Squamous Cell Cervical Cancer Research Articles

Relative gene copy numbers in various patterns of cervical cancer growth.

e18029 Background: Numerous studies on cervical cancer confirm an important role of specific genomic changes in the onset and development of cervical intraepithelial neoplasia and their effect on the progression of cervical cancer. Solid tumors are characterized by genomic changes leading to a change in the DNA sequence copy number. The purpose of the study was to reveal changes in the relative copy number of the ESR1, ESR2, GPER1, STS, SULT1A1, SULT1E1, CYP1A1, CYP1A2 genes responsible for the reception and metabolism of estrogens in cervical tissues in endophytic and exophytic patterns of tumor growth in order to find predictive markers of malignancy. Methods: The study included 40 patients aged 28-65 years with cervical cancer of endophytic (n = 20) and exophytic (n = 20) growth patterns. Eligibility criteria included a morphologically confirmed cervical squamous cell cancer T1b-2aN0M0, stage I-II. The Thermo Scientific GeneJET FFPE DNA Purification Kit was used for the DNA extraction from FFPE blocks of tumor and healthy tissues. DNA concentrations were measured on the Qubit 2.0 fluorimeter (Invitrogen, USA) using the Quant-iT dsDNA High-Sensitivity (HS) Assay Kit (Invitrogen, USA). Results: The relative copy number of the GPER1, SULT1A1, CYP1A1 genes in tumor samples increased (p < 0.05) compared with normal tissues in the total sample of patients diagnosed with cervical cancer. In contrast to the total sample, an increase in the SULT1A1 gene dosage did not reach a statistically significant level in any group (p = 0.242 and p = 0.157); the copy number of the GPER1 locus significantly increased only in the group with the endophytic growth pattern (p = 0.040), as well as the CYP1A2 gene dosage (p = 0.025). Patients of 36-55 years with endophytic tumors showed a statistically significant (p < 0.05) increase in the GPER1 and CYP1A1 gene copy numbers with the rates of 41.7% and 66.7%, respectively, as well as an increased amplification of the CYP1A2 gene in 41.67% of patients. In women of 56-75 years with endophytic tumors, an increase in the copy numbers of the ESR2, GPER1, SULT1A1 genes was observed with a frequency of 50%, 100% and 75%, respectively. Patients aged 20-35 and 36-55 years with exophytic tumors showed a statistically significant (p < 0.05) increase in the CYP1A1 gene copy numbers in 33.33% and 45.45%, respectively. Conclusions: The results suggest the use of the GPER1, SULT1A1 and CYP1A1 gene copy numbers as biomarkers of cervical tumors.

CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies.

To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E711-20-specific CD8+ T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical, and anal cancers. CUE-101 is an Fc fusion protein composed of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human IL2 molecules, and an effector attenuated human IgG1 Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model. CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E711-20-specific CD8+ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+ T cells in HLA-A2 (AAD) transgenic mice, and anticancer efficacy and immunologic memory was demonstrated in TC-1 tumor-bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy. Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+ T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing phase I trial (NCT03978689).

Downregulation of RAGE Inhibits Cell Proliferation and Induces Apoptosis via Regulation of PI3K/AKT Pathway in Cervical Squamous Cell Carcinoma.

