Development and validation of an automated Tomotherapy planning method for cervical cancer.

PURPOSE: This study aimed to develop an automated Tomotherapy (TOMO) planning method for cervical cancer treatment, and to validate its feasibility and effectiveness. MATERIALS AND METHODS: The study enrolled 30 cervical cancer patients treated with TOMO at our center. Utilizing scripting and Python environment within the RayStation (RaySearch Labs, Sweden) treatment planning system (TPS), we developed automated planning methods for TOMO and volumetric modulated arc therapy (VMAT) techniques. The clinical manual TOMO (M-TOMO) plans for the 30 patients were re-optimized using automated planning scripts for both TOMO and VMAT, creating automated TOMO (A-TOMO) and automated VMAT (A-VMAT) plans. We compared A-TOMO with M-TOMO and A-VMAT plans. The primary evaluated relevant dosimetric parameters and treatment plan efficiency were assessed using the two-sided Wilcoxon signed-rank test for statistical analysis, with a P-value < 0.05 indicating statistical significance. RESULTS: A-TOMO plans maintained similar target dose uniformity compared to M-TOMO plans, with improvements in target conformity and faster dose drop-off outside the target, and demonstrated significant statistical differences (P+ < 0.01). A-TOMO plans also significantly outperformed M-TOMO plans in reducing V50Gy, V40Gy and Dmean for the bladder and rectum, as well as Dmean for the bowel bag, femoral heads, and kidneys (all P+ < 0.05). Additionally, A-TOMO plans demonstrated better consistency in plan quality. Furthermore, the quality of A-TOMO plans was comparable to or superior than A-VMAT plans. In terms of efficiency, A-TOMO significantly reduced the time required for treatment planning to approximately 20 min. CONCLUSION: We have successfully developed an A-TOMO planning method for cervical cancer. Compared to M-TOMO plans, A-TOMO plans improved target conformity and reduced radiation dose to OARs. Additionally, the quality of A-TOMO plans was on par with or surpasses that of A-VMAT plans. The A-TOMO planning method significantly improved the efficiency of treatment planning.

The relationship between the radiation dose of pelvic-bone marrow and lymphocytic toxicity in concurrent chemoradiotherapy for cervical cancer.

OBJECTIVE: The purpose of this study is to verify the correlation between medium and low radiation doses of the pelvic-bone marrow and the incidence of lymphocytic toxicity during concurrent chemoradiotherapy for cervical cancer. MATERIALS AND METHODS: This research included 117 cervical cancer patients, who received concurrent chemoradiotherapy. Radiotherapy included external-beam radiation therapy and brachytherapy. The dosimetry parameters include the Volume receiving 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), 30 Gy (V30), 40 Gy (V40), 50 Gy (V50), and the mean dose (D mean) of the bone marrow. Lymphocytic toxicity was calculated from lowest lymphocytic count after two cycles of concurrent chemotherapy. RESULTS: During concurrent chemoradiotherapy, the incidence of lymphocytic toxicity is 94.88%. The incidence of grade 3-4 toxicity is 68.38%. Multivariate analysis findings show that the dosimetry parameters V5, V10, V20, and V30 are significantly correlated with lymphocytic toxicity. The patients are divided into small-volume subgroups and large-volume subgroups based on the cutoff values. The relative risk of both grade 1-4 and grade 3-4 lymphocytic toxicity is significantly lower in the small-volume subgroups than in the large-volume subgroups (P < 0.05). Kaplan-Meier analysis shows that the incidence of both grade 1-4 and grade 3-4 lymphocytic toxicity of the small-volume subgroups is significantly lower than that of the large-volume subgroups (P < 0.05). CONCLUSION: There is a significant correlation between a medium and low dose of pelvic-bone-marrow radiation and incidence of lymphocytic toxicity. Reducing the volume of medium and low radiation doses could effectively reduce incidence of lymphocytic toxicity.

Toripalimab combined with concurrent platinum-based Chemoradiotherapy in patients with locally advanced cervical Cancer: an open-label, single-arm, phase II trial.

