Immunohistochemical markers of prognosis in adult granulosa cell tumors of the ovary - a review.

BACKGROUND: Granulosa cell tumors (GCT) are rare malignant ovarian tumors. The two subtypes, adult and juvenile granulosa cell tumors, differ in clinical and molecular characteristics. GCT are low-malignant tumors and are generally associated with favorable prognosis. However, relapses are common even years and decades after diagnosis. Prognostic and predictive factors are difficult to assess in this rare tumor entity. The purpose of this review is to provide a comprehensive overview of the current state of knowledge on prognostic markers of GCT to identify patients with a high risk of recurrence. METHODS: Systematic research for adult ovarian granulosa cell tumors and prognosis revealed n = 409 English full text results from 1965 to 2021. Of these articles, n = 35 were considered for this review after title and abstract screening and topic-specific matching. A specific search for pathologic markers with prognostic relevance for GCT identified n = 19 articles that were added to this review. RESULTS: FOXL2 mutation and FOXL2 mRNA were inverse and immunohistochemical (IHC) expression of CD56, GATA-4 and SMAD3 was associated with reduced prognosis. IHC analysis of estrogen receptor, Anti-Mullerian hormone (AMH) and inhibin was not associated with prognosis for GCT. Analyses of mitotic rate, Ki-67, p53, ß-catenin and HER2 revealed inconsistent results.

Discordance of HER2-Low between Primary Tumors and Matched Distant Metastases in Breast Cancer.

We examined differences in HER2 expression between primary tumors and distant metastases, particularly within the HER2-negative primary breast cancer cohort (HER2-low and HER2-zero). The retrospective study included 191 consecutive paired samples of primary breast cancer and distant metastases diagnosed between 1995 and 2019. HER2-negative samples were divided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridization [ISH]-negative). The main objective was to analyze the discordance rate between matched primary and metastatic samples, focusing on the site of distant metastasis, molecular subtype, and de novo metastatic breast cancer. The relationship was determined by cross-tabulation and calculation of Cohen's Kappa coefficient. The final study cohort included 148 paired samples. The largest proportion in the HER2-negative cohort was HER2-low [primary tumor 61.4% (n = 78), metastatic samples 73.5% (n = 86)]. The discordance rate between the HER2 status of primary tumors and corresponding distant metastases was 49.6% (n = 63) (Kappa -0.003, 95%CI -0.15-0.15). Development of a HER2-low phenotype occurred most frequently (n = 52, 40.9%), mostly with a switch from HER2-zero to HER2-low (n = 34, 26.8%). Relevant HER2 discordance rates were observed between different metastatic sites and molecular subtypes. Primary metastatic breast cancer had a significantly lower HER2 discordance rate than secondary metastatic breast cancer [30.2% (Kappa 0.48, 95%CI 0.27-0.69) versus 50.5% (Kappa 0.14, 95% CI -0.03-0.32)]. This highlights the importance of evaluating potentially therapy-relevant discordance rates between a primary tumor and corresponding distant metastases.

Current Approaches to the Management of Sentinel Node Procedures in Early Vulvar Cancer in Germany: A Web-Based Nationwide Analysis of Practices.

BACKGROUND: Lymph node involvement is the most important prognostic factor for recurrence and survival in vulvar cancer. Sentinel node (SN) procedure can be offered in well-selected patients with early vulvar cancer. This study aimed to assess current management practices with respect to the sentinel node procedure in women with early vulvar cancer in Germany. METHODS: A Web-based survey was conducted. Questionnaires were e-mailed to 612 gynecology departments. Data were summarized as frequencies and analyzed using the chi-square test. RESULTS: A total of 222 hospitals (36.27%) responded to the invitation to participate. Among the responders, 9.5% did not offer the SN procedure. However, 79.5% evaluated SNs by ultrastaging. In vulvar cancer of the midline with unilateral localized positive SN, 49.1% and 48.6% of respondents, respectively, would perform ipsilateral or bilateral inguinal lymph node dissection. Repeat SN procedure was performed by 16.2% of respondents. For isolated tumor cells (ITCs) or micrometastases, 28.1% and 60.5% of respondents, respectively, would perform inguinal lymph node dissection, whereas 19.3% and 23.8%, respectively, would opt for radiation without further surgical intervention. Notably, 50.9% of respondents would not initiate any further therapy and 15.1% would opt for expectant management. CONCLUSIONS: The majority of German hospitals implement the SN procedure. However, only 79.5% of respondents performed ultrastaging and only 28.1% were aware that ITC may affect survival in vulvar cancer. There is a need to ensure that the management of vulvar cancer follows the latest recommendations and clinical evidence. Deviations from state-of-the-art management should only be after a detailed discussion with the concerned patient.

