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Background: Correct assessment of the significance of left main stem lesions is of pivotal importance to the patient with coronary artery disease. On the basis of clinical and angiographic information alone, this evaluation often cannot be done reliably. Limited data suggest that coronary pressure-derived fractional flow reserve (FFR) supports decision making in equivocal left main disease. Methods: All patients presenting to our institution between June 1999 and June 2004 with intermediate left main coronary artery disease (40%-80% diameter stenosis by angiography), or in whom left main coronary disease was suspected but could not be quantified angiographically, were included in this prospective single-center follow-up study. If FFR was <0.75 along the left main stem, surgical revascularization was recommended; if FFR was >0.80, medical treatment or percutaneous coronary intervention elsewhere in the coronary tree was chosen. If FFR was in the “gray zone,” between ≥0.75 and ≤0.80 treatment recommendation was dependent on additional individual criteria. Primary end points were freedom from death, myocardial infarction, any coronary revascularization procedure, and stroke. Results: Fifty-one patients (mean age 62.2 ± 9.6 years, 41 male) were included. In 27 patients (53%), coronary artery bypass surgery was performed. The remaining 24 patients (47%) were treated nonsurgically. Mean follow-up was 29 ± 16 months. Estimated survival after 4 years of follow-up was 81% among patients in the surgical group and 100% among patients in the nonsurgical group. Event-free survival was 66% in the surgical group and 69% in the nonsurgical group. Conclusions: Fractional flow reserve is helpful to identify patients with intermediate left main disease in whom deferral of surgical revascularization is associated with excellent survival and low event rates. [Copyright &y& Elsevier]

Mutation/loss of alpha-thalassemia/mental retardation syndrome X-linked ( ATRX) expression has been described in anaplastic gliomas. The present study explored the role of ATRX status in the molecular classification of anaplastic gliomas and its impact on survival in the biomarker cohort of the NOA-04 anaplastic glioma trial. Patients ( n = 133) of the NOA-04 trial were analyzed for ATRX expression using immunohistochemistry. ATRX status was correlated with age, histology, isocitrate dehydrogenase (IDH), 1p/19q, alternative lengthening of telomeres (ALT) and O6-methylguanine-DNA methyltransferase (MGMT) status, and the trial efficacy endpoints. Loss of ATRX expression was detected in 45 % of anaplastic astrocytomas (AA), 27 % of anaplastic oligoastrocytomas (AOA) and 10 % of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. The ALT phenotype was significantly correlated with ATRX loss. ATRX and 1p/19q status were used to re-classify AOA: AOA harboring ATRX loss shared a similar clinical course with AA, whereas AOA carrying 1p/19q co-deletion shared a similar course with AO. Accordingly, in a Cox regression model including ATRX and 1p/19q status, histology was no longer significantly associated with time to treatment failure. Survival analysis showed a marked separation of IDH mutant astrocytic tumors into two groups based on ATRX status: tumors with ATRX loss had a significantly better prognosis (median time to treatment failure 55.6 vs. 31.8 months, p = 0.0168, log rank test). ATRX status helps better define the clinically and morphologically mixed group of AOA, since ATRX loss is a hallmark of astrocytic tumors. Furthermore, ATRX loss defines a subgroup of astrocytic tumors with a favorable prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Appendiceal perforation in patients with acute appendicitis may cause a variety of potentially life-threatening complications. Escherichia coli endotoxin has been shown to impact physiological bile flow in vivo. This had led to the theory that hyperbilirubinemia in patients with appendicitis may have a predictive potential for the preoperative diagnosis of appendiceal perforation. The aim of this retrospective study was to investigate the diagnostic value of hyperbilirubinemia as a preoperative laboratory marker for appendiceal perforation in patients with acute appendicitis. Methods: We identified 538 patients (306 female; 232 male, mean age, 35.6 y) with histologically proved acute appendicitis who underwent laparoscopic or conventional appendectomy between January 2004 and December 2007 in a surgical department of an academic teaching hospital. A retrospective multiple chart review of the medical records including laboratory values and histologic results was conducted. Results: The mean bilirubin level of all patients was .9 mg/dL (±.6 SD mg/dL; range, .1–4.3 mg/dL; median, .7 mg/dL). Patients with appendiceal perforation, however, had a mean bilirubin level of 1.5 mg/dL (±.9 SD mg/dL; range, .4–4.3 mg/dL; median, 1.4 mg/dL), which was significantly higher than those with a nonperforated appendicitis (P < .05). The specificity of hyperbilirubinemia for appendiceal perforation was .86 compared with .55 for white blood count and .35 for C-reactive protein. Sensitivity was .7 compared with .81 for white blood count and .96 for C-reactive protein. Conclusions: Patients with hyperbilirubinemia and clinical symptoms of appendicitis should be identified as having a higher probability of appendiceal perforation than those with normal bilirubin levels. [Copyright &y& Elsevier]

