Uterine Cervical Cancer Research Articles

Leptomeningeal metastasis in primary uterine cervical cancer: a rare case and review of the literature

Objectives. Leptomeningeal metastasis (LM) of primary uterine cervical cancer is rare and treatment options are limited. In this case report and literature review, we aimed to present a patient with cervical cancer with LM and discuss previously reported cases in the literature. Case presentation. Our case was a 58-year-old patient who was initially diagnosed with metastatic primary uterine cervical cancer and treated with chemotherapy and chemoradiotherapy. During follow-up, she developed neurological symptoms, and LM was detected in the craniospinal regions. Cerebrospinal fluid cytology examination has confirmed metastatic disease. The patient was treated with concurrent intrathecal methotrexate and whole-brain radiotherapy (WBRT). A good clinical and cytological response was obtained. However, while intrathecal methotrexate was being continued after WBRT, she succumbed to hematological toxicity before the radiological response could be evaluated. Conclusions. LM is an extremely rare and catastrophic distant spread pattern in patients with cervical cancer. In the literature, a total of 26 patients were reported up to date. Median survival after detection of LM was nine weeks, including our case. Multimodal treatment combinations such as systemic and intrathecal chemotherapy and radiotherapy (RT) were used. However, most of these reports did not have detailed information about toxicity. Despite the combined use of aggressive treatment modalities, patients have limited survival and very high risks of hematologic toxicity. Concurrent use of intrathecal chemotherapy and radiotherapy should be avoided due to increased risk of morbidity.

Fan beam CT-guided online adaptive external radiotherapy of uterine cervical cancer: a dosimetric evaluation

PurposeTo discuss the dosimetric advantages and reliability of the accurate delivery of online adaptive radiotherapy(online ART) for uterine cervical cancer(UCC).Methods and materialsSix UCC patients were enrolled in this study. 95% of the planning target volume (PTV) reached 100% of the prescription dose (50.4 Gy/28fractions/6weeks) was required. The patients were scanned with uRT-Linac 506c KV-FBCT then the target volume (TV) and organs at risk (OARs) were delineated by doctors. The dosimeters designed and obtained a routine plan (Plan0). KV-FBCT was used for image guidance before subsequent fractional treatment. The online ART was processed after registration, which acquired a virtual nonadaptive radiotherapy plan (VPlan) and an adaptive plan (APlan). VPlan was the direct calculation of Plan0 on the fractional image, while APlan required adaptive optimization and calculation. In vivo dose monitoring and three-dimensional dose reconstruction were required during the implementation of APlan.ResultsThe inter-fractional volumes of the bladder and rectum changed greatly among the treatments. These changes influenced the primary gross tumor volume (GTVp) and the position deviation of GTVp and PTV and positively affected the prescription dose coverage of TV. GTVp decreased gradually along with dose accumulation. The Dmax, D98, D95, D50, and D2 of APlan were superior to those of VPlan in target dose distribution. APlan had good conformal index, homogeneity index and target coverage. The rectum V40 and Dmax, bladder V40, the small bowel V40 and Dmax of APlan were better than that of VPlan. The APlan’s fractional mean γ passing rate was significantly higher than the international standard and the mean γ passing rate of all cases after the three-dimensional reconstruction was higher than 97.0%.ConclusionOnline ART in external radiotherapy of UCC significantly improved the dose distribution and can become an ideal technology to achieve individualized precise radiotherapy.

The differences in immune features and genomic profiling between squamous cell carcinoma and adenocarcinoma – A multi-center study in Chinese patients with uterine cervical cancer