Intermittent Fasting-Short- and Long-Term Quality of Life, Fatigue, and Safety in Healthy Volunteers: A Prospective, Clinical Trial.

Background: Intermittent fasting (IF) is defined as an eating pattern without calorie restrictions, alternating between periods of fasting and eating. In the past decades IF has not only become a popular weight-reducing diet but is thought to improve Quality of Life (QoL) and fatigue. However, very little evidence exists for the general population. Thus, we aimed to assess the impact of a 16-h fasting period per day over a three-month study period on QoL and especially fatigue in healthy people. Methods: We conducted a prospective cohort study including healthy subjects. All participants fasted 16 h for at least five days a week while maintaining their normal lifestyle. In the study, we analysed blood samples as well as QoL through standardized questionnaires (WHO-5 questionnaire, Short Form Health 36). Furthermore, we measured the degree of fatigue with the Fatigue Assessment Scale (FAS) and Fatigue Severity Scale (FSS) as well as compliance, activity records, and weight alterations. All endpoints were evaluated at baseline, after two weeks, four weeks, and three months of IF. Results: A total of 30 participants fasted for the entire study period. The results of the WHO-5 questionnaire (15.6 ± 4.6 vs. 18 ± 3.6, p < 0.0019) demonstrated a significant increase in QoL. For long-term QoL six out of eight domains measured by the Short Form Health 36 (SF-36) significantly improved (e.g., physical health: 92.3 ± 11.6 vs. 96.5 ± 6.3, p = 0.015; mental health: 75.5 ± 12.0 vs. 81.7 ± 9.0; p < 0.001 and body pain: 74.1 ± 31.8 vs. 89.5 ± 14.9; p = 0.008) after three months. Fatigue significantly decreased from 10.3 ± 3.2 to 8.4 ± 2.5; p = 0.002 for mental fatigue and from 12.6 ± 3.8 to 10.7 ± 3.3; p = 0.002 measured by the FAS. The mean FSS-Score at baseline was 3.5 ± 1.2 compared to 2.9 ± 1.1 (scale 1−7) after three months (p < 0.001). Notably, the proliferation marker IGF-1 was significantly reduced. No clinically significant changes in laboratory parameters were observed that would have endangered a participant's safety. Conclusions: IF according to the 16:8 regime over a fasting period of three months significantly improved several aspects of the QoL and decreased fatigue in healthy people, while maintaining a good safety profile. The practicability of this diet was also demonstrated for shift workers and people with a high percentage of active labour. Apart from the improvement in QoL and fatigue, the significant reduction in IGF-1, which can act as an accelerator of tumour development and progression, might be an indicator of the potential benefits of IF for patients with cancer.

Prognostic Impact of LAG-3 mRNA Expression in Early Breast Cancer.

