Deep learning for automated scoring of immunohistochemically stained tumour tissue sections - Validation across tumour types based on patient outcomes.

We aimed to develop deep learning (DL) models to detect protein expression in immunohistochemically (IHC) stained tissue-sections, and to compare their accuracy and performance with manually scored clinically relevant proteins in common cancer types. Five cancer patient cohorts (colon, two prostate, breast, and endometrial) were included. We developed separate DL models for scoring IHC-stained tissue-sections with nuclear, cytoplasmic, and membranous staining patterns. For training, we used images with annotations of cells with positive and negative staining from the colon cohort stained for Ki-67 and PMS2 (nuclear model), the prostate cohort 1 stained for PTEN (cytoplasmic model) and ß-catenin (membranous model). The nuclear DL model was validated for MSH6 in the colon, MSH6 and PMS2 in the endometrium, Ki-67 and CyclinB1 in prostate, and oestrogen and progesterone receptors in the breast cancer cohorts. The cytoplasmic DL model was validated for PTEN and Mapre2, and the membranous DL model for CD44 and Flotillin1, all in prostate cohorts. When comparing the results of manual and DL scores in the validation sets, using manual scores as the ground truth, we observed an average correct classification rate of 91.5 % (76.9-98.5 %) for the nuclear model, 85.6 % (73.3-96.6 %) for the cytoplasmic model, and 78.4 % (75.5-84.3 %) for the membranous model. In survival analyses, manual and DL scores showed similar prognostic impact, with similar hazard ratios and p-values for all DL models. Our findings demonstrate that DL models offer a promising alternative to manual IHC scoring, providing efficiency and reproducibility across various data sources and markers.

Impact of molecular profile on prognosis and relapse pattern in low and intermediate risk endometrial cancer.

INTRODUCTION: 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. MATERIAL AND METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

CA-125 Early Dynamics to Predict Overall Survival in Women with Newly Diagnosed Advanced Ovarian Cancer Based on Meta-Analysis Data.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

Risk of recurrence after chemoradiotherapy identified by multimodal MRI and 18F-FDG-PET/CT in locally advanced cervical cancer.

BACKGROUND AND PURPOSE: 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. MATERIALS AND METHODS: 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). RESULTS: 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 (SUV50), patients with high HF were divided into an intermediate- and high-risk group with high and low SUV50, respectively. This defined a multimodality biomarker, HF/SUV50. HF/SUV50 increased the precision of detecting high-risk patients from 41% (HF alone) to 57% and showed prognostic significance in multivariable analysis for all endpoints. CONCLUSION: Multimodal combination of MR- and FDG-PET/CT-images improves classification of LACC patients compared to single modality images and clinical factors.

miR-200a/b/-429 downregulation is a candidate biomarker of tumor radioresistance and independent of hypoxia in locally advanced cervical cancer.

Many patients with locally advanced cervical cancer experience recurrence within the radiation field after chemoradiotherapy. Biomarkers of tumor radioresistance are required to identify patients in need of intensified treatment. Here, the biomarker potential of miR-200 family members was investigated in this disease. Also, involvement of tumor hypoxia in the radioresistance mechanism was determined, using a previously defined 6-gene hypoxia classifier. miR-200 expression was measured in pretreatment tumor biopsies of an explorative cohort (n = 90) and validation cohort 1 (n = 110) by RNA sequencing. Publicly available miR-200 data of 79 patients were included for the validation of prognostic significance. A score based on expression of the miR-200a/b/-429 (miR-200a, miR-200b, and miR-429) cluster showed prognostic significance in all cohorts. The score was significant in multivariate analysis of central pelvic recurrence. No association with distant recurrence or hypoxia status was found. Potential miRNA target genes were identified from gene expression profiles and showed enrichment of genes in extracellular matrix organization and cell adhesion. miR-200a/b/-429 overexpression had a pronounced radiosensitizing effect in tumor xenografts, whereas the effect was minor in vitro. In conclusion, miR-200a/b/-429 downregulation is a candidate biomarker of central pelvic recurrence and seems to predict cell adhesion-mediated tumor radioresistance independent of clinical markers and hypoxia.

Risk Stratification of Endometrial Cancer Patients: FIGO Stage, Biomarkers and Molecular Classification.