BackgroundSquamous cell carcinoma (SCC) and adenocarcinoma (AC) of the uterine cervix have distinct biological behaviors and different treatment responses. Studies on immune features and genomic profiling of these two pathologic types were limited and mainly focused on small patient cohorts. MethodsFrom 2014 to 2021, 336 (254 SCC vs. 82 AC) cervical cancer patients who were diagnosed/treated in 7 medical centers in China were enrolled in the study. Next-generation sequencing of 425 cancer-relevant genes was performed on tumor tissues and liquid biopsies. Somatic alterations and immune response-related biomarkers were analyzed. Patient prognosis and immune infiltration were analyzed using data from The Cancer Genome Atlas (TCGA). ResultsAC tended to have more immunotherapy resistance-related STK11 alterations (P = 0.039), a higher proportion of microsatellite instability (P = 0.21), and more actionable mutations (P = 0.161). In contrast, higher tumor mutational burdens (TMB; P = 0.01), a higher proportion of TMB-high patients (P = 0.016), and more PD-L1-high patients (P = 0.0013) were observed in SCC. Multiple genetic alterations and aberrant signaling pathways were specifically enriched in AC (e.g., TP53, KRAS, ERBB2, and ARID1A alterations) or SCC (e.g., PIK3CA, FBXW7, EP300, and BAP1 mutations). Notably, AC-enriched genetic changes were significantly associated with decreased infiltrations of various B cells, T cells, and dendritic cells, whereas SCC-associated molecular features tended to be associated with increased CD4+ T cell infiltrations. ConclusionsThis was the first multi-center study revealing the immunologic and genomic features between SCC and AC in Chinese patients with cervical cancer. Our findings have illustrated the difference in genetic profiles of those two cervical cancer subtypes, which may suggest the possibility of differential treatment regimens, with better immunotherapy efficacy in SCC and targeted therapy options more favorable in AC.

Intensity-modulated radiation therapy with the central shielding technique for patients with uterine cervical cancer

Abstract We aimed to examine outcomes and toxicities of intensity-modulated radiation therapy (IMRT) with the central shielding (CS) technique for patients with uterine cervical cancer. This retrospective study included 54 patients with International Federation of Gynecology and Obstetrics IB-IVA cancer. Whole pelvic radiotherapy or extended-field radiotherapy were performed at the dose of 50.4 Gy in 28 fractions with helical tomotherapy (HT). Six patients had para-aortic lymph node metastases. The CS technique with HT was utilized after a total dose of 28.8–41.4 Gy to reduce doses to the rectum and bladder. The prescribed dose of intracavitary brachytherapy was mainly 18–24 Gy in three or four fractions at point A. Concurrent chemotherapy was used for 47 patients (87%). Median follow-up time was 56 months. Seventeen patients (31%) developed recurrence. The recurrence of the cervix was observed in two patients (4%). The 5-year rates of the locoregional control, progression-free survival (PFS) and overall survival were 79, 66 and 82%, respectively. Among several factors evaluated, histological type of adenocarcinoma was only a significantly worse prognostic factor for PFS by multivariate analysis (hazard ratio, 4.9 [95% confidence interval, 1.3–18], P = 0.018). Grade 2 or higher late toxicities were observed in nine patients (17%). Two patients (4%) each had grade 3 proctitis and grade 3 ileus, respectively. No grade 4 toxicity or treatment-related death was observed. The results suggest that IMRT with the CS technique allows a high local control without increasing the risk of complications for cervical cancer patients.

The Utility of Contrast-Enhanced Magnetic Resonance Imaging in Uterine Cervical Cancer: A Systematic Review.

Correct staging of cervical cancer is essential to establish the best therapeutic procedure and prognosis for the patient. MRI is the best imaging modality for local staging and follow-up. According to the latest ESUR guidelines, T2WI and DWI-MR sequences are fundamental in these settings, and CE-MRI remains optional. This systematic review, according to the PRISMA 2020 checklist, aims to give an overview of the literature regarding the use of contrast in MRI in cervical cancer and provide more specific indications of when it may be helpful. Systematic searches on PubMed and Web Of Science (WOS) were performed, and 97 papers were included; 1 paper was added considering the references of included articles. From our literature review, it emerged that many papers about the use of contrast in cervical cancer are dated, especially about staging and detection of tumor recurrence. We did not find strong evidence suggesting that CE-MRI is helpful in any clinical setting for cervical cancer staging and detection of tumor recurrence. There is growing evidence that perfusion parameters and perfusion-derived radiomics models might have a role as prognostic and predictive biomarkers, but the lack of standardization and validation limits their use in a research setting.

