Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer.

Cervical cancer is the most common gynecologic cancer, etiologically related to persistent infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 ligase HUWE1. Functionally, activated STING inhibits cervical cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical cancer.

Re-irradiation for recurrent cervical cancer: A single institutional experience.

Purpose: Salvage treatment of recurrent cervical cancer of patients with a history of radiotherapy is currently a major clinical challenge. The purpose of our study was to retrospectively analyze clinical outcomes of radiation in patients with recurrent cancer who have previously received radiotherapy at our hospital and further explore the efficacy and safety of this treatment modality. Methods: All consecutive patients who underwent re-irradiation were included in our department between January 2015 and December 2017. All the patients received Volumetric Modulated Arc Therapy (VMAT) alone or VMAT followed by three dimensional-image-guided brachytherapy (3D-IGBT). The volume and dose for re-irradiation depended on previous radiation fields, dosimetry and recurrence sites. All patients received systemic chemotherapy before or after re-irradiation. Results: Fifty patients were included in our study. The median time from primary radiotherapy to re-irradiation was 12 months. Local recurrence, which was the most common failure following primary treatment, was present in 25 patients (50.0 %) while regional recurrence, loco-regional recurrence and distant recurrence combined in-filed recurrence was present in 8 (16.0 %), 9 (18.0 %) and 8 patients (16.0 %). Re-irradiation dose to lymph nodes was 45 Gy with or without a boost up to 55-60 Gy, and to the gross mass was 36-45 Gy with or without a boost up to 45-61 Gy. The median follow-up period was 22 (range,4-59) months. The 3-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 58.0, 38.7, and 44.4 %, respectively. The median time of PFS and OS was 14 and 26 months, respectively. The interval between two successive radiotherapies beyond 12 months was significantly associated with better LC and PFS (p ≤ 0.05), but without the benefit of OS (p > 0.05). Serum SCC antigen level less than 1.5 ng/ml had a significantly better impact on PFS (p ≤ 0.05). Overall, 14 patients (28 %) experienced ≥ grade 3 acute toxicities, while 9 (18 %) experienced ≥ grade 3 late toxicities. Conclusions: Re-irradiation with VMAT is an effective and safe salvage treatment option with a reasonably good clinical outcome and toxicity profile in selected patients. In our experience, recurrent cancer patients with an interval between two successive radiotherapy courses beyond 12 months and with a serum SCC-Ag level less than 1.5 ng/ml, had improved outcomes.

Definitive irradiation as a first treatment strategy for primary and metastatic sites of newly diagnosed IVB cervical cancer that presented with synchronous oligometastases.

BACKGROUND: The present study identified survival and progression-free rates and evaluated prognostic factors for IVB stage cervical cancer in patients that presented with synchronous oligometastases (sync-oligometastases) who received definitive irradiation for primary and metastatic sites. METHODS: The study retrospectively included 60 patients with newly diagnosed stage IVB cervical cancer. Patients received definitive radiation for both primary and metastatic sites through Volumetric Modulated Arc Therapy (VMAT) or intensity modulated radiation therapy (IMRT) followed by three dimensional-intracavitary/interstitial brachytherapy at our institution between July 2014 to December 2020. All patients were staged based on the International Federation of Gynecology and Obstetrics (FIGO) 2018 guidelines. Overall survival (OS), progression-free survival (PFS), and patient prognostic factors were analyzed. RESULTS: The 60 patients who received curative-intent irradiation for primary and metastatic sites showed a 5-year OS rate of 51.4% and a 5-year PFS rate of 25.9%. The median PFS was 52.3 months, and the median OS had not been reached. Lymphatic metastases had a better OS compared with hematogenous metastases (3-year OS rates: 57.2% vs. 20%, p = 0.017). Patients with one metastasis site showed a more favorable prognosis than patients with ≥ 2 metastases sites (3-year OS rates: 60.4% vs. 20.6%, p = 0.003). Patients that presented with tumors larger than 4 cm in diameter before treatment demonstrated a poorer prognosis (5-year OS rates: 41.2% vs. 65.2%, p = 0.029; 5-year PFS rates: 10.4% vs. 53.7%, p = 0.021). CONCLUSION: Definitive irradiation for both primary and oligo-metastatic sites for selected IVB patients is a feasible treatment strategy. Metastatic type, number of metastatic sites, and pre-treatment tumor diameter were significant prognostic factors. Neoadjuvant chemotherapy, the lymph nodal metastatic type (supraclavicular or inguinal), and number of lymphatic metastatic sites failed to reach statistical significance as prognostic factors.

