scholarly journals Mutation Analysis of Radioresistant Early-Stage Cervical Cancer

2021 ◽  
Vol 23 (1) ◽  
pp. 51
Author(s):  
Tae Oike ◽  
Yoshihito Sekiguchi ◽  
Yuya Yoshimoto ◽  
Takahiro Oike ◽  
Ken Ando ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Local Recurrence ◽  
Cancer Cells ◽  
Early Stage ◽  
Gene Set Enrichment Analysis ◽  
Definitive Treatment ◽  
Mesenchymal Transition ◽  
X Ray ◽  
Cervical Cancers ◽  
Early Stage Cervical Cancer

Radiotherapy is a definitive treatment for early-stage cervical cancer; however, a subset of this disease recurs locally, necessitating establishment of predictive biomarkers and treatment strategies. To address this issue, we performed gene panel-based sequencing of 18 stage IB cervical cancers treated with definitive radiotherapy, including two cases of local recurrence, followed by in vitro and in silico analyses. Simultaneous mutations in KRAS and SMAD4 (KRASmt/SMAD4mt) were detected only in a local recurrence case, indicating potential association of this mutation signature with radioresistance. In isogenic cell-based experiments, a combination of activating KRAS mutation and SMAD4 deficiency led to X-ray resistance, whereas either of these factors alone did not. Analysis of genomic data from 55,308 cancers showed a significant trend toward co-occurrence of mutations in KRAS and SMAD4. Gene Set Enrichment Analysis of the Cancer Cell Line Encyclopedia dataset suggested upregulation of the pathways involved in epithelial mesenchymal transition and inflammatory responses in KRASmt/SMAD4mt cancer cells. Notably, irradiation with therapeutic carbon ions led to robust killing of X-ray-resistant KRASmt/SMAD4mt cancer cells. These data indicate that the KRASmt/SMAD4mt signature is a potential predictor of radioresistance, and that carbon ion radiotherapy is a potential option to treat early-stage cervical cancers with the KRASmt/SMAD4mt signature.

scholarly journals Outcome and Subsequent Pregnancy after Fertility-Sparing Surgery of Early-Stage Cervical Cancers

2020 ◽  
Vol 17 (19) ◽  
pp. 7103
Author(s):  
Chia-Yi Lee ◽  
Yu-Li Chen ◽  
Ying-Cheng Chiang ◽  
Ching-Yu Cheng ◽  
Yen-Ling Lai ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Live Birth ◽  
Early Stage ◽  
Medical Center ◽  
Subsequent Pregnancy ◽  
Definitive Treatment ◽  
Clinicopathologic Characteristics ◽  
Fertility Sparing Surgery ◽  
Fertility Sparing ◽  
Early Stage Cervical Cancer

We aimed to investigate the outcomes and subsequent pregnancies of early-stage cervical cancer patients who received conservative fertility-sparing surgery. Women with early-stage cervical cancer who underwent conservative or fertility-sparing surgery in a tertiary medical center were reviewed from 2004 to 2017. Each patient’s clinicopathologic characteristics, adjuvant therapy, subsequent pregnancy, and outcome were recorded. There were 32 women recruited, including 12 stage IA1 patients and 20 stage IB1 patients. Twenty-two patients received conization/LEEP and the other 10 patients received radical trachelectomy. Two patients did not complete the definite treatment after fertility-sparing surgery. There were 11 women who had subsequent pregnancies and nine had at least one live birth. The live birth rate was 73.3% (11/15). We conclude that patients with early-stage cervical cancer who undergo fertility-sparing surgery can have a successful pregnancy and delivery. However, patients must receive a detailed consultation before surgery and undergo definitive treatment, if indicated, and regular postoperative surveillance.

scholarly journals Markers of Angiogenesis, Lymphangiogenesis, and Epithelial–Mesenchymal Transition (Plasticity) in CIN and Early Invasive Carcinoma of the Cervix: Exploring Putative Molecular Mechanisms Involved in Early Tumor Invasion

2020 ◽  
Vol 21 (18) ◽  
pp. 6515
Author(s):  
Olga Kurmyshkina ◽  
Pavel Kovchur ◽  
Ludmila Schegoleva ◽  
Tatyana Volkova
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Invasive Carcinoma ◽  
Driving Forces ◽  
Early Stage ◽  
Flow Cytometric Analysis ◽  
Cell Phenotype ◽  
Invasive Growth ◽  
Mesenchymal Transition