Lymphatic mapping for image-guided radiotherapy in patients with locally advanced uterine cervical cancer: a feasibility study

BackgroundLymph node metastasis is an important prognostic factor in locally advanced cervical cancer (LACC). No imaging method can successfully detect all (micro)metastases. This may result in (lymph node) recurrence after chemoradiation. We hypothesized that lymphatic mapping could identify nodes at risk and if radiation treatment volumes are adapted based on the lymphatic map, (micro)metastases not shown on imaging could be treated. We investigated the feasibility of lymphatic mapping to image lymph nodes at risk for (micro)metastases in LACC and assessed the radiotherapy dose on the nodes at risk.MethodsPatients with LACC were included between July 2020 and July 2022. Inclusion criteria were: ≥ 18 years old, intended curative chemoradiotherapy, investigation under anesthesia. Exclusion criteria were: pregnancy and extreme obesity. All patients underwent abdominal MRI, [18F]FDG-PET/CT and lymphatic mapping after administration of 6–8 depots of 99mTc]Tc-nanocolloid followed by planar and SPECT/CT images 2–4 and 24 h post-injection.ResultsSeventeen patients participated. In total, 40 nodes at risk were visualized on the lymphatic map in 13/17 patients with a median of two [range 0–7, IQR 0.5–3] nodes per patient, with unilateral drainage in 4/13 and bilateral drainage in 9/13 patients. No complications occurred. The lymphatic map showed more nodes compared to suspicious nodes on MRI or [18F]FDG-PET/CT in 8/14 patients. Sixteen patients were treated with radiotherapy with 34 visualized nodes on the lymphatic map. Of these nodes, 20/34 (58.8%) received suboptimal radiotherapy: 7/34 nodes did not receive radiotherapy at all, and 13/34 received external beam radiotherapy (EBRT), but no simultaneous integrated boost (SIB).ConclusionLymphatic mapping is feasible in LACC. Almost 60% of nodes at risk received suboptimal treatment during chemoradiation. As treatment failure could be caused by (micro)metastasis in some of these nodes, including nodes at risk in the radiotherapy treatment volume could improve radiotherapy treatment outcome in LACC.Trail registration The study was first registered at the International Clinical Trial Registry Platform (ICTRP) under number of NL9323 on 4 March 2021. Considering the source platform was not operational anymore, the study was retrospectively registered again on February 27, 2023 at CilicalTrials.gov under number of NCT05746156.

Identification of predictive biomarkers for diagnosis and radiation sensitivity of uterine cervical cancer using wide-targeted metabolomics.

Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer-specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide-targeted plasma metabolomics. We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra-high-performance liquid chromatography with tandem mass spectrometry. The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non-susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment. Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy.

A confirmatory trial of modified radical hysterectomy for patients with FIGO stage IB1 cervical cancer with tumor diameter preoperatively estimated at 2 cm or less: Japan Clinical Oncology Group study, JCOG1101.

5532 Background: The standard surgery for Stage IB1 uterine cervical cancer is radical hysterectomy (RH, Piver class III hysterectomy). However, RH is highly invasive, and there is a need to establish less invasive techniques. We conducted a single-arm confirmatory trial (JCOG1101) to evaluate the efficacy and safety of modified radical hysterectomy (MRH) in patients with tumor diameter ≤ 2 cm Stage IB1 cervical cancer (jRCT: jRCTs031180167). Methods: From January 2013 to August 2017, 240 patients were enrolled from 40 institutions in Japan. Eligibility criteria included: (1) FIGO 2008 Stage IB1 cervical cancer; (2) histologically proven squamous cell carcinoma, adenocarcinoma (mucinous or endometrioid) or adenosquamous carcinoma; (3) tumor diameter ≤ 2 cm (measured by MRI or conization specimen); and (4) neither distant LN metastasis nor distant metastasis in CT. In case that the cancer could be microinvasive, conization was required to exclude Stage IA cases. The protocol surgery involved cutting the anterior layer of the vesicouterine ligament of the uterus and dissecting regional lymph nodes. Only laparotomy was permitted: laparoscopy and robotic surgery were not allowed. Postoperative irradiation was administered in cases where pelvic LN or parametrial invasion was positive, depth in the cervical wall invasion was ≥ 2/3, or surgical margin was < 1 cm by pathological findings. The primary endpoint was 5-year overall survival (OS). We set the expected 5-year OS of MRH at 95.8% (5-year OS of RH in JCOG0806A, retrospective observational study) and the threshold 5-year OS at 90.8%. Results: Among 225 eligible patients, 193 (85.8%) were pT1b1 (UICC 7th), and 184 (81.8%) had pathological maximal tumor diameter ≤ 2 cm. Parametrial involvement, lymph node metastasis, ≥ 2/3 stromal invasion and < 1 cm surgical margin were observed in 3 (1.3%), 16 (7.1%), 30 (13.3%) and 11 (4.9%) patients, respectively. Thirty-nine patients (17.3%) underwent adjuvant (chemo)radiation. Median follow-up was 77.7 months. Five patients (2.2%) died, and 5-year OS was 98.2% (90% CI: 96.0-99.2, > 90.8%). Thirteen patients (5.8%) relapsed (8 local recurrence and 5 distant recurrence), and 5-year relapse-free survival was 94.7% (95% CI: 90.8-96.9%). Self-urination was observed in all patients, and residual urine disappearance up to 56 days after urethral catheter removal was observed in 213 patients (94.7%). Median time to disappearance of residual urine after urethral catheter removal was 1 day. There was no treatment-related death. Grade 3/4 non-hematological adverse events were observed in 17 patients (7.6%), including 8 infection and 4 hemorrhage. Conclusions: In this study, MRH was as effective as RH and less invasive. MRH can be considered a standard surgery for tumor diameter ≤ 2 cm Stage IB1 uterine cervical cancer. Clinical trial information: UMIN000009726 , jRCTs031180167 .