Background: Monoclonal antibodies against PD-1 or PD-L1 have been established in clinical practice for the treatment of both early and advanced/metastatic triple-negative breast cancer. Beyond the established immune checkpoints (ICPs) (PD-1 and CTLA-4), additional ICPs, such as lymphocyte activation gene-3 (LAG-3), are subject of current research. In the present retrospective gene-expression analysis, we evaluated the prognostic significance of LAG-3 in 461 patients with early breast cancer. In addition, we examined whether there was a correlation between the different ICP and CD8 expressions. Methods: Using microarray-based gene-expression analysis, we examined the prognostic significance of LAG-3 mRNA expression for metastasis-free survival (MFS) in the whole cohort of 461 breast cancer patients and among different molecular subtypes. Correlations were analyzed using Spearman's rho correlation coefficient. Results: In the whole cohort, LAG-3 expression had no significant impact on MFS (p = 0.712, log-rank). In the subgroup analyses, there was a trend that a higher LAG-3 expression was associated with a favorable outcome in the luminal B (p = 0.217), basal-like (p = 0.370) and HER2 (p = 0.089) subtypes, although significance was not reached. In contrast, in a multivariate Cox regression analysis, adjusted for age, tumor size, axillary nodal status, histological grade of differentiation and proliferation marker Ki-67, LAG-3 showed a significant influence on MFS (HR 0.574; 95% CI 0.369−0.894; p = 0.014). High LAG-3 significantly correlated with CD8 (ρ = 0.571; p < 0.001). Conclusions: LAG-3 expression had an independent impact on MFS. In addition to PD-1 and PD-L1, further immune checkpoints, such as LAG-3, could serve as therapeutic targets in breast cancer.

Long-term prognostic significance of HER2-low and HER2-zero in node-negative breast cancer.

BACKGROUND: Recently, novel antibody--drug conjugates (ADCs) showed clinical activity in a subset of advanced human epidermal growth factor receptor 2 (HER2)-negative patients. We investigated the prognostic significance of HER2-low and HER2-zero tumours. PATIENTS AND METHODS: The retrospective cohort study included 410 consecutive node-negative breast cancer patients without adjuvant systemic therapy treated between 1985 and 2000 (median follow-up: 16.73 [IQR 8.58-23.45] years). 351 (85.6%) were HER-2 negative and subdivided into HER2-zero (immunohistochemistry [IHC] score 0) and HER2-low (IHC score 1+ or 2+/in situ hybridisation [ISH]-negative). HER2 gene expression was available in 170 (48.4%) patients. Differences in HER2 status for immunohistochemistry, gene expression and clinico-pathologic parameters were assessed using Fisher's exact test, Pearson's correlation and Mann-Whitney test. Prognosis was investigated using the Kaplan-Meier method and Cox regression analyses. RESULTS: Of the 351 HER2-negative patients, 198 (56.4%) had HER2-low tumours and 153 (43.6%) were HER2-zero. Significant differences between HER2-zero and HER2-low tumours were found in histologic grading (P = 0.001), Ki-67 (P = 0.013) and HER2 gene expression (P = 0.002). HER2-low patients had significantly longer disease-free survival (DFS) (15-year rate: 67.5% [95% CI 61.0-74.7] vs. 47.3% [95% CI 39.9-56.1], P < 0.001) and overall survival (OS) (15-year rate: 75.4% [95% CI 69.4-81.9] vs. 66.8% [95% CI 59.5-74.9], P = 0.009). The OS difference was observed in hormone receptor (HR)-positive (P = 0.039) but not HR-negative (P = 0.086) tumours. The results of multivariable analyses confirmed the independent prognostic significance of HER2 status (DFS: HR, 0.546; 95% CI, 0.402-0.743; P < 0.001; OS: HR, 0.653; 95% CI, 0.458-0.932; P = 0.019). CONCLUSION: HER2-low patients had a better survival than HER2-zero patients.

Efficacy and Safety of Immunotherapy for Cervical Cancer-A Systematic Review of Clinical Trials.

PURPOSE: To systematically review the current body of evidence on the efficacy and safety of immunotherapy for cervical cancer (CC). MATERIAL AND METHODS: Medline, the Cochrane Central Register of Controlled Trials and Web of Science were searched for prospective trials assessing immunotherapy in CC patients in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Full-text articles in English and German reporting outcomes of survival, response rates or safety were eligible. RESULTS: Of 4655 screened studies, 51 were included (immune checkpoint inhibitors (ICI) n=20; therapeutic vaccines n = 25; adoptive cell transfer therapy n=9). Of these, one qualified as a phase III randomized controlled trial and demonstrated increased overall survival following treatment with pembrolizumab, chemotherapy and bevacizumab. A minority of studies included a control group (n = 7) or more than 50 patients (n = 15). Overall, response rates were low to moderate. No response to ICIs was seen in PD-L1 negative patients. However, few remarkable results were achieved in heavily pretreated patients. There were no safety concerns in any of the included studies. CONCLUSION: Strong evidence on the efficacy of strategies to treat recurrent or metastatic cervical cancer is currently limited to pembrolizumab in combination with chemotherapy and bevacizumab, which substantiates an urgent need for large confirmatory trials on alternative immunotherapies. Overall, there is sound evidence on the safety of immunotherapy in CC.

