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Purpose: To compare the severe late effects (Grade 3 or greater) for two groups of cervical cancer patients treated with the same external beam radiotherapy and two high-dose-rate intracavitary brachytherapy regimens and to investigate the influence of the dose delivered each week. Methods and Materials: For 120 patients, intracavitary brachytherapy was delivered with 33.6 Gy in eight fractions to Point A (HD group), and for 119, intracavitary brachytherapy was delivered with 29.4 Gy in seven fractions to Point A (LD group). The cumulative incidence of severe gastrointestinal and genitourinary late effects were calculated for both dose groups using Kaplan-Meier survival analysis. This method was also used to explore whether the number of weeks with different dose levels could predict the cumulative incidence of late effects. Results: The actuarial rate of developing severe gastrointestinal morbidity at 7 years was 10.7% and 8.3% for HD and LD groups, respectively. The rate for genitourinary morbidity was 6.6% for the HD group and 5.0% for the LD group, respectively. No significant difference was found between the two groups. The analyses showed that a marginally significant increase occurred in severe gastrointestinal complications as the number of weeks with a physical dose >20 Gy increased in the HD group (p = .047). Conclusion: To establish dose–response relationships for late complications, three-dimensional imaging and dose–volume histogram parameters are needed. We found some indications that 20 Gy/wk is an upper tolerance level when the dose to the International Commission on Radiation Units and Measurements rectum point is 81 Gyα/β=3 (isoeffective [equivalent] dose of 2-Gy fractions). However, additional investigations using three-dimensional data are needed. [Copyright &y& Elsevier]

Purpose: The aim of this cross-sectional study is to investigate the associations between pelvic radiotherapy (RT) and markers of intestinal absorption in cervical cancer survivors (CCSs). We compared patient data with normative data from a reference population and explored the associations between cobalamin status and clinically significant diarrhea and depression. Methods and Materials: Fifty-five CCSs treated with RT in 1994–1999 were included in 2005 in a follow-up questionnaire study exploring physical and psychological symptoms. Blood tests, including serum (S)-vitamin B12, S-methylmalonic acid, S-folate, erythrocyte-folate, and plasma homocysteine, were analyzed. Differences in median values between CCSs and reference populations were evaluated by using Wilcoxon tests. Associations between variables were examined by means of multiple regression analyses. Results: Median S-vitamin B12 level was significantly lower and median S-methylmalonic acid level was significantly higher in CCSs compared with the reference population (p < 0.001). Correction for renal function verified a likely cobalamin deficiency in 20% of CCSs (11 of 55). Diarrhea or depression was not significantly related to any of the mentioned markers of cobalamin or folate status. Fifteen percent of CCSs (8 of 55) had subnormal S-calcium values. Conclusions: Significant cobalamin deficiency was observed in 11 (20%) and low calcium level was observed in 8 CCSs (15%) 6–12 years after pelvic RT. Neither diarrhea nor depression was associated with this deficiency. Routine monitoring of S-vitamin B12 level is recommended, and regular intake of cobalamin should be considered in CCSs treated with RT. [Copyright &y& Elsevier]