Development and Validation of the Promising PPAR Signaling Pathway-Based Prognostic Prediction Model in Uterine Cervical Cancer.

A ligand-activated transcription factor, peroxisome proliferator-activated receptor (PPAR) regulates fatty acid uptake and transport. In several studies, upregulation of PPAR expression/activity by cancer cells has been associated with cancer progression. Worldwide, cancer of the cervix ranks fourth among women's cancers. Angiogenesis inhibitors have improved treatment for recurrent and advanced cervical cancer since their introduction 5 years ago. In spite of that, the median overall survival rate for advanced cervical cancer is 16.8 months, indicating that treatment effectiveness is still lacking. Thus, it is imperative that new therapeutic methods be developed. In this work, we first downloaded the PPAR signaling pathway-related genes from the previous study. In addition, the single-sample gene set enrichment analysis (ssGSEA) algorithm was applied to calculate the PPAR score of patients with cervical cancer. Furthermore, cervical cancer patients with different PPAR scores show different sensitivity to immune checkpoint therapy. In order to screen the genes to serve as the best biomarker for cervical cancer patients, we then construct the PPAR-based prognostic prediction model. The results revealed that PCK1, MT1A, AL096855.1, AC096711.2, FAR2P2, and AC099568.2 not only play a key role in the PPAR signaling pathway but also show good predictive value in cervical cancer patients. The gene set variation analysis (GSVA) enrichment analysis also proved that the PPAR signaling pathway is one of the most enriched pathways in the prognostic prediction model. Finally, further analysis revealed that AC099568.2 may be the most promising biomarker for the diagnosis, treatment, and prognosis in cervical cancer patients. Both the survival analysis and Receiver Operating Characteristic curve demonstrated that AC099568.2 plays a key role in cervical cancer patients. However, to our knowledge, this is the first time a study focused on the role of AC099568.2 in cervical cancer patients. Our work successfully revealed a new biomarker for cervical cancer patients, which also provides a new direction for future research.

Relationship between Human Papillomavirus Status and the Cervicovaginal Microbiome in Cervical Cancer.

Uterine cervical cancer (CC) is a complex, multistep disease primarily linked to persistent infection with high-risk human papillomavirus (HR-HPV). However, it is widely acknowledged that HR-HPV infection alone cannot account for the formation and progression of CC. Emerging evidence suggests that the cervicovaginal microbiome (CVM) also plays a significant role in HPV-related CC. Certain bacteria, such as Fusobacterium spp., Porphyromonas, Prevotella, and Campylobacter, are currently being considered as potential microbiomarkers for HPV-positive CC. However, the composition of the CVM in CC is inconsistent; thus, further studies are needed. This review comprehensively discusses the complex interplay between HPV and the CVM in cervical carcinogenesis. It is postulated that the dynamic interaction between HPV and the CVM creates an imbalanced cervicovaginal microenvironment that triggers dysbiosis, enhances HPV persistence, and promotes cervical carcinogenesis. Moreover, this review aims to provide updated evidence on the potential role of bacteriotherapy, particularly probiotics, in the treatment of CC.

