Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Targeting HIF-1 for cancer therapy

CA : A Cancer Journal for Clinicians

The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.

https://jcp.bmj.com/content/jclinpath/55/4/244.full.pdf

The causal relation between human papillomavirus and cervical cancer

Transitions between epithelial and mesenchymal states have crucial roles in embryonic development. Emerging data suggest a role for these processes in regulating cellular plasticity in normal adult tissues and in tumours, where they can generate multiple, distinct cellular subpopulations contributing to intratumoural heterogeneity. Some of these subpopulations may exhibit more differentiated features, whereas others have characteristics of stem cells. Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.

Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits

The molecular mechanisms that underlie tumour progression are still poorly understood, but recently our knowledge of particular aspects of some of these processes has increased. Specifically, the identification of Snail, ZEB and some basic helix-loop-helix (bHLH) factors as inducers of epithelial-mesenchymal transition (EMT) and potent repressors of E-cadherin expression has opened new avenues of research with potential clinical implications.

Snail, ZEB and bHLH factors in tumour progression: an alliance against the epithelial phenotype?

The aim of this study was to investigate the asso- ciation between the immunohistochemical expression of hypoxia-inducible factor (HIF)-1α and HIF-2α and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters K trans and kep in prostate cancer. Therefore, 15 patients with biopsy-confirmed prostate cancer underwent a pre-operative 3T DCE-MRI scan. Immunohistochemical analysis of HIF-1α and HIF-2α, and of CD31 for microvessel density (MVD) was performed. Tumor areas were delineated on whole-mount histopathological sections. Nuclear HIF expres- sion was correlated with the quantitative DCE-MRI parameters K trans and kep, MVD and Gleason score. HIF expression was highly heterogeneous within tumors and between patients. Pronounced expression of HIF-2α was present, while HIF-1α expression was more limited. Larger tumors showed higher HIF-2α expression (P=0.041). A correlation between HIF-2α and K trans p5 th was found (r=0.30, P=0.02), but no differences in K trans , kep and MVD were observed for different levels of HIF expression. HIF expression was not associated with Gleason score. In conclusion, in this whole-mount prostate cancer study, larger prostate tumors showed frequently high HIF-2α expression, suggesting that larger tumors are clinically most relevant. However, HIF-1α and HIF-2α were not correlated with DCE-MRI parameters. Given the pronounced expression of HIF-2α and independence of Gleason score, HIF expression may function as a biomarker to guide boost dose prescription.

/pdf/expression-of-hypoxia-inducible-factor-1a-and-2a-in-whole-2kzxvn9qma.pdf

Expression of hypoxia-inducible factor-1α and -2α in whole-mount prostate histology: Relation with dynamic contrast-enhanced MRI and Gleason score

Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective

Cervical cancer is the second most frequently diagnosed cancer in women worldwide. About one-third of patients experience recurrent disease. A better chance of survival might be achieved by the early detection of recurrent cervical cancer. [18F]fluoro-2-deoxy-D-glucose (FDG) PET could be a promising imaging modality for this purpose, given that FDG PET has high diagnostic efficacy. Ideally, pre-selection of patients should be performed before considering FDG PET. The purpose of this study was to investigate parameters of primary cervical cancer associated with recurrence as a basis for pre-selection of patients in whom FDG PET should be performed. Thirty-eight cervical cancer patients, clinically suspected of having recurrent disease, underwent FDG PET. Tissue from primary tumours and nine histologically confirmed metastases was analysed for biomarkers possibly related to glucose metabolism and prognosis (vascular endothelial growth factor, CD31 for microvessel density, glucose transporter-1, hexokinases I, II and III, Ki67, p53, hypoxia-inducible factor 1α, and degree of infiltration by lymphocytes and macrophages). Based on clinical outcome, sensitivity and specificity of FDG PET were 96% and 100%, respectively. Cox regression revealed microvessel density and p53 (tumour suppressor protein) to be the two most important biomarkers for prediction of recurrence (hazard ratios 2.54 and 2.28, respectively). By combining these two biomarkers in a parallel test, sensitivity and specificity in predicting recurrence were 87% and 71%, respectively. Leave-one-out cross-validation demonstrated predictive validity of a model based on microvessel density and p53. In this first study of its kind, we have demonstrated that microvessel density and p53 profiles could be important in pre-selecting cervical cancer patients for detection of recurrence by FDG PET.

