[The Rise of Artificial Intelligence - High Prediction Accuracy in Early Detection of Pigmented Melanoma]. / Künstliche Intelligenz auf dem Vormarsch ­ Hohe Vorhersage-Genauigkeit bei der Früherkennung pigmentierter Melanome.

The incidence of malignant melanoma is increasing worldwide. If detected early, melanoma is highly treatable, so early detection is vital.Skin cancer early detection has improved significantly in recent decades, for example by the introduction of screening in 2008 and dermoscopy. Nevertheless, in particular visual detection of early melanomas remains challenging because they show many morphological overlaps with nevi. Hence, there continues to be a high medical need to further develop methods for early skin cancer detection in order to be able to reliably diagnosemelanomas at a very early stage.Routine diagnostics for melanoma detection include visual whole body inspection, often supplemented by dermoscopy, which can significantly increase the diagnostic accuracy of experienced dermatologists. A procedure that is additionally offered in some practices and clinics is wholebody photography combined with digital dermoscopy for the early detection of malignant melanoma, especially for monitoring high-risk patients.In recent decades, numerous noninvasive adjunctive diagnostic techniques were developed for the examination of suspicious pigmented moles, that may have the potential to allow improved and, in some cases, automated evaluation of these lesions. First, confocal laser microscopy should be mentioned here, as well as electrical impedance spectroscopy, multiphoton laser tomography, multispectral analysis, Raman spectroscopy or optical coherence tomography. These diagnostic techniques usually focus on high sensitivity to avoid malignant melanoma being overlooked. However, this usually implies lower specificity, which may lead to unnecessary excision of benign lesions in screening. Also, some of the procedures are time-consuming and costly, which also limits their applicability in skin cancer screening. In the near future, the use of artificial intelligence might change skin cancer diagnostics in many ways. The most promising approach may be the analysis of routine macroscopic and dermoscopic images by artificial intelligence.For the classification of pigmented skin lesions based on macroscopic and dermoscopic images, artificial intelligence, especially in form of neural networks, has achieved comparable diagnostic accuracies to dermatologists under experimental conditions in numerous studies. In particular, it achieved high accuracies in the binary melanoma/nevus classification task, but it also performed comparably well to dermatologists in multiclass differentiation of various skin diseases. However, proof of the basic applicability and utility of such systems in clinical practice is still pending. Prerequisites that remain to be established to enable translation of such diagnostic systems into dermatological routine are means that allow users to comprehend the system's decisions as well as a uniformly high performance of the algorithms on image data from other hospitals and practices.At present, hints are accumulating that computer-aided diagnosis systems could provide their greatest benefit as assistance systems, since studies indicate that a combination of human and machine achieves the best results. Diagnostic systems based on artificial intelligence are capable of detecting morphological characteristics quickly, quantitatively, objectively and reproducibly, and could thus provide a more objective analytical basis - in addition to medical experience.

Deep learning can predict lymph node status directly from histology in colorectal cancer.

BACKGROUND: Lymph node status is a prognostic marker and strongly influences therapeutic decisions in colorectal cancer (CRC). OBJECTIVES: The objective of the study is to investigate whether image features extracted by a deep learning model from routine histological slides and/or clinical data can be used to predict CRC lymph node metastasis (LNM). METHODS: Using histological whole slide images (WSIs) of primary tumours of 2431 patients in the DACHS cohort, we trained a convolutional neural network to predict LNM. In parallel, we used clinical data derived from the same cases in logistic regression analyses. Subsequently, the slide-based artificial intelligence predictor (SBAIP) score was included in the regression. WSIs and data from 582 patients of the TCGA cohort were used as the external test set. RESULTS: On the internal test set, the SBAIP achieved an area under receiver operating characteristic (AUROC) of 71.0%, the clinical classifier achieved an AUROC of 67.0% and a combination of the two classifiers yielded an improvement to 74.1%. Whereas the clinical classifier's performance remained stable on the TCGA set, performance of the SBAIP dropped to an AUROC of 61.2%. Performance of the clinical classifier depended strongly on the T stage. CONCLUSION: Deep learning-based image analysis may help predict LNM of patients with CRC using routine histological slides. Combination with clinical data such as T stage might be useful. Strategies to increase performance of the SBAIP on external images should be investigated.