Abstract: Background: In intensive care patients the appearance of nucleated red blood cells (NRBC) in blood is associated with a variety of severe diseases. Generally, when NRBCs are detected in the patients'' blood the prognosis is poor. Material and methods: In the present study the detection of NRBCs was used for a day-to-day monitoring of 284 surgical intensive care patients. Results: NRBCs were found at least once in 32.0% of all patients. The mortality of NRBC-positive patients was 44.0% (40/91); this was significantly higher (P <0.001) than the mortality of NRBC-negative patients (4.2%, 8/193). With regard to intensive care mortality, NRBCs in blood showed sensitivity and specificity of 83.3% and 78.9%, respectively. The area under curve (C-statistic) was 0.86. Mortality increased with increasing NRBC concentration. All patients with more than 2000 NRBCs/μl died. Moreover, mortality increased with increasing frequency of occurrence. When after first detection of NRBCs in blood, during the further course of intensive care treatment the NRBCs have disappeared from the circulation, the mortality again decreased to values of NRBC-negative patients. The detection of NRBCs is associated with an increased mortality rate, the odds ratio after adjustment for other laboratory prognostic indicators being 1.8 (P <0.001) for each increase in the NRBC category (1–40/μl; 41–80/μl; 81–240/μl, >240/μl). NRBCs were detected for the first time, on average, 9 days (median 5 days) before death. Conclusions: The routine analysis of NRBC in blood is of potential prognostic power with regard to mortality of critically ill patients. Therefore, this parameter could possibly serve as a daily indicator of patients at high mortality risk. [Copyright &y& Elsevier]

Lymph node status is a prognostic marker and strongly influences therapeutic decisions in colorectal cancer (CRC). 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). 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. 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. 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. • We aimed to develop a new biomarker to predict lymph node status of patients with colorectal cancer (CRC). • Convolutional neural network–based image analysis and clinical data were used individually and in combination. • Models were trained and tested on haematoxylin and eosin slides of 3013 primary CRC tumours. • The combined model on the internal test set yielded the best results (area under receiver operating curve of 74.1%). • Studies should address generalisation of the image classifier to external data. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the performance of [68Ga]Ga-PSMA-11 PET/CT in the diagnosis of recurrent prostate cancer (PC) after prostatectomy in a large multicentre cohort. Methods: The centres, which contributed to this study, were the departments of nuclear medicine of Heidelberg (Germany), Technical University of Munich (Germany) and Albert Einstein Hospital of São Paulo (Brazil). A total of 2533 patients who were scanned with [68Ga]Ga-PSMA-11 PET/CT at 1 h p.i. due to recurrent PC after prostatectomy were included in this retrospective analysis. Exclusion criteria were as follows: patients with untreated primary tumour, previous chemotherapy or Xofigo®; those previously treated with exclusively external beam radiation therapy or HIFU; those referred for PSMA-therapy; and those treated with ADT (including first- and second-generation ADT) within the last 6 months. Potential influences of different factors such as PSA level, PSA doubling-time (PSADT), PSA velocity (PSAVel), Gleason Score (GSC, including the separate analysis of 7a and 7b), age and amount of injected tracer were evaluated in a multivariable analysis. Results: The rate of pathologic PET/CT-scans was 43% for PSA ≤ 0.2 ng/ml, 58% for PSA > 0.2 to ≤ 0.5, 72% for PSA > 0.5 to ≤ 1.0 and increased to a maximum of 93% for PSA > 10 ng/ml. A pathological PET/CT was significantly (p = 0.001) associated with PSA level and higher GSC. Amount of injected tracer, age, PSADT and PSAVel were not associated with a higher probability of a pathological scan. Conclusion: [68Ga]Ga-PSMA-11 PET/CT at 1 h p.i. confirmed its high performance in the largest patient cohort yet analysed. Tumour detection showed a clear association with higher PSA and higher GSC. No association was found between a pathological [68Ga]Ga-PSMA-11 PET/CT and age, amount of injected tracer, PSADT or PSAVel. [ABSTRACT FROM AUTHOR]

