undetectable.ConclusionsOur patient demonstrates that Isaacs’ syndrome could be the initial and only neuromuscular manifestation of malignant thymoma. His Isaacs’ syndrome is correlated well with the LGI1 antibody level. With an unresectable thymoma, long-term immunosuppressant therapy may be necessary for the management of Isaacs’ syndrome in addition to CCRT for thymoma.

Predictive Value of Albumin and Neutrophil-to-Lymphocyte Ratio Score for Treatment Completeness and Safety Profiles in Patients With Head and Neck Cancer Receiving Definitive Concurrent Chemoradiotherapy.

Malnutrition and inflammation are common conditions in patients with head and neck cancer (HNC). This study aimed to evaluate the predictive value of albumin combined with neutrophil-lymphocyte ratio (NLR), referring to the albumin-NLR score (ANS), in the prediction of treatment completeness and safety profiles in HNC patients receiving definitive concurrent chemoradiotherapy (CCRT). 461 consecutive HNC patients who received CCRT between 2016 and 2017 at three medical centers in Taiwan were prospectively enrolled and divided into three different groups based on their pretreatment ANS (ANS 0, high albumin and low NLR; ANS 1, low albumin or high NLR; and ANS 2, low albumin and high NLR) for treatment completeness and safety profiles comparison. Overall, 46 patients (10.0%) had incomplete CCRT treatment. Patients in the ANS 2 group experienced a higher rate of incomplete CCRT (20.9%) than those in the ANS 1 (7.4%) and ANS 0 (3.5%) groups. ANS had a better discriminatory ability in predicting CCRT completeness in terms of -2 log-likelihood value, chi-square value, and c-index than the prognostic nutritional index. Patients in the ANS 2 group had significantly higher incidences of grade 3 or higher leukopenia, anemia, neutropenia, thrombocytopenia, non-neutropenic infection, and hypokalemia than those in the other two ANS groups. Our study showed that the ANS can accurately predict the treatment completeness of CCRT in patients with HNC and can be widely used as a simple predictor of treatment tolerance and safety profiles in patients with HNC undergoing CCRT.

Pretreatment anemia status and elevated PLR affect the prognosis of locally advanced cervical squamous cell carcinoma patients treated with concurrent chemoradiotherapy

Objective: To assess the prognostic value of platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) in locally advanced cervical squamous cell carcinoma (LACSC) treated with concurrent chemoradiotherapy (CCRT) regimens. Methods: The contribution of systemic immune inflammatory response markers (NLR, PLR, LMR, SII), inflammatory cells (lymphocytes, neutrophils, monocytes, platelets), and hematocrit in predicting the outcomes of concurrent chemoradiotherapy treatment in LACSC patients was examined using the Kaplan-Meier univariate survival analysis method. Variables that were significant for the univariate analysis were included in the multivariate regression analysis to confirm the independent prognostic factors affecting concurrent chemoradiotherapy in LACSC patients. Results: Univariate analysis showed that age (p = 0.024), PLR (p = 0.007), NLR (p = 0.089), LMR (p = 0.021), SII (p = 0.087), and Hb (p = 0.004) were all prognostic factors affecting OS (over survival). Multivariate regression analysis revealed that PLR (p = 0.066) and Hb (p = 0.045) before concurrent chemoradiotherapy were independent risk factors of OS in the studied population. Moreover, these two factors were significantly correlated (correlation coefficient Rs = –0.426, p = 0.000). Conclusions: The results suggested that elevated PLR and anaemia are likely to have poorer prognoses in LACSC patients who initially received radical CCRT. Moreover, pre-treatment anemia status may exacerbate the prognostic effects of PLR.