Fecal Microbiota Transplantation Repairs Radiation Enteritis Through Modulating the Gut Microbiota-Mediated Tryptophan Metabolism.

Radiation enteritis is a common complication of abdominal and pelvic radiotherapy. Several previous studies showed that fecal microbiota transplantation (FMT) could alleviate radiation enteritis. In this study, we investigated the efficacy of FMT in alleviating radiation enteritis and explored the mechanisms by multi-omics approaches. Briefly, C57BL/6J mice were subjected to 9 Gy irradiation to the localized abdominal field, and randomized received FMT from healthy donor mice or saline. H&E staining of harvested small intestine showed FMT decreased epithelial injury. Radiation-induced microbiota dysbiosis, characterized by a decrease in beneficial bacteria Lactobacillaceae and Lachnospiraceae, while these bacteria were restored by FMT. Fecal metabolomics analysis revealed that FMT modulated metabolic dysregulation. Two tryptophan pathway metabolites, indole-3-acetaldehyde and N-Acetyl-5-hydroxytryptamine were decreased after irradiation, whereas these metabolites showed a pronounced recovery in mice receiving FMT. Proteomics analysis of small intestine indicated that radiation enteritis triggered immune-inflammatory responses, which were potentially mitigated by FMT. In 21 patients receiving pelvic radiotherapy for cervical cancer, those who developed enteritis (n = 15) had higher abundance in Lachnospiraceae. Moreover, Indole-3-acetaldehyde was reduced after irradiation. These findings provide insights into the therapeutic effects of FMT in radiation enteritis and highlight Lachnospiraceae and the tryptophan metabolite, Indole-3-acetaldehyde may protect against radiation enteritis.

Automatic reconstruction of interstitial needles using CT images in post-operative cervical cancer brachytherapy based on deep learning.

Purpose: The purpose of this study was to investigate the precision of deep learning (DL)-based auto-reconstruction in localizing interstitial needles in post-operative cervical cancer brachytherapy (BT) using three-dimensional (3D) computed tomography (CT) images. Material and methods: A convolutional neural network (CNN) was developed and presented for automatic reconstruction of interstitial needles. Data of 70 post-operative cervical cancer patients who received CT-based BT were used to train and test this DL model. All patients were treated with three metallic needles. Dice similarity coefficient (DSC), 95% Hausdorff distance (95% HD), and Jaccard coefficient (JC) were applied to evaluate the geometric accuracy of auto-reconstruction for each needle. Dose-volume indexes (DVI) between manual and automatic methods were used to analyze the dosimetric difference. Correlation between geometric metrics and dosimetric difference was evaluated using Spearman correlation analysis. Results: The mean DSC values of DL-based model were 0.88, 0.89, and 0.90 for three metallic needles. Wilcoxon signed-rank test indicated no significant dosimetric differences in all BT planning structures between manual and automatic reconstruction methods (p > 0.05). Spearman correlation analysis demonstrated weak link between geometric metrics and dosimetry differences. Conclusions: DL-based reconstruction method can be used to precisely localize the interstitial needles in 3D-CT images. The proposed automatic approach could improve the consistency of treatment planning for post-operative cervical cancer brachytherapy.

Evaluation of auto-segmentation for brachytherapy of postoperative cervical cancer using deep learning-based workflow.

Objective. The purpose of this study was to evaluate the accuracy of brachytherapy (BT) planning structures derived from Deep learning (DL) based auto-segmentation compared with standard manual delineation for postoperative cervical cancer.Approach. We introduced a convolutional neural networks (CNN) which was developed and presented for auto-segmentation in cervical cancer radiotherapy. The dataset of 60 patients received BT of postoperative cervical cancer was used to train and test this model for delineation of high-risk clinical target volume (HRCTV) and organs at risk (OARs). Dice similarity coefficient (DSC), 95% Hausdorff distance (95%HD), Jaccard coefficient (JC) and dose-volume index (DVI) were used to evaluate the accuracy. The correlation between geometric metrics and dosimetric difference was performed by Spearman's correlation analysis. The radiation oncologists scored the auto-segmented contours by rating the lever of satisfaction (no edits, minor edits, major edits).Main results. The mean DSC values of DL based model were 0.87, 0.94, 0.86, 0.79 and 0.92 for HRCTV, bladder, rectum, sigmoid and small intestine, respectively. The Bland-Altman test obtained dose agreement for HRCTV_D90%, HRCTV_Dmean, bladder_D2cc, sigmoid_D2ccand small intestine_D2cc. Wilcoxon's signed-rank test indicated significant dosimetric differences in bladder_D0.1cc, rectum_D0.1ccand rectum_D2cc(P< 0.05). A strong correlation between HRCTV_D90%with its DSC (R= -0.842,P= 0.002) and JC (R= -0.818,P= 0.004) were found in Spearman's correlation analysis. From the physician review, 80% of HRCTVs and 72.5% of OARs in the test dataset were shown satisfaction (no edits).Significance. The proposed DL based model achieved a satisfied agreement between the auto-segmented and manually defined contours of HRCTV and OARs, although the clinical acceptance of small volume dose of OARs around the target was a concern. DL based auto-segmentation was an essential component in cervical cancer workflow which would generate the accurate contouring.