Construction of refined staging classification systems integrating FIGO/T-categories and corpus uterine invasion for non-metastatic cervical cancer.

BACKGROUND: To investigate the prognostic value of corpus uterine invasion (CUI) in cervical cancer (CC), and determine the necessity to incorporate it for staging. METHODS: A total of 809 cases of biopsy-proven, non-metastatic CC were identified from an academic cancer center. Recursive partitioning analysis (RPA) method was used to develop the refined staging systems with respect to overall survival (OS). Internal validation was performed by using calibration curve with 1000 bootstrap resampling. Performances of the RPA-refined stages were compared against the conventional FIGO 2018 and 9th edition TNM-stage classifications by the receiver operating characteristic curve (ROC) and decision curve analysis (DCA). RESULTS: We identified that CUI was independently prognostic for death and relapse in our cohort. RPA modeling using a two-tiered stratification by CUI (positive and negative) and FIGO/T-categories divided CC into three risk groupings (FIGO I'-III'/T1'-3'), with 5-year OS of 90.8%, 82.1%, and 68.5% for proposed FIGO stage I'-III', respectively (p ≤ 0.003 for all pairwise comparisons), and 89.7%, 78.8%, and 68.0% for proposed T1'-3', respectively (p < 0.001 for all pairwise comparisons). The RPA-refined staging systems were well validated with RPA-predicted OS rates showed optimal agreement with actual observed survivals. Additionally, the RPA-refined stages outperformed the conventional FIGO/TNM-stage with significantly higher accuracy of survival prediction (AUC: RPA-FIGO vs. FIGO, 0.663 [95% CI 0.629-0.695] vs. 0.638 [0.604-0.671], p = 0.047; RPA-T vs. T, 0.661 [0.627-0.694] vs. 0.627 [0.592-0.660], p = 0.036). CONCLUSION: CUI affects the survival outcomes in patients with CC. Disease extended to corpus uterine should be classified as stage III/T3.

Clinical utility of pretreatment serum squamous cell carcinoma antigen for prognostication and decision-making in patients with early-stage cervical cancer.

Background: To investigate the prognostic role of pretreatment squamous cell carcinoma antigen (SCCA) in early-stage cervical cancer (CC). Methods: We enrolled 487 cases of pathology-proven early-stage [International Federation of Gynecology and Obstetrics (FIGO) I/II] squamous or adenosquamous CC that were treated from 2012 to 2015. Restricted cubic splines (RCS) with a full Cox regression model were used to evaluate the association between SCCA levels and survival outcomes. Recursive partitioning analysis (RPA) was used to construct a risk stratification model for overall survival (OS). The performance of the RPA-based model was assessed using a receiver operating characteristic (ROC) curve. Results: RCS analysis revealed an association between SCCA and OS and disease-free survival (DFS); SCCA ⩾2.5 ng/mL was robust for risk discrimination in our cohort. SCCA had an interaction effect with FIGO classification: Patients with FIGO I and SCCA ⩾2.5 ng/mL overlapped with those with FIGO II and SCCA < 2.5 ng/mL for OS [hazard ratio, 1.04 (95% confidence interval (CI): 0.49-2.24), p = 0.903] and DFS [1.05 (0.56-1.98), p = 0.876]. RPA modeling incorporating SCCA (<2.5 ng/mL and ⩾2.5 ng/mL) and FIGO classification divided CC into three prognostic groups: RPA I, FIGO stage I, and SCCA < 2.5 ng/mL; RPA II, FIGO stage I, and SCCA ⩾ 2.5 ng/mL, or FIGO stage II and SCCA < 2.5 ng/mL; and RPA III, FIGO stage II, and SCCA ⩾ 2.5 ng/mL; with 5-year OS of 94.0%, 85.1%, and 73.5%, respectively (p < 0.001). ROC analysis confirmed that the RPA model outperformed the FIGO 2018 stage with significantly improved accuracy for survival prediction [area under the curve: RPA versus FIGO, 0.663 (95% CI: 0.619-0.705] versus 0.621 (0.576-0.664), p = 0.045]. Importantly, the RPA groupings were associated with the efficacy of treatment regimens. Surgery followed by adjuvant treatment had a higher OS (p < 0.01) and DFS (p = 0.024) than other treatments for RPA III, whereas outcomes were comparable among treatment regimens for RPA I-II. Conclusion: Herein, the role of SCCA for prognostication was confirmed, and a robust clinicomolecular risk stratification system that outperforms conventional FIGO classification in early-stage squamous and adenosquamous CC was presented. The model correlated with the efficacy of different treatment regimes.

