Improving histotyping precision: The impact of immunohistochemical algorithms on epithelial ovarian cancer classification.

To improve the precision of epithelial ovarian cancer histotyping, Köbel et al. (2016) developed immunohistochemical decision-tree algorithms. These included a six- and four-split algorithm, and separate six-split algorithms for early- and advanced stage disease. In this study, we evaluated the efficacy of these algorithms. A gynecological pathologist determined the hematoxylin and eosin (H&E)-based histotypes of 230 patients. Subsequently, the final histotypes were established by re-evaluating the H&E-stained sections and immunohistochemistry outcomes. For histotype prediction using the algorithms, the immunohistochemical markers Napsin A, p16, p53, progesterone receptor (PR), trefoil factor 3 (TFF3), and Wilms' tumor 1 (WT1) were scored. The algorithmic predictions were compared with the final histotypes to assess their precision, for which the early- and advanced stage algorithms were assessed together as six-split-stages algorithm. The six-split algorithm demonstrated 96.1% precision, whereas the six-split-stages and four-split algorithms showed 93.5% precision. Of the 230 cases, 16 (7%) showed discordant original and final diagnoses; the algorithms concurred with the final diagnosis in 14/16 cases (87.5%). In 12.4%-13.3% of cases, the H&E-based histotype changed based on the algorithmic outcome. The six-split stages algorithm had a lower sensitivity for low-grade serous carcinoma (80% versus 100%), while the four-split stages algorithm showed reduced sensitivity for endometrioid carcinoma (78% versus 92.7-97.6%). Considering the higher sensitivity of the six-split algorithm for endometrioid and low-grade serous carcinoma compared with the four-split and six-split-stages algorithms, respectively, we recommend the adoption of the six-split algorithm for histotyping epithelial ovarian cancer in clinical practice.

Evaluation of the prognostic potential of histopathological subtyping in high-grade serous ovarian carcinoma.

High-grade serous ovarian carcinoma (HGSOC) can be categorized into four gene expression-based subtypes, with supposedly distinct prognoses and treatment responses. Murakami et al. translated these gene expression-based subtypes into the histopathological mesenchymal, immunoreactive, solid and proliferative, and papilloglandular subtypes, showing differences in survival outcomes. Miyagawa et al. refined these criteria to improve the interobserver concordance. The current retrospective study evaluated the interobserver variability and the prognostic differences between the histopathologic subtypes using the criteria of both Murakami et al. and Miyagawa et al. in 208 HGSOC cases. The mesenchymal subtype was considered first, followed by the immunoreactive subtype. Non-conforming cases were categorized as solid and proliferative or papilloglandular. The mesenchymal subtype was identified in 122 patients (58.7%) for both criteria. Using the criteria of Murakami et al., 10 cases (4.8%) were immunoreactive, 26 (12.5%) solid and proliferative, and 50 (24%) papilloglandular, with a concordance rate of 62.5% (κ = 0.34, p < .001). Using the Miyagawa et al. criteria, 23 cases (11%) were immunoreactive, 20 (9.6%) solid and proliferative, and 43 (20.7%) papilloglandular. No survival differences were observed between the subtypes. The fair reproducibility of the histopathological subtype classification of HGSOC and the lack of survival differences among these subtypes indicate the need for further refinement of the criteria and exploration of their correlation with overall survival outcomes before clinical application.

The Information Technology (IT) Infrastructure of the Multicenter Archipelago of Ovarian Cancer Research Biobank: A Potential Blueprint for Other Biobanks.

