Automated Quantification of HER2 Amplification Levels Using Deep Learning.

HER2 assessment is necessary for patient selection in anti-HER2 targeted treatment. However, manual assessment of HER2 amplification is time-costly, labor-intensive, highly subjective and error-prone. Challenges in HER2 analysis in fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) images include unclear and blurry cell boundaries, large variations in cell shapes and signals, overlapping and clustered cells and sparse label issues with manual annotations only on cells with high confidences, producing subjective assessment scores according to the individual choices on cell selection. To address the above-mentioned issues, we have developed a soft-sampling cascade deep learning model and a signal detection model in quantifying CEN17 and HER2 of cells to assist assessment of HER2 amplification status for patient selection of HER2 targeting therapy to breast cancer. In evaluation with two different kinds of clinical datasets, including a FISH data set and a DISH data set, the proposed method achieves high accuracy, recall and F1-score for both datasets in instance segmentation of HER2 related cells that must contain both CEN17 and HER2 signals. Moreover, the proposed method is demonstrated to significantly outperform seven state of the art recently published deep learning methods, including contour proposal network (CPN), soft label-based FCN (SL-FCN), modified fully convolutional network (M-FCN), bilayer convolutional network (BCNet), SOLOv2, Cascade R-CNN and DeepLabv3+ with three different backbones (p ≤ 0.01). Clinically, anti-HER2 therapy can also be applied to gastric cancer patients. We applied the developed model to assist in HER2 DISH amplification assessment for gastric cancer patients, and it also showed promising predictive results (accuracy 97.67 ±1.46%, precision 96.15 ±5.82%, respectively).

ATEC23 Challenge: Automated prediction of treatment effectiveness in ovarian cancer using histopathological images.

Ovarian cancer, predominantly epithelial ovarian cancer (EOC), is a global health concern due to its high mortality rate. Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70% of advanced patients are with recurrent cancer and disease. Bevacizumab is a humanized monoclonal antibody, which blocks VEGF signaling in cancer, inhibits angiogenesis and causes tumor shrinkage, and has been recently approved by the FDA as a monotherapy for advanced ovarian cancer in combination with chemotherapy. Unfortunately, Bevacizumab may also induce harmful adverse effects, such as hypertension, bleeding, arterial thromboembolism, poor wound healing and gastrointestinal perforation. Given the expensive cost and unwanted toxicities, there is an urgent need for predictive methods to identify who could benefit from bevacizumab. Of the 18 (approved) requests from 5 countries, 6 teams using 284 whole section WSIs for training to develop fully automated systems submitted their predictions on a test set of 180 tissue core images, with the corresponding ground truth labels kept private. This paper summarizes the 5 qualified methods successfully submitted to the international challenge of automated prediction of treatment effectiveness in ovarian cancer using the histopathologic images (ATEC23) held at the 26th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) in 2023 and evaluates the methods in comparison with 5 state of the art deep learning approaches. This study further assesses the effectiveness of the presented prediction models as indicators for patient selection utilizing both Cox proportional hazards analysis and Kaplan-Meier survival analysis. A robust and cost-effective deep learning pipeline for digital histopathology tasks has become a necessity within the context of the medical community. This challenge highlights the limitations of current MIL methods, particularly within the context of prognosis-based classification tasks, and the importance of DCNNs like inception that has nonlinear convolutional modules at various resolutions to facilitate processing the data in multiple resolutions, which is a key feature required for pathology related prediction tasks. This further suggests the use of feature reuse at various scales to improve models for future research directions. In particular, this paper releases the labels of the testing set and provides applications for future research directions in precision oncology to predict ovarian cancer treatment effectiveness and facilitate patient selection via histopathological images.

Deep learning to assess microsatellite instability directly from histopathological whole slide images in endometrial cancer.