Purpose: 68Ga-PSMA-11 PET/CT is commonly performed at 1 h post injection (p.i.). However, various publications have demonstrated that most prostate cancer (PC) lesions exhibit higher contrast at later imaging. The aim of this study was to compare the "common" protocol of 68Ga-PSMA-11 PET/CT with a modified protocol. Methods: In 2017, we used the following scanning protocol for 68Ga-PSMA-11 PET/CT in patients with recurrent PC: acquisition at 1 h p.i. without further preparations. From 2018, all scans were conducted at 1.5 h p.i. In addition, patients were orally hydrated with 1 L of water 0.5 h p.i. and were injected with 20 mg of furosemide 1 h p.i. Both protocols including 112 patients (2017) and 156 (modified protocol in 2018) were retrospectively compared. Rates of pathologic scans, maximum standardized uptake values (SUVmax), and tumor contrast (ratio lesion-SUVmax/background-SUVmean) as well as average standardized uptake values (SUVmean) of urinary bladder were analyzed. Results: Both tumor contrast and tracer uptake were significantly (p < 0.001) higher in the novel protocol. Although statistically not significant, the rates of pathologic scans were also higher in the modified protocol: 76.3% vs. 68.8% for all PSA values including 38.9% vs. 25.0% for PSA < 0.5 ng/ml and 60.0% vs. 56.7% for PSA > 0.5–≤ 2.0 ng/ml. Average SUVmean of the urinary bladder was significantly (p < 0.001) lower with the modified protocol. Conclusions: The modified protocol, which includes a combination of delayed image acquisition at 1.5 h p.i., hydration, and furosemide resulted in higher tumor contrast and seems to have the potential to increase the rates of pathological scans, especially at low PSA levels. [ABSTRACT FROM AUTHOR]

Blood-based protein biomarker signatures might be an alternative or supplement to existing methods for early detection of colorectal cancer (CRC) for population-based screening. The objective of this study was to derive a protein biomarker signature for early detection of CRC and its precursor advanced adenoma (AA). In a two-stage design, 270 protein markers were measured by liquid chromatography/multiple reaction monitoring/mass spectrometry in plasma samples of discovery and validation sets. In the discovery set consisting of 100 newly diagnosed CRC cases and 100 age- and sex-matched controls free of neoplasm at screening colonoscopy, the algorithms predicting the presence of early- or late-stage CRC were derived by Lasso regression and.632 + bootstrap. The prediction algorithms were then externally validated in an independent validation set consisting of participants of screening colonoscopy including 56 participants with CRC, 99 with AA and 99 controls without any colorectal neoplasms. Three different signatures for all-, early- and late-stage CRC consisting of five-, three- and eight-protein markers were obtained in the discovery set with areas under the curves (AUCs) after.632 + bootstrap adjustment of 0.85, 0.83 and 0.96, respectively. External validation in the representative screening population yielded AUCs of 0.79 (95% CI, 0.70–0.86), 0.79 (95% CI, 0.66–0.89) and 0.80 (95% CI, 0.70–0.89) for all-, early- and late-stage CRCs, respectively. The three-marker early-stage algorithm yielded an AUC of 0.65 (95% CI, 0.56–0.73) for detection of AA in the validation set. Although not yet competitive with available stool-based tests for CRC early detection, the identified proteins may contribute to the development of powerful blood-based tests for early detection of CRC and its precursors AAs. A three plasma protein biomarker signature derived in a clinical setting yielded an AUC of 0.83. When independently validated in a true screening setting (participants of screening colonoscopy) AUCs of 0.79 and 0.65 for distinguishing early stage colorectal cancer and advanced adenoma cases from controls free of neoplasms were obtained. These protein biomarkers may contribute to development of a blood based tests for population based screening. Image 1 • Participation rate is often low in endoscopy or stool-based colorectal cancer screening trials. • Blood based test could be an alternative or supplement to existing screening procedures. • With liquid chromatography-multiple reaction monitoring/mass spectrometry three stage specific signatures were identified. • 3-marker signature detected early-stage colorectal cancer and advanced adenomas with area under the curves of 0.79 and 0.65. • These proteins may serve as potential biomarkers for blood-based early detection of colorectal cancer and its precursors. [ABSTRACT FROM AUTHOR]

Purpose: So far, there have been very few studies which provide a direct comparison between MRI and PSMA-ligand PET/CT for the detection of recurrent prostate cancer (rPC). This present study therefore aims to provide further clinical data in order to resolve this urgent clinical question, and thereby strengthen clinical recommendations. Methods: A retrospective analysis was performed for patients who were scanned at our institution with whole-body PSMA-PET/CT (tracer: 68Ga-PSMA-11) between January 2017 and September 2018 in order to detect rPC. Amongst them, 43 underwent an additional pelvic MRI within 2 months. Both modalities were compared as follows: a consensus read of the PET data was performed by two nuclear physicians. All lesions were recorded with respect to their type and localization. The same process was conducted by two radiologists for pelvic MRI. Thereafter, both modalities were directly compared for every patient and lesion. Results: Overall, 30/43 patients (69.8%) presented with a pathologic MRI and 38/43 (88.4%) with a pathologic PSMA-PET/CT of the pelvis. MRI detected 53 pelvic rPC lesions (13 of them classified as "uncertain") and PSMA-PET/CT detected 75 pelvic lesions (three classified as "uncertain"). The superiority of PSMA-PET/CT was statistically significant only if uncertain lesions were classified as false-positive. Conclusions: PSMA-PET/CT detected more pelvic lesions characteristic for rPC when compared to MRI. In order to detect rPC, a potential future scenario could be conducting first a PSMA-PET/CT. Combining the advantages of both modalities in hybrid PET/MRI scanners would be an ideal future scenario. [ABSTRACT FROM AUTHOR]