Objective: Biobanks play a crucial role in fundamental and translational research by storing valuable biomaterials and data for future analyses. However, the design of their information technology (IT) infrastructures is often customized to specific requirements, thereby lacking the ability to be used for biobanks comprising other (types of) diseases. This results in substantial costs, time, and efforts for each new biobank project. The Dutch multicenter Archipelago of Ovarian Cancer Research (AOCR) biobank has developed an innovative, reusable IT infrastructure capable of adaptation to various biobanks, thereby enabling cost-effective and efficient implementation and management of biobank IT systems. Methods and Results: The AOCR IT infrastructure incorporates preexisting biobank software, mainly managed by Health-RI. The web-based registration tool Ldot is used for secure storage and pseudonymization of patient data. Clinicopathological data are retrieved from the Netherlands Cancer Registry and the Dutch nationwide pathology databank (Palga), both established repositories, reducing administrative workload and ensuring high data quality. Metadata of collected biomaterials are stored in the OpenSpecimen system. For digital pathology research, a hematoxylin and eosin-stained slide from each patient's tumor is digitized and uploaded to Slide Score. Furthermore, adhering to the Findable, Accessible, Interoperable, and Reusable (FAIR) principles, genomic data derived from the AOCR samples are stored in cBioPortal. Conclusion: The IT infrastructure of the AOCR biobank represents a new standard for biobanks, offering flexibility to handle diverse diseases and types of biomaterials. This infrastructure bypasses the need for disease-specific, custom-built software, thereby being cost- and time-effective while ensuring data quality and legislative compliance. The adaptability of this infrastructure highlights its potential to serve as a blueprint for the development of IT infrastructures in both new and existing biobanks.

Risk of venous thromboembolism and bleeding after major surgery for ovarian cancer: standard in-hospital versus extended duration of thromboprophylaxis.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication in patients with ovarian cancer after major surgery. Based on limited data, international guidelines recommend extended thromboprophylaxis for up to 28 days. OBJECTIVES: To assess the incidence of VTE and bleeding within 30 days following major surgery in patients with ovarian cancer and to evaluate the association between VTE and thromboprophylaxis duration. METHODS: This was a single-center, retrospective, "before-after" cohort study in patients with ovarian cancer undergoing major surgery. Before July 2019, the local protocol mandated a standard course of thromboprophylaxis during hospital stay only. From July 2019 onward, patients received extended thromboprophylaxis for 28 days. The cumulative incidences of VTE and major bleeding within 30 days after surgery were estimated using the Kaplan-Meier method, with 95% confidence intervals (CIs). Cox regression analysis was performed to evaluate the association between thromboprophylaxis duration and VTE incidence. RESULTS: Between January 2018 and December 2020, 250 women were included, of which 118 (47.2%) received extended and 132 (52.8%) standard thromboprophylaxis. During follow-up, 12 patients developed VTE (cumulative incidence, 4.8%; 95% CI, 2.1-7.4) and 2 major bleeding (cumulative incidence 0.8%; 95% CI, 0.0-1.9). Compared with standard thromboprophylaxis, VTE incidence was numerically lower with extended duration of thromboprophylaxis (5/118 [4.2%] vs 7/132 [5.3%]) but not significantly different (hazard ratio, 0.80; 95% CI, 0.25-2.52). The risk of major bleeding was similar in both groups (1/118 [0.8%] vs 1/132 [0.8%]; hazard ratio, 1.12; 95% CI, 0.07-17.89). CONCLUSIONS: The cumulative VTE incidence in patients with ovarian cancer following major surgery was considerable. Extended thromboprophylaxis was safe and associated with a numerically lower risk of VTE but not significantly different.

Establishment of the Dutch Nationwide, Interdisciplinary Infrastructure and Biobank for Fundamental and Translational Ovarian Cancer Research: Archipelago of Ovarian Cancer Research.

