Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy For Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors.

Mismatch repair-deficient (dMMR) endometrial cancer is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 study (NCT04634877) in newly-diagnosed, high-risk endometrial cancer after surgery with curative intent. Patients were randomized to pembrolizumab 200mg or placebo (6 cycles) plus carboplatin-paclitaxel (4-6 cycles) Q3W, then pembrolizumab 400mg or placebo Q6W (6 cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary endpoint. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31; 95%CI, 0.14-0.69); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95%CI, 84.4%-96.4%) and 80.2% (95%CI, 70.8%-86.9%), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis based on the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

Endometrial cancer risk stratification using MRI radiomics: corroborating with choline metabolism.

BACKGROUND AND PURPOSE: Radiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism. MATERIALS AND METHODS: From August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P < .05 denoted statistical significance. RESULTS: Rad-Score achieved 71.1% accuracy in the training and 71.0% in the testing cohorts. Incorporating clinical parameters of age, tumor type, size, and grade, Rad-Signature reached accuracies of 73.2% in training and 75.4% in testing cohorts, closely matching the performance to the post-operatively based ESMO's 70.7% and 78.3%. Rad-Score was significantly associated with increased total choline levels on MRS (P = .034) and tissue levels (P = .019). CONCLUSIONS: Development of a preoperative radiomics risk score, comparable to ESMO clinical standard and associated with altered choline metabolism, shows translational relevance for radiomics in high-risk EC patients. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov on 2015-08-01 with Identifier NCT02528864.

Human papillomavirus prevalence, genotype distribution, and prognostic factors of vaginal cancer.

We aimed to investigate human papillomavirus (HPV) prevalence and genotype distribution and prognostic factors in vaginal cancer (VC). VC patients who received treatment between 1989 and 2020 were retrospectively reviewed. L1 general polymerase chain reaction (PCR) followed by HPV Blot (King Car, I-Lan, Taiwan) and E6 type-specific-PCR were performed for genotyping firstly. P16 and p53 immunohistochemistry staining was performed. Univariate and multivariate analyses identified predictors of clinical outcomes.79 VC patients were eligible for analysis. 73 patients (92.4%) were squamous cell carcinoma (SCC) and 6 (7.6%) as non-SCC. The median follow-up time was 134.3 months (range 0.9-273.4). Among nine initially HPV-negative cases, seven were identified as being positive through HPV16/18/45/52/58 whole-genome amplification followed by Sanger sequencing (WGASS). HPV DNA sequences were detected in 98.6% of SCC and 83.3% of non-SCC, respectively, with HPV16 (49.4%), HPV52 (15.2%) and HPV58 (8.9%) being predominant. Patients with paraaortic lymph node (LN) metastasis had a 5-year cancer-specific survival (CSS) rate of 0%. Multivariate analysis revealed that only p16 and stage were significantly correlated with prognosis. Variables with strong correlations (p16- and HPV-positivity, LN metastasis and stage), were included in models 2-5 alternatively. Stage III/IV (hazard ratio [HR] = 3.64-4.56) and LN metastasis (HR = 2.81-3.44) were significant negative predictors of CSS, whereas p16-positivity (HR = 0.29-0.32) and HPV-positivity (HR = 0.14) were related to better prognosis. In conclusion, 97.5% of VCs were HPV-positive with WGASS. Stage III/IV and LN metastasis were significant negative predictors, whereas p16- and HPV-positivity were significantly associated with better prognosis.