Reduced Risk of Lymphedema With Intensity-modulated Radiation Therapy Compared With 3-dimensional Conformal Radiation Therapy in Patients With Cervical Cancer Who Received Postoperative Pelvic Radiation Therapy.

To compare the long-term adverse events of intensity-modulated radiation therapy (IMRT) with those of 3-dimensional conformal radiation therapy (3D-CRT) in patients with intermediate-risk and high-risk uterine cervical cancer who underwent postoperative pelvic radiation therapy (PORT). We reviewed the medical records of 177 patients with cervical cancer who underwent radical surgery and PORT. IMRT and 3D-CRT were administered to 93 and 84 patients, respectively. Follow-up and toxicity assessments were then carried out. The median follow-up period was 63 months (range: 3 to 177). There was a significant difference in the follow-up period between the IMRT and 3D-CRT cohorts (median: 59 vs. 112mo, P <0.0001). The crude incidences of acute grade 2+ and grade 3+ gastrointestinal toxicities were significantly lower with IMRT than with 3D-CRT (22.6% vs. 48.1%, P =0.002, and 3.2% vs. 11.1%, P =0.04, respectively). The Kaplan-Meier estimates of late toxicities revealed that IMRT significantly reduced grade 2+ genitourinary (GU) toxicity and lower-extremity lymphedema ([LEL] requiring intervention) compared with 3D-CRT ([6.8% vs. 15.2% at 5-year, P =0.048] and [3.1% vs. 14.6% at 5-year, P =0.0029], respectively). IMRT was the only significant predictor of reducing LEL risk. The risks of acute gastrointestinal toxicity, late GU toxicity, and LEL from PORT for cervical cancer were reduced by IMRT. Lower inguinal doses may have contributed to a lower risk of developing LEL, which should be validated in future studies.

Adjuvant Therapy in Early-Stage Cervical Cancer Patients with Intermediate-Risk Factors, Comparing Between Chemotherapy and Radiotherapy: A Systematic Review and Meta-Analysis

BACKGROUND: Patients with early-stage cervical cancer (ESCC) after radical hysterectomy surgery usually need additional adjuvant treatment, but it depends on the presence or absence of certain risk factors. Factors, such as large tumor size, deep stromal invasion, and lymphovascular space involvement, are classified as intermediate risks. Therefore, postoperative adjuvant concurrent chemo-radiotherapy (CRT) or radiotherapy (RT) is recommended for ESCC with risk factors. However, it remains controversial whether CRT is superior to RT as an adjuvant regimen for postoperative with risk factors. METHODS: A systematic search was performed within PubMed, Cochrane, Science Direct, and Google Scholar databases to research the outcome between CRT and RT in ESCC. Three reviewers independently reviewed titles, abstracts, and full article text to identify studies meeting inclusion and exclusion criteria. If there are any discrepancies, it will be resolved by discussion. In this analysis, the Newcastle–Ottawa scale was used to assess the risk of bias of non-randomized studies. We used review manager 5.4 to calculate the result of 95% CI for the outcomes using odds ratio (OR), random effect model was also used if there is heterogeneity. The primary endpoints of interest are recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 14 studies included in qualitative synthesis and meta-analysis with a total of 5.294 patients were identified. Patients who had RT after radical hysterectomy was found to significantly have a more favorable RFS rate with OR 0.57 95% CI (0.38–0.84), p = 0.005; I2 = 63%. Nine studies were found comparing the OS between adjuvant RT and adjuvant CRT in a patient with ESCC with intermediate risk, the result is quite similar favoring adjuvant RT with significantly better OS outcome OR 0.69 95% CI (0.54–0.87), p = 0.002; I2 =34%. 1.526 had hematologic toxicities, 797 were RT and 729 had CRT. The study showed RT had better outcomes with lesser toxicities (OR 0.11, 95% CI [0.03–0.44] p = 0.002; I2 = 91%). Non-hematological toxicity, with a total of 1.463 patients, 799 were RT and 664 had CRT. Random models were used due to heterogeneity. RT is significantly associated with lesser non- hematologic toxicities with OR 0.34, 95% CI (0.18–0.66) p = 0.001; I2 = 65%. DISCUSSION: During the last two decades, there were significant changes in practice to cure uterine cervical cancer. Based on the consistent results generated in several previous randomized controlled trials, cisplatin-based CCRT has become the standard treatment for advanced cervical cancer. A randomized prospective studies by Sedlis et al., randomized FIGO IB patients without residual tumor or involved lymph nodes but with two or more intermediate-risk factors later named the “Sedlis criteria” to receive observation or RT following radical surgery. Adjuvant RT led to a reduction of recurrence rates at the cost of an approximately 4% higher rate of grade 3/4 adverse events. There was no increase in OS but an improvement of long-term RFS. On the other hand, a study found that RFS and OS were significantly improved in the addition of chemotherapy, especially in patients with clinical-stage IA2, IB, and IIA with para-metric invasion, residual tumor and/or lymph node involvement. This study found that RT had better outcomes in RFS and OS, RT also had lesser hematologic toxicity and non-hematologic toxicity. After all, it is prudent to take into account the adverse events as well as the QOL for long-term survivors. CONCLUSION: Adjuvant RT shows a better outcome in RFS and OS. CRT is often associated with greater hematological and non-hematological toxicities. Further high-quality randomized clinical trials with larger sample size comparing the efficacy and toxicity of adjuvant CRT with RT are recommended.