Establishment of a risk stratification model based on the combination of post-treatment serum squamous cell carcinoma antigen levels and FIGO stage of cervical cancer for treatment and surveillance decision-making.

OBJECTIVE: To develop a risk stratification model based on the International Federation of Gynecology and Obstetrics (FIGO) staging combined with squamous cell carcinoma antigen (SCC-Ag) for the classification of patients with cervical squamous cell carcinoma (CSCC) into different risk groups. METHODS: We retrospectively reviewed the data of 664 women with stage IIA-IVB CSCC according to the 2018 FIGO staging system who received definitive radiotherapy from March 2013 to December 2017 at the department of radiation oncology of Sun Yat-sen University Cancer Center. Cutoff values for continuous variables were estimated using receiver operating characteristic curve analysis. Using recursive partitioning analysis (RPA) modeling, overall survival was predicted based on the prognostic factors determined via Cox regression analysis. The predictive performance of the RPA model was assessed using the consistency index (C-index). Intergroup survival differences were determined and compared using Kaplan-Meier analysis and the log-rank test. RESULTS: Multivariate Cox regression analysis identified post-treatment SCC-Ag (< 1.35 ng/mL and > 1.35 ng/mL; hazard ratio (HR), 4.000; 95% confidence interval (CI), 2.911-5.496; P < 0.0001) and FIGO stage (II, III, and IV; HR, 2.582, 95% CI, 1.947-3.426; P < 0.0001) as the independent outcome predictors for overall survival. The RPA model based on the above prognostic factors divided the patients into high-, intermediate-, and low-risk groups. Significant differences in overall survival were observed among the three groups (5-year overall survival: low vs. intermediate vs. high, 91.3% vs. 76.7% vs. 29.5%, P < 0.0001). The predictive performance of the RPA model (C-index, 0.732; 95% CI, 0.701-0.763) was prominently superior to that of post-treatment SCC-Ag (C-index, 0.668; 95% CI, 0.635-0.702; P < 0.0001) and FIGO stage (C-index, 0.663; 95% CI, 0.631-0.695; P < 0.0001). CONCLUSIONS: The RPA model based on FIGO staging and post-treatment SCC-Ag can predict the overall survival of patients with CSCC, thereby providing a guide for the formulation of risk-adaptive treatment and individualized follow-up strategies.

Analysis of Treatment Outcomes and Prognosis After Concurrent Chemoradiotherapy for Locally Advanced Cervical Cancer.

The aims of this study were to investigate the short-term and long-term efficacies and chronic radiotoxicity of concurrent chemoradiotherapy (CCRT) combined with image-guided adaptive brachytherapy (IGABT) in patients with locally advanced cervical cancer (LACC) and identify prognostic factors in this patient population. The clinical data of 204 patients with cervical cancer who completed CCRT and subsequent brachytherapy in our hospital between February 2015 and March 2017 were retrospectively analyzed. Short-term and long-term outcomes, chronic radiotoxicity, and prognostic factors were assessed. The median follow-up was 61.1 months. The short-term objective response (OR) rate was 85%. Lymph node metastasis before treatment was an independent predictor of OR (HR = 6.290, 95% CI: 2.211-17.897, p = 0.001). Fifty-two patients developed recurrence, with a median recurrence-free survival of 9.9 months (range, 2.4-52.2 months) and a post-recurrence survival of 12.1 months (range, 2.9-58.1 months). At 3 years, the cumulative incidence of overall recurrence was 26% (95% CI: 17-36). Multivariate analysis showed that Stage IIIB (HR = 2.332, 95% CI: 1.195-4.551, p = 0.013; reference, Stage IIB) and lymph node metastasis (HR = 4.462, 95% CI: 2.365-8.419, p < 0.001) were significant independent predictors of recurrence. Fifty-three patients developed chronic radiation proctitis (CRP). The incidence of severe CRP was approximately 5%, and the average rectal D 2 c m 3 accumulation in patients with severe CRP was 73.4 Gy which is 3.9 Gy higher than that in patients without CRP (p = 0.013). At 4 years, the overall survival (OS) and disease-free survival rates were 65% and 62%, respectively, and lymph node metastasis before treatment was an independent prognostic risk factor for OS. The short-term and long-term efficacies of CCRT combined with IGABT for the treatment of LACC patients were relatively satisfactory. However, the short-term and long-term efficacies of patients with lymph node metastasis before treatment were poor. For patients with lymph node metastasis before treatment, more active individualized treatment strategies should be adopted. When designing a radiotherapy plan, it is necessary to strictly limit the rectal D 2 c m 3 accumulation to prevent serious CRP.