Metronomic Chemotherapy for Metastatic Breast Cancer.

BACKGROUND: As disease control and quality of life play a leading role in metastatic breast cancer (MBC), metronomic chemotherapy (MCT) is gaining popularity alongside conventional chemotherapy (CCT) and targeted therapies. SUMMARY: MCT, defined as continuous administration of low-dose chemotherapeutic agents, is accepted as a therapy that exerts its effects via immunomodulation, anti-angiogenesis and direct cytotoxic effects. Oral administration of MCT is safe, easy to handle, and allows for flexible drug dosing. Dose accumulations associated with non-tolerable side effects are rare, so the medication can be administered for longer periods of time. Patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic disease resistant to endocrine-based therapy and not requiring rapid tumor response are generally suitable for MCT. However, MCT may also be promising in patients with triple-negative and HER2-positive tumors without aggressive disease who prefer a lower toxicity profile compared to CCT. The most commonly used agents are cyclophosphamide (CTX), methotrexate (MTX), capecitabine (CAPE), and vinorelbine (VRL), whereby a combination of agents is frequently applied. Key Messages: Based on the growing body of evidence, MCT can be considered as a suitable treatment option in selected MBC patients. Nevertheless, there is an urgent need for randomized controlled trials comparing MCT with CCT, but also with best supportive care. Due to the multimodal mechanisms of action, the combination with targeted and immunological therapies may represent a new promising approach for the treatment of MBC.

Prognostic Impact of Immunoglobulin Kappa C in Breast Cancer Patients Treated with Adjuvant Chemotherapy.

INTRODUCTION: Immunoglobulin κC (IGKC)-positive tumor-infiltrating plasma cells are associated with better prognosis in node-negative breast cancer patients without adjuvant systemic therapy. In the present study we evaluated the prognostic significance of IGKC in breast cancer patients treated with adjuvant chemotherapy ± tamoxifen. METHODS: IGKC expression was immunohistochemically analyzed in 193 breast cancer patients who were treated with adjuvant chemotherapy, either with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) between 1993 and 2001 with a median follow-up of 11 years. The prognostic impact of IGKC expression was evaluated by Kaplan-Meier survival analyses as well as uni- and multivariate Cox regression. An interaction term was used to investigate a possible association between tamoxifen treatment and prognostic effect of IGKC expression. RESULTS: Kaplan-Meier analyses identified IGKC as a prognostic marker for metastasis-free survival (MFS): higher IGKC expression was associated with a better outcome (p = 0.02, log rank). Results of univariate Cox regression confirmed the prognostic impact of IGKC expression: patients with a strong IGKC expression had a longer MFS (hazard ratio [HR] 1.931; 95% confidence interval [CI] 1.087-3.431; p = 0.025). Multivariate Cox regression analysis showed the independent prognostic significance of IGKC expression (HR 2.070; 95% CI 1.088-3.938; p = 0.027). The interaction term confirmed a significant interaction between tamoxifen treatment and the prognostic impact of IGKC expression (pinteraction = 0.04). CONCLUSION: IGKC expression had an independent prognostic impact in early breast cancer patients who received adjuvant chemotherapy. There was a significant interaction with the use of tamoxifen.

Pain experience and social support of endometriosis patients during the COVID-19 pandemic in Germany - results of a web-based cross-sectional survey.