Melanoma is the most dangerous type of skin cancer but is curable if detected early. Recent publications demonstrated that artificial intelligence is capable in classifying images of benign nevi and melanoma with dermatologist-level precision. However, a statistically significant improvement compared with dermatologist classification has not been reported to date. For this comparative study, 4204 biopsy-proven images of melanoma and nevi (1:1) were used for the training of a convolutional neural network (CNN). New techniques of deep learning were integrated. For the experiment, an additional 804 biopsy-proven dermoscopic images of melanoma and nevi (1:1) were randomly presented to dermatologists of nine German university hospitals, who evaluated the quality of each image and stated their recommended treatment (19,296 recommendations in total). Three McNemar's tests comparing the results of the CNN's test runs in terms of sensitivity, specificity and overall correctness were predefined as the main outcomes. The respective sensitivity and specificity of lesion classification by the dermatologists were 67.2% (95% confidence interval [CI]: 62.6%–71.7%) and 62.2% (95% CI: 57.6%–66.9%). In comparison, the trained CNN achieved a higher sensitivity of 82.3% (95% CI: 78.3%–85.7%) and a higher specificity of 77.9% (95% CI: 73.8%–81.8%). The three McNemar's tests in 2 × 2 tables all reached a significance level of p < 0.001. This significance level was sustained for both subgroups. For the first time, automated dermoscopic melanoma image classification was shown to be significantly superior to both junior and board-certified dermatologists (p < 0.001). • Recent publications demonstrated that deep learning is capable to classify images of benign nevi and melanoma with dermatologist-level precision. • A systematic outperformance of dermatologists was not demonstrated to date. • This study shows the first systematic (p < 0.001) outperformance of board-certified dermatologists in dermoscopic melanoma image classification. [ABSTRACT FROM AUTHOR]

The diagnosis of most cancers is made by a board-certified pathologist based on a tissue biopsy under the microscope. Recent research reveals a high discordance between individual pathologists. For melanoma, the literature reports 25–26% of discordance for classifying a benign nevus versus malignant melanoma. Deep learning was successfully implemented to enhance the precision of lung and breast cancer diagnoses. The aim of this study is to illustrate the potential of deep learning to assist human assessment for a histopathologic melanoma diagnosis. Six hundred ninety-five lesions were classified by an expert histopathologist in accordance with current guidelines (350 nevi and 345 melanomas). Only the haematoxylin and eosin stained (H&E) slides of these lesions were digitalised using a slide scanner and then randomly cropped. Five hundred ninety-five of the resulting images were used for the training of a convolutional neural network (CNN). The additional 100 H&E image sections were used to test the results of the CNN in comparison with the original class labels. The total discordance with the histopathologist was 18% for melanoma (95% confidence interval [CI]: 7.4–28.6%), 20% for nevi (95% CI: 8.9–31.1%) and 19% for the full set of images (95% CI: 11.3–26.7%). Even in the worst case, the discordance of the CNN was about the same compared with the discordance between human pathologists as reported in the literature. Despite the vastly reduced amount of data, time necessary for diagnosis and cost compared with the pathologist, our CNN archived on-par performance. Conclusively, CNNs indicate to be a valuable tool to assist human melanoma diagnoses. • A convolutional neural network (CNN) was trained with 595 histopathologic images of melanomas and nevi that were classified by an expert dermatohistopathologist. • The CNN was then tested with 100 additional images (melanoma/nevi = 1:1) and revealed a discordance of only 19% to the histopathologist. • Thus, even in the worst case, the discordance of the CNN is about the same compared with the discordance between human pathologists as reported in the literature (25–26%). [ABSTRACT FROM AUTHOR]