Endometrial cancer (EC) is the most common gynaecologic malignancy in developed countries. The main challenge in EC management is to correctly estimate the risk of metastases at diagnosis and the risk to develop recurrences in the future. Risk stratification determines the need for surgical staging and adjuvant treatment. Detection of occult, microscopic metastases upstages patients, provides important prognostic information and guides adjuvant treatment. The molecular classification subdivides EC into four prognostic subgroups: POLE ultramutated; mismatch repair deficient (MMRd); nonspecific molecular profile (NSMP); and TP53 mutated (p53abn). How surgical staging should be adjusted based on preoperative molecular profiling is currently unknown. Moreover, little is known whether and how other known prognostic biomarkers affect prognosis prediction independent of or in addition to these molecular subgroups. This review summarizes the factors incorporated in surgical staging (i.e., peritoneal washing, lymph node dissection, omentectomy and peritoneal biopsies), and its impact on prognosis and adjuvant treatment decisions in an era of molecular classification of EC. Moreover, the relation between FIGO stage and molecular classification is evaluated including the current gaps in knowledge and future perspectives.

Long-term oncological outcomes and recurrence patterns in early-stage cervical cancer treated with minimally invasive versus abdominal radical hysterectomy: The Norwegian Radium Hospital experience.

OBJECTIVE: To compare long-term oncological outcomes in early-stage cervical cancer (CC) patients treated with minimally invasive radical hysterectomy (MIRH) versus abdominal radical hysterectomy (ARH), with a focus on recurrence patterns, tumor sizes, and conization. METHODS: This single-institution, retrospective study consisted of stage IA1-IB1 (FIGO 2009) squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma of the cervix, who underwent radical hysterectomy between 2000 and 2017. RESULTS: Of the 582 patients included, 353 (60.7%) underwent ARH, and 229 (39.3%) MIRH. The median follow-up was 14.4 years in the ARH group and 6.1 years in the MIRH group (p < 0.0001). Among the 96 stage IA patients, only 3 (3.1%) experienced recurrence. Among stage IB1 patients, the risk of recurrence, after adjusting for standard prognostic variables, was twofold higher in the MIRH group versus the ARH group (HR 2.73, 95% CI: 1.56-4.80), and the relative difference was similar in terms of risk of cancer-specific survival (CSS) (HR 3.04, 95% CI: 1.28-7.20) and overall survival (OS) (HR 2.35, 95% CI: 1.21-4.59). In stage IB1 ≤ 2 cm patients without conization MIRH was associated with reduced time to recurrence (TTR) (HR 4.00, 95% CI: 1.67-9.57), CSS (HR 3.71, 95% CI: 1.19-11.58) and OS (HR 3.02, 95% CI: 1.24-7.34). Intraperitoneal combined recurrences accounted for 12 of 30 (40.0%) recurrences in the MIRH group but were not identified after ARH (p = 0.0001). CONCLUSIONS: MIRH was associated with reduced TTR, CSS and OS versus ARH in stage IB1 CC patients. The risk of peritoneal recurrence was high, even for tumors ≤2 cm without conization.

Salvage Radiation for Pelvic Relapse after Surgically Treated Endometrial Cancer.

(1) Background: This study evaluated the clinical outcome after salvage radiotherapy for first pelvic relapse after endometrial cancer (EC). (2) Methods: This multicenter retrospective study included EC patients with first central pelvic relapse without lymph node involvement treated with curative intent. Progression-free (PFS) and overall survival (OS) were calculated with the Kaplan-Meier method and possible predictive factors for risk of relapse and mortality were identified using the Cox model. (3) Results: We included 139 patients with median EQD2 (Equivalent Dose in 2 Gy fractions) to the clinical target volume of 70.0 Gy. During follow up of median 6.66 years, 39.6% patients developed a second relapse. Risk group classification at primary diagnosis based on histology, grading and FIGO stage and how the pelvic tumor boost was administered were independently associated with PFS and OS. Five-year OS was 68% (95% CI (59-75)) for the whole cohort. Five-year OS was 88% (95% CI (75-94)), 72% (95% CI (55-84)) and 38% (95% CI (15-60)) for the stage I low-, intermediate- and high-risk group, respectively. (4) Conclusions: The majority of central pelvic recurrences in RT-naive EC women can be successfully salvaged with radiotherapy. However, survival in patients with high-risk disease remains poor and warrants a more individualized approach to optimize outcome.

Prognostic Value of the Diversity of Nuclear Chromatin Compartments in Gynaecological Carcinomas.