Molecular classification, particularly microsatellite instability-high (MSI-H), has gained attention for immunotherapy in endometrial cancer (EC). MSI-H is associated with DNA mismatch repair defects and is a crucial treatment predictor. The NCCN guidelines recommend pembrolizumab and nivolumab for advanced or recurrent MSI-H/mismatch repair deficient (dMMR) EC. However, evaluating MSI in all cases is impractical due to time and cost constraints. To overcome this challenge, we present an effective and efficient deep learning-based model designed to accurately and rapidly assess MSI status of EC using H&E-stained whole slide images. Our framework was evaluated on a comprehensive dataset of gigapixel histopathology images of 529 patients from the Cancer Genome Atlas (TCGA). The experimental results have shown that the proposed method achieved excellent performances in assessing MSI status, obtaining remarkably high results with 96%, 94%, 93% and 100% for endometrioid carcinoma G1G2, respectively, and 87%, 84%, 81% and 94% for endometrioid carcinoma G3, in terms of F-measure, accuracy, precision and sensitivity, respectively. Furthermore, the proposed deep learning framework outperforms four state-of-the-art benchmarked methods by a significant margin (p < 0.001) in terms of accuracy, precision, sensitivity and F-measure, respectively. Additionally, a run time analysis demonstrates that the proposed method achieves excellent quantitative results with high efficiency in AI inference time (1.03 seconds per slide), making the proposed framework viable for practical clinical usage. These results highlight the efficacy and efficiency of the proposed model to assess MSI status of EC directly from histopathological slides.

Chronic infective arthritis with osteomyelitis of the ankle due to Pseudomonas aeruginosa infection in a middle-age woman: A rare causative pathogen requiring vigilance.

RATIONALE: Pseudomonas aeruginosa-induced septic arthritis is a relatively uncommon phenomenon. It has been documented in children with traumatic wounds, young adults with a history of intravenous drug use, and elderly patients with recent urinary tract infections or surgical procedures. PATIENT CONCERNS: Fifty-nine year-old female had no reported risk factors. The patient sought medical attention due to a 6-month history of persistent pain and swelling in her right ankle. DIAGNOSES: Magnetic resonance imaging and a 3-phase bone scan revealed findings suggestive of infectious arthritis with concurrent osteomyelitis. Histopathological examination of the synovium suggested chronic synovitis, and synovial tissue culture confirmed the presence of P aeruginosa. INTERVENTION: Arthroscopic synovectomy and debridement, followed by 6 weeks of targeted antibiotic therapy for P aeruginosa. OUTCOMES: Following treatment, the patient experienced successful recovery with no symptom recurrence, although she retained a mild limitation in the range of motion of her ankle. LESSONS: To our knowledge, this is the first reported case of chronic arthritis and osteomyelitis caused by P aeruginosa in a patient without conventional risk factors. This serves as a crucial reminder for clinicians to consider rare causative organisms in patients with chronic arthritis. Targeted therapy is imperative for preventing further irreversible bone damage and long-term morbidity.

Deep Learning Can Predict Bevacizumab Therapeutic Effect and Microsatellite Instability Directly from Histology in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) remains a significant cause of mortality among gynecologic cancers, with the majority of cases being diagnosed at an advanced stage. Before targeted therapies were available, EOC treatment relied largely on debulking surgery and platinum-based chemotherapy. Vascular endothelial growth factors have been identified as inducing tumor angiogenesis. According to several clinical trials, anti-vascular endothelial growth factor-targeted therapy with bevacizumab was effective in all phases of EOC treatment. However, there are currently no biomarkers accessible for regular therapeutic use despite the importance of patient selection. Microsatellite instability (MSI), caused by a deficiency of the DNA mismatch repair system, is a molecular abnormality observed in EOC associated with Lynch syndrome. Recent evidence suggests that angiogenesis and MSI are interconnected. Developing predictive biomarkers, which enable the selection of patients who might benefit from bevacizumab-targeted therapy or immunotherapy, is critical for realizing personalized precision medicine. In this study, we developed 2 improved deep learning methods that eliminate the need for laborious detailed image-wise annotations by pathologists and compared them with 3 state-of-the-art methods to not only predict the efficacy of bevacizumab in patients with EOC using mismatch repair protein immunostained tissue microarrays but also predict MSI status directly from histopathologic images. In prediction of therapeutic outcomes, the 2 proposed methods achieved excellent performance by obtaining the highest mean sensitivity and specificity score using MSH2 or MSH6 markers and outperformed 3 state-of-the-art deep learning methods. Moreover, both statistical analysis results, using Cox proportional hazards model analysis and Kaplan-Meier progression-free survival analysis, confirm that the 2 proposed methods successfully differentiate patients with positive therapeutic effects and lower cancer recurrence rates from patients experiencing disease progression after treatment (P < .01). In prediction of MSI status directly from histopathology images, our proposed method also achieved a decent performance in terms of mean sensitivity and specificity score even for imbalanced data sets for both internal validation using tissue microarrays from the local hospital and external validation using whole section slides from The Cancer Genome Atlas archive.