Clinical implementation of three-dimensional standardized template-guided brachytherapy for patients with locally advanced cervical cancer.

Purpose: Although customized three-dimensional (3D) templates have shown advantages in brachytherapy, widespread application is still full of challenges. The present work proposed the use of a commercial 3D standardized template-guided intracavitary/interstitial brachytherapy (IC/ISBT) that could provide simple and reproducible needles' insertion. Material and methods: 43 patients received external beam radiotherapy (EBRT) with 45-50.4 Gy and subsequent IC/ISBT with 28 Gy in 4 fractions. In terms of IC/ISBT, 24 patients were treated with 3D standardized templates (ST group), and 19 patients were treated using free-hand implantation (FH group). Consistency of implantation for all needles and dosimetric differences for target and organs at risk (OARs) were then compared between two groups. Results: The mean variation of tip position between insertions for needles was 1.41 mm and 2.74 mm in ST group and FH group, respectively (p < 0.001). ST group was superior in terms of dosimetric conformity index (CI) and D90 for high-risk clinical target volume (HR-CTV), significantly improving to 23.21% (p < 0.001) and 3.58% (p = 0.031) compared with FH group. The D2cc of the bladder and sigmoid in the ST group were lower than those in the FH group (p < 0.05). Meanwhile, a strong correlation between the volume of HR-CTV and its CI in the ST group (R = 0.865, p < 0.001) was found with Spearman's correlation analysis. Conclusions: The implementation of 3D standardized template can potentially improve the precision and consistency in the needle insertion procedure that may replace some customized 3D templates, and achieve clinical satisfied dose distribution in IC/ISBT plans for patients with LACC.

Association between the location of transposed ovary and ovarian dose in patients with cervical cancer treated with postoperative pelvic radiotherapy.

BACKGROUND AND PURPOSE: How to protect the ovarian function during radiotherapy is uncertain. The purpose of this study was to explore the association between the location of the transposed ovary and the ovarian dose in patients with cervical cancer received radical hysterectomy, ovarian transposition, and postoperative pelvic radiotherapy. METHODS: A retrospective analysis was conducted of 150 young patients with cervical cancer who received radical hysterectomy, intraoperative ovarian transposition, and postoperative adjuvant radiotherapy in Zhejiang Cancer Hospital. Association between location of the transposed ovaries and ovarian dose was evaluated. The transposed position of ovaries with a satisfactory dose was explored using a receiver operator characteristic curve (ROC) analysis. Patients' ovarian function was followed up 3 months and 1 year after radiotherapy. RESULTS: A total of 32/214 (15%) transposed ovaries were higher than the upper boundary of the planning target volume (PTV). The optimum cutoff value of > 1.12 cm above the iliac crest plane was significantly associated with ovaries above the upper PTV boundary. When the ovaries were below the upper boundary of PTV, the optimum cutoff value of transverse distance > 3.265 cm between the ovary and PTV was significantly associated with ovarian max dose (Dmax) ≤ 4Gy, and the optimum cutoff value of transverse distance > 2.391 cm was significantly associated with ovarian Dmax≤5Gy. A total of 77 patients had received complete follow-up, and 56 patients (72.7%) showed preserved ovarian function 1 year after radiotherapy, which was significantly increased compared with 3 months (44.2%) after radiotherapy. CONCLUSIONS: The location of transposed ovaries in patients with cervical cancer is significantly correlated with ovarian dose in adjuvant radiotherapy. We recommend transposition of ovaries > 1.12 cm higher than the iliac crest plane to obtain ovarian location above PTV. When the transposed ovary is below the upper boundary of PTV, ovarian Dmax ≤4Gy may be obtained when the transverse distance between the ovary and PTV was > 3.265 cm, and the ovarian Dmax≤5Gy may be obtained when the transverse distance was > 2.391 cm.

Prognostic value of the 2018 FIGO staging system for cervical cancer patients with surgical risk factors.