BACKGROUND: Concurrent chemoradiotherapy is currently the standard of care for patients with locally advanced cervical cancer. However, even with the application of modern radiotherapy techniques, a considerable number of patients still develop distant metastases. PD-L1 inhibitors show good efficacy in cervical cancer. This single-arm phase II study aims to explore the efficacy and tolerability of combining PD-L1 inhibitor with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. METHODS/DESIGN: The primary endpoint of the study was the objective response rate assessed according to RECIST v1.1 criteria. The inclusion criteria were previously untreated patients aged 18-75 years with stage III-IVA (FIGO 2018 staging system) locally advanced cervical cancer. During concurrent chemoradiotherapy and consolidation chemotherapy, the enrolled patients will receive toripalimab (240 mg) every 3 weeks. After consolidation chemotherapy, the enrolled patients will be treated with toripalimab (240 mg) once every 6 weeks until the whole treatment cycle reaches 1 year. Intensity modulated radiotherapy was used for external beam radiation, and high-dose rate brachytherapy was delivered under image-guidance. Weekly DDP (40 mg/m2) was given concurrently with radiotherapy while 6 cycles of consolidated chemotherapy (paclitaxel plus DDP) were given after radiotherapy every three weeks. Secondary objectives included safety and tolerability, toxicity profile, progression-free survival, and overall survival. DISCUSSION: PD-L1 inhibitor has shown good efficacy in recurrent/metastatic cervical cancer. However, there is still a lack of evidence about its combination with concurrent chemoradiotherapy in the treatment of locally advanced cervical cancer. The purpose of this study is to explore the efficacy and tolerance of this combination therapy, so as to lay the foundation for the future phase III randomized study. TRIAL REGISTRATION:  clinicaltrials.gov NCT05084677 . Retrospectively registered on Octorber 07, 2021.

Correction: Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer.

[This corrects the article DOI: 10.18632/oncotarget.11217.].

NS1-binding protein radiosensitizes esophageal squamous cell carcinoma by transcriptionally suppressing c-Myc.

BACKGROUND: Cisplatin-based chemotherapy with concurrent radiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma (ESCC). NS1-binding protein (NS1-BP), a member of the BTB-kelch protein family, has been shown to inhibit the proliferation of Hela cells by suppressing c-Myc. In the present study, we examined the potential function role of NS1-BP expression in ESCC, and particularly, the sensitivity of ESCC to radiotherapy. METHODS: NS1-BP expression was examined using immunohistochemistry in two cohorts (n = 98 for the training cohort; n = 46 for independent validation cohort) of ESCC patients receiving cisplatin-based chemotherapy and concurrent radiotherapy. Normal esophageal mucosal tissue blocks were used as a control. We also conducted a series of in vitro and in vivo experiments to examine the potential effects of over-expressing NS1-BP on ESCC cells, and particularly their sensitivity to ionizing irradiation. RESULTS: In the training cohort, NS1-BP downregulation was observed in 59% (85/144) of the ESCC specimens. NS1-BP downregulation was associated with chemoradiotherapeutic resistance and shorter disease-specific survival (DSS) in both the training and validation cohorts. Over-expressing NS1-BP in cultured ESCC cells substantially increased the cellular response to irradiation both in vitro and in vivo. NS1-BP also significantly enhanced IR-induced apoptosis, and abrogated IR-induced G2/M cell-cycle arrest and ATM/Chk1 phosphorylation. Immunoprecipitation assays indicated that NS1-BP could interact with c-Myc promoter regions to inhibit its transcription. In ESCC tissues, c-Myc expression was inversely correlated with NS1-BP levels, and was associated with a shorter DSS. CONCLUSIONS: Our findings highlight the role and importance of NS1-BP in radiosensitivity of ESCC. Targeting the NS1-BP/c-Myc pathway may provide a novel therapeutic strategy for ESCC.

Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer.

AIMS: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. PATIENTS AND METHODS: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. RESULTS: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. CONCLUSIONS: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

High expression of FUNDC1 predicts poor prognostic outcomes and is a promising target to improve chemoradiotherapy effects in patients with cervical cancer.

FUN14 domain containing 1 (FUNDC1) is an important molecule in receptor-dependent mitophagy. However, the roles of FUNDC1 in human cancer biology remain unknown. The aim of this study was to explore the expression and roles of FUNDC1 in cervical cancer. Immunohistochemistry and Western blotting were applied to detect the expression of FUNDC1, and small-hairpin RNA was applied to inhibit the expression of endogenous FUNDC1 in cervical cancer cells. MTT assays and Flow cytometric analysis were applied to examine cell proliferation and apoptosis. Immunofluorescence was used to detect the formation of γH2AX foci and evaluate the extent of DNA damage. Compared with corresponding adjacent noncancerous cervical tissues, the expression of FUNDC1 in cervical cancer cells was significantly increased. High expression of FUNDC1 and the prognosis of patients with cervical cancer were correlated negatively, which could be used as an independent prognostic factor for overall survival and disease-free survival. Depletion of FUNDC1 significantly inhibited the proliferation of tumor cells, induced apoptosis, and enhanced cell sensitivity to cisplatin and ionizing radiation (IR). Our data suggested that FUNDC1 can be used as a prognostic biomarker in patients with cervical cancer, and may be a new therapeutic target to improve the antitumor effects of chemoradiotherapy.