OBJECTIVES: Ovarian cancer has the worst overall survival rate of all gynecologic malignancies. For the majority of patients, the 5-year overall survival rate of less than 50% has hardly improved over the last decades. To improve the outcome of patients with all subtypes of ovarian cancer, large-scale fundamental and translational research is needed. To accommodate these types of ovarian cancer research, we have established a Dutch nationwide, interdisciplinary infrastructure and biobank: the Archipelago of Ovarian Cancer Research (AOCR). The AOCR will facilitate fundamental and translational ovarian cancer research and enhance interdisciplinary, national, and international collaboration. DESIGN: The AOCR biobank is a prospective ovarian cancer biobank in which biomaterials are collected, processed, and stored in a uniform matter for future (genetic) scientific research. All 19 Dutch hospitals in which ovarian cancer surgery is performed participate and collaborate in the AOCR biobank. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients of 16 years and older with suspected or diagnosed ovarian, fallopian tube, or primary peritoneal cancer are recruited for participation. Patients who agree to participate give written informed consent for collection, storage, and issue of their biomaterials for future studies. After inclusion, different blood samples are taken at various predefined time points both before and during treatment. In case of a diagnostic paracentesis or biopsy, the residual biomaterials of these procedures are stored in the biobank. During surgery, primary tumor tissue and, if applicable, tissue from metastatic sites are collected and stored. From each patient, a representative histological hematoxylin and eosin stained slide is digitalized for research purposes, including reassessment by a panel of gynecologic pathologists. Clinical and pathological data are obtained on a per-study basis from Dutch registries. Research proposals for the issue of biomaterials and data are evaluated by both the Archipelago Scientific Committee and the Steering Committee. Researchers using the biomaterials from the AOCR biobank are encouraged to enrich the biobank with data and materials resulting from their analyses and experiments. LIMITATIONS: The implementation and first 4 years of collection are financed by an infrastructural grant from the Dutch Cancer Society. Therefore, the main limitation is that the costs for sustaining the biobank after the funding period will have to be covered. This coverage will come from incorporation of budget for biobanking in future grant applications and from fees from external researchers and commercial parties using the biomaterials stored in the AOCR biobank. Moreover, we will apply for grants aimed at sustaining and improving research infrastructures and biobanks. CONCLUSIONS: With the establishment of the Dutch nationwide, interdisciplinary Archipelago of Ovarian Cancer Research infrastructure and biobank, fundamental and translational research on ovarian cancer can be greatly improved. The ultimate aim of this infrastructure is that it will lead to improved diagnostics, treatment, and survival of patients with ovarian cancer.

Abnormality classification and localization using dual-branch whole-region-based CNN model with histopathological images.

The task of classification and localization with detecting abnormalities in medical images is considered very challenging. Computer-aided systems have been widely employed to address this issue, and the proliferation of deep learning network architectures is proof of the outstanding performance reported in the literature. However, localizing abnormalities in regions of images that can support the confidence of classification continues to attract research interest. The difficulty of using digital histopathology images for this task is another drawback, which needs high-level deep learning models to address the situation. Successful pathology localization automation will support automatic acquisition planning and post-imaging analysis. In this paper, we address issues related to the combination of classification with image localization and detection through a dual branch deep learning framework that uses two different configurations of convolutional neural networks (CNN) architectures. Whole-image based CNN (WCNN) and region-based CNN (RCNN) architectures are systematically combined to classify and localize abnormalities in samples. A multi-class classification and localization of abnormalities are achieved using the method with no annotation-dependent images. In addition, seamless confidence and explanation mechanism is provided so that outcomes from WCNN and RCNN are mapped together for further analysis. Using images from both BACH and BreakHis databases, an exhaustive set of experiments was carried out to validate the performance of the proposed method in achieving classification and localization simultaneously. Obtained results showed that the system achieved a classification accuracy of 97.08%, a localization accuracy of 94%, and an area under the curve (AUC) of 0.10 for classification. Further findings from this study revealed that a multi-neural network approach could provide a suitable method for addressing the combinatorial problem of classification and localization anomalies in digital medical images. Lastly, the study's outcome offers means for automating the annotation of histopathology images and the support for human pathologists in locating abnormalities.

[Enhanced imaging in urological endoscopy]. / Erweiterte Bildgebung in der urologischen Endoskopie.

