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Background: Monitoring pyruvate metabolism in the spleen is important for assessing immune activity and achieving successful radiotherapy for cervical cancer due to the significance of the abscopal effect. We aimed to explore the feasibility of utilizing hyperpolarized (HP) [1-13C]-pyruvate magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to evaluate pyruvate metabolism in the human spleen, with the aim of identifying potential candidates for radiotherapy in cervical cancer. Methods: This prospective study recruited six female patients with cervical cancer (median age 55 years; range 39–60) evaluated using HP [1-13C]-pyruvate MRI/MRS at baseline and 2 weeks after radiotherapy. Proton (1H) diffusion-weighted MRI was performed in parallel to estimate splenic cellularity. The primary outcome was defined as tumor response to radiotherapy. The Student t-test was used for comparing 13C data between the groups. Results: The splenic HP [1-13C]-lactate-to-total carbon (tC) ratio was 5.6-fold lower in the responders than in the non-responders at baseline (p = 0.009). The splenic [1-13C]-lactate-to-tC ratio revealed a 1.7-fold increase (p = 0.415) and the splenic [1-13C]-alanine-to-tC ratio revealed a 1.8-fold increase after radiotherapy (p = 0.482). The blood leukocyte differential count revealed an increased proportion of neutrophils two weeks following treatment, indicating enhanced immune activity (p = 0.013). The splenic apparent diffusion coefficient values between the groups were not significantly different. Conclusions: This exploratory study revealed the feasibility of HP [1-13C]-pyruvate MRS of the spleen for evaluating baseline immune potential, which was associated with clinical outcomes of cervical cancer after radiotherapy. Trial registration: ClinicalTrials.gov NCT04951921, registered 7 July 2021. Relevance statement: This prospective study revealed the feasibility of using HP 13C MRI/MRS for assessing pyruvate metabolism of the spleen to evaluate the patients' immune potential that is associated with radiotherapeutic clinical outcomes in cervical cancer. Key points: • Effective radiotherapy induces abscopal effect via altering immune metabolism. • Hyperpolarized 13C MRS evaluates patients' immune potential non-invasively. • Pyruvate-to-lactate conversion in the spleen is elevated following radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the generalizability of transfer learning (TL) of automated tumor segmentation from cervical cancers toward a universal model for cervical and uterine malignancies in diffusion-weighted magnetic resonance imaging (DWI). Methods: In this retrospective multicenter study, we analyzed pelvic DWI data from 169 and 320 patients with cervical and uterine malignancies and divided them into the training (144 and 256) and testing (25 and 64) datasets, respectively. A pretrained model was established using DeepLab V3 + from the cervical cancer dataset, followed by TL experiments adjusting the training data sizes and fine-tuning layers. The model performance was evaluated using the dice similarity coefficient (DSC). Results: In predicting tumor segmentation for all cervical and uterine malignancies, TL models improved the DSCs from the pretrained cervical model (DSC 0.43) when adding 5, 13, 26, and 51 uterine cases for training (DSC improved from 0.57, 0.62, 0.68, 0.70, p < 0.001). Following the crossover at adding 128 cases (DSC 0.71), the model trained by combining data from adding all the 256 patients exhibited the highest DSCs for the combined cervical and uterine datasets (DSC 0.81) and cervical only dataset (DSC 0.91). Conclusions: TL may improve the generalizability of automated tumor segmentation of DWI from a specific cancer type toward multiple types of uterine malignancies especially in limited case numbers. Key points: Transfer learning (TL) improves performance of tumor segmentation on diffusion-weighted imaging (DWI) especially in limited case numbers. Training a model by combining sufficient data of different cancers exhibited the highest performance for segmenting mixed cervical and uterine datasets and also improved the pretrained cervical model. The TL model with fine-tuning the early layers of the encoder part outperformed those by fine-tuning the other layers. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this prospective study was to assess the usefulness of F-FDG PET/CT performed before and during treatment for predicting treatment failure in patients with advanced squamous cell carcinoma of the uterine cervix treated with concurrent chemoradiotherapy (CCRT). Methods: Patients with cervical squamous cell carcinoma, International Federation of Gynecology and Obstetrics stage III/IVA or positive pelvic or paraaortic lymph node (LN) metastasis without other distant metastasis on PET/CT entering a randomized trial of CCRT (AGOG 09-001) were eligible. PET/CT scans were performed at baseline, during week 3 of CCRT and 2 − 3 months after CCRT. PET/CT parameters were correlated with sites of failure and overall survival (OS). The resulting predictors developed from the study cohort were validated on two independent datasets using area under the curve values, sensitivities and specificities. Results: With a median follow-up of 54 months for survivors, 20 (36 %) of the 55 eligible patients were proven to have treatment failure. Sites of failure were local in five, regional in 11, and distant in 11. Four predictors for local failure, three for regional failure, and four for distant failures were identified. After validation with two independent cohorts of 31 and 105 patients, we consider the following as clinically useful predictors: pretreatment metabolic tumour volume (MTV) and during-treatment cervical tumour MTV for local failure; during-treatment SUVnode (maximum standardized uptake value of LNs) for regional and distant failure, and during-treatment MTV for distant failure. During-treatment SUVnode ( P = .001) and cervical tumour MTVratio ( P = .004) were independent significant predictors of OS by stepwise Cox regression. Conclusion: PET/CT imaging before and during treatment is useful for predicting failure sites and OS, making tailored therapeutic modifications feasible with potential outcome improvement during primary therapy. [ABSTRACT FROM AUTHOR]