Elevated risk of cervical cancer in elderly women with incident ulcerative colitis in South Korea

The association between ulcerative colitis (UC) and uterine cervical cancer is still unclear. To investigate cervical cancer risk in South Korean women with UC, we analyzed the Korean National Health Insurance claims data. UC was defined using both ICD-10 codes and UC-specific prescriptions. We analyzed incident cases of UC diagnosed between 2006 and 2015. Age-matched women without UC (control group) were randomly selected from the general population (1:3 ratio). Hazard ratios were calculated using multivariate Cox proportional hazard regression, and the event was defined as occurrence of cervical cancer. A total of 12,632 women with UC and 36,797 women without UC were enrolled. The incidence of cervical cancer was 38.8 per 100,000 women per year in UC patients and 25.7 per 100,000 women per year in controls, respectively. The adjusted HR for cervical cancer was 1.56 (95% CI 0.97–2.50) in the UC group with reference to the control group. When stratified by age, the adjusted HR for cervical cancer was 3.65 (95% CI 1.54–8.66) in elderly UC patients (≥ 60 years) compared to elderly control group (≥ 60 years). Within UC patients, increased age (≥ 40 years) and low socioeconomic status were associated with an increased risk of cervical cancer. The incidence of cervical cancer was found to be higher among elderly patients (≥ 60 years) with newly diagnosed UC in South Korea, compared to age-matched controls. Therefore, regular cervical cancer screening is recommended for elderly patients who have recently been diagnosed with UC.

The incidence of perioperative lymphatic complications after radical hysterectomy and pelvic lymphadenectomy between robotic and laparoscopic approach : a systemic review and meta-analysis.

Although many studies have reported perioperative complications after radical hysterectomy and pelvic lymph node dissection using robotic and laparoscopic approaches, the risk of perioperative lymphatic complications has not been well identified. The aim of this meta-analysis is to compare the risks of perioperative lymphatic complications after robotic radical hysterectomy and lymph node dissection (RRHND) with laparoscopic radical hysterectomy and lymph node dissection (LRHND) for early uterine cervical cancer. The authors searched the PubMed, Cochrane Library, Web of Science, ScienceDirect, and Google Scholar databases for studies published up to July 2022 comparing perioperative lymphatic complications after RRHND and LRHND while treating early uterine cervical cancer. Related articles and bibliographies of relevant studies were also checked. Two reviewers independently performed the data extraction. A total of 19 eligible clinical trials (15 retrospective studies and 4 prospective studies) comprising 3079 patients were included in this analysis. Only 107 patients (3.48%) had perioperative lymphatic complications, of which the most common was lymphedema ( n =57, 1.85%), followed by symptomatic lymphocele ( n =30, 0.97%), and lymphorrhea ( n =15, 0.49%). When all studies were pooled, the odds ratio for the risk of any lymphatic complication after RRHND compared with LRHND was 1.27 (95% CI: 0.86-1.89; P =0.230). In the subgroup analysis, study quality, country of research, and publication year were not associated with perioperative lymphatic complications. A meta-analysis of the available current literature suggests that RRHND is not superior to LRHND in terms of perioperative lymphatic complications.