AimThe receptor for advanced glycation endproducts (RAGE) expression has been reported to be implicated with cancer development. In this study, the role of RAGE in the regulation of cervical squamous cancer cell proliferation, apoptosis and the mechanism of RAGE involved in the biological behaviors were explored.MethodsThe RAGE expression was overexpressed or downregulated by lentivirus transfection. The effect of RAGE expression on cell proliferation was explored by CCK-8, MTT, and BrdU assay, and the effect of RAGE on tumor development was confirmed by the xenograft mouse model along with the immunohistochemistry stain of proliferating cell nuclear antigen (PCNA). Apoptosis was investigated by flow cytometry and TUNEL assay. Western blotting was performed to investigate the expression of possible proteins, including Bax, Bcl-2, PI3K, p-PI3K, AKT, and p-AKT.ResultsOverexpression of RAGE promoted proliferation of cervical squamous cancer cell and increased PCNA expression. In the meantime, RAGE overexpression inhibited cell apoptosis along with a decrease of Bax/Bcl-2 ratio, and induction of PI3K/AKT activation. The in vivo results showed that overexpression of RAGE enhanced tumor growth. Conversely, knockdown of RAGE exhibited opposed effects on cervical cancer cells and xenograft mouse model. Furthermore, RAGE inhibitor FPS-ZM1 effectively inhibited SiHa cell viability and PCNA expression, and increased cell apoptosis and Bax/Bcl-2 ratio. Moreover, PI3K inhibitor LY294002 effectively inhibited activation of PI3K and AKT, and further repressed RAGE overexpression-induced cell proliferation and apoptosis inhibition.ConclusionRAGE promotes the growth ability of cervical squamous cell carcinoma by inducing PCNA expression and inhibiting cell apoptosis via inactivation of the PI3K/AKT pathway.

Value of Intratumoral Metabolic Heterogeneity and Quantitative 18F-FDG PET/CT Parameters in Predicting Prognosis for Patients With Cervical Cancer.

OBJECTIVE. The purpose of this study is to evaluate the prognostic value of quantitative metabolic parameters from pretreatment PET/CT scans of patients with squamous cell cervical cancer. MATERIALS AND METHODS. This retrospective study included 120 patients with biopsy-proven squamous cell carcinoma of the cervix who underwent FDG PET/CT for initial tumor staging. The primary tumor maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean), tumor glycolytic activity, metabolic tumor volume (MTV), and metabolic intratumoral heterogeneity index (calculated as the AUC for the cumulative standardized uptake value [SUV]-volume histogram [CSH] index) were obtained. Information on patient demographic characteristics and tumor staging were collected. Median follow-up was 27.5 months. Overall survival (OS) and progression-free survival (PFS) were calculated using a multivariate Cox proportional hazards regression model and log-rank (Mantel-Cox) test to generate Kaplan-Meier survival plots. RESULTS. The mean (± SD) age of the patients was 54.4 ± 13.1 years. Twenty-two patients had stage I disease; 58, stage II; 23, stage III; and 17, stage IV. Thirty-three patients died, 82 were living, and five were lost to follow-up and were censored; 29 patients had disease progression. The median survival was 74.9 months (95% CI, 63.6-86.9 months). A higher MTV was significantly associated with reduced OS in multivariate analysis (hazard ratio, 1.085; 95% CI, 1.036-1.136; p = 0.0005). A higher AUC-CSH index (denoting lower tumor heterogeneity) was significantly associated with increased OS (hazard ratio, 0.662; 95% CI, 0.448-0.979; p = 0.04) and PFS (hazard ratio, 0.683; 95% CI, 0.471-0.991; p = 0.045) in multivariate analysis. Kaplan-Meier survival analysis using the median value for MTV (61 mL) significantly predicted OS (p = 0.0009). CONCLUSION. Tumor heterogeneity on pretreatment PET/CT is associated with OS and PFS in patients with cervical cancer. MTV is significantly associated with OS.

Genetic Polymorphisms of the Human Cytochrome P450 1A1 (CYP1A1) and Cervical Cancer Susceptibility among Northeast Thai Women.

Background:CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. Methods:A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. Results: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1–m2–m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. Conclusion:Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.