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer.

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. "Hot" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

Integrating multiple MRI sequences for pelvic organs segmentation via the attention mechanism.

PURPOSE: To create a network which fully utilizes multi-sequence MRI and compares favorably with manual human contouring. METHODS: We retrospectively collected 89 MRI studies of the pelvic cavity from patients with prostate cancer and cervical cancer. The dataset contained 89 samples from 87 patients with a total of 84 valid samples. MRI was performed with T1-weighted (T1), T2-weighted (T2), and Enhanced Dixon T1-weighted (T1DIXONC) sequences. There were two cohorts. The training cohort contained 55 samples and the testing cohort contained 29 samples. The MRI images in the training cohort contained contouring data from radiotherapist α. The MRI images in the testing cohort contained contouring data from radiotherapist α and contouring data from another radiotherapist: radiotherapist ß. The training cohort was used to optimize the convolution neural networks, which included the attention mechanism through the proposed activation module and the blended module into multiple MRI sequences, to perform autodelineation. The testing cohort was used to assess the networks' autodelineation performance. The contoured organs at risk (OAR) were the anal canal, bladder, rectum, femoral head (L), and femoral head (R). RESULTS: We compared our proposed network with UNet and FuseUNet using our dataset. When T1 was the main sequence, we input three sequences to segment five organs and evaluated the results using four metrics: the DSC (Dice similarity coefficient), the JSC (Jaccard similarity coefficient), the ASD (average mean distance), and the 95% HD (robust Hausdorff distance). The proposed network achieved improved results compared with the baselines among all metrics. The DSC were 0.834±0.029, 0.818±0.037, and 0.808±0.050 for our proposed network, FuseUNet, and UNet, respectively. The 95% HD were 7.256±2.748 mm, 8.404±3.297 mm, and 8.951±4.798 mm for our proposed network, FuseUNet, and UNet, respectively. Our proposed network also had superior performance on the JSC and ASD coefficients. CONCLUSION: Our proposed activation module and blended module significantly improved the performance of FuseUNet for multi-sequence MRI segmentation. Our proposed network integrated multiple MRI sequences efficiently and autosegmented OAR rapidly and accurately. We also discovered that three-sequence fusion (T1-T1DIXONC-T2) was superior to two-sequence fusion (T1-T2 and T1-T1DIXONC, respectively). We infer that the more MRI sequences fused, the better the automatic segmentation results.

Circulating Epstein-Barr virus DNA level post induction chemotherapy contributes to prognostication in advanced-stage nasopharyngeal carcinoma.

BACKGROUND: To investigate the value of post-induction chemotherapy (IC) cell-free Epstein-Barr virus DNA (cfEBV DNApostIC) for prognostication in locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: A total of 910 histologically proven LA-NPC undergoing radical IC + concurrent chemo-radiotherapy (CCRT) or targeted radiotherapy (CTRT) or both (CTCRT) were involved. The concentration of cfEBV DNA was measured by quantitative polymerase chain reaction pre-IC (cfEBV DNApreIC) and at IC completion. CfEBV DNApostIC was classified as undetectable (0 copy/ml) and detectable (>0 copy/ml). Recursive partitioning analysis (RPA) with respect to the overall survival (OS) was applied to construct a risk stratification system incorporating cfEBV DNApostIC and critical risk factors. RESULTS: We observed that 660 (72.5%) and 250 (27.5%) patients had cfEBV DNApostIC undetectable and detectable respectively. CfEBV DNApostIC positive was associated with a significant inferior 5-year OS (76.2% versus 85.9%), metastasis-free survival (DMFS, 71.7% versus 86.4%) and disease-free survival (DFS, 57.7% versus 80.1%) than cfEBV DNApostIC negative (P < 0.001 for all). Additionally, cfEBV DNApostIC was independently significant for OS (hazard ratio [HR] 1.90, 95% CI 1.40-2.59), DMFS (1.99, 1.45-2.71) and DFS (2.38, 1.86-3.06) in multivariate analyses (P < 0.001 for all). RPA modelling yielded three distinct risk groups: low-risk (N0-1 and undetectable cfEBV DNApostIC or N2-3 and pre-treatment cfEBV DNA [cfEBV DNApreIC] <7000), median-risk (N0-1 and detectable cfEBV DNApostIC or N2-3 and cfEBV DNApreIC ≥7000 with undetectable cfEBV DNApostIC) and high-risk (N2-3 and cfEBV DNApreIC ≥7000 with detectable cfEBV DNApostIC), with 5-year OS of 88.1%, 79.2% and 66.9%, respectively. Our risk stratification outperformed TNM classification for predicting death (AUC, 0.631 versus 0.562; P = 0.012) and distant metastasis (0.659 versus 0.562; P = 0.004). CONCLUSIONS: CfEBV DNApostIC represents an effective indicator of prognostication in LA-NPC. We developed a risk classification system that provides improved OS prediction over the current staging system by combining cfEBV DNApostIC, cfEBV DNApreIC and N-stage classification in LA-NPC.