• In cervical cancer, multiparametric MR images were fused into hypoxia images. • Imaging-based hypoxic fraction (HF) identified low-risk patients with 95% precision. • Integration of MRI (HF) and FDG-PET (SUV) improved detection of high-risk patients. • A candidate multimodal imaging biomarker, HF/SUV 50 , was defined. • HF/SUV 50 is based on standard diagnostic images and feasible in clinical practice. MRI, applying dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) sequences, and 18F-fluorodeoxyglucose (18F-FDG) PET/CT provide information about tumor aggressiveness that is unexploited in treatment of locally advanced cervical cancer (LACC). We investigated the potential of a multimodal combination of imaging parameters for classifying patients according to their risk of recurrence. Eighty-two LACC patients with diagnostic MRI and FDG-PET/CT, treated with chemoradiotherapy, were collected. Thirty-eight patients with MRI only were included for validation of MRI results. Endpoints were survival (disease-free, cancer-specific, overall) and tumor control (local, locoregional, distant). Ktrans, reflecting vascular function, apparent diffusion coefficient (ADC), reflecting cellularity, and standardized uptake value (SUV), reflecting glucose uptake, were extracted from DCE-MR, DW-MR and FDG-PET images, respectively. By applying an oxygen consumption and supply-based method, ADC and Ktrans parametric maps were voxel-wise combined into hypoxia images that were used to determine hypoxic fraction (HF). HF showed a stronger association with outcome than the single modality parameters. This association was confirmed in the validation cohort. Low HF identified low-risk patients with 95% precision. Based on the 50th SUV-percentile (SUV 50), patients with high HF were divided into an intermediate- and high-risk group with high and low SUV 50 , respectively. This defined a multimodality biomarker, HF/SUV 50. HF/SUV 50 increased the precision of detecting high-risk patients from 41% (HF alone) to 57% and showed prognostic significance in multivariable analysis for all endpoints. Multimodal combination of MR- and FDG-PET/CT-images improves classification of LACC patients compared to single modality images and clinical factors. [ABSTRACT FROM AUTHOR]

The role of molecular classification in patients with low/intermediate risk endometrial cancer (EC) is uncertain. Higher precision in diagnostics will inform the unsettled debate on optimal adjuvant treatment. We aimed to determine the association of molecular profiling with patterns of relapse and survival. This retrospective cohort study included patients referred to The Norwegian Radium Hospital, Oslo University Hospital from 2006–2017. Patients with low/intermediate risk EC were molecularly classified as pathogenic polymerase epsilon (POLE)-mutated, mismatch repair deficient (MMRd), p53 abnormal, or no specific molecular profile (NSMP). The main outcomes were time to recurrence (TTR) and cancer-specific survival (CSS). Of 626 patients, 610 could be molecularly classified. Fifty-seven patients (9%) had POLE-mutated tumors, 202 (33%) had MMRd tumors, 34 (6%) had p53 abnormal tumors and 317 (52%) had NSMP tumors. After median follow-up time of 8.9 years, there was a statistically significant difference in TTR and CSS by molecular groups. Patients with p53 abnormal tumors had poor prognosis, with 10 of the 12 patients with relapse presenting with para-aortic/distant metastases. Patients with POLE mutations had excellent prognosis. In the NSMP group, L1CAM expression was associated with shorter CSS but not TTR. The differences in outcome by molecular groups are driven by differences in relapse frequency and -patterns and demand a higher precision in diagnostics, also in patients with low/intermediate risk EC. Tailored adjuvant treatment strategies need to consider systemic treatment for patients with p53 abnormal tumors and de-escalated treatment for patients with POLE mutated tumors. • Clarifying the role of molecular classification in low/intermediate risk endometrial cancer. • Time to relapse and survival differed signifi cantly by molecular groups. • roboPatients with p53 abnormal tumors had poor outcome. • roboPatients with POLE mutated tumors had excellent survival. • pmMolecular classification is crucial for tailoring of adjuvant treatment. [ABSTRACT FROM AUTHOR]

Objective: To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. Methods: Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. Results: All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. Conclusion: This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy. [Copyright &y& Elsevier]

Development of cervical carcinomas is strongly associated with presence of human papilloma virus (HPV). Recently we found that young patients with breast cancer had a higher frequency of skewed X inactivation in peripheral blood cells, indicating an effect of X-linked genes on breast cancer development. In this study, we investigated the frequency of skewed X-inactivation pattern in blood and tumor biopsies from patients with cervical cancer. No difference in the frequency of skewed X inactivation in blood was found between 142 patients and 437 age-matched controls. Elderly females have a higher frequency of skewed X inactivation in blood cells than younger females. An age effect was confirmed in this study for blood cells in both patients and controls. A tendency to an age effect was also found in the tumor biopsies. The correlation between X inactivation in blood and biopsies was 0.39 (P<0.001), showing that the X inactivation in biopsies to some degree reflects skewing in blood. Furthermore, of eight patients with a skewing of &ges;75% in biopsies, seven patients had a skewing in the same direction in their blood cells (P = 0.03). Our results indicate that if X-inactivation analysis is to be used in clonality studies of cervical cancers, it is essential to consider both the age and the X-inactivation pattern in blood cells. [Copyright &y& Elsevier]

