Role of rs2366152 single-nucleotide variant located in the long noncoding RNA HOTAIR gene in the cervical cancer susceptibility in a Polish population.

Previous studies have demonstrated an association of the NC_000012.12:g.53962605A > G, (rs2366152) single-nucleotide variant (SNV) situated in the long noncoding homeobox transcript antisense intergenic RNA (HOTAIR) gene with HPV16-related cervical cancer pathogenesis. However, little is known about the role of rs2366152 in cervical cancer progression and how oral birth control pills use, parity, menopausal status, and cigarette smoking influence the role of rs2366152 in cervical carcinogenesis. HRM analysis was used to determine the rs2366152 SNV prevalence in patients with cervical squamous cell carcinoma (SCC) (n = 470) and control group (n = 499) in a Polish Caucasian population. Logistic regression analyses were adjusted for age, using birth control pills, parity, menopausal status, and cigarette smoking. Our genetic studies revealed that the G/A vs. A/A (p = 0.031, p = 0.002) and G/A + G/G vs. A/A (p = 0.035, p = 0.003) genotypes of rs2366152 SNV were significantly related to the grade of differentiation G3 and tumor stage III, respectively. Moreover, cervical cancer risk increased among patients with rs2366152 SNV who smoked cigarettes and used birth control pills. We conclude that rs2366152 may promote the invasion and rapid growth of cervical SCC. Moreover, rs2366152 with cigarette smoking and using birth control pills can also be a risk factor for cervical cancerogenesis.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Asphericity derived from [18F]FDG PET as a new prognostic parameter in cervical cancer patients.

The objective of this study was to assess the prognostic value of asphericity (ASP) and standardized uptake ratio (SUR) in cervical cancer patients. Retrospective analysis was performed on a group of 508 (aged 55 ± 12 years) previously untreated cervical cancer patients. All patients underwent a pretreatment [18F]FDG PET/CT study to assess the severity of the disease. The metabolic tumor volume (MTV) of the cervical cancer was delineated with an adaptive threshold method. For the resulting ROIs the maximum standardized uptake value (SUVmax) was measured. In addition, ASP and SUR were determined as previously described. Univariate Cox regression and Kaplan-Meier analysis with respect to event free survival (EFS), overall survival (OS), freedom from distant metastasis (FFDM) and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. In the survival analysis, MTV and ASP were shown to be prognostic factors for all investigated endpoints. Tumor metabolism quantified with the SUVmax was not prognostic for any of the endpoints (p > 0.2). The SUR did not reach statistical significance either (p = 0.1, 0.25, 0.066, 0.053, respectively). In the multivariate analysis, the ASP remained a significant factor for EFS and LRC, while MTV was a significant factor for FFDM, indicating their independent prognostic value for the respective endpoints. The alternative parameter ASP has the potential to improve the prognostic value of [18F]FDG PET/CT for event-free survival and locoregional control in radically treated cervical cancer patients.

Superficial high-dose-rate brachytherapy for primary tumors and relapses after surgery in patients with basal cell carcinoma of the head and neck region: results of a retrospective comparative cohort study.

Purpose: The recommended treatments for basal cell carcinoma (BCC) in the head and neck (H&N) region are Mohs surgery, standard surgical excision (SSE), and radiotherapy. According to the literature, local recurrence after surgical treatment in this area is associated with a worse prognosis in case of re-treatment. To our knowledge, there are no reports on high-dose-rate brachytherapy (HDR-BT) for BCC of the H&N region, both in primary lesions and relapses after SSE. This study aimed to fill this gap in the literature. Material and methods: Inclusion criteria were pathologically confirmed BCC, tumor location in the H&N region, treatment performed with superficial HDR-BT, and a minimum follow-up of 12 months. An analysis was performed on a group of 90 patients, in whom a total of 102 tumors were treated. Subsequently, tumors were divided into two sub-groups, including those treated initially, and treated due to local recurrence after previous SSE. Primary treatment group (PrG) included 59 tumors, whereas 43 tumors were included in recurrent group (ReG). Results: Statistical analysis did not reveal any significant differences between the groups in terms of age (p = 0.43), treatment duration (p = 0.17), follow-up time (p = 0.96), sex (p = 0.18), local advancement (p = 0.83), and location (p = 0.68). The estimated 5-year relapse-free survival was 96.4% in the PrG and 94.6% in the ReG group, and the difference was not statistically significant (p = 0.72). In the PrG, skin toxicity was as follows: early G1 - 20.3%, G2 - 28.8%, G3 - 42.4%, G4 - 8.5%; late G1 - 33.9%, G2 - 50.8%, G3 - 1.7%, G4 - 11.9%. Whereas, in the ReG, toxicity was as follows: early G1 - 16.3%, G2 - 41.9%, G3 - 37.2%, G4 - 4.6%; late G1 - 30.2%, G2 - 62.8%, G3 - 4.6%. There were no statistically significant differences in the early nor late toxicity between the groups (p = 0.54, p = 0.16). Conclusions: Superficial HDR-BT is a highly effective treatment for both primary and recurrent BCC of the H&N region, and is associated with acceptable skin toxicity.