Microvessel density and p53 in detecting cervical cancer by FDG PET in cases of suspected recurrence.

Objective To determine the feasibility and safety of breast endoscopic thulium laser ablation for treatment of intraductal neoplasia. Study design Ductoscopy is a minimally invasive endoscopic approach of the milk ducts of the breast via the nipple. Besides diagnosis in women with pathologic nipple discharge (PND), it allows non-invasive removal of intraductal lesions with a stalk like papillomas. Removal, however, is often incomplete and flat lesions cannot be targeted. We therefore developed laser ductoscopy. Methods Dosimetry of laser ductoscopy was assessed in thirteen mastectomy specimens, applying power settings of 1-5 W with 100-1000 ms pulsed exposure to a 375-μm outer diameter thulium fiber laser. Subsequently histology was obtained from the breast tissue that was treated with the Thulium laser. Results Endoscopic view was maintained during ductoscopic laser ablation at 1-3 W. Increasing power to 4-5 W caused impaired vision due to shrinkage of the main duct around the ductoscope tip. Histology revealed localized ablation of the duct wall. Conclusion We show for the first time that laser ductoscopy is technically feasible. The Thulium laser enables a superficial intraductal ablation and is a useful tool for intraductal interventions. An in vivo prospective study is needed to further demonstrate its potential. Lasers Surg. Med. 50:137-142, 2018. © 2017 Wiley Periodicals, Inc.

Ex vivo feasibility study of endoscopic intraductal laser ablation of the breast

Histologic grade of ductal carcinoma in situ of the breast (DCIS) may become the single biomarker that decides whether patients will be treated. Yet, evidence shows that grading variation in daily practice is substantial. To facilitate quality improvement, feedback reports, in which laboratory-specific case-mix adjusted proportions per grade were benchmarked against other laboratories, were sent to the individual laboratories by March 1, 2018. One year later, the effect of these feedback reports on inter-laboratory variation was studied. Synoptic pathology reports of all pure DCIS resection specimens between March 1, 2017 and March 1, 2019 were retrieved from PALGA (the nationwide Dutch pathology registry). Laboratory-specific proportions per grade were compared to the overall proportion in the year before and after feedback. The absolute deviation for all three grades at once, represented by the overall deviation score (ODS), was calculated as the sum of deviations from the grade-specific overall proportions. Case-mix adjusted, laboratory-specific odds ratios (ORs) for high- (grade III) versus low-grade (grade I-II) DCIS were obtained by multivariable logistic regression. Overall, 2954 DCIS reports from 31 laboratories were included. After feedback, the range between laboratories decreased by 22 and 6.5% for grades II and III, while an increase of 6.2% was observed for grade I. Both the mean ODS (27.2 to 24.1%) and maximum ODS (87.7 to 59.6%) decreased considerably. However, the range of case-mix adjusted ORs remained fairly stable and substantial (0.39 (95% CI: 0.18–0.86) to 3.69 (95% CI: 1.30–10.51)). A promising decrease in grading variation was observed after laboratory-specific feedback for DCIS grades II-III, while this was not observed for DCIS grade I. Overall, grading variation remained substantial which needs to be addressed considering its clinical implications. Nationwide consensus on a classification, and training of (expert breast) pathologists, for example by e-learning, may help to further improve grading standardization.

/pdf/grading-variation-in-2-934-patients-with-ductal-carcinoma-in-20n6umt4a6.pdf

Paul J. van Diest

Papers

Expression of hypoxia-inducible factor-1α and -2α in whole-mount prostate histology: Relation with dynamic contrast-enhanced MRI and Gleason score

Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective

Microvessel density and p53 in detecting cervical cancer by FDG PET in cases of suspected recurrence.

Ex vivo feasibility study of endoscopic intraductal laser ablation of the breast

Grading variation in 2,934 patients with ductal carcinoma in situ of the breast: the effect of laboratory- and pathologist-specific feedback reports