A microRNA Profile Regulates Inflammation-Related Signaling Pathways in Young Women with Locally Advanced Cervical Cancer.

Cervical cancer (CC) remains among the most frequent cancers worldwide despite advances in screening and the development of vaccines against human papillomavirus (HPV), involved in virtually all cases of CC. In mid-income countries, a substantial proportion of the cases are diagnosed in advanced stages, and around 40% of them are diagnosed in women under 49 years, just below the global median age. This suggests that members of this age group share common risk factors, such as chronic inflammation. In this work, we studied samples from 46 patients below 45 years old, searching for a miRNA profile regulating cancer pathways. We found 615 differentially expressed miRNAs between tumor samples and healthy tissues. Through bioinformatic analysis, we found that several of them targeted elements of the JAK/STAT pathway and other inflammation-related pathways. We validated the interactions of miR-30a and miR-34c with JAK1 and STAT3, respectively, through dual-luciferase and expression assays in cervical carcinoma-derived cell lines. Finally, through knockdown experiments, we observed that these miRNAs decreased viability and promoted proliferation in HeLa cells. This work contributes to understanding the mechanisms through which HPV regulates inflammation, in addition to its canonical oncogenic function, and brings attention to the JAK/STAT signaling pathway as a possible diagnostic marker for CC patients younger than 45 years. To our knowledge to date, there has been no previous description of a panel of miRNAs or even ncRNAs in young women with locally advanced cervical cancer.

Information needs during cancer care: Qualitative research with locally advanced cervical cancer patients in Brazil, China, Germany, & the US.

Objective: This study aimed to identify the information needs and factors for making informed treatment decisions among a diverse group of locally advanced cervical cancer (LACC) patients. Methods: Semi-structured interviews were conducted with LACC patients of diverse demographic and socioeconomic backgrounds within two years of their cancer diagnosis. Trained moderators asked open-ended questions about patients' cancer journeys. Transcripts were analyzed using NVivo software to identify emergent themes. Results: In 2022, 92 LACC patients in the United States (n = 26), Brazil (n = 25), China (n = 25), and Germany (n = 16) participated in the study. Physicians were valued sources of information, providing patients with details on prognosis, treatment options, and side effects. While most patients trusted their physicians, one-third sought a second opinion to validate their diagnosis or find a more trusted physician.Most patients conducted their own research on treatment options, side effects, causes of LACC, symptoms, and others' experiences. Challenges to information searches included understanding medical terms, finding relevant information, and evaluating source credibility.Overall, patients felt knowledgeable enough to participate in treatment decisions, either by accepting the recommended treatment or collaborating with their physicians. Nearly one-third of patients desired a more significant role in the decision-making process. Conclusion: This study highlights the importance of physicians providing LACC patients comprehensive and understandable information, while involving them in the decision-making process. Understanding LACC patients' motivations to seek information and their willingness to actively engage in treatment decisions can lead to improved patient satisfaction in their cancer care.

Optimal cisplatin cycles in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy.

PURPOSE: To analyze the effect of cisplatin cycles on the clinical outcomes of patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT). METHODS: This study included 749 patients with LACC treated with CCRT between January 2011 and December 2015. A receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off of cisplatin cycles in predicting clinical outcomes. Clinicopathological features of the patients were compared using the Chi-square test. Prognosis was assessed using log-rank tests and Cox proportional hazard models. Toxicities were compared among different cisplatin cycle groups. RESULTS: Based on the ROC curve, the optimal cut-off of the cisplatin cycles was 4.5 (sensitivity, 64.3%; specificity, 54.3%). The 3-year overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival for patients with low-cycles (cisplatin cycles < 5) and high-cycles (≥ 5) were 81.5% and 89.0% (P < 0.001), 73.4% and 80.1% (P = 0.024), 83.0% and 90.8% (P = 0.005), and 84.9% and 86.8% (P = 0.271), respectively. In multivariate analysis, cisplatin cycles were an independent prognostic factor for overall survival. In the subgroup analysis of high-cycle patients, patients who received over five cisplatin cycles had similar overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival to patients treated with five cycles. Acute and late toxicities were not different between the two groups. CONCLUSION: Cisplatin cycles were associated with overall, disease-free, and loco-regional relapse-free survival in LACC patients who received CCRT. Five cycles appeared to be the optimal number of cisplatin cycles during CCRT.