The establishment of a proangiogenic phenotype and epithelial-to-mesenchymal transition (EMT) are considered as critical events that promote the induction of invasive growth in epithelial tumors, and stimulation of lymphangiogenesis is believed to confer the capacity for early dissemination to cancer cells. Recent research has revealed substantial interdependence between these processes at the molecular level as they rely on common signaling networks. Of great interest are the molecular mechanisms of (lymph-)angiogenesis and EMT associated with the earliest stages of transition from intraepithelial development to invasive growth, as they could provide the source of potentially valuable tools for targeting tumor metastasis. However, in the case of early-stage cervical cancer, the players of (lymph-)angiogenesis and EMT processes still remain substantially uncharacterized. In this study, we used RNA sequencing to compare transcriptomes of HPV(+) preinvasive neoplastic lesions and early-stage invasive carcinoma of the cervix and to identify (lymph-)angiogenesis- and EMT-related genes and pathways that may underlie early acquisition of invasive phenotype and metastatic properties by cervical cancer cells. Second, we applied flow cytometric analysis to evaluate the expression of three key lymphangiogenesis/EMT markers (VEGFR3, MET, and SLUG) in epithelial cells derived from enzymatically treated tissue specimens. Overall, among 201 differentially expressed genes, a considerable number of (lymph-)angiogenesis and EMT regulatory factors were identified, including genes encoding cytokines, growth factor receptors, transcription factors, and adhesion molecules. Pathway analysis confirmed enrichment for angiogenesis, epithelial differentiation, and cell guidance pathways at transition from intraepithelial neoplasia to invasive carcinoma and suggested immune-regulatory/inflammatory pathways to be implicated in initiation of invasive growth of cervical cancer. Flow cytometry showed cell phenotype-specific expression pattern for VEGFR3, MET, and SLUG and revealed correlation with the amount of tumor-infiltrating lymphocytes at the early stages of cervical cancer progression. Taken together, these results extend our understanding of driving forces of angiogenesis and metastasis in HPV-associated cervical cancer and may be useful for developing new treatments.

Conization and lymph node evaluation as a fertility-sparing treatment for early stage cervical cancer

2021 ◽  
Vol 31 (3) ◽  
pp. 457-461
Author(s):  
Fabio Martinelli ◽  
Antonino Ditto ◽  
Francesca Filippi ◽  
Daniele Vinti ◽  
Giorgio Bogani ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Lymph Node ◽  
Early Stage ◽  
Figo Stage ◽  
Pelvic Lymphadenectomy ◽  
Definitive Treatment ◽  
Sentinel Node Mapping ◽  
Fertility Sparing ◽  
Early Stage Cervical Cancer ◽  
Lymph Node Evaluation

IntroductionTo evaluate oncological and obstetrical outcomes of early stage cervical cancer patients who underwent conservative management to retain childbearing potential.MethodsData of women (aged <40 years) who underwent fertility sparing treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with lymphovascular invasion (LVSI) and IB1 cervical cancer were prospectively collected. All patients underwent cervical conization/s and laparoscopic nodal evaluation (pelvic lymphadenectomy/sentinel node mapping). Oncological and obstetrical outcomes were assessed.ResultsOverall, 39 patients met inclusion criteria; 36 (92.3%) women were nulliparous. There were: 3 (7.7%) IA1-LVSI+; 11 (28.2%) IA2; and 25 (64.1%) IB1 cervical cancers, according to 2018 FIGO stage classification. Histological types were 22 (56.4%) squamous carcinoma and 17 (43.6%) adenocarcinoma. Pelvic lymphadenectomy was performed in 29 (74.4%) patients, while 10 (25.6%) patients had only sentinel node mapping. In 4 (10.3%) patients conservative treatment was discontinued due to nodal involvement and 2 (5.1%) patients requested definitive treatment (hysterectomy) after a negative lymph node evaluation. Among 33 (84.6%) patients who retained their childbearing potential, 17 (51.5%) had a second conization. 2 (6.1%) patients relapsed and underwent definitive treatment. After a median follow-up of 51 months (range 1–184) no deaths were reported. 22 (70.9%) patients attempted to conceive. There were 13 natural pregnancies among 12 (54.5%) women who got pregnant. Live birth rate was 76.9%: 9 (69.2%) term and 1 (7.7%) preterm (at 32 weeks) deliveries. 2 (15.4%) miscarriages (first and second trimester) and 1 (7.7%) termination of pregnancy for medical reasons were recorded.ConclusionConization plus laparoscopic nodal evaluation may be a safe and feasible conservative option in the setting of fertility-sparing treatment for early-stage cervical cancer patients.

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