Purpose: Tumor delineation within an atelectasis in lung cancer patients is not always accurate. When T staging is done by integrated 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG)-positron emission tomography (PET)/X-ray computer tomography (CT), tumors of neuroendocrine differentiation and slowly growing tumors can present with reduced FDG uptake, thus aggravating an exact T staging. In order to further exhaust information derived from [18F]FDG-PET/CT, we evaluated the impact of CT density and maximum standardized uptake value (SUVmax) for the classification of different tumor subtypes within a surrounding atelectasis, as well as possible cutoff values for the differentiation between the primary tumor and atelectatic lung tissue.Procedures: Seventy-two patients with histologically proven lung cancer and adjacent atelectasis were investigated. Non-contrast-enhanced [18F]FDG-PET/CT was performed within 2 weeks before surgery/biopsy. Boundaries of the primary within the atelectasis were determined visually on the basis of [18F]FDG uptake; CT density was quantified manually within each primary and each atelectasis.Results: CT density of the primary (36.4 Hounsfield units (HU) ± 6.2) was significantly higher compared to that of atelectatic lung (24.3 HU ± 8.3; p < 0.01), irrespective of the histological subtype. The discrimination between different malignant tumors using density analysis failed. SUVmax was increased in squamous cell carcinomas compared to adenocarcinomas. Irrespective of the malignant subtype, a possible cutoff value of 24 HU may help to exclude the presence of a primary in lesions below 24 HU, whereas a density above a threshold of 40 HU can help to exclude atelectatic lung.Conclusion: Density measurements in patients with lung cancer and surrounding atelectasis may help to delineate the primary tumor, irrespective of the specific lung cancer subtype. This could improve T staging and radiation treatment planning (RTP) without additional application of a contrast agent in CT, or an additional magnetic resonance imaging (MRI), even in cases of lung tumors of neuroendocrine differentiation or in slowly growing tumors with less avidity to [18F]FDG. [ABSTRACT FROM AUTHOR]

Purpose: Since the introduction of PSMA PET/CT with 68Ga-PSMA-11, this modality for imaging prostate cancer (PC) has spread worldwide. Preclinical studies have demonstrated that short-term androgen deprivation therapy (ADT) can significantly increase PSMA expression on PC cells. Additionally, retrospective clinical data in large patient cohorts suggest a positive association between ongoing ADT and a pathological PSMA PET/CT scan. The present evaluation was conducted to further analyse the influence of long-term ADT on PSMA PET/CT findings.Methods: A retrospective analysis was performed of all 1,704 patients who underwent a 68Ga-PSMA-11 PET/CT scan at our institution from 2011 to 2017 to detect PC. Of 306 patients scanned at least twice, 10 had started and continued ADT with a continuous clinical response between the two PSMA PET/CT scans. These ten patients were included in the current analysis which compared the tracer uptake intensity and volume of PC lesions on PSMA PET/CT before and during ongoing ADT.Results: Overall, 31 PC lesions were visible in all ten patients before initiation of ADT. However, during ongoing ADT (duration 42-369 days, median 230 days), only 14 lesions were visible in eight of the ten patients. The average tracer uptake values decreased in 71% and increased in 12.9% of the PC lesions. Of all lesions, 33.3% were still visible in six patients with a complete PSA response (≤0.1 ng/ml).Conclusion: Continuous long-term ADT significantly reduces the visibility of castration-sensitive PC on PSMA PET/CT. If the objective is visualization of the maximum possible extent of disease, we recommend referring patients for PSMA PET/CT before starting ADT. [ABSTRACT FROM AUTHOR]

Purpose: In patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL), primary staging, as well as intermediate and late response assessment, is often performed by integrated 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/X-ray computed tomography (PET/CT). The purpose of this analysis was to evaluate if findings in patients with histopathologically proven HL or NHL might correlate with semi-automated density measurements of target lesions (TLs) in the CT component of the integrated PET/CT examination.Procedures: After approval by the institutional review board, 176 lymph nodes (LN) in 90 PET/CT examinations of 90 patients were retrospectively analyzed (HL, 108 TLs out of 55 patients; NHL, 68 TLs out of 35 patients). PET/CT was performed for reasons of primary staging, response evaluation as interim PET, or as final examination after therapy, according to the clinical schedule. Analyses of TLs were performed on the basis of tracer uptake (SUV) 60 min after tracer injection and volumetric CT histogram analysis in non-contrast-enhanced CT.Results: All patients were diagnosed with HL or NHL in a pretreatment biopsy. Prior to therapy induction, staging of all patients was performed using contrast-enhanced CT of the neck to the pelvis, or by [18F]FDG PET/CT. Of the 176 TLs, 119 were classified as malignant, and 57 were benign. Malignant TLs had significantly higher CT density values compared to benign (p < 0.01).Conclusion: Density measurements of TLs in patients with HL and NHL correlate with the dignity of TLs and might therefore serve as a complementary surrogate parameter for the differentiation between malignant and benign TLs. A possible density threshold in clinical routine might be a 20-Hounsfield units (HU) cutoff value to rule out benignancy in TLs that are above the 20-HU threshold. [ABSTRACT FROM AUTHOR]