High precise dating on the variation of the Asian summer monsoon since 37 ka BP.

Comprehensive comparison of paleoclimate change based on records constrained by precise chronology and high-resolution is essential to explore the correlation and interaction within earth climate systems. Here, we propose a new stalagmite-based multidecadal resolved Asian summer monsoon (ASM) record spanning the past thirty-seven thousand years (ka BP, before AD 1950) from Furong Cave, southwestern China. This record is consistent with the published Chinese stalagmite sequences and shows that the dominant controls of the ASM dynamics include not only insolation and solar activity but also suborbital-scale hydroclimate events in the high latitudes of the northern hemisphere, such as the Heinrich events, Bølling-Allerød (BA), and Younger Dryas (YD). Benefit from the unprecedented accurate chronology, the timings of these events are precisely dated, with uncertainties of, at most, 40 years (2σ). The onset of the weak ASM during the YD began at 12.92 ka BP and lasted for 430 years. The occurrence of the 200-yr Older Dryas during the BA period was dated from 13.87 to 14.06 ka BP. The durations of the three Heinrich (H) events, H1, H2, and H3, are 14.33-18.29, 23.77-24.48, and 28.98-30.46 ka BP, respectively. Furong record shows surprisingly variable onset transitions of 980, 210, and 40 years for the corresponding weak ASM events. These discrepancies suggest different influences of the H events on ASM dynamics. During the periods of H 1-3, the obvious difference between our Furong record and NGRIP δ18O record indicated the decoupling correlation between the mid-low latitudes and high latitudes. On the other hand, synchronous climate change in high and low latitudes suggests another possibility which different to the dominant role of Northern high latitudes in triggering global climate change. Our high quality records also indicate a plausible different correlation between the high and mid-low latitudes under glacial and inter-glacial background, especially for the ASM regimes.

Long-term outcomes of individualized management after sentinel lymph-node biopsy for vulvar cancer.

BACKGROUND: The management for patients with vulvar cancer after sentinel lymph-node biopsy (SLNB) remains controversial. The aim of this study was to investigate the long-term outcomes of individualized management after SLNB for early stage vulvar cancer. METHODS: The medical records of patients with vulvar cancer treated by surgery involving SLNB between 2004 and 2019 were retrospectively reviewed. During this period, the inguinofemoral lymphadenectomy (IL) were performed with individualized strategy, while the postoperative intensity-modulated radiotherapy was planned with a consistent policy. RESULTS: We identified 138 patients with at least one sentinel node detected, of whom 64 underwent further IL while 74 had SLNB only. Nodal metastases (pN+) were confirmed in 22 patients with IL and 16 without. Radiotherapy was scheduled with the dose of 60-70 Gy for all pN+ patients and finally completed in 15 with IL and 15 without. The median follow-up time was 56 months (6-156 months). Recurrence was observed in 24 patients, of whom 10 were pN- at primary treatment. The 3-year overall survival (OS) was 97.2, 95.2, 68.3, and 71.8%; 3-year disease-free survival (DFS) was 94.5, 91.4, 60.2, and 59.2%, respectively, for patients with pN- and IL, pN- and SLNB, pN+ and IL, and pN+ and SLNB. Neither OS nor DFS showed significant difference between SLNB and IL in pN- (P = 0.564 for OS, P = 0.423 for DFS), or pN + patients (P = 0.920 for OS, P = 0.862 for DFS). CONCLUSIONS: With appropriate adjuvant radiotherapy, SLNB alone provided similar long-term survival compared with IL for both patients with and without sentinel node metastasis.