Background: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations.Methods: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic.Findings: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0-9·6; EORTC, 9·2 years [IQR 7·3-10·4]; CHORUS, 5·9 years [IQR 4·3-7·4]). Median age was 63 years (IQR 56-71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8-13·0). 55 (5%) women had FIGO stage II-IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1-51·3] and 26·9 months [12·7-50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86-1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7-53·7) and 23·6 months (10·5-46·9), respectively (HR 1·20, 95% CI 1·06-1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1-47·6] and 21·2 months [10·0-36·4], respectively; HR 0·76, 95% CI 0·58-1·00; p=0·048; median progression-free survival 10·6 months [7·9-15·0] and 9·7 months [5·2-13·2], respectively; HR 0·77, 95% CI 0·59-1·00; p=0·049).Interpretation: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC-IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status.Funding: National Cancer Institute and Vlaamse Liga tegen kanker (Flemish League against Cancer). [ABSTRACT FROM AUTHOR]

Purpose: The poor outcome of locally advanced cervical cancer has been associated with extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor. In the present study, measures of tumor hypoxia and IFP were provided using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) and related to the treatment outcomes.Methods and Materials: The data from 54 cervical cancer patients treated with concurrent cisplatin-based chemoradiotherapy were studied. A low-enhancing tumor volume (LETV) and peritumoral fluid flow velocity (v0) were used as measures of tumor hypoxia and IFP, respectively.Results: Poor disease-free survival and overall survival were associated with large LETV and high v0. The multivariate analysis results suggested that the prognostic power of v0 and LETV is independent of established clinical prognostic factors and that the prognostic power of v0 is strong compared with that of LETV. The outcomes was especially poor for patients with a high v0 combined with a large LETV and especially good for those with a low v0 combined with a small LETV, with 5-year disease-free survival and overall survival of 13% versus 100%, respectively.Conclusions: The outcome of locally advanced cervical carcinoma seems to be influenced strongly by the tumor IFP and to a lesser extent by tumor hypoxia. DCE-MRI might have the power to provide important biomarkers for the outcome of cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation.Methods: Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival.Findings: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer.Interpretation: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings.Funding: The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust. [ABSTRACT FROM AUTHOR]

Background and purpose Several investigators have indicated that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has the potential to provide biomarkers for personalized treatment of cervical carcinoma. However, some clinical studies have suggested that treatment failure is associated with low tumor signal enhancement, whereas others have reported associations between high signal enhancement and poor outcome. The purpose of this investigation was to clear up these conflicting reports and to provide a method for identifying biomarkers that easily can be implemented in routine DCE-MRI diagnostics. Methods The study involved 85 patients (FIGO stage IB through IVA) treated with concurrent chemoradiotherapy. Low-enhancing tumor volume (LETV) and low-enhancing tumor fraction (LETF), defined as the volume and fractional volume of low-enhancing voxels, respectively, were calculated from signal intensities recorded within 1 min after contrast administration by using two methods reported to give conflicting conclusions. Results Multivariate analysis involving tumor volume, lymph node status, FIGO stage, and LETV or LETF revealed that LETV and LETF provided independent prognostic information on treatment outcome, independent of the method of calculation. Conclusion Low signal enhancement is associated with poor prognosis in cervical carcinoma, and biomarkers predicting poor outcome can be provided by short-term DCE-MRI without advanced image analysis. [ABSTRACT FROM AUTHOR]