Comparative Dosimetric Study Using Various Applicators for Vaginal Cuff Brachytherapy; Three Ovoid Technique Proposal

Purpose: Vaginal-cuff brachytherapy is the adjuvant treatment in women with intermediate-high risk of endometrial or uterine cervical cancers. The most common applicators are single-channel vaginal cylinders and two-symmetric ovoid applicators according to the shape of the stump. For two-ovoid applicators, the distance between them depends on the therapist and vaginal size. A greater distance means a lower dose in the vaginal apex point. To overcome this problem, this study proposes brachytherapy plans using three-ovoid applicators to improve insufficient dose distribution.

Immunotherapy in oncogynaecology

Immune checkpoint inhibitors have deeply changed treatment paradigm of many tumor types, notably by providing long-term remissions, even in the metastatic setting. These immunotherapies aim to restore T-cells activity against tumour cells, in particular via the inhibition of PD1/PD-L1 interaction. As for lung or renal carcinomas, and melanomas, the management of endometrial and uterine cervical cancers has been disrupted by PD1/PD-L1 inhibitors efficacy. In locally advanced or metastatic cervical carcinomas, the combination of platinum-based chemotherapy with pembrolizumab demonstrated improved overall and progression-free survival in all subgroups of patients, and became the new standard of care. Regarding endometrial cancers, while single-agent immunotherapies have shown very limited activity in an unselected population, dostarlimab and pembrolizumab have been associated with remarkable antitumor activity in case of microsatellite instability (dMMR/MSI), detected in around 30% of patients. Finally, in endometrial cancer that has progressed after first-line chemotherapy, the association of pembrolizumab with an oral antiangiogenic kinase inhibitor (lenvatinib) has demonstrated its superiority over second-line chemotherapy regimens, regardless molecular subgroups, and has become the new standard of care in this indication.

Prognosis prediction of uterine cervical cancer using changes in the histogram and texture features of apparent diffusion coefficient during definitive chemoradiotherapy.

We investigated prospectively whether, in cervical cancer (CC) treated with concurrent chemoradiotherapy (CCRT), the Apparent diffusion coefficient (ADC) histogram and texture parameters and their change rates during treatment could predict prognosis. Fifty-seven CC patients treated with CCRT at our institution were included. They underwent MRI scans up to four times during the treatment course (1st, before treatment [n = 41], 2nd, at the start of image-guided brachytherapy (IGBT) [n = 41], 3rd, in the middle of IGBT [n = 27], 4th, after treatment [n = 53]). The entire tumor was manually set as the volume of interest (VOI) manually in the axial images of the ADC map by two radiologists. A total of 107 image features (morphology features 14, histogram features 18, texture features 75) were extracted from the VOI. The recurrence prediction values of the features and their change rates were evaluated by Receiver operating characteristics (ROC) analysis. The presence or absence of local and distant recurrence within two years was set as an outcome. The intraclass correlation coefficient (ICC) was also calculated. The change rates in kurtosis between the 1st and 3rd, and 1st and 2nd MRIs, and the change rate in grey level co-occurrence matrix_cluster shade between the 2nd and 3rd MRIs showed particularly high predictive powers (area under the ROC curve = 0.785, 0.759, and 0.750, respectively), which exceeded the predictive abilities of the parameters obtained from pre- or post-treatment MRI only. The change rate in kurtosis between the 1st and 2nd MRIs had good reliability (ICC = 0.765). The change rate in ADC kurtosis between the 1st and 2nd MRIs was the most reliable parameter, enabling us to predict prognosis early in the treatment course.