Proposal for modified inguinofemoral lymphadenectomy derived from investigation of anatomic distribution of sentinel and metastatic nodes in vulvar cancer.

OBJECTIVE: We aimed to develop a less invasive inguinofemoral lymphadenectomy (IFL) approach for vulvar cancer based on the investigation of the anatomic distribution of sentinel and metastatic nodes. METHODS: Patients with vulvar cancer treated by surgery between 1995 and 2019 were retrospectively reviewed. A seven-field method was adopted to assign the anatomic locations for lymph nodes removed via IFL or sentinel node biopsy. Only patients with nodal metastasis or sentinel nodes were included. RESULTS: A total of 102 patients with eligible data were analyzed. Nodal metastasis was confirmed in 118 groins undergoing IFL; sentinel node detection succeeded in 46 groins. The medial-inguinal field had the highest rate of nodal metastasis involvement (59.3%, 70/118) and sentinel nodes present (73.9%, 34/46). The inferior-femoral field was involved only in one groin with quadruple-field metastases. The lateral-inguinal field was not involved in any groin. Neither the lateral-inguinal nor the inferior-femoral field presented sentinel nodes. CONCLUSION: The lateral-inguinal and inferior-femoral fields of the groins have a low risk of developing nodal metastasis. Therefore, a modified IFL preserving these fields can be established to reduce surgical morbidity without sacrificing its therapeutic effect.

Clear Cell Adenocarcinoma of Uterine Cervix: A Single Institution Retrospective Experience.

PURPOSE: The purpose of the study is to summarize the clinical characteristics and identify the prognosis of clear cell adenocarcinoma of the uterine cervix (CCAUC) in patients without a history of diethylstilbestrol (DES) exposure. METHODS: Forty-two patients with CCAUC, treated initially at Sun Yat-sen University Cancer Center between 1985 and 2017, were studied. RESULTS: Of all the CCAUC patients, the median age was 47 years old, and the median tumor size was 3 cm. Thirty-four early stage patients (IB = 28, IIA = 6) underwent radical surgery. Eight advanced stage patients (IIB = 8) received concurrent chemoradiotherapy (n = 4) or radical surgery (n = 4). Survival analysis showed that patients with early stage (IB-IIA) had a significantly better 5-year progression-free survival (PFS) and overall survival (OS) than those with advanced stage (IIB) (p < 0.05). The patients with negative pelvic lymph node (PLN) had a significantly better 5-year PFS and OS than those with positive PLN (p < 0.05). Radiotherapy (RT) did not affect PFS or OS in early stage patients with intermediate risk factors (p > 0.05). Adjuvant chemotherapy (CT) did not affect PFS or OS in early stage patients without risk factors (p > 0.05). CONCLUSION: The FIGO stage and pelvic node status were important prognostic factors for both PFS and OS. For treatment modality, we recommended that radical surgery alone was used in early stage patients without high risk factors. Ovarian preservation in early stage patients involved some risk.

Small cell carcinoma of the uterine cervix: a multi-institutional experience.

OBJECTIVE: Small cell carcinoma of the uterine cervix is associated with a poor prognosis with a median overall survival that is quite low. The aim of this study was to determine the clinico-pathologic characteristics that have an impact on survival in patients with small cell carcinoma of the uterine cervix. METHODS: A total of 93 patients were involved in this retrospective study. Inclusion criteria were patients diagnosed with histopathologically confirmed small cell carcinoma of the uterine cervix and then later treated at three participating centers, between June 2001 and March 2015. Those without complete available follow-up records were excluded. The endpoints of this study were disease-free survival and overall survival. Kaplan-Meier and Cox regression methods were used for analyses. RESULTS: There were statistical differences in overall survival between patients in early and in advanced stages by using the 2009 International Federation of Gynecology and Obstetrics (FIGO) clinical stage. There were 75 patients with FIGO stage I to IIA (56 patients stage I, 17 patients stage IIA, and two patients stage IB or IIA because of uncertainty as to whether the fornix was involved); and 18 patients with FIGO stage IIB and above (10 patients IIB stage, five patients stage III, and three patients stage IV). Among the 76 patients who had surgery, 73 (96%) had a radical hysterectomy with pelvic lymph node dissection and three (4%) patients had a simple hysterectomy without lymph node dissection. For early-stage patients, the 5 year disease-free survival rate was 52.7% compared with 32.4% in the advanced stage group (p=0.022). The disease-free survival for the early-stage group was 64.4% compared with 36.7% in the advanced-stage group (p=0.047). For factors affecting overall survival, age at diagnosis, tumor homology, tumor size, depth of stromal invasion, lymph node involvement, and treatment modality failed to reach significance in both univariate and multivariate analysis. CONCLUSION: FIGO stage was a prognostic factor impacting survival-both overall survival and disease-free survival. Age at diagnosis, tumor histology (pure or mixed), tumor size, depth of stromal invasion, lymph node involvement, and treatment modality did not have an impact on overall survival.