Efficient Convolution Network to Assist Breast Cancer Diagnosis and Target Therapy.

Breast cancer is the leading cause of cancer-related deaths among women worldwide, and early detection and treatment has been shown to significantly reduce fatality rates from severe illness. Moreover, determination of the human epidermal growth factor receptor-2 (HER2) gene amplification by Fluorescence in situ hybridization (FISH) and Dual in situ hybridization (DISH) is critical for the selection of appropriate breast cancer patients for HER2-targeted therapy. However, visual examination of microscopy is time-consuming, subjective and poorly reproducible due to high inter-observer variability among pathologists and cytopathologists. The lack of consistency in identifying carcinoma-like nuclei has led to divergences in the calculation of sensitivity and specificity. This manuscript introduces a highly efficient deep learning method with low computing cost. The experimental results demonstrate that the proposed framework achieves high precision and recall on three essential clinical applications, including breast cancer diagnosis and human epidermal receptor factor 2 (HER2) amplification detection on FISH and DISH slides for HER2 target therapy. Furthermore, the proposed method outperforms the majority of the benchmark methods in terms of IoU by a significant margin (p<0.001) on three essential clinical applications. Importantly, run time analysis shows that the proposed method obtains excellent segmentation results with notably reduced time for Artificial intelligence (AI) training (16.93%), AI inference (17.25%) and memory usage (18.52%), making the proposed framework feasible for practical clinical usage.

Weakly supervised bilayer convolutional network in segmentation of HER2 related cells to guide HER2 targeted therapies.

Overexpression of human epidermal growth factor receptor 2 (HER2/ERBB2) is identified as a prognostic marker in metastatic breast cancer and a predictor to determine the effects of ERBB2-targeted drugs. Accurate ERBB2 testing is essential in determining the optimal treatment for metastatic breast cancer patients. Brightfield dual in situ hybridization (DISH) was recently authorized by the United States Food and Drug Administration for the assessment of ERRB2 overexpression, which however is a challenging task due to a variety of reasons. Firstly, the presence of touching clustered and overlapping cells render it difficult for segmentation of individual HER2 related cells, which must contain both ERBB2 and CEN17 signals. Secondly, the fuzzy cell boundaries make the localization of each HER2 related cell challenging. Thirdly, variation in the appearance of HER2 related cells is large. Fourthly, as manual annotations are usually made on targets with high confidence, causing sparsely labeled data with some unlabeled HER2 related cells defined as background, this will seriously confuse fully supervised AI learning and cause poor model outcomes. To deal with all issues mentioned above, we propose a two-stage weakly supervised deep learning framework for accurate and robust assessment of ERBB2 overexpression. The effectiveness and robustness of the proposed deep learning framework is evaluated on two DISH datasets acquired at two different magnifications. The experimental results demonstrate that the proposed deep learning framework achieves an accuracy of 96.78 ± 1.25, precision of 97.77 ± 3.09, recall of 84.86 ± 5.83 and Dice Index of 90.77 ± 4.1 and an accuracy of 96.43 ± 2.67, precision of 97.82 ± 3.99, recall of 87.14 ± 10.17 and Dice Index of 91.87 ± 6.51 for segmentation of ERBB2 overexpression on the two experimental datasets, respectively. Furthermore, the proposed deep learning framework outperforms 15 state-of-the-art benchmarked methods by a significant margin (P<0.05) with respect to IoU on both datasets.

Detection of ERBB2 and CEN17 signals in fluorescent in situ hybridization and dual in situ hybridization for guiding breast cancer HER2 target therapy.