Inhibition of nucleophosmin/B23 sensitizes ovarian cancer cells to immune check-point blockade via PD-L1 in ovarian cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) that against programmed cell death protein-1 (PD-1) and its ligand PD-L1 have been approved as a promising treatment of many human cancers. However, the responses to these ICIs were limited in patients with ovarian cancer. Studies have indicated that the response to PD-1/PD-L1 blockade might be correlated with the PD-L1 expression level in cancer cells. Nucleophosmin (NPM/B23) was found to be a potential target for immunotherapy. Whether NPM/B23 plays a role in cancer-associated immunity, such as PD-1/PD-L1 axis, and its underlying mechanisms remain largely unknown in ovarian cancer. METHODS: We applied ovarian cancer cell lines as research models. The effect of modulating PD-L1 by NPM/B23 was subsequently confirmed via Western blot, flow cytometry, qRT-PCR, luciferase reporter assays, and immunoprecipitation. Protein stability and ubiquitin assay assays were used to analyze the interplay between NPM/B23 and NF-ĸB/p65 in PD-L1 regulation. The MOSEC/Luc xenograft mouse model was used to validate the role of NPM/B23-PD-L1 through tumor growth in vivo. RESULTS: Our results revealed that NPM/B23 negatively regulates PD-L1 expression via a protein complex with NF-κB/p65 and through an IFN-γ pathway. Moreover, NPM/B23 inhibitor/modulator sensitized ovarian cancer cells to the anti-PD-1 antibody by regulating PD-L1 expression in the immunocompetent mouse model. Compared to anti-PD-1 antibody alone, a combination of anti-PD-1 antibody and NPM/B23 inhibitor/modulator showed reduced tumorigenesis and increased CD8+ T-cell expansion, thus contributing to prolonged survival on MOSEC/Luc-bearing mouse model. CONCLUSION: Targeting NPM/B23 is a novel and potential therapeutic approach to sensitize ovarian cancer cells to immunotherapy.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT).

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Hyperpolarized [1-13C]-pyruvate MRS evaluates immune potential and predicts response to radiotherapy in cervical cancer.

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.

Comparison of outcomes of laparotomic and minimally invasive radical hysterectomy in women with early-stage cervical cancer.

OBJECTIVE: This study compared the outcomes of laparotomic radical hysterectomy (LRH) and minimally invasive radical hysterectomy (MISRH) in patients with early-stage cervical cancer. METHODS: The clinical data of patients with early-stage cervical cancer who underwent LRH or MISRH (laparoscopic/robotic) at Chang Gung Memorial Hospital, Linkou Branch, from 2002 to 2017 were retrospectively reviewed. The surgical safety (operation time, blood loss, blood transfusion rate, length of postoperative stay, and perioperative complications), overall survival (OS), disease-free survival (DFS), and recurrence pattern were analyzed. Propensity score matching (PSM) at a 3:1 ratio was performed to balance prognostic variables. RESULTS: Of the 760 patients (entire cohort), 614 underwent LRH and 146 underwent MISRH. After PSM, 394 and 140 patients were included in the LRH and MISRH groups, respectively. The 5-year OS rate was significantly lower in the MISRH group than in the LRH group (85.6% vs. 93.2%, p=0.043), and the 5-year DFS rate (p=0.21) did not differ significantly. After PSM, the 5-year OS rates did not differ significantly between the MISRH and LRH groups (87.1% vs. 92.1%, p=0.393). The MISRH group had a significantly shorter operation time (p<0.001), lower intraoperative blood loss (p<0.001), lower blood transfusion rate (p<0.001), and shorter postoperative stay (p<0.001) but a significantly higher rate of intraoperative bladder injury (p<0.001) than the LRH group. CONCLUSION: After PSM, MISRH is associated with nonsignificantly lower OS but a significantly higher risk of intraoperative urological complications than LRH.

Consistency in human papillomavirus type detection between self-collected vaginal specimens and physician-sampled cervical specimens.