Atomically resolved probe-type scanning tunnelling microscope for use in harsh vibrational cryogen-free superconducting magnet.

We present a probe-type scanning tunnelling microscope (STM) with atomic resolution that is designed to be directly inserted and work in a harsh vibrational cryogen-free superconducting magnet system. When a commercial variable temperature insert (VTI) is installed in the magnet and the STM is housed in the VTI, a lowest temperature of 1.6 K can be achieved, at which the STM still operates well. We tested the STM in an 8 T superconducting magnet cooled with a pulse-tube cryocooler and obtained atomically resolved graphite and NbSe2 images as well as the scanning tunnelling spectrum (i.e., dI/dV spectrum) data of the latter near its critical temperature, which show the formation process of the superconducting gap as a function of temperature. The drifting rates of the STM at 1.6 K in the X-Y plane and Z direction are 1.15 and 1.71 pm/min, respectively. Noise analysis for the tunnelling current shows that the amplitudes of the dominant peaks (6.84 and 10.25 Hz) are as low as 1.5 pA.Hz-1/2 when we set the current to 0.5 nA and open the feedback loop. This is important as a cryogen-free magnet system has long been considered too harsh for any atomic resolution measurement.

Prognostic impact of cigarette smoking on the survival of patients with established esophageal squamous cell carcinoma receiving radiotherapy: A retrospective study from southern China.

Cigarette smoking is associated with the development of esophageal squamous cell carcinoma (ESCC); however, the influence of smoking on survival of patients with ESCC receiving radiotherapy, with or without chemotherapy, has remained elusive. The present study retrospectively analyzed 479 patients with ESCC from southern China who were categorized based on their smoking history (never, previous or current). To consider the cumulative effect of smoking, the number of pack years (PYs) was used as a representative variable. Associations between cigarette smoking and survival were evaluated using the Kaplan-Meier analysis and Cox proportional hazards model. Among the 497 patients, 308 (64.3%) had reported a history of cigarette smoking. The 5-year overall survival for patients void of a smoking history, former smokers and current smokers was 50.9, 27.0 and 34.3%, respectively. The adjusted hazard ratios (HRs) for previous and current smoking vs. no smoking history were 1.57 [95% confidence interval (CI), 1.06-2.32] and 3.01 (95% CI, 1.15-7.86), respectively. Heavy smokers with a high number of PYs had a HR for death of 1.75 (95% CI, 1.28-2.41) compared with light smokers. In the cohort of 407 patients treated with intensity-modulated radiotherapy/three-dimensional conformal radiotherapy, similarly significant results were obtained. In conclusion, cigarette smoking is an independent and poor prognostic factor for patients with ESCC treated with radiotherapy and/or chemotherapy. It is associated with an increased risk of death, and the risk increases with the increase in PYs. This result may help to manage tobacco use among patients with ESCC. The smoking status should be taken into consideration in prospective studies on ESCC. More frequent follow-ups are recommended for those patients with ESCC with a history of smoking.

Deep Learning for Automated Contouring of Primary Tumor Volumes by MRI for Nasopharyngeal Carcinoma.