Tumour-Related Parameters as a Prognostic Factor in Patients with Advanced Cervical Cancer: 20-Year Follow-Up of Diagnostic and Treatment Changes during Chemioradiotherapy.

Concurrent radiochemotherapy (RCHT) has been the standard treatment for locally advanced cervical cancer since 1999. During this 20-year period, both diagnostic and radiotherapy techniques have developed, such as positron emission tomography (PET) or brachytherapy (BT) planning. The aim of the study was to assess the relationships between prognostic factors and the results of treatment in patients with advanced cervical cancer independent of these changes. The analysis included 266 patients with stage IIB or IIIB FIGO 2009 cervical cancer divided into two groups: one including 147 patients diagnosed with physical examination and ultrasonography (USG) and treated with RCHT with 2D BT from 2001 to 2005; another including 119 patients with metastatic pelvic lymph node diagnosed with PET and treated from 2010 to 2016 with RCHT and 3D BT. The mean five-year overall survival (OS) rate was 59.2% in the first vs. 65.5% in the second group (p = 0.048). However, in both groups, stage IIB patients had a significantly higher 5-year OS rate, despite the presence of nodal metastases in group 2. In the first group it was 75.1% in IIB vs. 54.8% in IIIB (p = 0.040) 5-year OS and 77.5% vs. 55.8% (p = 0.034) in the second group. Important was also a significant association between the dose of BT and survival in group 2: 45.7% vs. 69.2% for dose <28 Gy and 28 Gy (p = 0.018). Evolution in the diagnosis and treatment of patients with cervical cancer had led to improvement in the survival of patients and precise treatment with an appropriate stage assessment. However local advance of the tumour is still the most important prognostic factor.

Prognostic Value of Pretherapeutic Primary Tumor MTV from [18F]FDG PET in Radically Treated Cervical Cancer Patients.

The aim of this study was to assess the usefulness of pretherapeutic primary tumor metabolic tumor volume (MTV) in the prognosis of radically treated cervical cancer patients. Retrospective, single-centre analysis was performed on a group of 508 cervical cancer patients. All patients underwent a pretreatment [18F]FDG PET/CT study for the assessment of the disease stage. Several PET-derived parameters-namely, maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG) and MTV, as well as the clinical parameters, were analysed in terms of the overall survival (OS), event-free survival (EFS), locoregional control (LRC) and freedom from distant metastases (FFDM). Hyperthermia and brachytherapy were prognostic for EFS, OS, and LRC.FIGO stage > II showed a significant effect on EFS, OS, and FFDM. Moreover, hysterectomy was prognostic for OS and histology was prognostic for FFDM. From the PET-derived parameters only MTV of the primary tumor had a significant influence on OS (cutoff point: >12.7 mL, HR: 2.8, 1.75-4.48 95% CI, p < 0.001), LRC (cutoff point: >13.7 mL, HR 2.82, 1.42-5.61 95% CI, p = 0.003), EFS (cutoff point: >10.4 mL, HR: 2.57, 1.67-3.97 95% CI, p < 0.001) and FFDM (cutoff point: >10.4 mL, HR: 5.04, 1.82-13.99 95% CI, p = 0.002). Pretreatment MTV from the primary tumor is the only independent prognostic parameter in OS, LRC, EFS, and FFDM in radically treated cervical cancer patients and should be used in clinical practice in assessing prognosis in these patients.

Pretreatment [18F]FDG PET/CT Prognostic Factors in Patients with Squamous Cell Cervical Carcinoma FIGO IIIC1.