FOLR1 was up-regulated in cervical squamous cell carcinoma and correlated with the patients’ progression free survival

Abstract Objective The aim of the present work was to evaluate the folate-receptor 1 (FOLR1) expression in cervical squamous cell carcinoma and its clinical significance. Methods FOLR1 mRNA expression level was detected in the cancer genome atlas (TCGA) database for multiple carcinomas. The FOLR1 mRNA relative expression between tumor tissue and normal cervix tissue of the cervical squamous cell cancer patients was compared by the online data analysis tool of GEPIA. The overall survival (OS) and progression free survival (PFS) between the FOLR1 high and low expression groups were compared by the log-rank test. Thirty one cervical squamous cancer patients and 20 healthy controls were included in and tested for serum FOLR1 protein level detection. Eighty one cervical squamous cell cancer patients who received surgery were included for FOLR1 protein expression detected by immunohistochemistry assay (IHC). The correlation between FOLR1 protein expression and patients’ clinical features was analyzed. Results FOLR1 mRNA was up-regulated in tumor tissue compared to corresponding normal cervical tissue of cervical squamous cell carcinoma. Top 20 genes interacted with FOLR1 was identified through the network with the edges of 146. UBXN10 (r=0.668, P<0.01) and GBP6 (r-=0.606, P<0.01) were the top 2 genes that most correlated with FOLR1. The serum level of FR-α (FOLR1 coding protein) were 275.50±83.79 and 161.70±66.62 (ng/L) for the cervical cancer and healthy control subjects respectively with significant statistical difference (P<0.05). Using the serum FR-α as serological marker for cervical cancer detection, the diagnostic sensitivity, specificity and AUC were 80.0% (58.40% to 91.93%), 80.65% (63.72% to 90.81%) and 0.85(95%CI:0.74-0.96), respectively. Immunohistochemical assay indicated that of the 81 cancer tissue samples, 45 (55.6%) was FOLR1 protein positive. FOLR1 protein positive expression rate in FIGO stage Ⅲ/Ⅳ was significant higher than in the stage Ⅰ/Ⅱ with statistical difference (P<0.05). The progression free survival (PFS) was significant different between FOLR1 high and low expression group (HR=2.48, 95%CI:1.1-5.58, P=0.023). However, the overall survival (OS) was not statistical different between the two groups (HR=1.34, 95%CI:0.84-2.15, P=0.22). Conclusion: FOLR1 was up-regulated in both serum and cancer tissue of cervical squamous cell carcinoma which may act as diagnostic and prognostic maker for cervical squamous cell cancer.

Elevated Expression of Inhibitor of Apoptosis-stimulating Protein of p53 (iASPP) and Methyltransferase-like 3 (METTL3) Correlate with Poor Prognosis in FIGO Ib1-IIa Squamous Cell Cervical Cancer.

Background: Clinical outcomes of patients with early stage cervical cancer are determined by unique molecular events. Therefore, exploring novel biomarkers for the diagnosis and prognosis of cervical cancer is essential for guidance of cervical cancer treatment.Methods: Patients with FIGO Ib1-IIa cervical cancer who were treated with radical hysterectomy at the first affiliated hospital of Guangxi Medical University, China were included in the study. iASPP and METTL3 expression in the tumor specimens and adjacent non-tumor cervical tissues was determined by immunohistochemistry and western blot, and its relationship with clinicopathologic factors and prognosis of cervical cancer patients was analyzed.Results: Of 112 patients, 41 were stage Ib1, 22 Ib2, and 49 IIa. Their mean age was 45.3 years (range 25-75 years). Tumor size was 0.3 to 5.0 cm (mean 2.8 cm). Mean follow-up was 56.6 months (range 19-72 months). iASPP and METTL3 were higher in cervical cancer than normal cervix samples (p<0.001 and p<0.01, respectively). iASPP and METTL3 overexpression correlated with higher FIGO staging (p=0.013 and p=0.039, respectively), pelvic lymph node metastasis (p=0.002 and p=0.001, respectively), and poor 5-year recurrence-free survival, distant metastasis-free survival, progression-free survival, and overall survival rates (p=0.002, p=0.007, p=0.001, p=0.016, p=0.001, p<0.001, p=0.037, and p=0.042, respectively). High iASPP and METTL3 expression were independent prognostic factors (all p<0.05). The expression of iASPP was positively related with METTL3 (p=0.002).Conclusions: iASPP and METTL3 levels were elevated in cervical cancer, and they were both independent indicators for poor prognosis in early stage cervical cancer patients.