Background Nasopharyngeal carcinoma (NPC) may be cured with radiation therapy. Tumor proximity to critical structures demands accuracy in tumor delineation to avoid toxicities from radiation therapy; however, tumor target contouring for head and neck radiation therapy is labor intensive and highly variable among radiation oncologists. Purpose To construct and validate an artificial intelligence (AI) contouring tool to automate primary gross tumor volume (GTV) contouring in patients with NPC. Materials and Methods In this retrospective study, MRI data sets covering the nasopharynx from 1021 patients (median age, 47 years; 751 male, 270 female) with NPC between September 2016 and September 2017 were collected and divided into training, validation, and testing cohorts of 715, 103, and 203 patients, respectively. GTV contours were delineated for 1021 patients and were defined by consensus of two experts. A three-dimensional convolutional neural network was applied to 818 training and validation MRI data sets to construct the AI tool, which was tested in 203 independent MRI data sets. Next, the AI tool was compared against eight qualified radiation oncologists in a multicenter evaluation by using a random sample of 20 test MRI examinations. The Wilcoxon matched-pairs signed rank test was used to compare the difference of Dice similarity coefficient (DSC) of pre- versus post-AI assistance. Results The AI-generated contours demonstrated a high level of accuracy when compared with ground truth contours at testing in 203 patients (DSC, 0.79; 2.0-mm difference in average surface distance). In multicenter evaluation, AI assistance improved contouring accuracy (five of eight oncologists had a higher median DSC after AI assistance; average median DSC, 0.74 vs 0.78; P < .001), reduced intra- and interobserver variation (by 36.4% and 54.5%, respectively), and reduced contouring time (by 39.4%). Conclusion The AI contouring tool improved primary gross tumor contouring accuracy of nasopharyngeal carcinoma, which could have a positive impact on tumor control and patient survival. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Chang in this issue.

Distribution and health risk assessment of dissolved heavy metals in the Three Gorges Reservoir, China (section in the main urban area of Chongqing).

The Three Gorges Project (TGP) is the largest hydropower station ever built in the world. A better understanding of the concentrations of heavy metals in the aquatic environment of the Three Gorges Reservoir (TGR) is crucial for national drinking water security and sustainable ecosystem development. To thoroughly investigate the impact of heavy metals on water quality after the impoundment to the maximum level of 175 m in the TGR, the concentrations of the dissolved heavy metals (Cr, Cu, Zn, Cd, Pb, As) were measured in April and August 2015, by inductively coupled plasma mass spectrometry (ICP-MS). (1) Except Zn and Pb, most of the heavy metal concentrations in the water of the TGR reached the level of the National Surface Water Environmental Quality Standards (GB3838-2002) I of China, revealing that the water quality of the TGR was good overall. (2) There were significant positive correlations among the concentrations of Cu, As, and Cd, revealing that they may exhibit similar geochemical behaviors. (3) The spatial distribution of the heavy metal concentrations was diverse and complex. The Zn concentration obviously increased in the rainy season from upstream to downstream in the Yangtze River, while the other heavy metals exhibited no significant changes in their concentrations. The distribution characteristics of the heavy metal concentrations on both sides and the middle of the river were different at different sites. (4) The health risk of the six elements was assessed through a human health risk assessment (HHRA), and the assessment results were lower than the maximum acceptable risk level designed by the US EPA and International Commission on Radiological Protection (ICRP). The HHRA model in the aquatic environment revealed that the risk of non-carcinogenic heavy metals (Cu, Zn, and Pb) was at a negligible risk level of 10-11∼10-9 a-1. At all the study sites, the risk of carcinogenic heavy metals (Cr, Cd, and As) was higher than the risk of non-carcinogenic heavy metals. As was the most important risk factor, followed by Cr. The results of this study hold great significance for a timely understanding of the changing water quality for affected departments to ensure the health of the residents in the TGR area.

Anti-atherogenic effects of centipede acidic protein in rats fed an atherogenic diet.

AIM OF THE STUDY: To investigate the effects of centipede acidic protein (CAP) on atherosclerotic rats and the mechanisms involved. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly divided into five groups: control, atherosclerotic, low-dose CAP (L-CAP), high-dose CAP (H-CAP) and simvastatin group (n=12 in each group). Atherosclerotic model was established by a single dose of vitamin D(3) and an atherogenic diet. Rats of H-CAP and simvastatin groups simultaneously received CAP or simvastatin daily for 6 weeks. At the completion of the experiment, the changes in lipid profile, hemorrheology, nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA) and superoxide desmutase (SOD) were measured, and the histological changes in aorta and liver were observed. RESULTS: Treatment of atherosclerotic rats with either low or high doses of CAP led not only to significant decreases in plasma total cholesterol, triglyceride, low density lipoprotein and increase in plasma high density lipoprotein, but also to improvement of the hemorrheologic abnormalities. On the other hand, CAP suppressed the lipid peroxidation, regulated the levels of ET-1 and NO. From the histopathological examination, treatment with CAP ameliorated the pathological changes in thoracic aorta and liver in atherosclerotic rats. CONCLUSIONS: These results suggest that CAP significantly suppress the development of atherosclerosis, improves the hemorrheological disturbances and histopathological changes in the atherogenic diet fed rat model. These effects may partly attribute to reverse of dyslipidemia, inhibition of lipid peroxidation, regulation of NO and ET-1 system.