Purpose: To compare clinical behaviors and treatment outcomes between patients with squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix treated with radical hysterectomy (RH) and adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). Methods and Materials: A total of 318 Stage IB–IIB cervical cancer patients, 202 (63.5%) with SCC and 116 (36.5%) with AC/ASC, treated by RH and adjuvant RT/CCRT, were included. The indications for RT/CCRT were deep stromal invasion, positive resection margin, parametrial invasion, or lymph node (LN) metastasis. Postoperative CCRT was administered in 65 SCC patients (32%) and 80 AC/ASC patients (69%). Patients with presence of parametrial invasion or LN metastasis were stratified into a high-risk group, and the rest into an intermediate-risk group. The patterns of failure and factors influencing survival were evaluated. Results: The treatment failed in 39 SCC patients (19.3%) and 39 AC/ASC patients (33.6%). The 5-year relapse-free survival rates for SCC and AC/ASC patients were 83.4% and 66.5%, respectively (p = 0.000). Distant metastasis was the major failure pattern in both groups. After multivariate analysis, prognostic factors for local recurrence included younger age, parametrial invasion, AC/ASC histology, and positive resection margin; for distant recurrence they included parametrial invasion, LN metastasis, and AC/ASC histology. Compared with SCC patients, those with AC/ASC had higher local relapse rates for the intermediate-risk group but a higher distant metastasis rate for the high-risk group. Postoperative CCRT tended to improve survival for intermediate-risk but not for high-risk AC/ASC patients. Conclusions: Adenocarcinoma/adenosquamous carcinoma is an independent prognostic factor for cervical cancer patients treated by RH and postoperative RT. Concurrent chemoradiotherapy could improve survival for intermediate-risk, but not necessarily high-risk, AC/ASC patients. [Copyright &y& Elsevier]

Abstract: Objective: Patients with cervical cancer and supraclavicular lymph nodes (SLN) recurrence have a poor but heterogeneous prognosis. The aim of this study was to identify potential prognostic factors – including FDG-PET results – that may affect survival and treatment outcomes in patients with this group of patients. Methods: Between January 2001 and December 2008, we identified a total of 31 consecutive patients with cervical cancer who had evidence of SLN recurrence. All participants underwent FDG-PET. Survival was measured from the date of documented SLN recurrence. The latency period was defined as the length of time from the date of first diagnosis to the date of SLN recurrence. Results: The median follow-up time was 22.8months (range: 4.7–105.1). The 3- and 5-year survival rates were 41% and 27.3%, respectively. Patients with intermediate SUV values (between 4.3 and 8) had a significantly better prognosis than subjects with both high (>8) or low (<4.3) SUV values (p =0.004). Latency period <2years, SCC-Ag levels ≥4ng/mL, recurrence extend beyond SLN, and SUV of <4.3 >8 were significant adverse prognostic factors by multivariate analysis. The 3-year overall survival (OS) rate of patients carrying 0–1 adverse prognostic factors was 90% (low-risk group), while 3-year OS rates for intermediate-risk group (2 factors) and high-risk group (3–4 factors) were 30% and 0%, respectively (p =0.001). Conclusion: Our results justify the use of PET (accurate extent of relapse and SUV) as a prognostic tool in patients with cervical cancer and SLN recurrence. [Copyright &y& Elsevier]