Overexpression and biological function of PRDX6 in human cervical cancer.

Background: Our previous study demonstrated that the peroxiredoxin 6 (PRDX6) protein was downregulated in squamous cervical cancer samples after neoadjuvant chemotherapy compared with the expression level before chemotherapy. However, the effect of PRDX6 on the biological behavior of cervical cancer is still uncertain. Thus, the purpose of this study was to explore the functional impacts of PRDX6 gene on the biological behavior of cervical squamous cancer cells.Methods: An immunofluorescence assay was applied to evaluate the expression difference of PRDX6 between cervical cancer tissue and normal cervical tissue samples. A lentivirus was used to upregulate and downregulate PRDX6 expression in SiHa cells. Furthermore, the role of PRDX6 on cell proliferation, apoptosis, migration and invasion was evaluated. Additionally, the effect of PRDX6 on the progression of the cervical cancer was investigated via a xenograft model in BALB/c nude mice that either overexpressed or underexpressed PRDX6.Results: The expression of PRDX6 was generally increased in cervical cancer tissues. Furthermore, the overexpression of PRDX6 stimulated the proliferation, migration and invasion of cervical squamous cancer cells, and suppressed cell apoptosis. The opposite results were also obtained after successful knockdown of PRDX6. In addition, the overexpression of PRDX6 significantly promoted the growth of cervical carcinoma in vivo.Conclusions: PRDX6 promoted the proliferation, migration and invasion, and inhibited apoptosis in cervical cancer cells, indicating that PRDX6 is an important promoter of cervical cancer tumorigenicity.

Immune Negative Regulator TIPE2 Inhibits Cervical Squamous Cancer Progression Through Erk1/2 Signaling.

Tumor necrosis factor (TNF)-α-induced protein-8-like 2, or TIPE2, is a newly found immune negative regulatory molecule. This study further investigated the role of TIPE2 on proliferation and invasion of cervical squamous cancer cells. Expression of TIPE2 was compared in cervical squamous cancer tissues and adjacent normal tissues by Western blot and immunohistochemistry (IHC). Cervical squamous cancer cell lines, SiHa and C33A, were transfected with recombinant plasmid encoding TIPE2 and tested for cytologic characteristics. The impact of TIPE2 on phosphorylation of extracellular signal-regulated kinase (Erk) signaling pathway was also tested by Western blot analysis of key factors. TIPE2 expression was higher in cervical cancer tissues than that in normal tissue. IHC score of tumor tissue was negatively associated with lymphatic metastasis. Over expression of TIPE2 effectively inhibited the proliferation of cervical cancer cells. Wound healing and transwell assay showed that over expression of TIPE2 suppressed cell migration and invasion in vitro. Meanwhile, phosphorylation of Erk1/2 and upstream mitogen-activated protein kinase kinase (MEK) 1/2 was reduced by TIPE2. TIPE2 is negatively related with development of cervical squamous cancer. TIPE2 is an inhibitory factor of proliferation and invasion of cervical squamous cancer cells, probably through inhibiting Erk signaling pathway.

Prognostic factors affecting survival and recurrence in patients with early cervical squamous cell cancer following radical hysterectomy.