PURPOSE: This study aims to determine whether semiquantitative parameters obtained from both the primary tumor and metastatic pelvic lymph nodes (PLN) diagnosed in fluoro-18-deoxy-glucose positron emission tomography (FDG-PET-CT) are associated with disease-free survival (DFS), local control (LC), distant metastasis-free survival (DMFS) and overall survival (OS) in patients with locally advanced squamous cervical cancer (LACC) and metastatic pelvic lymph nodes. MATERIALS: Retrospective analysis was performed on 93 female patients with FIGO IIIC1. The median age was 53 years (27-75). The PET parameters both in the primary tumor and metastatic pelvic lymph nodes, including SUVmax, SUVmean, TLG, MTV, heterogeneity, along with clinical variables, before radical cisplatin-based radiochemotherapy (RCT) were analyzed. The p-values < 0.05 were considered statistically significant. RESULTS: Median follow-up was 38 months (4.5-92.6). Three years and five years OS were 75% and 70% respectively. Patients with SUVmax above 12.6, SUVmean above 7.6 and with TLG in tumors >245.7 lived longer (p < 0.05). The higher SUVmax or SUVmean reduced increased DMFS (HR 0.3 95%CI 0.56-0.96 and 0.59 95%CI 0.37-0.93). The clinical factors and other FDG PET CT parameters were not found to be statistically relevant in terms of OS, DFS, DM and LC. CONCLUSIONS: This study is the first report showing that in LACC patient population with PLN involvement treated with definitive RCT, high SUVmean, SUVmax and TLG of the primary tumor in FDG-PET-CT were linked with longer OS. Lower SUVmean and SUVmax were linked with shorter DMFS. None of the clinical factors and the nodal FDG-PET-CT parameters influenced the outcome.

Differences between [18F]FLT and [18F]FDG Uptake in PET/CT Imaging in CC Depend on Vaginal Bacteriology.

This study aims to investigate if vaginal bacteriology obtained prior to treatment influences the 3'-deoxy-3 18F-fluorothymidine (FLT) [18F]FLT and 2-deoxy-2-[18F]fluoro-d-glucose (2-[18F]FDG) [18F]FDG parameters in positron emission tomography (PET/CT) in cervical cancer (CC) patients. METHODS: Retrospective analysis was performed on 39 women with locally advanced histologically confirmed cervical cancer who underwent dual tracer PET/CT examinations. The [18F]FLT and [18F]FDG PET parameters in the primary tumor, including SUVmax, SUVmean, MTV, heterogeneity, before radiotherapy (RT) were analyzed, depending on the bacteriology. The p-values < 0.05 were considered statistically significant. RESULTS: In the vaginal and/or cervical smears, there were 27 (79.4%) positive results. In seven (20.6%) cases, no opportunistic pathogen growth was observed (No Bacteria Group). In positive bacteriology, eleven (32%) Gram-negative bacilli (Bacteria group 2) and fifteen (44%) Gram-positive bacteria (Bacteria group 1) were detected. Five patients with unknown results were excluded from the analysis. Data analysis shows a statistically significant difference between the SUVmax, and SUVmin values for three independent groups for the [18F]FLT. CONCLUSIONS: The lowest values of SUVmax and SUVmin for [18F]FLT are registered in Gram-negative bacteria, higher are in Gram-positive, and the absence of bacteria causes the highest [18F]FLT values.

Comparison of semiquantitative metabolic parameters of the primary tumor obtained in PET/CT with 18F-FDG and 18F-FLT in patients with cervical cancer.