With the rising need for accessible cervical cancer screening, self-sampling methods offer a promising alternative to traditional physician-led sampling. This study aims to evaluate the efficacy of the HygeiaTouch Self Sampling Kit for Women in detecting human papillomavirus (HPV) types and predicting cervical lesions. We studied the concordance in identifying high-risk HPV (hrHPV) types between samples collected by physicians and those self-collected by women using a self-sampling kit for validation. Women aged 21-65, fitting into specific categories based on their cervical health history were eligible. Cohen's kappa coefficient to gauge concordance between the two specimen types and relative accuracy metrics in identifying cervical intraepithelial neoplasia (CIN) were also calculated, with physician-sampled specimens serving as a reference. A total of 1210 participants from three institutes were involved. The self-sampling kit closely matched the physician-led method in terms of collecting valid specimens (100% vs. 100%), identifying hrHPV types (kappa: 0.75, 95% confidence interval [95% CI]: 0.72-0.79; agreement: 87.7%, 95% CI: 85.8-89.6) and predicting CIN grade 2 or worse (CIN2+) (relative sensitivity: 0.949, relative accuracy: 0.959). Kappa values varied between 0.71 and 0.83 for different hrHPV types and combinations, with an overall value 0.75 (95% CI: 0.72-0.79) signifying robust compatibility between the two methods. Our study underscores the potential of the HygeiaTouch Self Sampling Kit as a reliable, efficient, and user-friendly alternative to traditional sampling methods. This suggests that self-sampling could be pivotal in expanding cervical cancer screening accessibility and enhancing detection rates.

Clinical factor-based risk stratification for precision therapy in locally advanced squamous cell carcinoma of the uterine cervix.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is the standard of care for locally advanced cervical cancer. In this study, we analyzed the pretreatment clinical and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) characteristics of patients with locally advanced cervical squamous cell carcinoma (SCC) to develop a scoring prototype for risk stratification. METHODS: Two cohorts were constructed in this study. Cohort 1 comprised patients with cervical SCC with 2009 FIGO stage III-IVA or stage I-II with positive pelvic or para-aortic lymph node (PALN) on PET/CT from AGOG09-001 trial. Cohort 2 comprised patients with similar characteristics who had received adequate therapy in our hospital between 2016 and 2021. Pretreatment patient characteristics and PET/CT parameters including maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of primary tumor and nodal SUVmax were assessed for cancer-specific survival (CSS) using multivariate Cox regression. RESULTS: Analysis of combined data from cohorts 1 (n = 55) and 2 (n = 128) indicated age ≥ 66 years, primary tumor MTV ≥87 mL, and positive PALN on PET/CT to be independently significant adverse predictors for CSS (p < 0.001, p = 0.014, and p = 0.026, respectively) with a median follow-up duration of 51 months. Assigning a score of 1 to each adverse predictor, patients with cumulative risk scores of 0, 1, 2, and 3 were discovered to have a 5-year CSS of 86.9%, 71.0%, 32.2%, and 0%, respectively (p < 0.001). CONCLUSION: Age, primary tumor MTV, and positive PALN on PET/CT may serve as independent predictors of poor survival in patients with locally advanced cervical SCC. Our findings indicate that patients without any adverse factors can receive standard CCRT, whereas those with at least one adverse factor can consider novel combination therapies or clinical trials.

Comparison of immediate germline sequencing and multi-step screening for Lynch syndrome detection in high-risk endometrial and colorectal cancer patients.

OBJECTIVE: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome with a significantly increased risk of colorectal and endometrial cancers. Current standard practice involves universal screening for LS in patients with newly diagnosed colorectal or endometrial cancer using a multi-step screening protocol (MSP). However, MSP may not always accurately identify LS cases. To address this limitation, we compared the diagnostic performance of immediate germline sequencing (IGS) with MSP in a high-risk group. METHODS: A total of 31 Taiwanese women with synchronous or metachronous endometrial and colorectal malignancies underwent MSP which included immunohistochemical staining of DNA mismatch repair (MMR) proteins, MLH1 promoter hypermethylation analysis, and germline sequencing to identify pathogenic variants. All patients who were excluded during MSP received germline sequencing for MMR genes to simulate IGS for the detection of LS. RESULTS: Our findings indicate that IGS surpassed MSP in terms of diagnostic yield (29.0% vs. 19.4%, respectively) and sensitivity (90% vs. 60%, respectively). Specifically, IGS successfully identified nine LS cases, which is 50% more than the number detected through MSP. Additionally, germline methylation analysis revealed one more LS case with constitutional MLH1 promoter hypermethylation, bringing the total LS cases to ten (32.3%). Intriguingly, we observed no significant differences in clinical characteristics or overall survival between patients with and without LS in our cohort. CONCLUSION: Our study suggests that IGS may potentially offer a more effective approach compared to MSP in identifying LS among high-risk patients. This advantage is evident when patients have been pre-selected utilizing specific clinical criteria.

Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer.

Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.

Hypoxia-associated genetic signature in ovarian steroid cell tumor NOS.

Steroid cell tumors, not otherwise specified (SCT-NOS), are uncommon ovarian neoplasms accompanied by virilization symptoms due to hyperandrogenism, which are malignant in approximately one-third of the cases. Given the rarity of SCT-NOS, their molecular underpinnings have not yet been studied in depth. In this case series, we performed the first comprehensive analysis of the genetic landscape of this rare ovarian tumor. A detailed clinicopathological description of an index case is also provided. Over a 20-year period, a total of eight patients were seen at our institution. Total nucleic acids (RNA and DNA) were extracted from evaluable formalin-fixed, paraffin-embedded tumor specimens (n = 7) and subjected to TruSight Oncology 500 testing and/or exome sequencing. The results identified pathogenic variants in several hypoxia-related genes - including HIF1A, VHL, SDHB, SRC, IDH2, and FOXO4. As the first comprehensive genetic analysis of SCT-NOS, this study shows that dysregulation in the hypoxia signaling pathway is a key molecular feature of this rare tumor. Clinically, long-term follow-up with periodic measurements of androgen levels should be pursued in all cases since recurrences may occur several years after the initial diagnosis.

East Asian Gynecologic Oncology Trial Group (EAGOT): founding history and future perspective.

Racial and regional differences exist in morbidity, histology, drug response, toxicity, and prognosis of gynecologic cancer. However, most large-scale phase III studies have been conducted in Western countries, and these data on Asians, who account for more than half of the world's population, are limited. To build a global clinical trial network in Asia, four clinical trial groups with high expertise and international competitiveness in East Asia, namely the Japanese Gynecologic Oncology Group in Japan, the Korean Gynecologic Oncology Group in Korea, the Taiwanese Gynecologic Oncology Group in Taiwan, and the Chinese Gynecologic Cancer Society in the People's Republic of China, established a new group called the East Asia Gynecologic Oncology Trial Group (EAGOT) on November 19, 2021. It includes four committees: the Cervical Cancer Committee, Uterine Corpus Cancer Committee, Ovarian Cancer Committee, and Translational Research Committee. The purpose of EAGOT is to conduct international clinical trials in an effort to provide the best treatments for Asian women affected by gynecologic cancer. Discussions on new collaborative clinical trials have already begun. The first Annual EAGOT Meeting was held on May 25-27, 2023 in Niigata, Japan. EAGOT, the largest healthcare/investigational innovation network in Asia in the area of gynecologic cancers, will become a platform for establishing standards of care and lead to guidelines for Asian women suffering from gynecologic cancer. The harmonization of regulatory/investigator-initiated clinical trials, simultaneous approval of unapproved drugs in the four countries under a common protocol, and expansion of indications will improve the prognosis of gynecologic cancers in Asia in the near future.

Managing the transition in cervical screening methods for Taiwan: Policy recommendations and perspectives.