The overexpression of the human epidermal growth factor receptor 2 (HER2) is a predictive biomarker in therapeutic effects for metastatic breast cancer. Accurate HER2 testing is critical for determining the most suitable treatment for patients. Fluorescent in situ hybridization (FISH) and dual in situ hybridization (DISH) have been recognized as FDA-approved methods to determine HER2 overexpression. However, analysis of HER2 overexpression is challenging. Firstly, the boundaries of cells are often unclear and blurry, with large variations in cell shapes and signals, making it challenging to identify the precise areas of HER2-related cells. Secondly, the use of sparsely labeled data, where some unlabeled HER2-related cells are classified as background, can significantly confuse fully supervised AI learning and result in unsatisfactory model outcomes. In this study, we present a weakly supervised Cascade R-CNN (W-CRCNN) model to automatically detect HER2 overexpression in HER2 DISH and FISH images acquired from clinical breast cancer samples. The experimental results demonstrate that the proposed W-CRCNN achieves excellent results in identification of HER2 amplification in three datasets, including two DISH datasets and a FISH dataset. For the FISH dataset, the proposed W-CRCNN achieves an accuracy of 0.970±0.022, precision of 0.974±0.028, recall of 0.917±0.065, F1-score of 0.943±0.042 and Jaccard Index of 0.899±0.073. For DISH datasets, the proposed W-CRCNN achieves an accuracy of 0.971±0.024, precision of 0.969±0.015, recall of 0.925±0.020, F1-score of 0.947±0.036 and Jaccard Index of 0.884±0.103 for dataset 1, and an accuracy of 0.978±0.011, precision of 0.975±0.011, recall of 0.918±0.038, F1-score of 0.946±0.030 and Jaccard Index of 0.884±0.052 for dataset 2, respectively. In comparison with the benchmark methods, the proposed W-CRCNN significantly outperforms all the benchmark approaches in identification of HER2 overexpression in FISH and DISH datasets (p<0.05). With the high degree of accuracy, precision and recall , the results show that the proposed method in DISH analysis for assessment of HER2 overexpression in breast cancer patients has significant potential to assist precision medicine.

Robotic Hysterectomy with Ureter Identification and Uterine Artery Ligation for Benign Gynecological Conditions: An Early-Year Single-Center Experience.

The use and application of robotic systems with a high-definition, three-dimensional vision system and advanced EndoWrist technology have become widespread. We sought to share our clinical experience with ureter identification and preventive uterine artery ligation in robotic hysterectomy. The records of patients undergoing robotic hysterectomy between May 2014 and December 2015, including patient preoperative characteristics, operative time, and postoperative outcomes, were analyzed. We evaluated the feasibility and safety of using early ureteral identification and preventive uterine artery ligation in robotic hysterectomy in patients with benign gynecological conditions. Overall, 49 patients diagnosed with benign gynecological conditions were evaluated. The mean age of the patients and mean uterine weight were 46.2 ± 5.3 years and 348.7 ± 311.8 g, respectively. Robotic hysterectomy achieved satisfactory results, including a short postoperative hospital stay (2.7 ± 0.8 days), low conversion rate (n = 0), and low complication rate (n = 1; 2%). The average estimated blood loss was 109 ± 107.2 mL. Our results suggest that robotic hysterectomy using early ureteral identification and preventive uterine artery ligation is feasible and safe in patients with benign gynecological conditions.

Interpretable attention-based deep learning ensemble for personalized ovarian cancer treatment without manual annotations.

Inhibition of pathological angiogenesis has become one of the first FDA approved targeted therapies widely tested in anti-cancer treatment, i.e. VEGF-targeting monoclonal antibody bevacizumab, in combination with chemotherapy for frontline and maintenance therapy for women with newly diagnosed ovarian cancer. Identification of the best predictive biomarkers of bevacizumab response is necessary in order to select patients most likely to benefit from this therapy. Hence, this study investigates the protein expression patterns on immunohistochemical whole slide images of three angiogenesis related proteins, including Vascular endothelial growth factor, Angiopoietin 2 and Pyruvate kinase isoform M2, and develops an interpretable and annotation-free attention based deep learning ensemble framework to predict the bevacizumab therapeutic effect on patients with epithelial ovarian cancer or peritoneal serous papillary carcinoma using tissue microarrays (TMAs). In evaluation with five-fold cross validation, the proposed ensemble model using the protein expressions of both Pyruvate kinase isoform M2 and Angiopoietin 2 achieves a notably high F-score (0.99±0.02), accuracy (0.99±0.03), precision (0.99±0.02), recall (0.99±0.02) and AUC (1.00±0). Kaplan-Meier progression free survival analysis confirms that the proposed ensemble is able to identify patients in the predictive therapeutic sensitive group with low cancer recurrence (p<0.001), and the Cox proportional hazards model analysis further confirms the above statement (p=0.012). In conclusion, the experimental results demonstrate that the proposed ensemble model using the protein expressions of both Pyruvate kinase isoform M2 and Angiopoietin 2 can assist treatment planning of bevacizumab targeted therapy for patients with ovarian cancer.