AIM: The aim of the study was to compare semiquantitative metabolic parameters of primary tumor assessed in vivo in 18F-FDG- and 18F-FLT in cervical cancer patients. MATERIAL & METHODS: 39 patients with histologically confirmed cervical cancer underwent PET/CT scans acquired on separate days 60 min after i. v. injection of 364 ±â€Š75 MBq of 18F-FDG and 259 ±â€Š40 MBq of 18F-FLT. The reconstructed PET images were evaluated using a dedicated workstation for primary tumor semiquantitative parameters: SUVmax, MTV, TLG (for 18F-FLT-TLP) and heterogeneity (AUC-CSH). Wilcoxon-Mann-Whitney test and ROC curves were used for statistical analysis. Based on data from the local cancer registry and 3y- to -5y follow up patients were divided into 2 groups with regard to prognosis. Also differences between histopathological type and FIGO classification in two tracers were assessed. RESULTS: Depending on PET/CT results, patients were divided into 3 groups: group 1 with disease limited only to the cervix, group 2 with disease limited to the cervix and iliac lymph nodes, and group 3 with disseminated disease. Statistically significant differences were found between keratinizing and non-keratinizing SCC in SUVmax (p = 0.03) and AUC-CSH (p = 0.04) only in 18F-FLT-PET/CT. Following cut-off values for nodal involvement in SUVmax, MTV, TLG/TLP and AUC-CSH were calculated using ROC curves: 13.5, 39.22, 255.94, 0.59 respectively for 18F-FDG and 12.1, 37.59, 140.01, 0.46 respectively for 18F-FLT. Higher values in both tracers in MTV and TLG/TLP were found in a group with worse prognosis. CONCLUSION: This preliminary study suggests that higher values in MTV and TLG/TLP in both tracers might be associated with worse outcome in cervical cancer patients.

Adjuvant therapy for early endometrial cancer - who benefits the most from a radiation therapy?

OBJECTIVES: Since 1990s the number of patients diagnosed with endometrial cancer (EC) has doubled. The standard treatment method for treating early endometrial cancer is surgery. Some patients require a subsequent adjuvant therapy. In early endometrial cancers its application is limited to the populations with a high risk of recurrence. The aim of this study was to assess the effectiveness of early endometrial cancer treatment based on an analysis of 5-year follow up of EC patients. MATERIAL AND METHODS: The analysis consisted in a retrospective non-randomized interventional study of patients treated for early endometrial cancer (FIGO stage IA, IB, II). Its end point was either local (small pelvis) or distant recurrence of the disease. Intervention involved an adjuvant treatment applied in selected patients according to the current guidelines for EC treatment. There was no randomization for adjuvant and non-adjuvant EC treatment. The study included a total of 419 patients treated for EC from 2010 to 2012. RESULTS: The analysis revealed that 108 patients (25.8%) were diagnosed with the recurrent disease. Out of 112 patients treated for stage IA endometrial cancer 32 (28.6%) experienced recurrence. Out of 216 patients at FIGO Stage IB, recurrence was diagnosed in 38 (17.6%). In the group of 91 patients treated for FIGO stage II, EC the recurrence was diagnosed in 38 (41.2%) cases. CONCLUSIONS: Early EC treatment results were unsatisfactory and should be improved. The best outcomes were achieved in patients with IA stage of EC who received a radiation therapy.

The effect of different segmentation methods on primary tumour metabolic volume assessed in 18F-FDG-PET/CT in patients with cervical cancer, for radiotherapy planning.

INTRODUCTION: Gynaecological cancers, including cervical cancer, often require a multidisciplinary approach that includes external beam radiotherapy, chemotherapy, and/or surgical treatment. Biological parameters of the tumour evaluated in 18F-FDG-PET/CT are used for target volume delineation in radiotherapy planning. The choice of segmentation method may affect the assessment of metabolic tumour volume (MTV) in 18F-FDG-PET/CT. AIM OF THE STUDY: To find the optimal segmentation method for the assessment of primary MTV in 18F-FDG-PET/CT in cervical cancer patients for radiotherapy planning. MATERIAL AND METHODS: Retrospective analysis was performed on a group of 30 patients with newly diagnosed, histologically confirmed cervical cancer. The primary MTVs were assessed by SUVmax and SUVmean values; three segmentation methods were used to assess the primary MTV: constant threshold of SUVmax of 2.5, threshold of SUVmax 35%, and threshold of SUV max 45%. The MTVs were compared with the tumour volumes obtained in magnetic resonance imaging (MRI), which was the "gold standard", to select the best optimal segmentation method reflecting the tumour size. Wilcoxon-Mann-Whitney and t-test were used for statistical analysis. RESULTS: Depending on the segmentation method chosen, significant differences in the MTVs were obtained (p < 0.001). The highest volumes were obtained using the method based on constant SUVmax of 2.5, while the smallest in case of threshold of SUVmax of 45%. Regarding the volume determined by MRI, a 35% SUVmax threshold was chosen as the most reliable method. CONCLUSIONS: The choice of appropriate segmentation method has a significant impact on the primary MTV assessment in 18F-FDG-PET/CT in patients with cervical cancer.