Statistical texture analysis of cancer cell nuclei stained for DNA has recently been used to develop a pan-cancer prognostic marker of chromatin heterogeneity. In this study, we instead analysed chromatin organisation by automatically quantifying the diversity of chromatin compartments in cancer cell nuclei. The aim was to investigate the prognostic value of such an assessment in relation to chromatin heterogeneity and as a potential supplement to pathological risk classifications in gynaecological carcinomas. The diversity was quantified by calculating the entropy of both chromatin compartment sizes and optical densities within compartments. We analysed a median of 281 nuclei (interquartile range (IQR), 273 to 289) from 246 ovarian carcinoma patients and a median of 997 nuclei (IQR, 502 to 1452) from 791 endometrial carcinoma patients. The prognostic value of the entropies and chromatin heterogeneity was moderately strongly correlated (r ranged from 0.68 to 0.73), but the novel marker was observed to provide additional prognostic information. In multivariable analysis with clinical and pathological markers, the hazard ratio associated with the novel marker was 2.1 (95% CI, 1.3 to 3.5) in ovarian carcinoma and 2.4 (95% CI, 1.5 to 3.9) in endometrial carcinoma. Integration with pathological risk classifications gave three risk groups with distinctly different prognoses. This suggests that the novel marker of diversity of chromatin compartments might possibly contribute to the selection of high-risk stage I ovarian carcinoma patients for adjuvant chemotherapy and low-risk endometrial carcinoma patients for less extensive surgery.

MRI Distinguishes Tumor Hypoxia Levels of Different Prognostic and Biological Significance in Cervical Cancer.

Tumor hypoxia levels range from mild to severe and have different biological and therapeutical consequences but are not easily assessable in patients. Here we present a method based on diagnostic dynamic contrast enhanced (DCE) MRI that reflects a continuous range of hypoxia levels in patients with tumors of cervical cancer. Hypoxia images were generated using an established approach based on pixel-wise combination of DCE-MRI parameters ν e and K trans, representing oxygen consumption and supply, respectively. Using two tumor models, an algorithm to retrieve surrogate measures of hypoxia levels from the images was developed and validated by comparing the MRI-defined levels with hypoxia levels reflected in pimonidazole-stained histologic sections. An additional indicator of hypoxia levels in patient tumors was established on the basis of expression of nine hypoxia-responsive genes; a strong correlation was found between these indicator values and MRI-defined hypoxia levels in 63 patients. Chemoradiotherapy outcome of 74 patients was most strongly predicted by moderate hypoxia levels, whereas more severe or milder levels were less predictive. By combining gene expression profiles and MRI-defined hypoxia levels in cancer hallmark analysis, we identified a distribution of levels associated with each hallmark; oxidative phosphorylation and G2-M checkpoint were associated with moderate hypoxia, epithelial-to-mesenchymal transition, and inflammatory responses with significantly more severe levels. At the mildest levels, IFN response hallmarks together with HIF1A protein expression by IHC appeared significant. Thus, our method visualizes the distribution of hypoxia levels within patient tumors and has potential to distinguish levels of different prognostic and biological significance. SIGNIFICANCE: These findings present an approach to image a continuous range of hypoxia levels in tumors and demonstrate the combination of imaging with molecular data to better understand the biology behind these different levels.

Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumour heterogeneity.

BACKGROUND: Emerging biomarkers from medical imaging or molecular characterization of tumour biopsies open up for combining the two and exploiting their synergy in treatment planning of cancer patients. We generated a paired data set of imaging- and gene-based hypoxia biomarkers in cervical cancer, appraised the influence of intratumour heterogeneity in patient classification, and investigated the benefit of combining the methodologies in prediction of chemoradiotherapy failure. METHODS: Hypoxic fraction from dynamic contrast enhanced (DCE)-MR images and an expression signature of six hypoxia-responsive genes were assessed as imaging- and gene-based biomarker, respectively in 118 patients. FINDINGS: Dichotomous biomarker cutoff to yield similar hypoxia status by imaging and genes was defined in 41 patients, and the association was validated in the remaining 77 patients. The two biomarkers classified 75% of 118 patients with the same hypoxia status, and inconsistent classification was not related to imaging-defined intratumour heterogeneity in hypoxia. Gene-based hypoxia was independent on tumour cell fraction in the biopsies and showed minor heterogeneity across multiple samples in 9 tumours. Combining imaging- and gene-based classification gave a significantly better prediction of PFS than one biomarker alone. A combined dichotomous biomarker optimized in 77 patients showed a large separation in PFS between more and less hypoxic tumours, and separated the remaining 41 patients with different PFS. The combined biomarker showed prognostic value together with tumour stage in multivariate analysis. INTERPRETATION: Combining imaging- and gene-based biomarkers may enable more precise and informative assessment of hypoxia-related chemoradiotherapy resistance in cervical cancer. FUNDING: Norwegian Cancer Society, South-Eastern Norway Regional Health Authority, and Norwegian Research Council.