ObjectiveThis study aimed to investigate the clinical and histological features affecting the survival of patients with early cervical squamous cell cancer treated with radical hysterectomy.MethodsWe retrospectively analyzed clinical and histological data for patients with stage IB-IIA cervical cancer treated by radical hysterectomy at Zhejiang Cancer Hospital from August 2008 to January 2013.ResultsA total of 1435 patients were included in the study. Cox regression analysis identified tumor size >4 cm, lymphovascular space involvement (LVSI), lymph node ratio (LNR), and squamous cell carcinoma antigen (SCC-Ag) >2.65 ng/mL as independent prognostic risk factors. Among 1096 patients without high pathological risk factors, the 5-year local recurrence rates for SCC-Ag ≤2.65 and >2.65 ng/mL were 6.6% and 25.7%, respectively. Among 332 patients with lymph node positivity, the overall survival rates for LNR ≤0.19 and >0.19 were 87.8% and 55.6%, respectively.ConclusionsLVSI, tumor size >4 cm, LNR >0.19, and SCC-Ag >2.65 ng/mL may predict a poor prognosis in patients with early cervical squamous cell cancer treated with radical hysterectomy. SCC-Ag >2.65 ng/mL may be a useful prognostic factor guiding the use of postoperative radiotherapy in patients without pathologic risk factors.

The Association of Parametrial Invasion with the Expression of Vascular Endothelial Growth Factor-C and Other Factors in Squamous Cell Cervical Carcinoma Stage IB and IIA

BACKGROUND: The presence of parametrial invasion in early stage squamous cell cervical cancer (SCCC) indeed indicates worse prognosis and need more adjuvant treatment. This study aimed to investigate the association between parametrial invasion and clinicohystopathology variables.METHODS: This retrospective study used specimens of squamous cell carcinoma stage IB-IIA. The inclusion criteria were cervical cancer stage IB-IIA and post radical hysterectomy with lymph node dissection and exclusion criteria was damaged and or insufficient histological preparations. The clinicohystopathology variables included age, tumour size and stage, differentiation and inflammation grade, lymphatic vascular and parametrial invasion, and lymph node metastasis. Histopathology staining, immunohistochemistry examination, and vascular endothelial growth factor-C (VEGF-C) expression were evaluated according to the standard procedure. The independent-T, Chi square, and Fisher’s exact test were applied to evaluate the association. The significance was set at p&lt;0.05.RESULTS: Seventy-five cases were eligible. Parametrial invasion was found in 15 cases (20%). Three variables demonstrated a significant association with parametrial invasion, tumor size &gt;4 cm (OR 4.32, 95% CI 1.29-14.38, p=0.01), lymphatic node metastasis (OR 3.90, 95% CI 1.17-13.03, p=0.02), and VEGF-C (OR 0.75, 95% CI 0.65- 0.87, p=0.03).CONCLUSION: Tumor size of &gt;4 cm and lymph node metastasis (LNM) had a higher risk of parametrial invasion in SCCC stage IB-IIA.KEYWORDS: cervical carcinoma, parametrial invasion, vascular invasion, peritumoral stroma, VEGF-C expression

A case report of carcinoma of uterine cervix throwing heterochronous metastasis to the skin, spleen, and pancreas: the role of multimodality treatment approach