The incidence of inflammation among patients suffering from cervix cancer with positive beta haemolytic streptococci cultures from genital tract.

AIM: The main goal of this investigation was to evaluate the influence of positive beta haemolytic streptococci culture from the genital tract on patients receiving radiation therapy who suffer from cervical cancer. The other aim was to observe radiation therapy complications. BACKGROUND: Group B streptococci (GBS), group C streptococci (GCS) and group G streptococci (GGS) have been described as frequent invasive pathogens in elderly patients, often in association with underlying medical conditions including immunodeficiency and cancer. MATERIALS AND METHODS: In the years 2006-2015, vaginal swabs from 452 patients were examined. A total of 118 women with positive beta haemolytic streptococci (BHS) groups A, B, C, F, G cultures were analysed, of whom 111 were diagnosed with cervix cancer of IB to IVA degree according to the FIGO 1988 clinical classification. RESULTS: Of the 452 patients suffering from cervix cancer 26.1% were positive for A, B, C, F or G group BHS isolated from the genital tract. All of the 114 examined strains were sensitive to beta-lactam antibiotics. The antimicrobials for which resistance was noted were erythromycin, clindamycin, ciprofloxacin and tetracycline. CONCLUSIONS: Positive cultures of BHS from the genital tract were demonstrated to occur in patients with cervix cancer. Complications were found during radiotherapy in 30 (27%) of these patients, including 20 (18%) patients suffering from clinical symptoms of inflammation. When beta-lactam antibiotics are not recommended because of allergy, sensitivity tests to other drugs are necessary.

Influence of Biological Parameters Assessed in [18F]FDG PET/CT on Overall Survival in Cervical Cancer Patients.

AIM: The aim of this study was to estimate the influence of biological parameters assessed in [F]FDG PET/CT on overall survival (OS) in cervical cancer patients. METHODS: Retrospective analysis was performed on a group of 371 patients with newly diagnosed and histologically confirmed cervical cancer. PET biological parameters in primary tumor including SUVmax, SUVmean, total lesion glycolysis (TLG), metabolic tumor volume (MTV), heterogeneity, and parameters referring both to primary tumor and metastatic lesions: SUVtotal, TLGtotal, and MTVtotal, were analyzed. RESULTS: Based on PET/CT results, 3 subgroups were identified: cervical only-with disease limited only to the cervix (38%), +regional nodes-where increased glucose accumulation in addition to the cervical area was also observed in regional lymph nodes (36%), and +distal metastases-where PET scan showed a disseminated disease (26%). Depending on the stage of the disease, in the cervical-only group, 5-year survival rate was 86%; in the +regional nodes group, it was 80%; whereas in the +distal metastases group, 5-year survival rate was only 55%. However, based on Cox regression model, significant influence on OS was found only in heterogeneity of primary tumor; more inhomogeneous tumors suggest worse prognosis (0.25 ± 0.04 vs 0.16 ± 0.09, P < 0.001), SUVtotal (76.6 ± 130.1 vs 45.4 ± 73.4, P = 0.002), and MTVtotal (79.03 ± 88.27 vs 63.00 ± 83.80 cm, P = 0.03). For heterogeneity, cutoff point suggesting worse prognosis was 0.18; for SUVtotal, 52.3; and for MTVtotal, 66.55 cm. CONCLUSIONS: Stage of disease assessed in [F]FDG PET/CT significantly influences survival rate in patients with cervical cancer. SUVtotal, MTVtotal, and heterogeneity of primary tumor are independent prognostic factors on OS in cervical cancer patients.

Influence of 18F-FDG-PET/CT on staging of cervical cancer.