Halofuginone inhibits radiotherapy-induced epithelial-mesenchymal transition in lung cancer.

Radiotherapy is used to treat many different human tumors. Paradoxically, radiation can activate TGF-ß1 signaling and induce the epithelial-mesenchymal transition (EMT), which is associated with enhanced tumor progression. This study investigated the inhibitory effects of halofuginone, a plant-derived alkaloid that has been shown to inhibit TGF-ß1 signaling, on radiation-induced EMT and explored the underlying mechanisms using a Lewis lung carcinoma (LLC) xenograft model. The cells and animals were divided into five treatment groups: Normal Control (NC), Halofuginone alone (HF), Radiotherapy alone (RT), Radiotherapy combined with Halofuginone (RT+HF), and Radiotherapy combined with the TGF-ß1 inhibitor SB431542 (RT+SB). Radiation induced EMT in lung cancer cells and xenografts, as evidenced by increased expression of the mesenchymal markers N-cadherin and Vimentin, and reduced expression of the epithelial markers E-cadherin and Cytokeratin. Further, radiotherapy treatment increased the migration and invasion of LLC cells. Halofuginone reversed the EMT induced by radiotherapy in vitro and in vivo, and inhibited the migration and invasion of LLC cells. In addition, TGF-ß1/Smad signaling was activated by radiotherapy and the mRNA expression of Twist and Snail was elevated; this effect was reversed by halofuginone or the TGF-ß1 inhibitor SB431542. Our results demonstrate that halofuginone inhibits radiation-induced EMT, and suggest that suppression of TGF-ß1 signaling may be responsible for this effect.

The prognosis factor of adjuvant radiation therapy after surgery in uterine sarcomas.

OBJECTIVE: This retrospective study evaluated the role of adjuvant radiotherapy (AR) after surgery in patients with uterine sarcoma and analyzed the prognostic factors of local-regional failure-free survival (LRFFS) and overall survival (OS). PATIENTS AND METHODS: A study of a total of 182 patients with uterine sarcoma was conducted between June 1994 and October 2014. Adjuvant radiotherapy was defined as postoperative external beam radiation to the pelvis (30-50 Gray/10-25 fractions at five fractions/week). The primary end point was LRFFS, and the secondary end point was OS. Kaplan-Meier curves were compared using the log-rank test. Cox regression analyses were used to determine prognosticators for LRFFS and OS. RESULTS: The median follow-up time of all patients was 75 months, with a 5-year LRFFS of 62.1%. The 2-year and 5-year LRFFS rates were longer for those who received AR than for those who did not receive AR (83.4% vs 70.3%; 78% vs 55.3%; P=0.013). The 5-year OS of all patients was 56.2%, and no significant differences were observed in the 2-year and 5-year OS rates between these two groups (82.7% vs 71.4%; 64.1% vs 51.7%; P=0.067). Importantly, in patients with leiomyosarcoma, the 2-year and 5-year LRFFS and OS rates were longer for those who received AR than for those who did not receive AR (P=0.04 and P=0.02 for the 2-year and 5-year LRFFS, respectively). CONCLUSION: Patients with uterine sarcoma who were treated with AR after surgery demonstrated an improved LRFFS compared with those who were treated with surgery alone, especially those patients with leiomyosarcoma. Therefore, the role of personalized adjuvant radiation for patients with uterine sarcoma still requires further discussion.

Similar Outcomes of Standard Radiotherapy and Hypofractionated Radiotherapy Following Breast-Conserving Surgery.

BACKGROUND: Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. MATERIAL AND METHODS: Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. RESULTS: The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. CONCLUSIONS: A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.

Preliminary analysis of the risk factors for radiation pneumonitis in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy.