Digital Natives' Preferences on Mobile Artificial Intelligence Apps for Skin Cancer Diagnostics: Survey Study.

BACKGROUND: Artificial intelligence (AI) has shown potential to improve diagnostics of various diseases, especially for early detection of skin cancer. Studies have yet to investigate the clear application of AI technology in clinical practice or determine the added value for younger user groups. Translation of AI-based diagnostic tools can only be successful if they are accepted by potential users. Young adults as digital natives may offer the greatest potential for successful implementation of AI into clinical practice, while at the same time, representing the future generation of skin cancer screening participants. OBJECTIVE: We conducted an anonymous online survey to examine how and to what extent individuals are willing to accept AI-based mobile apps for skin cancer diagnostics. We evaluated preferences and relative influences of concerns, with a focus on younger age groups. METHODS: We recruited participants below 35 years of age using three social media channels-Facebook, LinkedIn, and Xing. Descriptive analysis and statistical tests were performed to evaluate participants' attitudes toward mobile apps for skin examination. We integrated an adaptive choice-based conjoint to assess participants' preferences. We evaluated potential concerns using maximum difference scaling. RESULTS: We included 728 participants in the analysis. The majority of participants (66.5%, 484/728; 95% CI 0.631-0.699) expressed a positive attitude toward the use of AI-based apps. In particular, participants residing in big cities or small towns (P=.02) and individuals that were familiar with the use of health or fitness apps (P=.02) were significantly more open to mobile diagnostic systems. Hierarchical Bayes estimation of the preferences of participants with a positive attitude (n=484) revealed that the use of mobile apps as an assistance system was preferred. Participants ruled out app versions with an accuracy of ≤65%, apps using data storage without encryption, and systems that did not provide background information about the decision-making process. However, participants did not mind their data being used anonymously for research purposes, nor did they object to the inclusion of clinical patient information in the decision-making process. Maximum difference scaling analysis for the negative-minded participant group (n=244) showed that data security, insufficient trust in the app, and lack of personal interaction represented the dominant concerns with respect to app use. CONCLUSIONS: The majority of potential future users below 35 years of age were ready to accept AI-based diagnostic solutions for early detection of skin cancer. However, for translation into clinical practice, the participants' demands for increased transparency and explainability of AI-based tools seem to be critical. Altogether, digital natives between 18 and 24 years and between 25 and 34 years of age expressed similar preferences and concerns when compared both to each other and to results obtained by previous studies that included other age groups.

Gastrointestinal cancer classification and prognostication from histology using deep learning: Systematic review.

BACKGROUND: Gastrointestinal cancers account for approximately 20% of all cancer diagnoses and are responsible for 22.5% of cancer deaths worldwide. Artificial intelligence-based diagnostic support systems, in particular convolutional neural network (CNN)-based image analysis tools, have shown great potential in medical computer vision. In this systematic review, we summarise recent studies reporting CNN-based approaches for digital biomarkers for characterization and prognostication of gastrointestinal cancer pathology. METHODS: Pubmed and Medline were screened for peer-reviewed papers dealing with CNN-based gastrointestinal cancer analyses from histological slides, published between 2015 and 2020.Seven hundred and ninety titles and abstracts were screened, and 58 full-text articles were assessed for eligibility. RESULTS: Sixteen publications fulfilled our inclusion criteria dealing with tumor or precursor lesion characterization or prognostic and predictive biomarkers: 14 studies on colorectal or rectal cancer, three studies on gastric cancer and none on esophageal cancer. These studies were categorised according to their end-points: polyp characterization, tumor characterization and patient outcome. Regarding the translation into clinical practice, we identified several studies demonstrating generalization of the classifier with external tests and comparisons with pathologists, but none presenting clinical implementation. CONCLUSIONS: Results of recent studies on CNN-based image analysis in gastrointestinal cancer pathology are promising, but studies were conducted in observational and retrospective settings. Large-scale trials are needed to assess performance and predict clinical usefulness. Furthermore, large-scale trials are required for approval of CNN-based prediction models as medical devices.

Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours.

AIM: Sentinel lymph node status is a central prognostic factor for melanomas. However, the surgical excision involves some risks for affected patients. In this study, we therefore aimed to develop a digital biomarker that can predict lymph node metastasis non-invasively from digitised H&E slides of primary melanoma tumours. METHODS: A total of 415 H&E slides from primary melanoma tumours with known sentinel node (SN) status from three German university hospitals and one private pathological practice were digitised (150 SN positive/265 SN negative). Two hundred ninety-one slides were used to train artificial neural networks (ANNs). The remaining 124 slides were used to test the ability of the ANNs to predict sentinel status. ANNs were trained and/or tested on data sets that were matched or not matched between SN-positive and SN-negative cases for patient age, ulceration, and tumour thickness, factors that are known to correlate with lymph node status. RESULTS: The best accuracy was achieved by an ANN that was trained and tested on unmatched cases (61.8% ± 0.2%) area under the receiver operating characteristic (AUROC). In contrast, ANNs that were trained and/or tested on matched cases achieved (55.0% ± 3.5%) AUROC or less. CONCLUSION: Our results indicate that the image classifier can predict lymph node status to some, albeit so far not clinically relevant, extent. It may do so by mostly detecting equivalents of factors on histological slides that are already known to correlate with lymph node status. Our results provide a basis for future research with larger data cohorts.

Integrating Patient Data Into Skin Cancer Classification Using Convolutional Neural Networks: Systematic Review.

BACKGROUND: Recent years have been witnessing a substantial improvement in the accuracy of skin cancer classification using convolutional neural networks (CNNs). CNNs perform on par with or better than dermatologists with respect to the classification tasks of single images. However, in clinical practice, dermatologists also use other patient data beyond the visual aspects present in a digitized image, further increasing their diagnostic accuracy. Several pilot studies have recently investigated the effects of integrating different subtypes of patient data into CNN-based skin cancer classifiers. OBJECTIVE: This systematic review focuses on the current research investigating the impact of merging information from image features and patient data on the performance of CNN-based skin cancer image classification. This study aims to explore the potential in this field of research by evaluating the types of patient data used, the ways in which the nonimage data are encoded and merged with the image features, and the impact of the integration on the classifier performance. METHODS: Google Scholar, PubMed, MEDLINE, and ScienceDirect were screened for peer-reviewed studies published in English that dealt with the integration of patient data within a CNN-based skin cancer classification. The search terms skin cancer classification, convolutional neural network(s), deep learning, lesions, melanoma, metadata, clinical information, and patient data were combined. RESULTS: A total of 11 publications fulfilled the inclusion criteria. All of them reported an overall improvement in different skin lesion classification tasks with patient data integration. The most commonly used patient data were age, sex, and lesion location. The patient data were mostly one-hot encoded. There were differences in the complexity that the encoded patient data were processed with regarding deep learning methods before and after fusing them with the image features for a combined classifier. CONCLUSIONS: This study indicates the potential benefits of integrating patient data into CNN-based diagnostic algorithms. However, how exactly the individual patient data enhance classification performance, especially in the case of multiclass classification problems, is still unclear. Moreover, a substantial fraction of patient data used by dermatologists remains to be analyzed in the context of CNN-based skin cancer classification. Further exploratory analyses in this promising field may optimize patient data integration into CNN-based skin cancer diagnostics for patients' benefits.