Purpose: To study the outcomes of patients with adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix primarily treated with radiotherapy (RT), identify the prognostic factors, and evaluate the efficacy of concurrent chemoradiotherapy (CCRT) or salvage surgery. Methods and Materials: A total of 148 patients with Stage I-IVA AC/ASC of cervix after full-course definitive RT were included. Of the 148 patients, 77% had advanced stage disease. Treatment failure was categorized as either distant or local failure. Local failure was further separated into persistent tumor or local relapse after complete remission. The effectiveness of CCRT with cisplatin and/or paclitaxel was examined, and the surgical salvage rate for local failure was reviewed. Results: The 5-year relapse-free survival rate was 68%, 38%, 49%, 30%, and 0% for those with Stage IB/IIA nonbulky, IB/IIA bulky, IIB, III, and IVA disease, respectively, and appeared inferior to that of those with squamous cell carcinoma of the cervix treated using the same RT protocol. Incomplete tumor regression after RT, a low hemoglobin level, and positive lymph node metastasis were independent poor prognostic factors for relapse-free survival. CCRT with weekly cisplatinum did not improve the outcome for our AC/ASC patients. Salvage surgery rescued 30% of patients with persistent disease. Conclusion: Patients with AC/ASC of the cervix primarily treated with RT had inferior outcomes compared to those with squamous cell carcinoma. Incomplete tumor regression after RT was the most important prognostic factor for local failure. Salvage surgery for patients with persistent tumor should be encouraged for selected patients. Our results did not demonstrate a benefit of CCRT with cisplatin for this disease. [ABSTRACT FROM AUTHOR]

Purpose: To study the prognostic value of the human papillomavirus (HPV) genotypes in cervical cancer patients undergoing radiotherapy. Patients and Methods: A total of 1,010 patients with cervical cancer after radiotherapy between 1993 and 2000 were eligible for this study. The HPV genotypes were determined by a genechip, which detects 38 types of HPV. The patient characteristics and treatment outcomes were analyzed using the Cox regression hazard model and classification and regression tree decision tree method. Results: A total of 25 genotypes of HPV were detected in 992 specimens (98.2%). The leading 8 types were HPV16, 58, 18, 33, 52, 39, 31, and 45. These types belong to two high-risk HPV species: alpha-7 (HPV18, 39, 45) and alpha-9 (HPV16, 31, 33, 52, 58). Three HPV-based risk groups, which were independent of established prognostic factors, such as International Federation of Gynecology and Obstetrics stage, age, pathologic features, squamous cell carcinoma antigen, and lymph node metastasis, were associated with the survival outcomes. The high-risk group consisted of the patients without HPV infection or the ones infected with the alpha-7 species only. Patients co-infected with the alpha-7 and alpha-9 species belonged to the medium-risk group, and the others were included in the low-risk group. Conclusion: The results of the present study have confirmed the prognostic value of HPV genotypes in cervical cancer treated with radiotherapy. The different effect of the alpha-7 and alpha-9 species on the radiation response deserves additional exploration. [ABSTRACT FROM AUTHOR]

The α7-human papillomavirus (HPV)-related cervical squamous cell carcinoma (SCC) is associated with poor prognosis. We compared the genomic profiles of this disease in a cohort corresponding to the 2001–2014 period with various responses to radiotherapy or concurrent chemoradiation through microRNA (miR) profiling involving miR 4.0 array and human transcriptome array 2.0 analyses. A real-time quantitative polymerase chain reaction was then conducted to identify the predictive biomarkers. A significantly lower expression of miR143-3p in recurrent tumors (p = 0.0309) relative to that in nonrecurrent tumors was observed. The miR143-3p targeted the mRNA expression of the baculoviral inhibitor of the apoptosis protein (IAP) repeat-containing 2 (BIRC2; p = 0.0261). The BIRC2 protein levels (p = 0.0023) were significantly higher in recurrent tumors than in nonrecurrent tumors. Moreover, the miR-143-3p sensitized the response of α7-HPV-related cervical SCC to chemotherapy by targeting BIRC2. A combination of BIRC2-inhibitor LCL161 and topotecan exerted synergistic effects on cancer cells and animal tumor models. In a pooled cohort of α7-HPV-related cervical SCC (including mixed infections with non-α7-HPV) treated between 1993 and 2014, high BIRC2 expression was associated with significantly worse outcomes (cancer-specific survival, hazard ratio (HR) = 1.42, p = 0.008; progression-free survival, HR = 1.64; p = 0.005). Summarily, BIRC2 constitutes a novel prognostic factor and therapeutic target for α7-HPV-related cervical SCC. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Clinical outcomes of cervical cancer patients with distant lymph node (LN) metastases are poor. [18F] fluorodeoxyglucose positron emission tomography (PET) or PET/computed tomography (CT) scans could potentially benefit treatment plan. Methods: Patients with cervical cancer whose CT/magnetic resonance imaging (MRI)-based imaging showed limited metastases to para-aortic lymph node (PALN), inguinal (ILN), and/or supraclavicular (SLN) were prospectively enrolled to evaluate whether PET or PET/CT influenced management. The clinical impact of PET or PET/CT was determined on a patient basis. Results: Between November 2001 and April 2007, 47 patients were enrolled for suspected metastasis to PALN with (n =8) or without other distant nodal involvement (n =31), ILN (n =6), or SLN metastasis (n =2). Additional PET or PET/CT had positive clinical impact in 21 (44.7%) of the 47 study patients, 23 had no impact, and three had negative impact. Positive impact included disclosing additional curable sites (n =8), down-staging (n =6), offering metabolic biopsy (n =4) or change to palliation (n =3). The 2-year overall survival (OS) of the study patients was 56.9% with median follow-up time of 47.0 months (range: 8–71 months) in surviving patients. The 2-year OS rates for PALN (based on histology or CT/MRI-PET consensus) and histology-proven SLN metastasis were 50.6% and 24.7%, respectively. Two (40.0%) of the five patients with histology-proven ILN metastases had no evidence of disease. Conclusions: PET or PET/CT added benefit to primary treatment planning in cervical cancer with MRI-defined suspected distant nodal metastasis. [Copyright &y& Elsevier]