Purpose: Since the introduction of 68Ga-PSMA-11 PET/CT for imaging prostate cancer (PC) we have frequently observed mediastinal lymph nodes (LN) showing tracer uptake despite being classified as benign. The aim of this evaluation was to further analyze such LN.Methods: Two patient groups with biphasic 68Ga-PSMA-11 PET/CT at 1 h and 3 h p.i. were included in this retrospective evaluation. Group A (n = 38) included patients without LN metastases, and group B (n = 43) patients with LN metastases of PC. SUV of mediastinal/paraaortal LN of group A (n = 100) were compared to SUV of LN metastases of group B (n = 91). Additionally, 22 randomly selected mediastinal and paraaortal LN of patients without PC were immunohistochemically (IHC) analyzed for PSMA expression.Results: In group A, 7/38 patients (18.4%) presented with at least one PSMA-positive mediastinal LN at 1 h p.i. and 3/38 (7.9%) positive LN at 3 h p.i. with a SUVmax of 2.3 ± 0.7 at 1 h p.i. (2.0 ± 0.7 at 3 h p.i.). A total of 11 PSMA-positive mediastinal/paraaortal LN were detected in nine patients considering both imaging timing points. SUVmax of LN-metastases was 12.5 ± 13.2 at 1 h p.i. (15.8 ± 17.0 at 3 h p.i.). SUVmax increased clearly (> 10%) between 1 h and 3 h p.i. in 76.9% of the LN metastases, and decreased significantly in 72.7% of the mediastinal/paraaortal LN. By IHC, PSMA-expression was observed in intranodal vascular endothelia of all investigated LN groups and to differing degrees within germinal centers of 15/22 of them (68.1%). Expression was stronger in mediastinal nodes (p = 0.038) and when follicular hyperplasia was present (p = 0.050).Conclusion: PSMA-positive mediastinal/paraaortal benign LN were visible in a notable proportion of patients. PSMA-positivity on the histopathological level was associated with the activation state of the LN. However, in contrast to LN metastases of PC, they presented with significantly lower uptake, which, in addition, usually decreased over time. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2+ HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or ∼5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease. [ABSTRACT FROM AUTHOR]

Objective: To assess if pulmonary CT angiography (CTA) can predict outcome in patients with pulmonary embolism (PE).Methods: Retrospective analysis of CTA studies of patients with PE and documentation of pulmonary artery (PA)/aorta ratio, right ventricular (RV)/left ventricular (LV) ratio, superior vena cava (SVC) diameter, pulmonary obstruction index (POI), ventricular septal bowing (VSB), venous contrast reflux (VCR), pulmonary infarction and pleural effusion. Furthermore, duration of total hospital stay, necessity for/duration of ICU therapy, necessity for mechanical ventilation and mortality were recorded. Comparison was performed by logistic/linear regression analysis with significance at 5%.Results: 152 patients were investigated. Mean duration of hospital stay was 21  ±  24 days. 66 patients were admitted to the ICU; 20 received mechanical ventilation. Mean duration of ICU therapy was 3  ±  8 days. Mortality rate was 8%. Significant positive associations of POI, VCR and pulmonary infarction with necessity for ICU therapy were shown. VCR was significantly associated with necessity for mechanical ventilation and duration of ICU treatment. Pleural effusions were significantly associated with duration of total hospital stay whereas the RV/LV ratio correlated with mortality.Conclusion: Selected CTA findings showed significant associations with the clinical course of PE and may thus be used as predictive parameters. [ABSTRACT FROM AUTHOR]

Abstract: Background: Decisions for coronary revascularisation are frequently based on visual assessment of the severity of a stenosis. In patients with intermediate left main stem lesions clinical decision making based on FFR is safe and feasible. This study was performed to assess the accuracy of visual angiographic assessment of intermediate or equivocal left main coronary artery (LMCA) stenoses by experienced interventional cardiologists when taking fractional flow reserve (FFR) measurements as the gold standard. Methods: Fifty-one patients with intermediate (40–80% diameter stenosis by angiography) or equivocal LMCA disease were evaluated by FFR. Angiograms were then reviewed by 4 experienced interventionalists from different university hospitals blinded to FFR results. Lesions were visually assessed and their significance classified as ‘significant’, ‘not significant’, or ‘unsure’ if the observer was unable to make a decision regarding lesion significance based on the angiogram. Results: Results were compared with two different FFR cutoff values (<0.75 and ≤0.80) for hemodynamic significance. The 4 reviewers achieved correct lesion classification in no more than approximately 50% of cases each, regardless of FFR threshold. The interobserver agreement between two reviewers in excess of the agreement expected due to chance was outperformed on average by only 16%. Furthermore, interobserver variability was large resulting in unanimously correct lesion classification in only 29% of all cases. Conclusions: The functional significance of intermediate and equivocal LMCA stenoses should not be based solely on angiographic assessment even by experienced interventional cardiologists. [Copyright &y& Elsevier]