DCE-MRI of locally-advanced carcinoma of the uterine cervix: Tofts analysis versus non-model-based analyses.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide biomarkers of the outcome of locally-advanced cervical carcinoma (LACC). There is, however, no agreement on how DCE-MR recordings should be analyzed. Previously, we have analyzed DCE-MRI data of LACC using non-model-based strategies. In the current study, we analyzed DCE-MRI data of LACC using the Tofts pharmacokinetic model, and the biomarkers derived from this analysis were compared with those derived from the non-model-based analyses. METHODS: Eighty LACC patients given cisplatin-based chemoradiotherapy with curative intent were included in the study. Treatment outcome was recorded as disease-free survival (DFS) and overall survival (OS). DCE-MRI series were analyzed voxelwise to produce Ktrans and ve frequency distributions, and ROC analysis was used to identify the parameters of the frequency distributions having the greatest potential as biomarkers. The prognostic power of these parameters was compared with that of the non-model-based parameters LETV (low-enhancing tumor volume) and TVIS (tumor volume with increasing signal). RESULTS: Poor DFS and OS were associated with low values of Ktrans, whereas there was no association between treatment outcome and ve. The Ktrans parameters having the greatest prognostic value were p35-Ktrans (the Ktrans value at the 35 percentile of a frequency distribution) and RV-Ktrans (the tumor subvolume with Ktrans values below 0.13 min- 1). Multivariate analysis including clinical parameters and p35-Ktrans or RV-Ktrans revealed that RV-Ktrans was the only independent prognostic factor of DFS and OS. There were significant correlations between RV-Ktrans and LETV and between RV-Ktrans and TVIS, and the prognostic power of RV-Ktrans was similar to that of LETV and TVIS. CONCLUSIONS: Biomarkers of the outcome of LACC can be provided by analyzing DCE-MRI series using the Tofts pharmacokinetic model. However, these biomarkers do not appear to have greater prognostic value than biomarkers determined by non-model-based analyses.

Pharmacokinetic analysis of DCE-MRI data of locally advanced cervical carcinoma with the Brix model.

Background: There is significant evidence that DCE-MRI may have the potential to provide clinically useful biomarkers of the outcome of locally advanced cervical carcinoma. However, there is no consensus on how to analyze DCE-MRI data to arrive at the most powerful biomarkers. The purpose of this study was to analyze DCE-MRI data of cervical cancer patients by using the Brix pharmacokinetic model and to compare the biomarkers derived from the Brix analysis with biomarkers determined by non-model-based analysis [i.e., low-enhancing tumor volume (LETV) and tumor volume with increasing signal (TVIS)] of the same patient cohort. Material and methods: DCE-MRI recordings of 80 patients (FIGO stage IB-IVA) treated with concurrent cisplatin-based chemoradiotherapy were analyzed voxel-by-voxel, and frequency distributions of the three parameters of the Brix model (ABrix, kep, and kel) were determined. Moreover, risk volumes were calculated from the Brix parameters and termed RV-ABrix, RV-kep, and RV-kel, where the RVs represent the tumor volume with voxel values below a threshold value determined by ROC analysis. Disease-free survival (DFS) and overall survival (OS) were used as measures of treatment outcome. Results: Significant associations between the median value or any other percentile value of ABrix, kep, or kel and treatment outcome were not found. However, RV-ABrix, RV-kep, and RV-kel correlated with DFS and OS. Multivariate analysis revealed that the prognostic power of RV-ABrix, RV-kep, and RV-kel was independent of well-established clinical prognostic factors. RV-ABrix, RV-kep, and RV-kel correlated with each other as well as with LETV and TVIS. Conclusion: Strong biomarkers of the outcome of locally advanced cervical carcinoma can be provided by subjecting DCE-MRI series to pharmacokinetic analysis using the Brix model. The prognostic power of these biomarkers is not necessarily superior to that of biomarkers identified by non-model-based analyses.

Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes.

PURPOSE: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort. EXPERIMENTAL DESIGN: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings. RESULTS: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm2 could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. CONCLUSIONS: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.

Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials.

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).

DCE-MRI-Derived Measures of Tumor Hypoxia and Interstitial Fluid Pressure Predict Outcomes in Cervical Carcinoma.

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.