Plan quality association between dummy run and individual case review in a prospective multi-institutional clinical trial of postoperative cervical cancer patients treated with intensity-modulated radiotherapy: Japan clinical Oncology Group study (JCOG1402)

Background and purposeThe Japan Clinical Oncology Group (JCOG) 1402 conducted a multicenter clinical trial of postoperative intensity-modulated radiotherapy (IMRT) for high-risk uterine cervical cancer patients. We assess effectiveness of the quality assurance (QA) program in central review through dummy runs (DRs) performed before patient enrollment and post-treatment individual case review (ICR), and clarify the pitfalls in treatment planning. Material and methodsThe ICRs were conducted using the same QA program as the DR for 214 plans. The deviations were compared with those demonstrated in the DRs, and the pitfalls were clarified. Fifteen face-to-face meetings were held with physicians at participating institutions to provide feedback. ResultsTwo-hundred and eighty-eight deviations and nine violations were detected in the 214 plans. The patterns of the deviations observed in the ICRs were similar to that in the DR. Frequent deviations were observed in clinical target volume (CTV) delineations, 50% in the DRs and 37% in the ICRs, respectively. In the ICRs, approximately 1.4 deviations/violations were observed per plan, which was lower than DR. Nine violations included inaccurate CTV delineation and improper PTV (planning target volume) margin, which had risks in loco-regional failures by inadequate dose coverage. ConclusionsOur developed QA program commonly used in DR and ICR clarified the pitfalls in treatment plans. Although the frequent deviations in CTV delineations were observed in the ICR, the deviations decreased compared to that in the DR. More specified face-to-face meetings with participating institutions will be necessary to maintain the quality of IMRT in the clinical protocol.

Inhibition of IDH3α Enhanced the Efficacy of Chemoimmunotherapy by Regulating Acidic Tumor Microenvironments

In recent years, chemoimmunotherapy has become effective in some advanced cancers, but its effect is still limited. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) can promote tumor initiation and progression. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy in cancers. Here, we found that IDH3α was elevated in uterine cervical cancer (UCC) and lung adenocarcinoma (LUAD) samples by using public databases. High expression of IDH3α could promote the epithelial-mesenchymal transition (EMT), alter the intracellular redox status, promote glycolysis, and induce an acidic microenvironments in cancer cells. Furthermore, we found that inhibition of IDH3α combined with chemoimmunotherapy (cisplatin and programmed cell death ligand 1 (PD-L1) antibodies) activated the cGAS-STING pathway, promoted CD8+ T cell infiltration, and decreased tumor growth in mouse models of cervical cancer. In conclusion, our data indicate that silencing IDH3α sensitizes tumors to chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS-STING pathway.

Dynamics in the expression of programmed death ligand 1 and cluster of differentiation 163 in the tumor microenvironment of uterine cervical cancer: a single-center retrospective study

BackgroundRadiotherapy (RT) destroys cancer cells and activates the immune system while suppressing the immunity of tumor-associated tissues, including the tumor microenvironment (TME). However, to date, no anti-tumor therapeutic strategy that uses these immune mechanisms has been established. This study investigated changes in the immunity of the TME during standard radical RT for cervical cancer combined with external beam RT and brachytherapy and determined whether these changes affect prognosis.MethodsTwenty-six patients who had completed radical RT for cervical cancer were categorized into the following two groups according to whether the cancer recurred and/or metastasized within 2 years after the start of treatment: treatment failure (n = 14) and treatment success (n = 12). We assessed the expression of programmed death 1, programmed death ligand 1 (PD-L1), cluster of differentiation (CD) 8, CD68, CD163, Forkhead box protein P3, and hypoxia-inducible factor-1α in the TME of cervical tissues collected periodically during treatment and evaluated the difference in expression rates of each marker between the success and failure groups and assessed its effect on prognosis.ResultsThe expression levels of PD-L1 and CD163 in the TME in the treatment success group were lower than those in the treatment failure group at the midpoint during brachytherapy (p < 0.01 and p = 0.08, respectively), and the 2-year progression-free-survival (PFS) rate depended on the expression levels of PD-L1 and CD163 (p = 0.04 and p = 0.02, respectively).ConclusionsThe expression rates of CD163 and PD-L1 in the TME during brachytherapy were related to treatment response and the 2-year PFS. This study may increase our understanding of tumor-associated immunity in the TME and aid in the development of therapies targeting PD-L1 or M2 macrophages in the TME in conjunction with RT, especially brachytherapy, for cervical cancer patients.