Annotation-Free Deep Learning-Based Prediction of Thyroid Molecular Cancer Biomarker BRAF (V600E) from Cytological Slides.

Thyroid cancer is the most common endocrine cancer. Papillary thyroid cancer (PTC) is the most prevalent form of malignancy among all thyroid cancers arising from follicular cells. Fine needle aspiration cytology (FNAC) is a non-invasive method regarded as the most cost-effective and accurate diagnostic method of choice in diagnosing PTC. Identification of BRAF (V600E) mutation in thyroid neoplasia may be beneficial because it is specific for malignancy, implies a worse prognosis, and is the target for selective BRAF inhibitors. To the authors' best knowledge, this is the first automated precision oncology framework effectively predict BRAF (V600E) immunostaining result in thyroidectomy specimen directly from Papanicolaou-stained thyroid fine-needle aspiration cytology and ThinPrep cytological slides, which is helpful for novel targeted therapies and prognosis prediction. The proposed deep learning (DL) framework is evaluated on a dataset of 118 whole slide images. The results show that the proposed DL-based technique achieves an accuracy of 87%, a precision of 94%, a sensitivity of 91%, a specificity of 71% and a mean of sensitivity and specificity at 81% and outperformed three state-of-the-art deep learning approaches. This study demonstrates the feasibility of DL-based prediction of critical molecular features in cytological slides, which not only aid in accurate diagnosis but also provide useful information in guiding clinical decision-making in patients with thyroid cancer. With the accumulation of data and the continuous advancement of technology, the performance of DL systems is expected to be improved in the near future. Therefore, we expect that DL can provide a cost-effective and time-effective alternative tool for patients in the era of precision oncology.

A Soft Label Deep Learning to Assist Breast Cancer Target Therapy and Thyroid Cancer Diagnosis.

According to the World Health Organization Report 2022, cancer is the most common cause of death contributing to nearly one out of six deaths worldwide. Early cancer diagnosis and prognosis have become essential in reducing the mortality rate. On the other hand, cancer detection is a challenging task in cancer pathology. Trained pathologists can detect cancer, but their decisions are subjective to high intra- and inter-observer variability, which can lead to poor patient care owing to false-positive and false-negative results. In this study, we present a soft label fully convolutional network (SL-FCN) to assist in breast cancer target therapy and thyroid cancer diagnosis, using four datasets. To aid in breast cancer target therapy, the proposed method automatically segments human epidermal growth factor receptor 2 (HER2) amplification in fluorescence in situ hybridization (FISH) and dual in situ hybridization (DISH) images. To help in thyroid cancer diagnosis, the proposed method automatically segments papillary thyroid carcinoma (PTC) on Papanicolaou-stained fine needle aspiration and thin prep whole slide images (WSIs). In the evaluation of segmentation of HER2 amplification in FISH and DISH images, we compare the proposed method with thirteen deep learning approaches, including U-Net, U-Net with InceptionV5, Ensemble of U-Net with Inception-v4, Inception-Resnet-v2 encoder, and ResNet-34 encoder, SegNet, FCN, modified FCN, YOLOv5, CPN, SOLOv2, BCNet, and DeepLabv3+ with three different backbones, including MobileNet, ResNet, and Xception, on three clinical datasets, including two DISH datasets on two different magnification levels and a FISH dataset. The result on DISH breast dataset 1 shows that the proposed method achieves high accuracy of 87.77 ± 14.97%, recall of 91.20 ± 7.72%, and F1-score of 81.67 ± 17.76%, while, on DISH breast dataset 2, the proposed method achieves high accuracy of 94.64 ± 2.23%, recall of 83.78 ± 6.42%, and F1-score of 85.14 ± 6.61% and, on the FISH breast dataset, the proposed method achieves high accuracy of 93.54 ± 5.24%, recall of 83.52 ± 13.15%, and F1-score of 86.98 ± 9.85%, respectively. Furthermore, the proposed method outperforms most of the benchmark approaches by a significant margin (p <0.001). In evaluation of segmentation of PTC on Papanicolaou-stained WSIs, the proposed method is compared with three deep learning methods, including Modified FCN, U-Net, and SegNet. The experimental result demonstrates that the proposed method achieves high accuracy of 99.99 ± 0.01%, precision of 92.02 ± 16.6%, recall of 90.90 ± 14.25%, and F1-score of 89.82 ± 14.92% and significantly outperforms the baseline methods, including U-Net and FCN (p <0.001). With the high degree of accuracy, precision, and recall, the results show that the proposed method could be used in assisting breast cancer target therapy and thyroid cancer diagnosis with faster evaluation and minimizing human judgment errors.