Background and purpose High tumor interstitial fluid pressure (IFP) is associated with poor outcome in locally advanced carcinoma of the uterine cervix. We have recently developed a noninvasive assay of the IFP of tumors, and in this assay, the outward interstitial fluid flow velocity at the tumor surface ( v 0 ) is measured by Gd-DTPA-based DCE-MRI and used as a parameter for IFP. Here, we investigated the independent prognostic significance of v 0 in cervical cancer patients given cisplatin-based concurrent chemoradiotherapy with curative intent. Patients The study involved 62 evaluable patients from a cohort of 74 consecutive patients (Stage IB through IIIB) with a median follow-up of 5.5 years. Results The actuarial disease-free survival (DFS) and overall survival (OS) at 5 years were 67% and 76%, respectively. Significant associations were found between v 0 dichotomized about the median value and DFS and OS, both in the total patient cohort and a subcohort of 40 Stage IIB patients. Multivariate analysis involving stage, tumor volume, lymph node status, and v 0 revealed that only v 0 provided independent prognostic information about DFS and OS. Conclusion This investigation demonstrates a strong, independent prognostic impact of the pretreatment peritumoral fluid flow velocity in cervical cancer. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: ABrix , kep , kel , Tofts: Ktrans , νe ). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: ABrix , kel , and Ktrans were significantly (P <0.05) positively associated with both clinical LRC and PFS, while νe was significantly positively correlated with PFS only. kep showed no association with any endpoint. ABrix was positively correlated with Ktrans and νe , and showed the strongest association with endpoint in the log-rank testing. kel and Ktrans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure. [Copyright &y& Elsevier]

Abstract: Purpose: We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage. Materials and methods: Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases. Results: EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p =0.016, membrane; p =0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p <0.001). Moreover, an increase in the phosphorylation in both the membrane (p =0.014) and cytoplasm (p =0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage. Conclusion: In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer. [Copyright &y& Elsevier]

Abstract: Aberrations in the Wnt/β-catenin signalling pathway are suggested as mediators of chromosomal instability and carcinogenesis. β-catenin acts both as a component of the membranous adhesion system, and as a transcription activator in the nucleus. β-Catenin immunoreactivity was evaluated in 353 uterine sarcomas (US) including 231 leiomyosarcomas (LMS), 82 endometrial stromal sarcomas (ESS), 22 adenosarcomas (AS) and 18 undifferentiated uterine sarcomas (UUS). Up-regulated membranous β-catenin was observed in 25% of the LMS (p =0.039), 21% of the ESS (p =0.072) and 39% of the UUS (p =0.025). Cytoplasmic β-catenin was up-regulated in 36% of the LMS (p =0.008) and 33% of the UUS (p =0.028). Nuclear β-catenin expression was observed in 23% of the LMS (p =0.051), 61% of ESS (p =0.628) and in the sarcoma component of 68% of the AS. In patients with LMS, membranous β-catenin was associated with poor crude survival in univariate (p =0.045), but not in multivariate analyses. In patients with ESS, nuclear β-catenin expression was related to spread of tumour (p =0.033), but not to survival. The observation of up-regulated β-catenin expression in US might suggest a so far undocumented role for the Wnt/β-catenin pathway in these malignancies. [Copyright &y& Elsevier]

Purpose: Descriptions of late morbidity after radiotherapy in cervical cancer survivors (CCSs) are usually based on observations made by physicians, and rarely by patients themselves. We describe and compare physician-assessed morbidity with patient-rated symptoms more than 5 years after pelvic radiotherapy. Methods and Materials: In 147 CCSs treated between 1994 and 1999 at The Norwegian Radiumhospital, morbidity data were regularly documented by physicians at least for 5 years after radiotherapy. Information on patient-rated symptoms was collected by a questionnaire from 91 (62%) of the 147 survivors after a median follow-up time of 96 months (65–131 months). The results were compared with physician-assessed morbidity scores recorded at 5 years, and to selected normative data using descriptive statistics. Physician-assessed morbidity data were modeled using Kaplan-Meier method. Agreement between physician data and patient data was expressed using weighted kappa statistics. Results: The 5-year Kaplan-Meier estimates of physician-assessed intestinal, bladder, and vaginal morbidity Grade 3-4 were 15%, 13%, and 23%, respectively. The prevalence of patient-rated severe symptoms from these organs was much higher (intestines 45%, bladder 23%, and 58% vaginal discomfort among sexually active CCSs). Poor agreement was confirmed by low values of kappa: For bladder the concordance was slight (κ = 0.16) and for intestine it was fair (κ = 0.27). Stress incontinence, diarrhea, nausea, and sexual problems were significantly (p < 0.001) more prevalent when compared with a control sample from the general female population. Conclusions: Morbidity is common after pelvic radiotherapy. However, our data indicate that physicians underreport patients symptoms. It is important to incorporate patient-reported outcomes in the evaluation of treatment-related morbidity. [Copyright &y& Elsevier]