Since government-provided annual cervical cytology testing for all Taiwanese women aged 30 years or older became available in 1995, both cervical cancer incidence and death have decreased significantly. However, with the 2018 introduction of the national immunization program for human papillomavirus (HPV) vaccination in all schoolgirls aged 13-15 years old, the positive predictive value of cytology testing is expected to decrease with rising vaccination rates, and therefore a transition to more sensitive HPV-based testing may be needed. This position paper, derived from discussions by a panel of experts in cervical cancer screening, provides short-, medium-, and long-term policy recommendations to manage the transition between cervical screening methods for Taiwan. The recommendations include concrete suggestions regarding testing procedures, standards, accreditation, monitoring, promotion, and implementation. It is hoped that comprehensive preparation and management of this transition will enable Taiwan to repeat the previous successes of the cervical cytology testing program.

Small cell neuroendocrine carcinoma of the cervix: From molecular basis to therapeutic advances.

Small cell neuroendocrine carcinoma of the cervix (SCNECC) is an uncommon but aggressive uterine malignancy, the cause of which is generally associated with human papillomavirus (HPV) infection. A lack of clinical trials and evidence-based treatment guidelines poses therapeutic challenges to this rare tumor. At present, published data remain limited to case series and case reports. While clinical management has traditionally followed those of small cell neuroendocrine (SCNE) lung cancer relying on surgery, chemoradiation, and systemic chemotherapy, the prognosis remains dismal. Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies that target programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1), atezolizumab and durvalumab have proven effective in extensive-stage SCNE lung cancer. Moreover, pembrolizumab has also proven beneficial effects when added onto chemotherapy in metastatic and recurrent HPV-associated non-SCNE cervical cancer. It holds promise to use ICIs in combination with chemoradiation to improve the clinical outcomes of patients with SCNECC. Future advances in our understanding of SCNECC biology - associated with the study of its genomic and molecular aberrations as well as knowledge from SCNE of lung and other extrapulmonary sites- would be helpful in discovering new molecular targets for drug development. Collaborative efforts and establishment of a SCNECC-specific biobank will be essential to achieve this goal.

Starvation-inactivated MTOR triggers cell migration via a ULK1-SH3PXD2A/TKS5-MMP14 pathway in ovarian carcinoma.

ABBREVIATIONS: AMPK: AMP-activated protein kinase; CHX: cycloheximide; RAD001: everolimus; HBSS: Hanks' balanced salt solution; LC-MS/MS: liquid chromatography-mass spectrometry/mass spectrometry; MMP14: matrix metallopeptidase 14; MTOR: mechanistic target of rapamycin kinase; MAPK: mitogen-activated protein kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; PtdIns3P: phosphatidylinositol-3-phosphate; PX: phox homology; SH3: Src homology 3; SH3PXD2A/TKS5: SH3 and PX domains 2A; SH3PXD2A-[6A]: S112A S142A S146A S147A S175A S348A mutant; ULK1: unc-51 like autophagy activating kinase 1.

Birth outcomes following pelvic ring injury: A retrospective study.

OBJECTIVE: To report obstetric outcomes in pregnant women with previous pelvic ring injury (PRI) and investigate the correlation between residual pelvic deformity and the mode of delivery. DESIGN: Retrospective cohort study. SETTING: Single medical centre in Taiwan. POPULATION: Forty-one women with PRI histories from 2000 to 2021 who subsequently underwent pregnancy and delivery. METHODS: All patients had complete PRI treatment and radiological follow up for at least 1 year. The demographic data, radiological outcomes after PRI and obstetric outcomes were collected to investigate the potential factors of delivery modes using non-parametric approaches and logistic regression. Caesarean section (CS) rates among different subgroups were reported. MAIN OUTCOME MEASURES: Comparisons of demographic data and radiological outcomes (Matta/Tornetta criteria and Lefaivre criteria) after PRI among patients who had subsequent pregnancy and underwent vaginal deliveries (VD) or CS. RESULTS: There were 14 VD and 27 CS in 41 patients. Nine patients underwent CS because of their PRI history, 12 patients underwent CS for other obstetric indications and 20 underwent trial of labour. Based on the logistic regression model, retained trans-iliosacral implants did not significantly increase the risk of CS (odds ratio [OR] 1.20; 95% CI 0.17-8.38). Higher pelvic asymmetry value by Lefaivre criteria was a potential risk factor for CS after previous PRI (OR 1.52; 95% CI 1.043-2.213). CONCLUSIONS: VD is possible after PRI. Retained trans-iliosacral implants do not affect the delivery outcome. Residual pelvic asymmetry after PRI by Lefaivre criteria is a potential risk factor for CS.