BACKGROUND: Endometriosis is a chronic pain condition in premenopausal women. Pain is mainly characterized by pain intensity and may induce disability in all areas of daily life. Nevertheless, pain is influenced by emotional and social factors as well. Social distancing measures or quarantine, as reaction to rapidly rising infections with the COVID-19 virus due to the SARS-CoV-2 pandemic, were implemented across Europe to prevent the spread of the virus and social distancing measures were imposed by the German government by beginning of March 2020 with initiation of the lockdown by the end of March 2020. The objective of this study was to assess, how social distancing measures during the lockdown impacted the various aspects of pain perception in a group of chronic pain patients, such as women suffering from endometriosis. METHODS: Between 6th to 27th April 2020, an online questionnaire was activated at internet platforms of endometriosis patients support groups. Participants were asked retrospectively at one time point about their visual pain intensity measured by the visual analogue scale (VAS) and pain disability via pain disability index (PDI) prior to initiation of social distancing measures in Germany (VASP, PDIP), as well as the pain intensity and pain disability since implementation of social distancing measures (VASI, PDII). Differences of VAS and PDI previous and after implementation of social distancing measures were displayed as ΔVAS and ΔPDI. Pain experience and social support were assessed by a 5-point Likert scale. RESULTS: 285 participants completed at least one question regarding pain intensity, disability, pain experience or social support. Dysmenorrhea, the symptom with the highest level of pain assessed by VAS, decreased significantly during the SARS-CoV-2 pandemic compared to the time period prior to social isolation (45.30% respondents experienced improvemenet vs 40.50% who experienced worsening; p = 0.025). The global physical impairment improved significantly (improvement of pain induced disability in 48.20% vs 40.90% with worsening of pain symptoms; p = 0.032) after the implementation of social distancing measures. Pain experience was negatively affected by social distancing measures, since frequency of pain awareness increased in 43.6% (p<0.001) of participants and 30.0% (p<0.001) more participants experienced pain as a threat. Verbalization of pain experience was reduced in 36.6% (p = 0.001) of participants and 14.6% (p = 0.91), 21.9% (p<0.001) and 31.5% (p<0.001) of participants reported less social support from their partner, family and friends. CONCLUSIONS: Physical pain and disability on one hand and emotional and social pain experience on the other were differentially affected by the emerged emotional, social and health care constraints related to the SARS-CoV-2 pandemic.

Prognostic Impact of Immunoglobulin Kappa C (IGKC) in Early Breast Cancer.

We studied the prognostic impact of tumor immunoglobulin kappa C (IGKC) mRNA expression as a marker of the humoral immune system in the FinHer trial patient population, where 1010 patients with early breast cancer were randomly allocated to either docetaxel-containing or vinorelbine-containing adjuvant chemotherapy. HER2-positive patients were additionally allocated to either trastuzumab or no trastuzumab. Hormone receptor-positive patients received tamoxifen. IGKC was evaluated in 909 tumors using quantitative real-time polymerase chain reaction, and the influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates. Interactions were analyzed using Cox regression. IGKC expression, included as continuous variable, was independently associated with DDFS in a multivariable analysis also including age, molecular subtype, grade, and pT and pN stage (HR 0.930, 95% CI 0.870-0.995, p = 0.034). An independent association with DDFS was also found in a subset analysis of triple-negative breast cancers (TNBC) (HR 0.843, 95% CI 0.724-0.983, p = 0.029), but not in luminal (HR 0.957, 95% CI 0.867-1.056, p = 0.383) or HER2-positive (HR 0.933, 95% CI 0.826-1.055, p = 0.271) cancers. No significant interaction between IGKC and chemotherapy or trastuzumab administration was detected (Pinteraction = 0.855 and 0.684, respectively). These results show that humoral immunity beneficially influences the DDFS of patients with early TNBC.

Prognostic Significance of Interferon-γ and Its Signaling Pathway in Early Breast Cancer Depends on the Molecular Subtypes.

Interferons are crucial for adaptive immunity and play an important role in the immune landscape of breast cancer. Using microarray-based gene expression analysis, we examined the subtype-specific prognostic significance of interferon-γ (IFN-γ) as a single gene as well as an IFN-γ signature covering the signaling pathway in 461 breast cancer patients. Prognostic significance of IFN-γ, as well as the IFN-γ signature for metastasis-free survival (MFS), were examined using Kaplan-Meier as well as univariate and multivariate Cox regression analyses in the whole cohort and in different molecular subtypes. The independent prognostic significance of IFN-γ as a single gene was limited to basal-like breast cancer (hazard ratio (HR) 2.779, 95% confidence interval (95% CI) 1.117-6.919, p = 0.028). In contrast, the IFN-γ-associated gene signature was an independent prognostic factor in the whole cohort (HR 2.287, 95% CI 1.410-3.633, p < 0.001) as well as in the basal-like (HR 3.458, 95% CI 1.154-10.359, p = 0.027) and luminal B (HR 2.690, 95% CI 1.416-5.112, p = 0.003) molecular subtypes. These results underline the subtype-dependent prognostic influence of the immune system in early breast cancer.