BackgroundCancer of cervix often fails locally and/or within the pelvis. One to two percent of cervical squamous cell carcinoma patients have lung metastases at presentation, and 5–35% develop pulmonary metastases later on. Common sites of metastases are the liver, bone, and bowel. We report a rare case presentation of cervical squamous cell cancer where heterochronous metastasis occurred in the skin, spleen, and pancreas without loco-regional recurrence and skipping of visceral organs such as the lung, liver, and brain.Case presentationA 55-year-old, postmenopausal lady presented with a complaint of bleeding of the vagina for 2 months duration. Cervical biopsy revealed squamous cell carcinoma of the cervix, and she was staged as a case of FIGO stage IIIB. She received external beam-beam radiotherapy of 50 Gy in 25 fractions along with concurrent weekly cisplatin at 35 mg/m2 followed by 3 fractions of intracavitary brachytherapy of 6 Gy each. After 30 months of follow-up, she presented with a skin lesion of 6 × 5 cm2 in the infrascapular region for 2 months duration. Biopsy revealed metastatic squamous cell carcinoma. Her metastatic work-up revealed no other lesions. Palliative radiotherapy to local site of 8 Gy in single fraction was delivered. The lesion disappeared within 4 weeks. She was given 6 cycles of cisplatin and paclitaxel salvage chemotherapy. After 30 months of follow-up, she presented with a skin lesion of 6 × 5 cm2 in the infrascapular region. Biopsy revealed metastatic squamous cell carcinoma. Her metastatic work-up revealed no other lesions. Palliative radiotherapy to the local site was planned, and a dose of 8 Gy in a single fraction was delivered. The lesion disappeared within 4 weeks. She was given 6 cycles of cisplatin and paclitaxel salvage chemotherapy. Six months after the completion of salvage therapy, she reported with the complaints of recurrent bouts of hematemesis and melena. Her CECT scan revealed 2 × 1.5 cm2 growth in the body of the pancreas and a subcentric splenic hilum node. She underwent open splenectomy with distal pancreatectomy. Histopathology report showed metastatic infiltration in pancreatic tissue by squamous cell carcinoma and one metastatic node in the splenic hilum. Post-treatment, 6 months, the patient was asymptomatic with no recurrence.ConclusionsThis is a rare heterochronous metastatic presentation of cervical cancer without loco-regional recurrence and visceral organs such as the lung, liver, and brain. The optimal treatment remains undefined for these patients. Multimodality treatment is necessary to manage the patients.

The assessment of spectral Doppler parameters in uterine arteries of patients with locally advanced squamous cell cervical cancer.

Evaluate spectral Doppler parameters peak systolic velocity (PSV), end diastolic velocity (EDV), resistance index(RI) and pulsatility index (PI) in infiltrated and non-infiltrated uterine arteries of patients with locally advanced (stages II B,III B) squamous cell cervical cancer and their changes during treatment. the study group included 36 patients aged 35-78 years old. At diagnosis, PSV, EDV, RI and PI inuterine arteries were examined and compared with MRI findings. All patients underwent transvaginal doppler ultrasonographyprior to the treatment, after external beam radiation therapy and six weeks after the last application of brachytherapy. The median PSV value in the first examination was higher in infiltrated uterine arteries than compared to non-infiltratedones (p = 0.001). The PSV values for all vessels decreased between the first and the third observation (p < 0.001).There was a significant difference in PI values between infiltrated and non-infiltrated uterine arteries between the first andthe third examination (p = 0.027). In patients with locally advanced cervical cancer of uterine arteries, assessment of PSV but not EDV, RI or PIcan be helpful in differentiating infiltrated from non-infiltrated vessels. In this group of patients, radiotherapy decreasesPSV, but not EDV, RI or PI values in uterine arteries. An observation conducted from the onset of radiotherapy to end ofthe follow-up in uterine arteries reveals that PI, but not RI, PSV or EDV, is different in infiltrated and non-infiltrated vessels.

Whole lesion histogram analysis of apparent diffusion coefficients on MRI predicts disease-free survival in locally advanced squamous cell cervical cancer after radical chemo-radiotherapy

BackgroundThe aim was to investigate the prognostic value of MR apparent diffusion coefficients (ADC) using histogram analysis (HA) in predicting disease-free survival (DFS) of cervical cancer after chemo-radiation therapy.MethodsWe retrospectively analyzed 103 women with pathologically proven squamous cell uterine cancer who received chemo-radiation therapy between 2009 and 2013. All patients were followed up for more than 2 years. Pre-treatment MR images were retrieved and imported for HA using an in-house developed software program based on 3D Slicer. Regions of interest of whole tumors were drawn manually on DWI with reference to T2WI. HA features (mean, max, min, 50, 10, 90%, kurtosis, and skewness) were extracted from apparent diffusion coefficient (ADC) maps and compared between the recurrence and non-recurrence groups after the 2-year follow-up. Univariate and multivariate Cox regression analysis was used to correlate ADC HA features and relevant clinical variables (age, grade, maximal diameter of tumor, FIGO stage, SCC-Ag) with DFS.ResultsOne hundred three patients with stage IB-IV cervical cancers were followed up for 2.0–94.6 months (median 48.9 months). Twenty patients developed recurrence within 2 years. In the recurrence group, the min (P = 0.001) and 10% (P = 0.048) ADC values were significantly lower than those of the non-recurrence group. Univariate and multivariate Cox regression analysis revealed that ADCmin (P = 0.006, HR = 0.110) was significantly correlated with DFS.ConclusionPre-treatment volumetric ADCmin in histogram analysis is an independent factor that is correlated with DFS in cervical cancer patients treated with chemo-radiation therapy.

