Quantifying the effects of data augmentation and stain color normalization in convolutional neural networks for computational pathology

Stain variation is a phenomenon observed when distinct pathology laboratories stain tissue slides that exhibit similar but not identical color appearance. Due to this color shift between laboratories, convolutional neural networks (CNNs) trained with images from one lab often underperform on unseen images from the other lab. Several techniques have been proposed to reduce the generalization error, mainly grouped into two categories: stain color augmentation and stain color normalization. The former simulates a wide variety of realistic stain variations during training, producing stain-invariant CNNs. The latter aims to match training and test color distributions in order to reduce stain variation. For the first time, we compared some of these techniques and quantified their effect on CNN classification performance using a heterogeneous dataset of hematoxylin and eosin histopathology images from 4 organs and 9 pathology laboratories. Additionally, we propose a novel unsupervised method to perform stain color normalization using a neural network. Based on our experimental results, we provide practical guidelines on how to use stain color augmentation and stain color normalization in future computational pathology applications.Comment: Accepted in the Medical Image Analysis journa

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures.

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR

Loss of signal transducer and activator of transcription 1 is associated with prostate cancer recurrence

STAT1 loss has previously been implicated in cell line studies to modify prostate cancer cell growth and survival, however the clinical significance of this has not previously been established. This study investigated if STAT1 loss was associated with patient outcome measures and the phenotypic consequence of STAT1 silencing. STAT1 expression was assessed in two patient cohorts with localised (n = 78) and advanced prostate cancer at initial diagnosis (n = 39) by immunohistochemistry (IHC). Impact of STAT1 silencing on prostate cancer cells lines was assessed using Cell Death detection ELISA, TLDA gene signature apoptosis arrays, WST-1 assay, xCELLigence system, clonogenic assay, and wound healing assay. In the localised patient cohort, low expression of STAT1 was associated with shorter time to disease recurrence (3.8 vs 7.3 years, P = 0.02) and disease specific survival (6.6 vs 9.3 years, P = 0.05). In the advanced patient cohort, low expression was associated with shorter time to disease recurrence (2.0 vs 3.9 years, P = 0.001). When STAT1 was silenced in PC3 cells (AR negative) and LNCaP cells (AR positive) silencing did not influence levels of apoptosis in either cell line and had little effect on cell viability in the LNCaP cells. In contrast, STAT1 silencing in the PC3 cells resulted in a pronounced increase in cell viability (WST-1 assay: mock silenced vs STAT1 silenced, P < 0.001), clonagenicity (clonogenic assay: mock silenced vs STAT1 silenced, P < 0.001), and migration (wound healing: mock silenced vs STAT1 silenced, P < 0.001). In conclusion, loss of STAT1 may promote prostate cancer recurrence in AR negative patients via increasing cell viability

Prospective Study of Sex Hormone Levels Among Prostate Cancer Patients Attending University of Port Harcourt Teaching Hospital Clinic

Background: Longstanding and diverse body of evidence supports the view that sex steroids play a role in the development of prostate cancer. Epidemiological and demographic studies in humans as well as animalexperiments have sought to determine the independent effect on risk as well as the interrelationship between these hormones. In this study, we investigated the variations in testosterone and oestradiol levels among prostate cancer patients attending UPTH clinics with the objective of determining the role played by sex hormone variations in the development of cancer of prostate in patients attending the University of Port Harcourt Teaching, Port Harcourt.Methods: Newly diagnosed patients with cancer of the prostate attending the Urology clinic of University of Port Harcourt Teaching, Port Harcourt from December 2011 to April 2012 were recruited for the study. Their Prostate Specific Antigen (PSA) testosterone and oestrogens levels were measured using Elisa Kits. Correlation between individual hormone levels in control subjects were assessed by Spearman correlation coefficients (R). Student t-test was used to assess if there was any significant difference between the patients and controls in the level of these hormones. We computed the ratio of oestradiol to testosterone and compared case patients with control subjects by use of t-test at 95% confidence interval. Test cases were also divided into two groups by age to study variations across subgroups.Results: 105 patients recently diagnosed with prostate cancer and 40 normal subjects were analyzed. We observed a negative correlation between testosterone and oestradiol (r = -0.66). Testosterone and oestradiol levels in prostate cancer patients were also significantly different from that of controls. Mean testosterone level in control was 3.2 ng/ml while that of the patients was 4.0 ng /ml. Mean oestradiol level in controls was 32.8 pg/ml while that of the patients was 21.2pg/ml (p < 0.05 in both cases). The ratio of oestradiol to testosterone was also significantly alteredin prostate cancer patients (p < 0.05). The mean levels of hormones and hormone ratios across the two sub-age groups were not substantially different in patients with prostate cancer (p > 0.05).Conclusion: This study indicates that increased levels of testosterone in circulation are associated with risk of prostate cancer. This risk is further associated with low levels of circulating oestradiol. The relative levels or ratio of these hormones are very important in the development of prostate cancer. Age of the patient appear not to be strongly related with these changes after the cancerous state has set in.Key Words: Prostate cancer, oestrogens, testosterone, Prostate Specific Antigen (PSA)

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Roles of tumor suppressors in regulating tumor-associated inflammation.

Loss or silencing of tumor suppressors (TSs) promotes neoplastic transformation and malignant progression. To date, most work on TS has focused on their cell autonomous effects. Recent evidence, however, demonstrates an important noncell autonomous role for TS in the control of tumor-associated inflammation. We review evidence from clinical data sets and mouse model studies demonstrating enhanced inflammation and altered tumor microenvironment (TME) upon TS inactivation. We discuss clinical correlations between tumor-associated inflammation and inactivation of TS, and their therapeutic implications. This review sets forth the concept that TS can also suppress tumor-associated inflammation, a concept that provides new insights into tumor-host interactions. We also propose that in some cases the loss of TS function in cancer can be overcome through inhibition of the resulting inflammatory response, regardless whether it is a direct or an indirect consequence of TS loss