Prognostic impact of CD4-positive T cell subsets in early breast cancer: a study based on the FinHer trial patient population.

BACKGROUND: The clinical importance of tumor-infiltrating cluster of differentiation 4 (CD4) T cells is incompletely understood in early breast cancer. We investigated the clinical significance of CD4, forkhead box P3 (FOXP3), and B cell attracting chemokine leukocyte chemoattractant-ligand (C-X-C motif) 13 (CXCL13) in early breast cancer. METHODS: The study is based on the patient population of the randomized FinHer trial, where 1010 patients with early breast cancer were randomly allocated to adjuvant chemotherapy containing either docetaxel or vinorelbine, and human epidermal growth factor receptor 2 (HER2)-positive patients were also allocated to trastuzumab or no trastuzumab. Breast cancer CD4, FOXP3, and CXCL13 contents were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and their influence on distant disease-free survival (DDFS) was examined using univariable and multivariable Cox regression and Kaplan-Meier estimates in the entire cohort and in selected molecular subgroups. Interactions between variables were analyzed using Cox regression. The triple-negative breast cancer (TNBC) subset of the HE10/97 randomized trial was used for confirmation. RESULTS: High CXCL13 was associated with favorable DDFS in univariable analysis, and independently in multivariable analysis (HR 0.44, 95% CI 0.29-0.67, P ≤ 0.001), most strongly in TNBC (HR 0.39, 95% CI 0.19-0.79, P = 0.009). No significant interaction with chemotherapy or trastuzumab administration was detected. Neither tumor CD4 content nor FOXP3 content was associated with DDFS. The favorable prognostic influence of CXCL13 was confirmed in the HE10/97 trial patient population with TNBC (HR 0.30, 95% CI 0.09-0.93; P = 0.038). CONCLUSIONS: The results provide a high level of evidence that humoral immunity influences the survival outcomes of patients with early breast cancer, in particular of those with TNBC. TRIAL REGISTRATION: The study reports retrospective biomarker analyses in the prospective FinHer trial and the prospective HE10/97 trial. ISRCTN76560285 . Registered on 18 March 2005. ACTRN12611000506998 . Registered on 16 May 2011.

Prognostic Significance of Focal Adhesion Kinase in Node-Negative Breast Cancer.

BACKGROUND: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays an important role as a mediator of cell migration, invasion, proliferation and survival. Conflicting results for the prognostic role of FAK in breast cancer (BC) prompted us to determine its impact. METHODS: Patients with node-negative BC entered this retrospective study. FAK expression was determined by immunohistochemistry (n = 335). The prognostic impact of FAK was examined with Cox regression analyses and Kaplan-Meier estimation in the whole cohort as well as in different molecular subtypes. RESULTS: 151 (45.1%) had a FAK-positive BC. In univariate analyses, FAK expression showed a significant impact for shorter disease-free survival (DFS) (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, p = 0.030) but not for metastasis-free survival and overall survival. Significant prognostic relevance for DFS (HR 1.76, 95% CI 1.05-2.97, p = 0.033) was observed in particular in estrogen receptor-positive HER2-negative BC patients, most notably in luminal B-like tumors (HR 2.32, CI 1.20-4.48, p = 0.012). However, FAK lost its prognostic impact in multivariate Cox regression analysis. CONCLUSION: FAK was associated with impaired DFS in univariate analysis. Prognostic relevance for DFS was most pronounced in luminal B-like BC. However, FAK expression was not associated with an independent impact on survival for BC in multivariate analysis.

The value of advanced MRI techniques in the assessment of cervical cancer: a review.