Objective: To determine the predictive value of the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system for cervical cancer patients with surgical risk factors. Methods: Data of 662 cervical cancer patients (stages IB and IIA) with surgical risk factors treated at Zhejiang Cancer Hospital between 2008 and 2011 were retrospectively reviewed. Univariate log-rank test and multivariate Cox regression models were adopted to evaluate the relationship between 2018 FIGO stage and survival. Results: On re-staging of patients, 17.3%, 44.5%, 25.4%, and 37.1% of the patients with FIGO 2009 stage IB1, IB2, IIA1, and IIA2, respectively, were upgraded to FIGO 2018 IIIC1P stage, and 2.1%, 3.0%, 3.1%, and 2.1% patients, respectively, were upgraded to IIIC2P stage. The 5-year overall survival (OS) rates of patients with FIGO 2018 stage IB1, IB2, IB3, IIA1, IIA2, IIIC1P, and IIIC2P were 95.3%, 95.1%, 90.4%, 92.4%, 86.4%, 81.9%, and 56.3%, respectively. The 5-year progression-free survival (PFS) rates were 94.0%, 91.0%, 88.5%, 91.4%, 86.4%, 79.5%, and 43.8%, respectively. The 5-year OS rates of patients with 1-2 positive pelvic lymph nodes (PLNs) and those with >2 positive PLNs were 86.0% and 73.7%, respectively, and the 5-year PFS rates were 84.2% and 70.2%, respectively. OS and PFS of patients with 1-2 positive PLNs in stage IIIC1P were similar to those of patients in stage IIA2 without lymph node metastasis, but significantly better than those of patients with >2 positive PLNs. Multivariate analysis showed FIGO 2018 stage to be an independent prognostic factor for OS and PFS. Conclusion: The 2018 FIGO staging system for cervical cancer appears to be useful for predicting prognosis of patients with risk factors after radical surgery. Survival of stage IIA1 patients is better than that of stage IB3 patients. Stage IIIC1 is not homogenous; survival in stage IIIC1P depends on the number of positive PLNs.

A comprehensive analysis of the factors of positive pelvic lymph nodes on survival of cervical cancer patients with 2018 FIGO stage IIIC1p.

Objective: To evaluate the factors associated with positive pelvic lymph nodes (LNs) on the survival of patients with 2018 FIGO stage IIIC1p cervical cancer. Methods: We retrospectively analyzed 155 patients with pelvic lymph node metastasis (LNM) confirmed by pathology after radical resection of cervical cancer treated at Zhejiang Cancer Hospital, China, between March 2008 and October 2011. We analyzed the influence of the factors associated with positive pelvic LNs on the survival of patients. Results: The 5-year progress-free survival (PFS) and overall survival (OS) of patients were 78.1% and 81.9%, respectively. The 5-year PFS and OS of patients with more than 2 LNM were worse compared with patients with 1 or 2 LNM (68.4% vs 83.7%, p=0.013; 72.4% vs 87.6%, p=0.017, respectively). The 5-year PFS and OS of patients with more than 2 LNM sites were worse than that of patients with 1 or 2 LNM sites (60.0% vs 82.4%, p=0.008; 70.0% vs 84.8%, p=0.045, respectively). The 5-year PFS and OS of patients with common iliac LNM was poorer than that of patients without common iliac LNM (60.7% vs 81.9%, p=0.008; 67.9% vs 85.0%, p=0.020, respectively). Compared with other patients, the survival of patients with these three factors (more than 2 LNM, more than 2 LNM sites, and common iliac LNM) was the worst (p<0.05). Conclusion: More than 2 LNM, more than 2 LNM sites, and common iliac LNM were predictive factors of poor survival in stage IIIC1p cervical cancer patients. Survival of patients with stage IIIC1p cervical cancer declined with increasing presence of such factors. The combined evaluation of the factors associated with positive pelvic LNs is a more comprehensive and pragmatic approach in evaluating the prognosis of cervical cancer.

Cisplatin concurrent chemoradiotherapy vs adjuvant radiation in stage IB/IIA cervical cancer with intermediate risk factors, treated with radical surgery: a retrospective study.

PURPOSE: To determine if postoperative cisplatin concurrent chemoradiotherapy (CCRT) improves the outcome in stage IA/IIB cervical cancer patients with intermediate risk factors, when compared with radiation therapy (RT) alone, and identify the potential eligible populations for this treatment. PATIENTS AND METHODS: We reviewed medical records of 1,240 patients with stage IA/IIB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy in our hospital between January 2008 and December 2011. Of the 1,240 patients, 436 displayed 1 or more intermediate risk factors. Of these, we screened 306 patients who underwent RT only or CCRT. We analyzed the effects of CCRT on survival and prognosis. RESULTS: The 5-year progress-free survival (PFS) in the CCRT group was superior to that in the RT-only group (96.0% vs 89.0%, respectively; P=0.031). The 5-year overall survivals (OSs) were not different between the 2 groups (P=0.141). Compared with RT-only group, CCRT did not improve PFS or OS in patients with 1 risk factor, large tumor size, or deep stromal invasion (P>0.05). Compared with RT-only group, CCRT improved PFS (97.9% vs 82.8%; P=0.017) but did not increase OS (97.9% vs 89.7%; P=0.109) in patients with lymphovascular space invasion plus deep stromal invasion/large tumor size. OS (92.3% vs 70.6%; P=0.048) and PFS (92.3% vs 64.7%; P=0.020) in the CCRT group were superior to those in the RT-only group with 3 risk factors. Compared with RT-only group, CCRT was an independent prognostic factor for favorable PFS (hazard ratio [HR] =0.238; 95% CI =0.0827-0.697, P=0.009) and OS (HR =0.192; 95% CI =0.069-0.533, P=0.002). CONCLUSION: Postoperative CCRT improved survival in stage IA/IIB cervical cancer patients with intermediate risk factors. Patients with 2 or more intermediate risk factors, including lymphovascular space invasion, may benefit from CCRT.