Effectiveness of Concomitant Chemoradiotherapy with Gemcitabine in Locally Advanced Cervical Cancer Patients with Comorbidities.

PURPOSE: The standard treatment for locally advanced cervical cancer (LACC) is concomitant chemoradiotherapy with cisplatin (CDDP) followed by brachytherapy. The presence of comorbidities are risk factors for nephrotoxicity and are associated with lower survival. Gemcitabine is a radiosensitizing drug that has shown efficacy and safety in this context. The effectiveness of concomitant chemoradiotherapy with gemcitabine was evaluated versus cisplatin in LACC patients with comorbidities and preserved renal function. MATERIALS AND METHODS: An observational, longitudinal and paired study was carried out that included patients treated between February 2003 and December 2015. The primary objectives were to evaluate response rates, progression-free survival, and overall survival; the secondary objectives were to evaluate toxicity and renal function. RESULTS: Sixty-three patients treated with gemcitabine at 300 mg/m2 weekly and 126 patients treated with CDDP 40 mg/m2 weekly were included. There were no significant differences in response rates and survival rates. Treatment with cisplatin presented a higher frequency of hematological toxicities, while gemcitabine presented a higher frequency of gastrointestinal toxicities. A decrease in glomerular filtration rate (GFR; baseline vs. 1-year post-treatment) was observed in the cisplatin group (p=0.002), while not in the gemcitabine group (p=0.667). In a multivariate analysis, it is observed that only CDDP correlates with the decrease in GFR (hazard ratio, 2.42; p=0.012). CONCLUSION: In LACC patients with comorbidities, gemcitabine and CDDP show the same efficacy, with different toxicity profiles. Treatment with cisplatin is associated with a significant decrease in GFR during follow-up, compared to treatment with gemcitabine that does not decrease it.

Pharmacodynamics of current and emerging treatments for cervical cancer.

Introduction: Beyond early stages of cervical cancer (1A1, IA2, IB1, IIA1,), locally advanced disease (IB2, IIA2, IIA2, IIB, IIIA, IIIB, IIIC, IVA) and advanced (metastatic, recurrent or persistent disease) patients require drug therapy either as radiosensitizer, adjuvant or as palliative systemic chemotherapy. Areas covered: This review briefly discusses the achievements in treating cervical cancer. Expert opinion: Two studies are ongoing to optimize treatment after radical hysterectomy. These studies compare chemoradiation versus radiation in intermediate-risk patients or increasing treatment intensity (chemoradiation plus adjuvant chemotherapy versus chemoradiation) for high-risk and locally advanced cervical cancer. Concerning advanced disease, bevacizumab increased median survival for only 3.5 months when added to a cisplatin-doublet. Although this increase is slightly superior to the 2.9 months gained with cisplatin topotecan versus cisplatin, (0.6 months of difference), the doublet plus bevacizumab is considered the standard of care. Recently, pembrolizumab became an alternative for advanced disease that progresses to first-line treatment. Beyond that, the number of phase II and phase III trials in advanced disease is limited but on the increase. HPV E6/E7 oncoproteins are the Achilles Heel of cervical cancer, and there is cautious optimism that antagonists of these oncoproteins will be further developed.

Laparoscopic paraaortic surgical staging in locally advanced cervical cancer: a single-center experience.