OBJECTIVES: To assess the value of new magnetic resonance imaging (MRI) techniques in cervical cancer. METHODS: We searched PubMed and MEDLINE and reviewed articles published from 1990 to 2016 to identify studies that used MRI techniques, such as diffusion weighted imaging (DWI), intravoxel incoherent motion (IVIM) and dynamic contrast enhancement (DCE) MRI, to assess parametric invasion, to detect lymph node metastases, tumour subtype and grading, and to detect and predict tumour recurrence. RESULTS: Seventy-nine studies were included. The additional use of DWI improved the accuracy and sensitivity of the evaluation of parametrial extension. Most studies reported improved detection of nodal metastases. Functional MRI techniques have the potential to assess tumour subtypes and tumour grade differentiation, and they showed additional value in detecting and predicting treatment response. Limitations included a lack of technical standardisation, which limits reproducibility. CONCLUSIONS: New advanced MRI techniques allow improved analysis of tumour biology and the tumour microenvironment. They can improve TNM staging and show promise for tumour classification and for assessing the risk of tumour recurrence. They may be helpful for developing optimised and personalised therapy for patients with cervical cancer. TEACHING POINTS: • Conventional MRI plays a key role in the evaluation of cervical cancer. • DWI improves tumour delineation and detection of nodal metastases in cervical cancer. • Advanced MRI techniques show promise regarding histological grading and subtype differentiation. • Tumour ADC is a potential biomarker for response to treatment.

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy.

BACKGROUND: In breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery. METHODS: Affymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer. RESULTS: Ten late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer. CONCLUSIONS: Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.

Prognostic influence of cyclooxygenase-2 protein and mRNA expression in node-negative breast cancer patients.

BACKGROUND: Cyclooxygenases (COX) play a key role in prostaglandin metabolism and are important for tumor development and progression. The aim of this study was to analyze the prognostic impact of COX-2 expression in a cohort of lymph node-negative breast cancer patients not treated in the adjuvant setting. METHODS: COX-2 expression was determined by immunohistochemistry (IHC) in tumor tissue of 193 node-negative breast cancer patients. Additionally, mRNA expression was determined in corresponding tumor samples using microarray based gene-expression data. Univariate and multivariate Cox regression analyses adjusted for age at diagnosis, tumor size, histological grade, human epithelial growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) were performed to evaluate the association of both COX-2 protein and mRNA expression with survival. Survival rates were determined by the Kaplan-Meier method. Correlations between COX-2 expression and established prognostic factors were analyzed using the Chi-square test. A potential correlation between COX-2 protein expression and COX-2 mRNA expression was assessed utilizing the Kruscal-Wallis-H-test. RESULTS: COX-2 protein expression was positive in 24.9% of the breast cancer samples. Univariate analysis showed that COX-2 protein expression was associated with shorter disease-free survival (DFS) (P = 0.0001), metastasis-free survival (MFS) (P = 0.002) as well as breast cancer specific overall survival (OS) (P = 0.043). In multivariate analysis COX-2 expression retained its significance independent of established prognostic factors for shorter DFS (P < 0.001, HR = 2.767, 95% CI = 1.563-4.901) and for inferior MFS (P = 0.002, HR = 2.7, 95% CI = 1.469-5.263) but not for OS (P = 0.096, HR = 1.929, 95% CI = 0.889-4.187). In contrast, COX-2 mRNA expression was not related to survival and failed to show a correlation with protein expression (P = 0.410). CONCLUSIONS: The present findings support the hypothesis that COX-2 protein but not mRNA expression is associated with an unfavorable outcome in node-negative breast cancer.

Prognostic influence of pre-operative C-reactive protein in node-negative breast cancer patients.