Economic Burden of Cervical and Head and Neck Cancer in Taiwan from a Societal Perspective.

BACKGROUND: Head and neck cancers (HNC) are increasingly recognized as important human papillomavirus (HPV)-related malignancies in addition to cervical cancer (CC). However, data on the socioeconomic impact of HNC and CC in Taiwan are limited. METHODS: A retrospective cohort study was conducted to estimate the total direct medical cost and indirect productivity loss from CC and HNC between 2014 and 2015. Patient data from the Taiwan National Cancer Registry were analyzed, with matched non-cancer controls from the Taiwan National Healthcare Reimbursement Database. Indirect costs due to premature deaths were calculated using public data from Taiwanese government reports. RESULTS: In the direct cost analysis, 2083 patients with newly diagnosed CC and 11,078 with newly diagnosed HNC (10,036 males) were identified between 2014 and 2015 and followed up through the end of 2016 or until death. The total direct medical costs incurred in 2014 and 2015 due to HNC were 11.54 times higher in males than in females, and 4.55 times higher than CC. Indirect cost analysis showed the total annual productivity loss was New Taiwan Dollar (NTD) $12 billion in 2019, and 79.99% was attributed to male HNC. CONCLUSION: In Taiwan, the socioeconomic burden associated with male HNC is high and greater than that seen with CC. While not all HNCs are attributable to HPV infection, prevention of HNC through HPV vaccination should be considered for both sexes.

Generalizable transfer learning of automated tumor segmentation from cervical cancers toward a universal model for uterine malignancies in diffusion-weighted MRI.

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.

Mutations in circulating tumor DNA detected in the postoperative period predict poor survival in patients with ovarian cancer.

BACKGROUND: We investigated whether mutations in plasma circulating tumor DNA (ctDNA) can provide prognostic insight in patients with different histological types of ovarian carcinoma. We also examined the concordance of mutations detected in ctDNA samples with those identified in the corresponding formalin-fixed paraffin-embedded (FFPE) tumor specimens. METHODS: Between July 2016 and December 2017, 29 patients with ovarian carcinoma were prospectively enrolled. FFPE tumor specimens were obtained from all participants. A total of 187 blood samples for ctDNA analysis were collected before surgery (C0), immediate after surgery before adjuvant chemotherapy (C1), and at six-month intervals. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. RESULTS: The study cohort consisted of 13 (44.8%) patients with high-grade serous carcinomas (HGSC), 9 (31.0%) with clear cell carcinoma, 2 (6.9%) with mucinous carcinomas, 4 (13.8%) with low-grade serous carcinomas, and 1 (3.4%) with endometrioid carcinoma. Twenty-four (82.8%) patients had at least one detectable ctDNA variant. The concordance rate between mutations identified in pretreatment ctDNA and corresponding FFPE tumor specimens was 92.3% for patients with HGSC and 58.6% for the entire cohort. The median follow-up time was 33.15 months (range: 0.79-46.13 months). Patients with an advanced stage disease more likely had detectable ctDNA mutations before surgery (C0) and after surgery at C1, while those with HGSC more likely had ctDNA mutations detected before surgery. The presence of ctDNA mutations at C1 was an independent predictor of worse OS with a hazard ratio of 6.56 (95% confidence interval, (1.07-40.17) for detectable versus undetectable C1 ctDNA variants, p = 0.042). CONCLUSIONS: ctDNA mutations are common in patients with ovarian carcinoma. The presence of ctDNA mutations after surgery was an independent predictor of less favorable PFS and OS.