Abstract: The CTNNB1 gene and its product β-catenin, a regulator of the Wnt signalling pathway, is often mutated and deregulated in human malignancies. Down stream targets of the Wnt signalling pathway are linked to genomic instability. In this study, the impact of β-catenin expression on genomic instability in ovarian carcinoma, as determined by DNA ploidy, was investigated. Expression of β-catenin was examined by immunohistochemistry in 253 ovarian carcinomas. The results were related to genomic instability and clinicopathological features of the patients. Membrane associated staining of β-catenin was detected in nearly all cases with no correlation to clinical parameters. Most of the samples also had cytoplasmic (84%), while only 13% had nuclear β-catenin localisation. A significant association between β-catenin expression (cytoplasmic and nuclear) and histological subtype and degree of differentiation was observed. Nuclear β-catenin was almost exclusively present in endometroid carcinomas. 53% of all endometroid tumours were positive for nuclear β-catenin expression (P &#60;0.0001). Mucinous carcinomas had the highest degree of cytoplasmic β-catenin expression (92%), followed by endometroid (92%), mixed (90%), serous (82%), unclassified adenocarcinomas (81%), carcinomas clear cell and (70%), (P =0.01). Tumours with differentiation grade 1 (16%) and 2 (24%) had higher nuclear β-catenin expression than grade 3 and clear cell carcinomas (6%) (P =0.012). Better prognostic outcome was found for patients with nuclear β-catenin localisation as compared to the cases without (P =0.027). In conclusion, the study showed no correlation between β-catenin expression in ovarian carcinoma and FIGO stage and genomic instability as determined by DNA ploidy status. However, nuclear β-catenin expression was strongly associated with endometroid histological subtype. Finally, in ovarian cancer, although β-catenin staining seems to be of prognostic importance with respect to nuclear staining in univariate analysis, only DNA ploidy status, histological grade and FIGO staging were of independent prognostic significance in multivariate analysis. [Copyright &y& Elsevier]

Purpose: To systematically screen the tumor contrast enhancement of locally advanced cervical cancers to assess the prognostic value of two descriptive parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods and Materials: This study included a prospectively collected cohort of 81 patients who underwent DCE-MRI with gadopentetate dimeglumine before chemoradiotherapy. The following descriptive DCE-MRI parameters were extracted voxel by voxel and presented as histograms for each time point in the dynamic series: normalized relative signal increase (nRSI) and normalized area under the curve (nAUC). The first to 100th percentiles of the histograms were included in a log-rank survival test, resulting in p value and relative risk maps of all percentile–time intervals for each DCE-MRI parameter. The maps were used to evaluate the robustness of the individual percentile–time pairs and to construct prognostic parameters. Clinical endpoints were locoregional control and progression-free survival. The study was approved by the institutional ethics committee. Results: The p value maps of nRSI and nAUC showed a large continuous region of percentile–time pairs that were significantly associated with locoregional control (p < 0.05). These parameters had prognostic impact independent of tumor stage, volume, and lymph node status on multivariate analysis. Only a small percentile–time interval of nRSI was associated with progression-free survival. Conclusions: The percentile–time screening identified DCE-MRI parameters that predict long-term locoregional control after chemoradiotherapy of cervical cancer. [ABSTRACT FROM AUTHOR]