White light cystoscopy and the concise documentation of pathological findings are standard diagnostic procedures in urology. Additional imaging modalities and technical innovations may support clinicians in the detection of bladder tumors. Modern endoscopy systems provide ultra-high-resolution imaging and the option of digital contrast enhancement. Photodynamic diagnostics and narrow band imaging are well-established in clinical routine and have shown significant benefits in the detection of bladder cancer. By means of multispectral imaging, different modalities can now be combined in real-time. Probe-based procedures such as optical coherence tomography (OCT) or Raman spectroscopy can further contribute to advanced imaging through an "optical biopsy" which may primarily improve diagnostics in the upper urinary tract. The aim of all techniques is to optimize the detection rate in order to achieve a more accurate diagnosis, resection and lower recurrence rates. Current research projects aim to digitalize the documentation of endoscopy and also make it more patient- and user-friendly. In the future, the use of image processing and artificial intelligence may automatically support the surgeon during endoscopy.

Mixed reality for teaching catheter placement to medical students: a randomized single-blinded, prospective trial.

BACKGROUND: Cost-effective methods to facilitate practical medical education are in high demand and the "mixed-reality" (MR) technology seems suitable to provide students with instructions when learning a new practical task. To evaluate a step-by-step mixed reality (MR) guidance system for instructing a practical medical procedure, we conducted a randomized, single-blinded prospective trial on medical students learning bladder catheter placement. METHODS: We enrolled 164 medical students. Students were randomized into 2 groups and received instructions on how to perform bladder catheter placement on a male catheterization training model. One group (107 students) were given their instructions by an instructor, while the other group (57 students) were instructed via an MR guidance system using a Microsoft HoloLens. Both groups did hands on training. A standardized questionnaire covering previous knowledge, interest in modern technologies and a self-evaluation was filled out. In addition, students were asked to evaluate the system's usability. We assessed both groups's learning outcome via a standardized OSCE (objective structured clinical examination). RESULTS: Our evaluation of the learning outcome revealed an average point value of 19.96 ± 2,42 for the control group and 21.49 ± 2.27 for the MR group - the MR group's result was significantly better (p = 0.00). The self-evaluations revealed no difference between groups, however, the control group gave higher ratings when evaluating the quality of instructions. The MR system's assessment showed less usability, with a cumulative SUS (system usability scale) score of 56.6 (lower half) as well as a cumulative score of 24.2 ± 7.3 (n = 52) out of 100 in the NASA task load index. CONCLUSIONS: MR is a promising tool for instructing practical skills, and has the potential to enable superior learning outcomes. Advances in MR technology are necessary to improve the usability of current systems. TRIAL REGISTRATION: German Clinical Trial Register ID: DRKS00013186.

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions.

BACKGROUND: Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. METHODS: We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1. RESULTS: We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression. CONCLUSIONS: Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.

High temporal resolution gastric emptying breath tests in mice.

BACKGROUND: Gastric emptying is a complex physiological process regulating the division of a meal into smaller partitions for the small intestine. Disrupted gastric emptying contributes to digestive disease, yet current measures may not reflect different mechanisms by which the process can be altered. METHODS: We have developed high temporal resolution solid and liquid gastric emptying breath tests in mice using [13 C]-octanoic acid and off axis- integrated cavity output spectroscopy (OA-ICOS). Stretched gamma variate and 2-component stretched gamma variate models fit measured breath excretion data. KEY RESULTS: These assays detect acceleration and delay using pharmacological (7.5 mg/kg atropine) or physiological (nutrients, cold exposure stress, diabetes) manipulations and remain stable over time. High temporal resolution resolved complex excretion curves with 2 components, which was more prevalent in mice with delayed gastric emptying following streptozotocin-induced diabetes. There were differences in the gastric emptying of Balb/c vs C57Bl6 mice, with slower gastric emptying and a greater occurrence of two-phase gastric emptying curves in the latter strain. Gastric emptying of C57Bl6 could be accelerated by halving the meal size, but with no effect on the occurrence of two-phase gastric emptying curves. A greater proportion of two-phase gastric emptying was induced in Balb/c mice with the administration of PYY (8-80 nmol) 60 min following meal ingestion. CONCLUSIONS AND INFERENCES: Collectively, these results demonstrate the utility of high temporal resolution gastric emptying assays. Two-phase gastric emptying is more prevalent than previously reported, likely involves intestinal feedback, but contributes little to the overall rate of gastric emptying.