Deep Learning Using Endobronchial-Ultrasound-Guided Transbronchial Needle Aspiration Image to Improve the Overall Diagnostic Yield of Sampling Mediastinal Lymphadenopathy.

Lung cancer is the biggest cause of cancer-related death worldwide. An accurate nodal staging is critical for the determination of treatment strategy for lung cancer patients. Endobronchial-ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has revolutionized the field of pulmonology and is considered to be extremely sensitive, specific, and secure for lung cancer staging through rapid on-site evaluation (ROSE), but manual visual inspection on the entire slide of EBUS smears is challenging, time consuming, and worse, subjective, on a large interobserver scale. To satisfy ROSE's needs, a rapid, automated, and accurate diagnosis system using EBUS-TBNA whole-slide images (WSIs) is highly desired to improve diagnosis accuracy and speed, minimize workload and labor costs, and ensure reproducibility. We present a fast, efficient, and fully automatic deep-convolutional-neural-network-based system for advanced lung cancer staging on gigapixel EBUS-TBNA cytological WSIs. Each WSI was converted into a patch-based hierarchical structure and examined by the proposed deep convolutional neural network, generating the segmentation of metastatic lesions in EBUS-TBNA WSIs. To the best of the authors' knowledge, this is the first research on fully automated enlarged mediastinal lymph node analysis using EBUS-TBNA cytological WSIs. We evaluated the robustness of the proposed framework on a dataset of 122 WSIs, and the proposed method achieved a high precision of 93.4%, sensitivity of 89.8%, DSC of 82.2%, and IoU of 83.2% for the first experiment (37.7% training and 62.3% testing) and a high precision of 91.8 ± 1.2, sensitivity of 96.3 ± 0.8, DSC of 94.0 ± 1.0, and IoU of 88.7 ± 1.8 for the second experiment using a three-fold cross-validation, respectively. Furthermore, the proposed method significantly outperformed the three state-of-the-art baseline models, including U-Net, SegNet, and FCN, in terms of precision, sensitivity, DSC, and Jaccard index, based on Fisher's least significant difference (LSD) test (p<0.001). For a computational time comparison on a WSI, the proposed method was 2.5 times faster than U-Net, 2.3 times faster than SegNet, and 3.4 times faster than FCN, using a single GeForce GTX 1080 Ti, respectively. With its high precision and sensitivity, the proposed method demonstrated that it manifested the potential to reduce the workload of pathologists in their routine clinical practice.

Weakly supervised deep learning for prediction of treatment effectiveness on ovarian cancer from histopathology images.

Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70 % of advanced patients are with recurrent cancer and decease. Surgical debulking of tumors following chemotherapy is the conventional treatment for advanced carcinoma, but patients with such treatment remain at great risk for recurrence and developing drug resistance, and only about 30 % of the women affected will be cured. Bevacizumab is a humanized monoclonal antibody, which blocks VEGF signaling in cancer, inhibits angiogenesis and causes tumor shrinkage, and has been recently approved by FDA as a monotherapy for advanced ovarian cancer in combination with chemotherapy. Considering the cost, potential toxicity, and finding that only a portion of patients will benefit from these drugs, the identification of new predictive method for the treatment of ovarian cancer remains an urgent unmet medical need. In this study, we develop weakly supervised deep learning approaches to accurately predict therapeutic effect for bevacizumab of ovarian cancer patients from histopathological hematoxylin and eosin stained whole slide images, without any pathologist-provided locally annotated regions. To the authors' best knowledge, this is the first model demonstrated to be effective for prediction of the therapeutic effect of patients with epithelial ovarian cancer to bevacizumab. Quantitative evaluation of a whole section dataset shows that the proposed method achieves high accuracy, 0.882 ± 0.06; precision, 0.921 ± 0.04, recall, 0.912 ± 0.03; F-measure, 0.917 ± 0.07 using 5-fold cross validation and outperforms two state-of-the art deep learning approaches Coudray et al. (2018), Campanella et al. (2019). For an independent TMA testing set, the three proposed methods obtain promising results with high recall (sensitivity) 0.946, 0.893 and 0.964, respectively. The results suggest that the proposed method could be useful for guiding treatment by assisting in filtering out patients without positive therapeutic response to suffer from further treatments while keeping patients with positive response in the treatment process. Furthermore, according to the statistical analysis of the Cox Proportional Hazards Model, patients who were predicted to be invalid by the proposed model had a very high risk of cancer recurrence (hazard ratio = 13.727) than patients predicted to be effective with statistical signifcance (p < 0.05).