AIM: Cervical cancer is one of the most common cancers of the female reproductive system. The aim of the study was to assess the usefulness of the 18F-FDG-PET/CT study in staging of cervical cancer, with focus on the primary tumor parameters. MATERIAL & METHODS: 105 patients (mean age 56 ±â€…11y) with newly diagnosed cervical cancer underwent PET/CT examination which was performed 60 min after IV injection of 18F-FDG with a mean activity of 364 ±â€…75MBq. 68 patients were diagnosed with stage IIIA/IIIB, 19 patients with IIB, 10 patients with IB, 8 patients with stage IVA/IVB. Wilcoxon-Mann-Whitney test and ROC curves were used for statistical analysis. RESULTS: In 35 cases 18F-FDG-PET/CT did not show active proliferative process outside the cervix. In 38 cases metastases were found in iliac lymph nodes and in 32 patients scans showed metastases above the aortic bifurcation including lymph nodes and other organs. The largest volumes of primary tumor occurred in patients with distant metastases, while the lowest in patients with disease limited only to cervix. In 63 % of the patients PET/CT result was compatible with FIGO classification, in 20 % patients PET/CT result showed less advanced disease and in 17 % of the patients PET/CT results were higher than FIGO classification. CONCLUSION: PET/CT using 18F-FDG has an important impact on the assessment of the stage of cervical cancer. In over 30 % of patients, this study resulted in a radical change in the treatment plan.

Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer: A Randomized Clinical Trial.

Importance: There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival. Objective: This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2). Design, Setting, and Participants: An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study. Interventions: Patients were randomized 1:1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m2 intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m2 intravenously in 28-day cycles. Main Outcomes and Measures: Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received ≥1 dose of study drug). Results: The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug. Conclusions and Relevance: The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted. Trial Registration: ClinicalTrials.gov identifier: NCT01091428.

Hyperthermia in cervical cancer - current status.

BACKGROUND: This article reviews the salient features of recent results of clinical studies. It puts a special emphasis on technical aspects, mechanisms of action together with radiotherapy and chemotherapy and points out areas for additional investigation. AIM: To present the current state of knowledge on hyperthermia (HT) and to highlight its role in the treatment of cervical cancer. MATERIALS AND METHODS: The literature on the clinical use of combined hyperthermia for cervical cancer was analyzed. Clinical outcomes together with the technical aspects and the role of HT were also evaluated. RESULTS: Clinically randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in the treatment of cervical cancer without significant acute or late morbidities. The technological advances have led to an effective and safer treatment delivery, thermal treatment planning, thermal dose monitoring and online adaptive temperature modulation. CONCLUSIONS: Due to rapid development over the last decade of hyperthermia systems and new studies at the basic science and clinical level, the perception of hyperthermia as a part of multimodality treatment in cervical cancer has been changed. However, there is still a need for multicentre randomized clinical trials.

Studies on selected molecular factors in endometrial cancers.

BACKGROUND: Endometrial carcinomas (EC) differ in etiology, clinical course and prognosis. OBJECTIVES: This multi-center study aimed at a closer recognition of molecular factors linked to heterogeneity of EC by evaluating estrogen and progesterone receptors, proteins dependent on MMR genes, proteins linked to poor prognosis and metastases, and mutations in BRCA1. MATERIAL AND METHODS: Using sections of paraffin-embedded preparations, in 115 patients with EC type I and 31 with EC type II, expression of ERα, ERß1, PR, MLH1, and MSH2 proteins, as well as ARID1A, c-MET and BRCA1, was estimated by immunohistochemistry using specific antibodies. RESULTS: Expression of ERß1 was augmented in EC type II, in poorly differentiated cancers and with growing clinical advancement. An augmented expression of ERα was noted in well-differentiated EC and at lower clinical stage. An increased expression of PR and decreased of MLH1 were detected in type I EC. The expression of ARID1A and c-MET proteins showed no differences between the types of EC, stages of clinical advancement or grading. In 51.6% patients with type II EC, a loss of BRCA1 expression was disclosed; in this group of cancers a decreased expression of ERα was noted. CONCLUSIONS: An augmented expression of ERß1 was linked to type II EC. A higher expression of ERα in EC cancers was associated with a lower histopathological grade. A decreased expression of MLH1 protein was estimated in EC type I. Type II EC may be connected to BRCA1 mutation.

The association of CCAT2 rs6983267 SNP with MYC expression and progression of uterine cervical cancer in the Polish population.