Micro-fluorescence lifetime and spectral imaging of ytterbium doped laser materials.

We present the application of a confocal fluorescence microscope to the analysis of Yb-doped solid-state laser materials, with examples of Yb-doped crystals, photonic crystal fibers and fiber preforms made with different manufacturing processes. Beside the fluorescence lifetime image itself, a microscopic spectral fluorescence emission analysis is presented and spatially resolved emission cross sections are obtained. Doping concentration and its distributions and other laser optical parameters are measured, which help to analyze manufacturing steps. Further properties like photodarkening and saturation are addressed.

Predictors of survival stratification in patients with wild-type cardiac amyloidosis.

OBJECTIVES: To analyze clinical predictors of mortality in wild-type transthyretin amyloidosis (wt-ATTR). METHODS: In total, 191 patients (73.8 ± 0.5 years; 176 males, 15 females) with histologically proven wt-ATTR amyloidosis and genetic exclusion of a transthyretin gene variant were included. Comprehensive clinical characteristics, ECG, biomarkers, and echocardiography were analyzed retrospectively. Strain analyses were performed offline using TomTec Imaging Systems, Germany. Univariable and multivariable analyses predicting all-cause mortality were carried out. RESULTS: Patients presented with significant heart failure (NYHA 2.5 ± 0.8; NT-proBNP 3644 (4981) pg/ml; LV ejection fraction 45.8 ± 15.0%). LogNT-proBNP correlated with indicators of disease severity. Similar results were obtained for basal and midventricular, but not apical longitudinal strain. During median follow-up of 26.2 ± 1.7 months 46 (25.5%) patients died (40 males, 23%; six females, 40%). In female patients 1-/2-year survival was lower [92.9/67.7%; median survival 30.6 (21.1-40.1) months] when compared to male patients [96.5%/86.6%; median survival 63.9 (45.8-82.0) months]. Parameters associated with survival were NT-proBNP, NYHA class, heart rate, midventricular longitudinal strain, mitral annular plane systolic excursion (MAPSE), Karnofsky Index, systolic blood pressure, estimated glomerular filtration rate. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of mortality in the whole cohort and midventricular strain in the subgroup of patients in sinus rhythm. CONCLUSIONS: No sex-specific bias was observed between male and female patients with wt-ATTR regarding age at onset and morphological characteristics. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of survival in the whole cohort, whereas midventricular longitudinal strain was the only independent predictor in patients in sinus rhythm.

Single mode 4.3 kW output power from a diode-pumped Yb-doped fiber amplifier.

We investigate the average power scaling of two diode-pumped Yb-doped fiber amplifiers emitting a diffraction-limited beam. The first fiber under investigation with a core diameter of 30 µm was able to amplify a 10 W narrow linewidth seed laser up to 2.8 kW average output power before the onset of transverse mode instabilities (TMI). A further power scaling was achieved using a second fiber with a smaller core size (23µm), which allowed for a narrow linewidth output power of 3.5 kW limited by stimulated Brillouin scattering (SBS). We mitigated SBS using a spectral broadening mechanism, which allowed us to further increase the output power to 4.3 kW only limited by the available pump power. Up to this power level, a high slope efficiency of 90% with diffraction-limited beam quality and without any sign of TMI or stimulated Raman scattering for a spectral dynamic range of higher than -80 dB was obtained.

[Urinary Stone Analysis - What does the Future Hold in Store?] / Harnsteindiagnostik ­ Was bringt uns die Zukunft?

Analysis of the composition of a urinary stone is one of the most important steps in the clinical management of patients with urolithiasis. Fourier transform infrared spectroscopy, X-ray diffractometry and petrographic microscopy are the techniques currently used. Novel technical developments in recent years - such as Raman spectroscopy and hyperspectral imaging - have resulted in new approaches to improve urinary stone analysis. In future, table-top portable systems may be used that allow stones to be rapidly examined directly after the operation. These systems may even be integrated into lithotripsy laser systems.