A Weakly Supervised Deep Learning Method for Guiding Ovarian Cancer Treatment and Identifying an Effective Biomarker.

Ovarian cancer is a common malignant gynecological disease. Molecular target therapy, i.e., antiangiogenesis with bevacizumab, was found to be effective in some patients of epithelial ovarian cancer (EOC). Although careful patient selection is essential, there are currently no biomarkers available for routine therapeutic usage. To the authors' best knowledge, this is the first automated precision oncology framework to effectively identify and select EOC and peritoneal serous papillary carcinoma (PSPC) patients with positive therapeutic effect. From March 2013 to January 2021, we have a database, containing four kinds of immunohistochemical tissue samples, including AIM2, c3, C5 and NLRP3, from patients diagnosed with EOC and PSPC and treated with bevacizumab in a hospital-based retrospective study. We developed a hybrid deep learning framework and weakly supervised deep learning models for each potential biomarker, and the experimental results show that the proposed model in combination with AIM2 achieves high accuracy 0.92, recall 0.97, F-measure 0.93 and AUC 0.97 for the first experiment (66% training and 34%testing) and high accuracy 0.86 ± 0.07, precision 0.9 ± 0.07, recall 0.85 ± 0.06, F-measure 0.87 ± 0.06 and AUC 0.91 ± 0.05 for the second experiment using five-fold cross validation, respectively. Both Kaplan-Meier PFS analysis and Cox proportional hazards model analysis further confirmed that the proposed AIM2-DL model is able to distinguish patients gaining positive therapeutic effects with low cancer recurrence from patients with disease progression after treatment (p < 0.005).

Ovarian steroid cell tumor causing isosexual pseudoprecocious puberty in a young girl: an instructive case and literature review.

BACKGROUND: Steroid cell tumors (SCTs) are very rare sex cord-stromal tumors and account only for less than 0.1% of ovarian neoplasms. SCTs might comprise diverse steroid-secreting cells; hence, the characteristic clinical features were affected by their propensity to secrete a variety of hormones rather than mass effect resulting in compression symptoms and signs. To date, ovarian SCTs have seldom been reported in children, particularly very young children; and pseudoprecocious puberty (PPP) as its unique principal manifestation should be reiterated. CASE PRESENTATION: We reported a 1-year-8-month-old girl presenting with rapid bilateral breast and pubic hair development within a 2-month period. Undetectable levels of LH and FSH along with excessively high estradiol after stimulation with gonadotropin-releasing hormone (GnRH), as well as a heterogeneous mass inside left ovary shown in pelvic sonography indicate isosexual PPP. Her gonadal hormones returned remarkably to the prepubertal range the day after surgery, and histology of the ovary mass demonstrated SCTs containing abundant luteinized stromal cells. CONCLUSION: The case highlighted that SCTs causing isosexual PPP should be taken into consideration in any young children coexistent with rapidly progressive puberty given a remarkable secretion of sex hormones. This article also reviewed thoroughly relevant reported cases to enrich the clinical experience of SCTs in the pediatric group.

Histopathological whole slide image dataset for classification of treatment effectiveness to ovarian cancer.

Ovarian cancer is the leading cause of gynecologic cancer death among women. Regardless of the development made in the past two decades in the surgery and chemotherapy of ovarian cancer, most of the advanced-stage patients are with recurrent cancer and die. The conventional treatment for ovarian cancer is to remove cancerous tissues using surgery followed by chemotherapy, however, patients with such treatment remain at great risk for tumor recurrence and progressive resistance. Nowadays, new treatment with molecular-targeted agents have become accessible. Bevacizumab as a monotherapy in combination with chemotherapy has been recently approved by FDA for the treatment of epithelial ovarian cancer (EOC). Prediction of therapeutic effects and individualization of therapeutic strategies are critical, but to the authors' best knowledge, there are no effective biomarkers that can be used to predict patient response to bevacizumab treatment for EOC and peritoneal serous papillary carcinoma (PSPC). This dataset helps researchers to explore and develop methods to predict the therapeutic effect of patients with EOC and PSPC to bevacizumab.