Successful management of cutaneous lymphangitis carcinomatosa arising from cervical cancer with paclitaxel-cisplatin and bevacizumab combination therapy: a case report and review of the literature

BackgroundGlobally, cervical cancer is the fourth most common cancer in women. Here, we report a case of cutaneous lymphangitis carcinomatosa arising from cervical cancer, an extremely rare and treatment-resistant condition.Case presentationA 64-year-old Japanese woman presented with genital bleeding. She was diagnosed as having stage IB1 squamous cell cervical cancer and subsequently treated with radiotherapy. Approximately 2 years after the curative radiotherapy, she developed itching, skin rash, and small nodules on her left femoral and pubic area. Slight 18F-fluorodeoxyglucose uptake was detected at her left femoral skin on positron emission tomography with computed tomography. A histopathological examination was performed on a biopsy sample from an erythematous macule on her left femoral skin and vulva. Consequently, she was diagnosed as having cutaneous lymphangitis carcinomatosa arising from cervical cancer. Paclitaxel (135 mg/m2), cisplatin (50 mg/m2), and bevacizumab (15 mg/kg) combination therapy was administered every 21 days. Both itching and rash improved after three treatment cycles. After the completion of six cycles, skin erythema in the femoral and vulval area disappeared completely. Our patient experienced a 25-month symptom-free interval after the last chemotherapy session.ConclusionOur findings suggest that combination chemotherapy plus bevacizumab is an effective therapeutic option in patients with cutaneous lymphangitis carcinomatosa arising from cervical cancer.

Quantitative Changes in the Population of Cancer Stem Cells after Radiation Exposure in a Dose of 10 Gy as a Prognostic Marker of Immediate Results of the Treatment of Squamous Cell Cervical Cancer.

Prognostic significance of the proportion of cancer stem cells in cervical scrapings from 38 patients with uterine cervical cancer before treatment and after irradiation in a total dose of 10 Gy was assessed for immediate results of radio- and combined chemoradiotherapy evaluated by the degree of tumor regression in 3-6 months after the treatment. Cancer stem cells were detected as cells with CD44+CD24low immunophenotype by flow cytometry. The proportion of cancer stem cells in patients with the complete tumor regression decreased by on average 2.2±1.1% after irradiation, while in patients with partial regression this indicator increased by on average 3.3±2.3% (p=0.03). Multiple regression analysis revealed two independent indicators affecting tumor regression: the stage of the disease (which is quite expected) and change in the proportion of cancer stem cells after the first irradiation sessions (R=0.60, p<0.002 for the model in the whole). The proportion of cancer stem cells before the treatment did not have prognostic significance.

Association of human papillomavirus related squamous cell carcinomas of the oropharynx and cervix

BackgroundHuman Papillomavirus (HPV) infection is well established in oropharyngeal squamous cell carcinoma (OPSCC) and cervical cancer (CC). However, the association between both HPV related cancers remains unclear. The purpose of this study was to investigate the association between HPV related cancers of the oropharynx and cervix. MethodsA provincial cancer registry was used to retrospectively identify all patients diagnosed with OPSCC from 1997-2015. The standardized incidence ratio (SIR) of CC history in women with p16+/-OPSCC was measured. ResultsFrom 372 women with OPSCC included, the SIR of CC was significantly higher across all ages compared to the general population in Alberta, Canada (p < 0.0001). ConclusionsWomen with HPV/p16+ OPSCC have a significantly higher risk of CC compared to the general population.