Abstract: Background: Our aims were to evaluate the genotype distribution of human papillomavirus (HPV) and the correlation between HPV parameters and clinicopathological/treatment variables with prognosis in cervical adeno-adenosquamous carcinoma (AD/ASC). Patients and methods: Consecutive patients who received primary treatment for cervical AD/ASC International Federation of Gynecology and Obstetrics (FIGO) stages I–IV between 1993 and 2008 were retrospectively reviewed. Prognostic models were constructed and followed by internal validation with bootstrap resampling. Results: A total of 456 AD/ASC patients were eligible for HPV genotyping, while 452 were eligible for survival analysis. HPV18 was detected in 51.5% and HPV16 in 36.2% of the samples. Age >50years old, FIGO stages III–IV and HPV16-negativity were significantly related to cancer relapse, and age >50, FIGO stages III–IV, HPV16-negativity and HPV58-positivity were significant predictors for cancer-specific survival (CSS) by multivariate analyses. HPV16-positivity was also significantly associated with good prognosis in those receiving primary radiotherapy or concurrent chemoradiation (RT/CCRT) (CSS: hazard ratio 0.41, 95% confidence interval 0.21–0.78). Patients with FIGO stages I–II and HPV16-negative AD/ASC treated with primary RH-PLND had significantly better CSS (p <0.0001) than those treated with RT/CCRT. Conclusions: Age >50years old, FIGO stages III–IV and HPV16-negativity were significant poor prognostic factors in cervical AD/ASC. Patients with HPV16-negative tumour might better be treated with primary surgery (e.g. radical hysterectomy for stages I–II and pelvic exenteration for stage IVA). Those with unresectable HPV16-negative tumour (stage IIIB) should undergo CCRT in combination with novel drugs. The inferences of a single-institutional retrospective study require prospective studies to confirm. [Copyright &y& Elsevier]

Abstract: Objective: Our aim was to investigate the clinical features and outcomes following recurrence after primary radical hysterectomy for cervical cancer. Methods: Clinical data of 121 documented recurrent cervical cancer patients who received primary radical hysterectomy and bilateral pelvic lymphadenectomy between 1993 and 2000 at Chang Gung Memorial Hospital were retrospectively reviewed. Clinicopathological variables, primary treatment, failure pattern, salvage treatment and outcomes were analyzed. Outcomes of the current study were compared to those treated between 1982 and 1992 (1982–1992 cohort). Results: Cancer recurrence was documented at a median time to recurrence (TTR) of 28.4months (1.2–129.9months). Assessable failure patterns (n=106) included loco-regional in 46.3%, distant in 47.2% and combined pelvic-distant in 6.6%. 5-year survival of the 121 patients was 22.3% after cancer recurrence. The median survival after recurrence (SAR) was 16.4months (range 0–144.2months). By multivariate analysis, extravaginal sites of recurrence (HR 2.56, 1.28–5.12; p =0.008) and HPV16-positive (HR 0.60, 0.38–0.96; p =0.033) were significant prognostic factors for SAR. Non-squamous histology or pelvic node metastasis at primary surgery were not significant (5-year SAR of 16.4% and 20.0%, respectively), though they were (0% and 0%) in the 1993–2000 cohort. Salvage surgery and concurrent chemoradiation were more frequently used in the 1993–2000 cohort (48.3% versus 12.4%). Conclusion: HPV16-negativity and extravaginal relapse were significant poor prognostic factors. Future randomized controlled trials for recurrent cervical cancer could be stratified for these two factors if further studies using external validation confirm these results. [Copyright &y& Elsevier]