Loss of ten-eleven translocation 1 (TET1) expression as a diagnostic and prognostic biomarker of endometrial carcinoma.

Endometrial carcinoma (EC) is the most common gynecological cancer. However, there is currently no routinely used biomarker for differential diagnosis of malignant and premalignant endometrial lesions. Ten-eleven translocation (TET) proteins, especially TET1, were found to play a significant role in DNA demethylation, via conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC). TET1, 5-mC, and 5-hmC expression profiles in endometrial carcinogenesis are currently unclear. We conducted a hospital-based retrospective review of the immunohistochemical expression of TET1, 5-mC, and 5-hmC in 181 endometrial samples. A "high" TET1 and 5-hmC expression score was observed in all cases of normal endometrium (100.0% and 100.0%, respectively) and in most samples of endometrial hyperplasia without atypia (90.9% and 78.8%, respectively) and atypical hyperplasia (90.6% and 93.8%, respectively), but a "high" score was found in only less than half of the EC samples (48.8% and 46.5%, respectively). The TET1 and 5-hmC expression scores were significantly higher in normal endometrium and premalignant endometrial lesions than in ECs (p < 0.001). A "high" 5-mC expression score was observed more frequently for ECs (81.4%) than for normal endometrium (40.0%), endometrial hyperplasia without atypia (51.5%), and atypical hyperplasia (53.1%) (p < 0.001). We also found that TET1 mRNA expression was lower in ECs compared to normal tissues (p = 0.0037). TET1 immunohistochemistry (IHC) scores were highly proportional to the TET1 mRNA levels and we summarize that the TET1 IHC scoring can be used for biomarker determinations. Most importantly, a higher TET1 score in EC cases was associated with a good overall survival (OS) rate, with a hazard ratio (HR) of 0.31 for death (95% confidence interval: 0.11-0.84). Our findings suggest that TET1, 5-mC, and 5-hmC expression is a potential histopathology biomarker for the differential diagnosis of malignant and premalignant endometrial lesions. TET1 is also a potential prognostic marker for EC.

AIM2 Inflammasome in Tumor Cells as a Biomarker for Predicting the Treatment Response to Antiangiogenic Therapy in Epithelial Ovarian Cancer Patients.

Antiangiogenic therapy, such as bevacizumab (BEV), has improved progression-free survival (PFS) and overall survival (OS) in high-risk patients with epithelial ovarian cancer (EOC) according to several clinical trials. Clinically, no reliable molecular biomarker is available to predict the treatment response to antiangiogenic therapy. Immune-related proteins can indirectly contribute to angiogenesis by regulating stromal cells in the tumor microenvironment. This study was performed to search biomarkers for prediction of the BEV treatment response in EOC patients. We conducted a hospital-based retrospective study from March 2013 to May 2020. Tissues from 78 Taiwanese patients who were newly diagnosed with EOC and peritoneal serous papillary carcinoma (PSPC) and received BEV therapy were collected. We used immunohistochemistry (IHC) staining and analyzed the expression of these putative biomarkers (complement component 3 (C3), complement component 5 (C5), and absent in melanoma 2 (AIM2)) based on the staining area and intensity of the color reaction to predict BEV efficacy in EOC patients. The immunostaining scores of AIM2 were significantly higher in the BEV-resistant group (RG) than in the BEV-sensitive group (SG) (355.5 vs. 297.1, p < 0.001). A high level of AIM2 (mean value > 310) conferred worse PFS after treatment with BEV than a low level of AIM2 (13.58 vs. 19.36 months, adjusted hazard ratio (HR) = 4.44, 95% confidence interval (CI) = 2.01-9.80, p < 0.001). There were no significant differences in C3 (p = 0.077) or C5 (p = 0.326) regarding BEV efficacy. AIM2 inflammasome expression can be a histopathological biomarker to predict the antiangiogenic therapy benefit in EOC patients. The molecular mechanism requires further investigation.