Prognostic values of lymphocyte and eosinophil counts in resectable cervical squamous cell carcinoma.

Aim: Cervical cancer is one of the leading causes of cancer mortality in women. Peripheral white blood cell parameters such as neutrophil (NE), eosinophil (EO), basophil (BA), as well as lymphocyte (LY) and monocyte (MO), are correlated with tumor outcomes. Methods: In total, 110 cervical squamous cell carcinoma patients were recruited in this study. The potential prognostic factors were evaluated by univariate and multivariate survival analysis. Results: Cox regression analysis model indicated that higher pretreatment EO level and increased post-/preradiotherapy EO ratio were independently associated with worse progression-free survival. Lower pretreatment LY or higher EO levels and increased post-/preradiotherapy EO ratio were independently associated with worse overall survival. Conclusion: LY and EO are correlated with outcomes of cervical squamous cell cancer.

ΔNp63α exerts antitumor functions in cervical squamous cell carcinoma.

The molecular basis underlying the aggressive nature and excessive proliferation of cervical squamous cancer cell remains unclear. ΔNp63α is the predominant isotype of p63 expressed in the epithelia and regulates epithelial cell differentiation. The pro-/anti-tumor role of ΔNp63α in different kinds of solid tumors remains controversial and the precise molecular mechanisms are still elusive. In this study, we uncovered the molecular functions of ΔNp63α in cervical squamous cell carcinoma to clarify its roles as a tumor suppressor. We demonstrated that ΔNp63α suppressed cell migration, invasiveness, and tumor growth in SiHa and ME-180 cells with both in vivo and in vitro assays. Mechanistic investigation via RNA-sequencing and chromatin immunoprecipitation-sequencing revealed that ΔNp63α exerted its antitumor capacity via regulating the expression of a cohort of cell junction genes. Further, we showed that ZNF385B and CLDN1 were two direct ΔNp63α targets with significant relevance to cervical squamous cell carcinoma examined in cell cultures, tumor xenografts, and clinic tumors. We also demonstrated that ΔNp63α downregulated NFATC1 to reduce cisplatin resistance. These findings shed new lights on functions of ΔNp63α in tumors and providing novel insights in targeted therapy of cervical cancers.

Weighted Gene Co-Expression Network Analysis Combined with Machine Learning to Identify Prognostic Biomarkers for Cervical Squamous Cell Carcinoma

Cervical cancer represents the fourth most frequently diagnosed malignancy affecting women all over the world. However, effective prognostic biomarkers are still limited for accurate identifying high-risk patients. Here, we provide a co-expression network and machine learning-based signature to predict the survival of cervical cancer. Utilizing expression profiles of The Cancer Genome Atlas datasets, we identified differentially expressed genes (DEGs) and the most significantly module by differential expression analysis and Weighted Gene Co-expression Network Analysis, respectively. The candidate genes were obtained by combining both results. Then the prognostic classifier was constructed by LASSO COX regression analysis and validated in testing set. Finally, survival receiver operating characteristic and Cox proportional hazards analysis was used to assess the performance of prognostic prediction. We identified 190 differentially expressed genes (DEGs) between cervical squamous cell cancer (CSCC) and normal samples in purple module. Next we built an 8-mRNA-based signature, and determined an optimal cutoff value with sensitivity of 0.889 and specificity of 0.785. Patients were classified into high-risk and low-risk group with significantly different overall survival (training set: p<0.0001; testing set: p=0.039). Furthermore, the prognostic classifier was an independent and powerful prognostic biomarker for OS (HR = 7.05, 95% CI: 2.52-19.71, p <0.001). The prognostic classifier is a promising predictor of CSCC patients, the novel co-expression network and machine learning-based strategy described in the study may have a broad application in precision medicine.