Chromatin organisation and cancer prognosis: a pan-cancer study.

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.

[Properties of cancer cell DNA affects the prognosis]. / Egenskaper ved kreftcellenes DNA påvirker prognosen.

BACKGROUND: When diagnosing cancer, it is often difficult to predict the further growth and spread of the tumour. One of the features of cancer is an abnormality in the amount of DNA in cancer cell nuclei, so-called DNA aneuploidy. Extensive abnormalities are often due to an unstable genome, which leads to an accumulation of mutations, dysregulation of genes and loss of cell cycle control. This article aims to provide an overview of the prognostic value of DNA ploidy analyses in ovarian, endometrial, prostate and colorectal carcinoma. MATERIAL AND METHOD: This review article is based on literature searches in PubMed for the period 2000­2016. RESULTS: The search resulted in 308 articles. Thirty-three of these, representing an analysis of more than 18 000 tumours, fulfilled the inclusion criteria. In 30 of the 33 articles, a significant correlation was found between DNA ploidy and disease outcome for patients with ovarian, endometrial, prostate and colorectal carcinoma. Patients with aneuploid tumours had a poorer prognosis than those with diploid tumours. INTERPRETATION: DNA ploidy analysis is a prognostic method for patients with ovarian and endometrial carcinoma, and is used as a guide to options for supplemental treatment and fertility-sparing surgery. A review of publications in recent years of DNA ploidy analyses for prostate and colorectal carcinoma reveals that these patient groups may also benefit from these measurements. In general terms, DNA ploidy analyses may help to increase knowledge of who needs supplemental treatment and who does not ­ which may be advantageous in avoiding overtreatment.

A national, prospective observational study of first recurrence after primary treatment for gynecological cancer in Norway.

INTRODUCTION: Gynecological cancer patients are routinely followed up for five years after primary treatment. However, the value of such follow up has been debated, as retrospective studies indicate that first recurrence is often symptomatic and occurs within two to three years of primary treatment. We prospectively investigated time to first recurrence, symptoms at recurrence, diagnostic procedures, and recurrence treatment in gynecological cancer patients after primary curative treatment. MATERIAL AND METHODS: Clinicians from 21 hospitals in Norway interviewed 680 patients with first recurrence of gynecological cancer (409 ovarian, 213 uterine, and 58 cervical cancer patients) between 2012 and 2016. A standardized questionnaire was used to collect information on self-reported and clinical variables. RESULTS: Within two years of primary treatment, 72% of ovarian, 64% of uterine, and 66% of cervical cancer patients were diagnosed with first recurrence, and 54, 67, and 72%, respectively, had symptomatic recurrence. Of symptomatic patients, 25-50% failed to make an appointment before their next scheduled follow-up visit. Computer tomography was the most common diagnostic procedure (89% of ovarian, 76% of uterine, and 62% of cervical cancer patients), and recurrence treatment in terms of chemotherapy was most frequently planned (86% of ovarian, 46% of uterine, and 62% of cervical cancer patients). CONCLUSIONS: A majority of patients experienced symptomatic recurrence, but many patients failed to make an appointment earlier than scheduled. Most first recurrences occurred within two years of primary treatment; the mean annual incidence rate for years 3-5 after primary treatment was <7%. New models for follow up of gynecological cancer patients could be considered.

Pretreatment late-phase DCE-MRI predicts outcome in locally advanced cervix cancer.

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide prognostic biomarkers for cervix carcinoma. We have shown previously that the early phase of the signal intensity-versus-time curve (SITC) may have significant prognostic power. The purpose of the present investigation was to explore the prognostic value of the late phase of the SITC. MATERIAL AND METHODS: DCE-MRI data of 80 patients (FIGO stage IB-IVA) treated with concurrent chemoradiotherapy were examined. Four parameters were calculated from the late-phase SITC: tumor volume with decreasing signal, tumor fraction with decreasing signal, tumor volume with increasing signal (TVIS), and tumor fraction with increasing signal. RESULTS: Multivariate analysis involving clinical parameters and late-phase SITC parameters suggested that TVIS is a strong independent prognostic factor for both disease-free and overall survival. When early-phase SITC parameters were included in the multivariate analysis, the early-phase SITC, but not the late-phase SITC, was found to have independent prognostic value. CONCLUSION: The late-phase SITC can provide prognostic factors for the outcome of cervix carcinoma, that is, a large tumor volume with increasing late-phase SITCs is associated with poor outcome. However, the prognostic power of the late-phase SITC is not as strong as that of the early-phase SITC.