PURPOSE: The aim of this study was to investigate radiation pneumonitis and its associated risk factors in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy. MATERIALS AND METHODS: We conducted an analysis of patients with nonoperable stage IIIA-IV non-small-cell lung cancer who were treated with concurrent thoracic radiotherapy and erlotinib (ClinicalTrials.gov identifier: NCT00973310). The Common Terminology Criteria for Adverse Events version 3.0 grading system was applied to evaluate the incidence of radiation pneumonitis. The lung dosimetric parameters were recorded in accordance with the treatment plan, and the study endpoint was radiation pneumonitis at grade 2 or more. RESULTS: Among the 24 selected clinical cases, nine were identified with radiation pneumonitis of grade 2 or above (37.5%). This included four cases with grade 2 (16.7%), two cases with grade 3 (8.3%), and three cases with grade 5 (12.5%). The results showed that the planning target volume was a significant factor affecting the incidence of radiation pneumonitis. All lung dosimetric parameters exhibited statistically significant differences between patients with pneumonitis and patients without pneumonitis. The receiver operating characteristic (ROC) curve analysis showed that all lung dosimetric parameters were useful in predicting the incidence of radiation pneumonitis. In addition, the threshold values of V5, V10, V15, V20, V30, and mean lung dose were >44%, >29%, >27%, >22%, >17% and >1,027 cGy, respectively. CONCLUSION: Special attention should be paid to the adverse effects of radiation pneumonitis in concurrent thoracic radiotherapy and erlotinib treatment. Lung dosimetric parameters are important predictive factors in radiation pneumonitis.

[Concurrent chemoradiotherapy for stage III non-small cell lung cancer].

OBJECTIVE: To evaluate the immediate efficacy and acute toxicity of cisplatin-based induction chemotherapy followed by weekly concomitant chemoradiotherapy and concomitant chemoradiotherapy followed by consolidation chemotherapy in unresectable stage III NSCLC. METHODS: A total of 118 patients were pathologically diagnosed as stage III N SCLC. Among them, 77 patients (A group) received two cycles of cisplatin-based induction chemotherapy, followed by 6 weekly cycles of paclitaxel 45 mg/m(2) (n = 45) and gemcitabine 350 mg/m(2) (n = 32) in combination with thoracic radiotherapy; 41 patients (B group) received concomitant chemoradiotherapy (cisplatin 50 mg/m(2), d1, 8, 29, 36/etoposide 50 mg/m(2), d1-5, 29-33, n = 18, paclitaxel 45 mg/m(2)/weekly × 6/carboplatin AUC = 2/weekly × 6, n = 23) followed by consolidation chemotherapy. All thoracic radiotherapy dose are 2 Gy per fraction and day to a total dose of 58-60 Gy. RESULTS: The total response rate of A and B groups was 80.5% and 75.6% respectively (P = 0.534). According to subgroup analyses, no statistically significant differences existed according to chemotherapy (P = 0.557). The main side-effects were neutropenia, radiation esophagitis, radiation pneumonitis and nausea/vomiting. The gemcitabine group was statistically significant different in neutropenia. CONCLUSION: Different chemotherapeutic agents in combination with thoracic radiotherapy are clinically feasible with a moderate toxicity. Their profiles of efficacy and toxicity are comparable to each other.

[The relationship between Helicobacter pylori in oral cavity and the Hp infection in stomach].

OBJECTIVE: To analyze the relationship between Helicobacter pylori (Hp) in oral cavity and the Hp infection in stomach. METHODS: 102 patients with gastric Hp infection and periodontitis were enrolled in this study. DNA was extracted from subgingival plaques, mouthwashes and stomach mucosa samples by using the glass-milk (SiO2) purification method. To identify the presence of Hp in these samples, PCR (polymerase chain reaction) was carried out, and two pairs of oligonucleotide primer were used to amplify a portion of gene urease C and gene cag A of Hp. RESULTS: The rate of Hp detected in oral cavity was significantly higher in patients with positive Hp in stomach (43.1%, n=58) than in those with negative Hp in stomach (22.7%, n=44, P<0.05). After the treatment for gastric Hp infection for 4 weeks, the eradication rate of Hp in stomach was lower, but only slightly in patients with positive oral Hp (16/25, 64%) than in those with negative oral Hp (24/33, 72.7%). However, this difference became apparent (36.0% vs 63.6%, P<0.05) after one year of the treatment. CONCLUSIONS: The effectiveness of the eradication therapy for gastric Hp infection is affected by the presence of Hp in oral cavity. Oral colonization of Hp may imply that there is a risk of the relapses of gastric and duodenal Hp infection and ulcer after the antibiotics treatment for the eradication of Hp.