BACKGROUND: One aim of this study was to assess the efficacy and safety of laparoscopic paraaortic lymphadenectomy for paraaortic lymph node staging in locally advanced cervical carcinoma. The second aim was to identify prognostic factors in the evolution of this disease and to evaluate how the results of the surgery modify the oncological treatment of patients. MATERIALS AND METHODS: We analyzed 59 patients diagnosed with locally advanced cervical cancer International Federation of Gynecology and Obstetrics stage IB2-IVA who underwent laparoscopic paraaortic lymphadenectomy at our hospital between 2009 and 2015. Depending on the results of the paraaortic lymphadenectomy, treatment consisted of pelvic- or extended-field chemoradiotherapy. RESULTS: The mean age at diagnosis was 52.3 years. The median operative time was 180 min. The mean hospital stay was 1.7 days. The mean number of paraaortic lymph nodes excised was 16.4. Eight patients (13.5%) had positive paraaortic lymph nodes. Thirteen patients (22%) underwent surgery via the transperitoneal route, and 46 (78%) underwent surgery via the retroperitoneal route. The sensitivity and specificity of computerized axial tomography (CT) scanning for detecting paraaortic lymph node involvement was 75 and 86%, respectively. The statistically significant prognostic factors that affected survival were surgical paraaortic lymph node involvement, radiological pelvic lymph node involvement, and radiological tumor size as assessed with nuclear magnetic resonance. The rate of serious complications was 1.7%. CONCLUSIONS: Pretherapeutic laparoscopic paraaortic lymphadenectomy for locally advanced cervical carcinoma allows the adaption of radiotherapy fields to avoid false-positive and false-negative imaging results.

Gene signature based on degradome-related genes can predict distal metastasis in cervical cancer patients.

Cervical cancer is one of the leading causes of death in women worldwide, which mainly affects developing countries. The patients who suffer a recurrence and/or progression disease have a higher risk of developing distal metastases. Proteases comprising the degradome given its ability to promote cell growth, migration, and invasion of tissues play an important role during tumor development and progression. In this study, we used high-density microarrays and quantitative reverse transcriptase polymerase chain reaction to evaluate the degradome profile and their inhibitors in 112 samples of patients diagnosed with locally advanced cervical cancer. Clinical follow-up was done during a period of 3 years. Using a correlation analysis between the response to treatment and the development of metastasis, we established a molecular signature comprising eight degradome-related genes (FAM111B, FAM111A, CFB, PSMB8, PSMB9, CASP7, PRSS16, and CD74) with the ability to discriminate patients at risk of distal metastases. In conclusion, present results show that molecular signature obtained from degradome genes can predict the possibility of metastasis in patients with locally advanced cervical cancer.

Comprehensive transcriptome analysis identifies pathways with therapeutic potential in locally advanced cervical cancer.

OBJECTIVE: The objective of the present study was to provide genomic and transcriptomic information that may improve clinical outcomes for locally advanced cervical cancer (LACC) patients by searching for therapeutic targets or potential biomarkers through the analysis of significantly altered signaling pathways in LACC. METHODS: Microarray-based transcriptome profiling of 89 tumor samples from women with LACC was performed. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, significantly over-expressed genes in LACC were identified; these genes were validated by quantitative reverse transcription-polymerase chain reaction in an independent cohort, and the protein expression data were obtained from the Human Protein Atlas. RESULTS: A transcriptome analysis revealed 7530 significantly over-expressed genes in LACC samples. By KEGG analysis, we found 93 dysregulated signaling pathways, including the JAK-STAT, NOTCH and mTOR-autophagy pathways, which were significantly upregulated. We confirmed the overexpression of the relevant genes of each pathway, such as NOTCH1, JAK2, STAM1, SOS1, ADAM17, PSEN1, NCSTN, RPS6, STK11/LKB1 and MLTS8/GBL in LACC compared with normal cervical tissue epithelia. CONCLUSIONS: Through comprehensive genomic and transcriptomic analyses, this work provides information regarding signaling pathways with promising therapeutic targets, suggesting novel target therapies to be considered in future clinical trials for LACC patients.