PURPOSE: Previous studies have reported a significant contribution of NC_000008.10:g.128413305 G>T (rs6983267) single-nucleotide polymorphism (SNP) in the MYC enhancer region to the susceptibility of various cancers. However, the role of rs6983267 SNP in cervical cancer (CC) development and progression has not been demonstrated to date. Therefore, we evaluated the role of rs6983267 SNP in MYC expression in cervical cancers and non-cancerous cervical tissues. In addition, we assessed the role of this SNP in the development and progression of CC. METHODS: Using high-resolution melting analysis, we evaluated rs6983267 SNP frequency in women diagnosed with cervical squamous cell carcinoma (SCC) (n = 481) and controls (n = 502) in a Polish Caucasian population. Logistic regression analysis was employed to adjust for the effects of age, parity, oral contraceptive use, tobacco smoking, and menopausal status. RESULTS: Dividing patients based on clinical characteristics demonstrated an association of the rs6983267 genotype with tumor stage III and grade of differentiation G2 and G3. The p trend value calculated for the rs6983267 SNP in patients with stage III was 0.0006. We also observed a significant contribution of rs6983267 SNP to tumor grade of differentiation G2 and G3. Additional contributors were oral contraceptive use, smoking, and postmenopausal age. We found statistically significant increase of MYC transcript levels in cervical SCC tissues from carriers of the GG vs. T/T (p < 0.00001), G/T vs. T/T (p = 0.0002), and in the non-cancerous cervical tissues from carriers of the GG vs. T/T (p = 0.00046). CONCLUSION: The rs6983267 SNP may contribute to the increased MYC expression as well as the spread and rapid growth of cervical SCC as compared to lower grade carcinomas.

Strategy and early results of treatment of advanced cervical cancer patients with synchronous cancers observed in PET-CT imaging.

OBJECTIVES: The aim of this study was to present strategy and early results of treatment of advanced cervical cancer patients with synchronous cancers observed in PET-CT imaging, treated at the Greater Poland Cancer Center. MATERIAL AND METHODS: The study included a group of 200 patients with diagnosed stage IIB-IIIB cervical cancer who received PET-CT for the purpose of radiotherapy treatment planning. RESULTS: Among our study group, four patients (2%) were found to have a synchronous cancer. Two of the cases were diagnosed as breast cancer. However, cancers diagnosed in the other two patients were head and neck malignancies - hypopharyngeal and laryngeal cancer. The choice of an optimal therapeutic approach requires taking into account characteristics of particular malignancies, their stage and histopathology. The whole therapy included radiotherapy of cervical cancer with various combinations of systemic treatment, radiotherapy or surgery of synchronous cancer. According to treatment results, patients diagnosed with breast cancer and hypopharyngeal cancer achieved complete remission of both primary and secondary tumour. Patient diagnosed with laryngeal malignancy, despite achieving complete remission of cervical cancer, finished radiotherapy of the synchronous cancer at a palliative dose. CONCLUSIONS: The growing availability of PET-CT and other imaging methods in cancer diagnosis will increase the number of diagnosed synchronous cancers. Second primary cancers are often detected at an early stage, where radical treatment can be performed for both primary and secondary tumour. However, treatment of such complicated clinical cases as synchronous cancers should be carried out by multidisciplinary teams.

Role of rs13117307 single nuclear polymorphism in the risk of uterine cervical cancer from Polish population and its impact on exocyst complex component 1 expression.

We evaluated the role of NM_001024924.1:c.1330+1646C>T (rs13117307) single nucleotide polymorphism (SNP), situated in the intronic region of exocyst complex component 1 (EXCO1), in the development and spreading of cervical squamous cell carcinoma (SCC). Utilizing high resolution melting curve analysis, we analyzed this polymorphism in patients with cervical SCC (n=485) and controls (n=509) in the Polish Caucasian population. Logistic regression analysis was used to adjust for age, parity, oral contraceptive use, tobacco smoking, and menopausal status. The influence of this polymorphism on the expression of EXCO1 was assessed by reverse transcription and real-time quantitative PCR analysis. For all patients with SCC, the p trend value calculated for rs13117307 was statistically significant (ptrend=0.0158). The adjusted odds ratio (OR) for T/T vs. C/C was 1.434 (95 % CI 1.105-1.861, p=0.007). We also found a significant contribution of rs13117307 to tumor stages III, IV and grade of differentiation G3. Other contributors are parity, oral contraceptive use, smoking, and women of postmenopausal age. We observed significant upregulation of EXCO1 transcript levels in the non-cancerous cervical tissues in carriers of the T/T vs. C/C (p=0.016), as well as an increase in the EXCO1 transcript levels in the cervical SCC tissue in carriers of the T/T vs. C/C (p=0.029) and for T/T vs C/T (p=0.0032). The rs13117307 SNP variants may upregulate the transcription of EXCO1, as well as the risk of development and spreading of cervical SCC.