Combining CNN-based histologic whole slide image analysis and patient data to improve skin cancer classification.

BACKGROUND: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses. OBJECTIVES: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone. METHODS: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as 'uncertain' (CNN output score <0.7), the decision of the CNN was replaced by the decision of the patient data classifier. RESULTS: The CNN on its own achieved the best performance (mean ± standard deviation of five individual runs) with AUROC of 92.30% ± 0.23% and balanced accuracy of 83.17% ± 0.38%. While the classification performance was not significantly improved in general by any of the tested fusions, naive strategy of replacing the image classifier with the patient data classifier on slides with low output scores improved balanced accuracy to 86.72% ± 0.36%. CONCLUSION: In most cases, the CNN on its own was so accurate that patient data integration did not provide any benefit. However, incorporating patient data for lesions that were classified by the CNN with low 'confidence' improved balanced accuracy.

Deep learning approach to predict lymph node metastasis directly from primary tumour histology in prostate cancer.

OBJECTIVE: To develop a new digital biomarker based on the analysis of primary tumour tissue by a convolutional neural network (CNN) to predict lymph node metastasis (LNM) in a cohort matched for already established risk factors. PATIENTS AND METHODS: Haematoxylin and eosin (H&E) stained primary tumour slides from 218 patients (102 N+; 116 N0), matched for Gleason score, tumour size, venous invasion, perineural invasion and age, who underwent radical prostatectomy were selected to train a CNN and evaluate its ability to predict LN status. RESULTS: With 10 models trained with the same data, a mean area under the receiver operating characteristic curve (AUROC) of 0.68 (95% confidence interval [CI] 0.678-0.682) and a mean balanced accuracy of 61.37% (95% CI 60.05-62.69%) was achieved. The mean sensitivity and specificity was 53.09% (95% CI 49.77-56.41%) and 69.65% (95% CI 68.21-71.1%), respectively. These results were confirmed via cross-validation. The probability score for LNM prediction was significantly higher on image sections from N+ samples (mean [SD] N+ probability score 0.58 [0.17] vs 0.47 [0.15] N0 probability score, P = 0.002). In multivariable analysis, the probability score of the CNN (odds ratio [OR] 1.04 per percentage probability, 95% CI 1.02-1.08; P = 0.04) and lymphovascular invasion (OR 11.73, 95% CI 3.96-35.7; P < 0.001) proved to be independent predictors for LNM. CONCLUSION: In our present study, CNN-based image analyses showed promising results as a potential novel low-cost method to extract relevant prognostic information directly from H&E histology to predict the LN status of patients with prostate cancer. Our ubiquitously available technique might contribute to an improved LN status prediction.

Overdiagnosis of melanoma - causes, consequences and solutions.

Malignant melanoma is the skin tumor that causes most deaths in Germany. At an early stage, melanoma is well treatable, so early detection is essential. However, the skin cancer screening program in Germany has been criticized because although melanomas have been diagnosed more frequently since introduction of the program, the mortality from malignant melanoma has not decreased. This indicates that the observed increase in melanoma diagnoses be due to overdiagnosis, i.e. to the detection of lesions that would never have created serious health problems for the patients. One of the reasons is the challenging distinction between some benign and malignant lesions. In addition, there may be lesions that are biologically equivocal, and other lesions that are classified as malignant according to current criteria, but that grow so slowly that they would never have posed a threat to patient's life. So far, these "indolent" melanomas cannot be identified reliably due to a lack of biomarkers. Moreover, the likelihood that an in-situ melanoma will progress to an invasive tumor still cannot be determined with any certainty. When benign lesions are diagnosed as melanoma, the consequences are unnecessary psychological and physical stress for the affected patients and incurred therapy costs. Vice versa, underdiagnoses in the sense of overlooked melanomas can adversely affect patients' prognoses and may necessitate more intense therapies. Novel diagnostic options could reduce the number of over- and underdiagnoses and contribute to more objective diagnoses in borderline cases. One strategy that has yielded promising results in pilot studies is the use of artificial intelligence-based diagnostic tools. However, these applications still await translation into clinical and pathological routine.