Observing Consistency in Online Communication Patterns for User Re-Identification.

Comprehension of the statistical and structural mechanisms governing human dynamics in online interaction plays a pivotal role in online user identification, online profile development, and recommender systems. However, building a characteristic model of human dynamics on the Internet involves a complete analysis of the variations in human activity patterns, which is a complex process. This complexity is inherent in human dynamics and has not been extensively studied to reveal the structural composition of human behavior. A typical method of anatomizing such a complex system is viewing all independent interconnectivity that constitutes the complexity. An examination of the various dimensions of human communication pattern in online interactions is presented in this paper. The study employed reliable server-side web data from 31 known users to explore characteristics of human-driven communications. Various machine-learning techniques were explored. The results revealed that each individual exhibited a relatively consistent, unique behavioral signature and that the logistic regression model and model tree can be used to accurately distinguish online users. These results are applicable to one-to-one online user identification processes, insider misuse investigation processes, and online profiling in various areas.

[Stone treatment tomorrow and the day after]. / Steintherapie morgen und übermorgen.

Urological and surgical treatment of urinary stones are highly technological and technology-driven disciplines in present-day surgery. German medical engineering has always been recognized for its technical innovations in endoscopic surgery. Current and future trends are indicative of further miniaturization and automation of surgical instruments and assist systems to facilitate endourological procedures as well as improvements in the quality of results and ergonomics. These technologies include, e. g. 3D-tracking to facilitate access to the pelvicaliceal system for percutaneous nephrolithotomy (PNL) or robotic master-slave systems for endourology. The aim of all future stone treatment should be complete stone removal. This could be achieved by improved stone fragmentation ("micron-sized debris") or complete removal of fragments (e. g. using a "stone glue"). Integration of diagnostic procedures and treatments will constitute a key aspect of future developments in medical engineering. Intelligent laser systems may be capable of distinguishing stones from mucosa and artificial surfaces and may be used for immediate stone analysis during surgery. A simpler and faster availability of metabolic ("metabolomics") and genetic ("genomics") diagnostics will help to facilitate and improve individual metaphylaxis, e. g. in patient self-management. Nanotechnology and microrobots that may be used for endoluminal diagnostics and treatment of the urinary tract are already in development.

Narrow linewidth, single mode 3 kW average power from a directly diode pumped ytterbium-doped low NA fiber amplifier.

We report on a newly designed and fabricated ytterbium-doped large mode area fiber with an extremely low NA (~0.04) and related systematic investigations on fiber parameters that crucially influence the mode instability threshold. The fiber is used to demonstrate a narrow linewidth, continuous wave, single mode fiber laser amplifier emitting a maximum output power of 3 kW at a wavelength of 1070 nm without reaching the mode-instability threshold. A high slope efficiency of 90 %, excellent beam quality, high temporal stability, and an ASE suppression of 70 dB could be reached with a signal linewidth of only 170 pm.

Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress.

In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.

A Comprehensive and Harmonized Digital Forensic Investigation Process Model.

Performing a digital forensic investigation (DFI) requires a standardized and formalized process. There is currently neither an international standard nor does a global, harmonized DFI process (DFIP) exist. The authors studied existing state-of-the-art DFIP models and concluded that there are significant disparities pertaining to the number of processes, the scope, the hierarchical levels, and concepts applied. This paper proposes a comprehensive model that harmonizes existing models. An effort was made to incorporate all types of processes proposed by the existing models, including those aimed at achieving digital forensic readiness. The authors introduce a novel class of processes called concurrent processes. This is a novel contribution that should, together with the rest of the model, enable more efficient and effective DFI, while ensuring admissibility of digital evidence. Ultimately, the proposed model is intended to be used for different types of DFI and should lead to standardization.