The importance of inflammation is increasingly noticed in cancer. The aim of this study was to analyze the prognostic influence of pre-operative serum C-reactive protein (CRP) in a cohort of 148 lymph node-negative breast cancer patients. The prognostic significance of CRP level for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) was evaluated using univariate and multivariate Cox regression, also including information on age at diagnosis, tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, proliferation index (Ki67) and molecular subtype, as well as an assessment of the presence of necrosis and inflammation in the tumor tissue. Univariate analysis showed that CRP, as a continuous variable, was significantly associated with DFS (P = 0.002, hazard ratio [HR] = 1.04, 95% confidence interval [CI] = 1.02-1.07) and OS (P = 0.036, HR= 1.03, 95% CI = 1.00-1.06), whereas a trend was observed for MFS (P = 0.111). In the multivariate analysis, CRP retained its significance for DFS (P = 0.033, HR= 1.01, 95% CI = 1.00-1.07) as well as OS (P = 0.023, HR= 1.03, 95% CI = 1.00-1.06), independent of established prognostic factors. Furthermore, large-scale gene expression analysis by Affymetrix HG-U133A arrays was performed for 72 (48.6%) patients. The correlations between serum CRP and gene expression levels in the corresponding carcinoma of the breast were assessed using Spearman's rank correlation, controlled for false-discovery rate. No significant correlation was observed between CRP level and gene expression indicative of an ongoing local inflammatory process. In summary, pre-operatively elevated CRP levels at the time of diagnosis were associated with shorter DFS and OS independent of established prognostic factors in node-negative breast cancer, supporting a possible link between inflammation and prognosis in breast cancer.

Synchronous ovarian and endometrial cancer--an international multicenter case-control study.

OBJECTIVES: This study aimed to compare the prognosis of patients with synchronous endometrial and ovarian cancer (SEOC) to matched controls with either endometrial cancer (EC) or ovarian cancer (OC). METHODS: A retrospective case-control study including all patients with SEOC who had been treated at 5 European tertiary gynecologic oncology centers between 1996 and 2011 and patients with either EC or OC matched for age, International Federation of Gynecology and Obstetrics (FIGO) stage, histology, year of diagnosis, and Eastern Cooperative Oncology Group performance score. RESULTS: The study cohort comprised 77, 132, and 126 patients with SEOC, EC, and OC, respectively. The patient characteristics confirmed an equal distribution of matching factors, and the median follow-up did not differ (P = 0.44). 48.1% of the patients with SEOC showed early FIGO stage I for both EC and OC. The 5-year PFS rates differed between SEOC and EC (76.3% vs 86.3%; P = 0.047) but not the 5-year overall survival rates (71.6% vs 79.8%; P = 0.12) and did not differ between SEOC and OC (76.3% vs 63.8%; P = 0.19 and 71.6% vs 69.3%; P = 0.61, respectively). After the adjustment for the FIGO stage of the 2 components of SEOC, neither PFS nor overall survival rates were different. CONCLUSIONS: Prognosis of patients with SEOC tended to be the same in comparison with matched controls with either one EC or OC. Therefore, it could be considered that patients with SEOC may be eligible for clinical trials of the advanced tumor component if no additional therapy is indicated for the other component.

Extensive Osler-Rendu disease in a breast cancer patient: increasing hepatic arteriovenous malformations under endocrine therapy mimicking liver metastases.

BACKGROUND: Undefined, increasing hepatic lesions are a common issue in the follow-up care of breast cancer patients and frequently result in invasive diagnostic procedures. CASE REPORT: This case report describes the diagnostic approach in the case of a 58-year-old breast cancer patient with a previously unknown visceral involvement of Osler-Rendu disease. The patient was admitted to our institution because of newly diagnosed, increasing hepatic lesions occurring during endocrine treatment with aromatase inhibitors. On the basis of ultrasound findings, secondary liver metastases were suspected. After a thorough clinical and imaging examination, we reviewed the literature on typical radiological findings of visceral involvement of Osler-Rendu disease, and the impact of endocrine treatment on arteriovenous malformations. Multislice computed tomography scan identified the hepatic lesions as arteriovenous malformations. In the current literature, there are no reports available on the interaction between aromatase inhibitors and arteriovenous malformations. However, some data do show an effect of endocrine therapy with estrogen/progesterone, or tamoxifen on arteriovenous malformations, although some of the results are partially contradictory. CONCLUSION: This case report demonstrates that for undefined hepatic lesions in breast cancer patients, extensive Osler-Rendu disease should be considered as a potential differential diagnosis. Furthermore, we discuss the possible influence of aromatase inhibitors on arteriovenous malformations.