Artificial Intelligence in Skin Cancer Diagnostics: The Patients' Perspective.

Background: Artificial intelligence (AI) has shown promise in numerous experimental studies, particularly in skin cancer diagnostics. Translation of these findings into the clinic is the logical next step. This translation can only be successful if patients' concerns and questions are addressed suitably. We therefore conducted a survey to evaluate the patients' view of artificial intelligence in melanoma diagnostics in Germany, with a particular focus on patients with a history of melanoma. Participants and Methods: A web-based questionnaire was designed using LimeSurvey, sent by e-mail to university hospitals and melanoma support groups and advertised on social media. The anonymous questionnaire evaluated patients' expectations and concerns toward artificial intelligence in general as well as their attitudes toward different application scenarios. Descriptive analysis was performed with expression of categorical variables as percentages and 95% confidence intervals. Statistical tests were performed to investigate associations between sociodemographic data and selected items of the questionnaire. Results: 298 individuals (154 with a melanoma diagnosis, 143 without) responded to the questionnaire. About 94% [95% CI = 0.91-0.97] of respondents supported the use of artificial intelligence in medical approaches. 88% [95% CI = 0.85-0.92] would even make their own health data anonymously available for the further development of AI-based applications in medicine. Only 41% [95% CI = 0.35-0.46] of respondents were amenable to the use of artificial intelligence as stand-alone system, 94% [95% CI = 0.92-0.97] to its use as assistance system for physicians. In sub-group analyses, only minor differences were detectable. Respondents with a previous history of melanoma were more amenable to the use of AI applications for early detection even at home. They would prefer an application scenario where physician and AI classify the lesions independently. With respect to AI-based applications in medicine, patients were concerned about insufficient data protection, impersonality and susceptibility to errors, but expected faster, more precise and unbiased diagnostics, less diagnostic errors and support for physicians. Conclusions: The vast majority of participants exhibited a positive attitude toward the use of artificial intelligence in melanoma diagnostics, especially as an assistance system.

Detergent fractionation with subsequent subtractive suppression hybridization as a tool for identifying genes coding for plasma membrane proteins.

The identification of tumor-specific proteins located at the plasma membrane is hampered by numerous methodological pitfalls many of which are associated with the post-translational modification of such proteins. Here, we present a new combination of detergent fractionation of cells and of subtractive suppression hybridization (SSH) to gain overexpressed genes coding for membrane-associated or secreted proteins. Fractionation of subcellular components by digitonin allowed sequestering mRNA of the rough Endoplasmatic reticulum and thereby increasing the percentage of sequences coding for membrane-bound proteins. Fractionated mRNAs from the cutaneous T-cell lymphoma (CTCL) cell line HuT78 and from normal peripheral blood monocytes were used for SSH leading to the enrichment of sequences overexpressed in the tumor cells. We identified some 21 overexpressed genes, among them are GPR137B, FAM62A, NOMO1, HSP90, SLIT1, IBP2, CLIF, IRAK and ARC. mRNA expression was tested for selected genes in CTCL cell lines, skin specimens and peripheral blood samples from CTCL patients and healthy donors. Several of the detected sequences are clearly related to cancer, but have not yet been associated with CTCL. qPCR confirmed an enrichment of these mRNAs in the rough endoplasmic reticulum fraction. RT-PCR confirmed the expression of these genes in skin specimens and peripheral blood of CTCL patients. Western blotting verified protein expression of HSP90 and IBP2 in HuT78. GPR137B could be detected by immunohistology in HuT78 and in keratinocytes of dysplastic epidermis, but also in sweat glands of healthy skin. In summary, we developed a new technique, which allows identifying overexpressed genes coding preferentially for membrane-associated proteins.