• Low-dose paclitaxel treatment reduces MDSC frequencies in melanoma patients resistant to prior treatments. • Activity of T cells was enhanced by low-dose paclitaxel treatment in these patients. • Application of low-dose paclitaxel could improve the clinical outcome of melanoma patients. The low dose application of chemotherapeutic agents such as paclitaxel was previously shown to initiate anti-tumor activity by neutralizing myeloid-derived suppressor cells (MDSCs) in melanoma mouse models. Here, we investigated immunomodulating effects of low-dose paclitaxel in 9 metastatic melanoma patients resistant to prior treatments. Three patients showed response to therapy (two partial responses and one stable disease). In responding patients, paclitaxel decreased the frequency and immunosuppressive pattern of MDSCs in the peripheral blood and skin metastases. Furthermore, paclitaxel modulated levels of inflammatory mediators in the serum. In addition, responders displayed enhanced frequencies of tumor-infiltrating CD8+ T cells and their activity indicated by the upregulation of CD25 and TCR ζ-chain expression. Our study suggests that low-dose paclitaxel treatment could improve clinical outcome of some advanced melanoma patients by enhancing anti-tumor immunity and might be proposed for combined melanoma immunotherapy. [ABSTRACT FROM AUTHOR]

Accurate melanoma diagnosis is crucial for patient outcomes and reliability of AI diagnostic tools. We assess interrater variability among eight expert pathologists reviewing histopathological images and clinical metadata of 792 melanoma-suspicious lesions prospectively collected at eight German hospitals. Moreover, we provide access to the largest panel-validated dataset featuring dermoscopic and histopathological images with metadata. Complete agreement is achieved in 53.5% of cases (424/792), and a majority vote ( ≥ five pathologists) in 90.9% (720/792). Considerable discordance is observed for non-invasive melanomas (complete agreement in only 10/73 cases). The expert panel disagrees with the local pathologists' and dermatologists' diagnoses in 14.9% and 33.5% of cases, respectively. This variability highlights the diagnostic challenges of early-stage melanomas and the need to reconsider how ground truth is established in routine care and AI research. Including at least two pathologists or virtual panels may contribute to more consistent diagnostic results., Competing Interests: Competing interests: Prof Utikal reported personal fees from Amgen, Bristol Myers Squibb, GSK, Immunocore, LEO Pharma, Merck Sharp & Dohme, Novartis, Pierre Fabre, Rheacell, Roche, and Sanofi outside the submitted work. Dr Wohlfeil received honoraria from Bristol Myers Squibb, Novartis, and Sun Pharma outside the submitted work. Prof Meier reported grants from Novartis and Roche and others (travel support or/and speaker’s fees or/and advisor’s honoraria) from BMS, MSD, and Pierre Fabre outside the submitted work. Dr Hobelsberger reported clinical trial support and advisor’s honoraria from Almirall, speaker’s honoraria from Almirall, UCB, and AbbVie, and travel support from UCB, Janssen Cilag, Almirall, Novartis, Lilly, LEO Pharma, and AbbVie outside the submitted work. Prof Heinzerling reported other (clinical studies) from BMS, MSD, Pierre Fabre, Replimune, and Sanofi; personal fees from Biomedx, BMS, MSD, Sun, Pierre Fabre, Novartis, and Sanofi; and grants from Therakos outside the submitted work. Prof Haferkamp reported speaker’s fees and advisor’s honoraria from BMS, MSD, Novartis, and Pierre Fabre outside the submitted work. Dr Schlaak reported personal fees from BMS, Novartis, Immunocore, Sun Pharma, MSD, Recordati, and Sanofi Aventis outside the submitted work. Prof Berking reported personal fees from BMS, MSD, InflaRx, Novartis, Sanofi, LEO Pharma, Almirall Hermal, Pierre Fabre, Immunocore, and Delcath outside the submitted work. Dr Erdmann received travel support and speaker’s honoraria from Immunocore, Novartis, Pierre Fabre, and Sanofi outside the submitted work. Dr Sondermann reported grants from Almirall, Novartis, and Medi GmbH; and personal fees from AbbVie, Almirall, BMS, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, Sanofi Genzyme, and UCB outside the submitted work. Prof Goebeler reported grants for clinical studies from Argenx, Novartis, Janssen, and Galderma; personal fees from Almirall (consulting), Janssen (advisory board, speaker), GSK (advisory board, speaker), and Lilly (speaker) outside the submitted work. Dr Llamas-Velasco reported fees as an advisory board member, consultant, research support, participation in clinical trials, and honorary for speaking with the following pharmaceutical companies: Abbvie, Almirall, Amgen, Boehringer, BMS, Celgene, Janssen, Leo, Lilly, Kyowa kirin, Novartis and UCB, outside the submitted work. Dr. Kather declares consulting services for Owkin, France; DoMore Diagnostics, Norway; Panakeia, UK; AstraZeneca, UK; Scailyte, Switzerland; Mindpeak, Germany; and MultiplexDx, Slovakia. Furthermore, he holds shares in StratifAI GmbH, Germany, has received a research grant from GSK, and has received honoraria from AstraZeneca, Bayer, Eisai, Janssen, MSD, BMS, Roche, Pfizer, and Fresenius. Dr Gabriela Poch received travel support and speaker’s honoraria from MSD, BMS, Novartis, Sun Pharma, and Amgen outside the submitted work. Dr Brinker reported being the owner of Smart Health Heidelberg GmbH outside the submitted work. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Objectives: Recently, results on colorectal cancer (CRC) incidence and mortality reduction by the offer of screening colonoscopy were reported for the first time from a randomized controlled trial (RCT), the Nordic-European Initiative on Colorectal Cancer (NordICC) trial. Despite randomization, there was a substantially lower proportion of postrandomization exclusions of CRC cases due to cancer registry-recorded date of diagnosis before recruitment in the invited group than in the usual-care group. We aimed to evaluate the impact of such differential exclusions on the trial's effect estimates on CRC risk., Study Design and Setting: We compared reported postrandomization exclusions of CRC cases due to cancer registry-recorded date of diagnosis, and we derived adjusted effect estimates on CRC risk accounting for the reported differential postrandomization exclusion of CRC cases in the invited group and the usual-care group., Results: Reported postrandomization exclusion proportions of CRC cases were originally reported as 52/31,472 (0.17%) and 159/63,133 (0.25%) in the invited and usual-care group, respectively, (P < .005) in an analysis, including participants from all four NordICCstudy countries and as 52/28,277 (0.20%) and 164/56,529 (0.29%) in the recent analysis of 10-year follow-up data from three of the countries (P = .018). Accounting for the differential exclusion proportions increased the estimated CRC risk reduction (95% CI) from originally reported 18% (7%-30%) to 25% (95% CI 13%-35%) in intention-to-screen analysis. Estimated reduction of CRC risk among screening attenders increased from originally reported 31% (17%-45%) to 50% (25%-69%) in adjusted per-protocol analysis., Conclusion: Accounting for differential postrandomization exclusions of CRC cases leads to stronger-than-reported effect estimates in the so far only RCT on long-term effects of screening colonoscopy., Competing Interests: Declaration of competing interest There are no competing interests for any author., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objective: Data on interaction of patients with artificial intelligence (AI) are limited, primarily derived from small-scale studies, cross-sectional surveys, and qualitative reviews. Most patients have not yet encountered AI in their clinical experience. This study explored patients' confidence in AI, specifically large language models, after a direct interaction with a chatbot in a clinical setting. Through hands-on experience, the study sought to reduce potential biases due to an anticipated lack of AI experience in a real-world urological patient sample., Methods: A total of 300 patients scheduled for counseling were enrolled from February to July 2024. Participants voluntarily conversed about their medical questions with a GPT-4 powered chatbot, followed by a survey assessing their confidence in clinical capabilities of AI compared with their counseling urologists. Clinical capabilities included history taking, diagnostics, treatment recommendation, anxiety reduction, and time allocation., Key Findings and Limitations: Of the 292 patients who completed the study, AI was significantly preferred to physicians for consultation time allocation ( p  < 0.001). However, urologists were overwhelmingly favored for all other capabilities, especially treatment recommendations and anxiety reduction. Notably, age did not influence patients' confidence in AI. Limitations include a potential social desirability bias., Conclusions and Clinical Implications: Our study demonstrates that urological patients prefer AI as a powerful complement to-rather than a replacement for-human expertise in clinical care. Patients appreciated the additional consultation time provided by AI. Interestingly, age was not associated with confidence in AI, suggesting that large language models are user-friendly tools for patients of all age groups., Patient Summary: In this report, we explored how patients feel about using an artificial intelligence (AI)-powered chatbot in a medical setting. Patients interacted with the AI for medical questions and compared its skills with those of doctors through a survey. They appreciated the AI for providing more time during consultations but preferred doctors for other tasks, for example, diagnostics, recommendation of treatments, and reduction of anxieties., (© 2024 The Author(s).)

Studies have shown that colorectal cancer prognosis can be predicted by deep learning-based analysis of histological tissue sections of the primary tumor. So far, this has been achieved using a binary prediction. Survival curves might contain more detailed information and thus enable a more fine-grained risk prediction. Therefore, we established survival curve-based CRC survival predictors and benchmarked them against standard binary survival predictors, comparing their performance extensively on the clinical high and low risk subsets of one internal and three external cohorts. Survival curve-based risk prediction achieved a very similar risk stratification to binary risk prediction for this task. Exchanging other components of the pipeline, namely input tissue and feature extractor, had largely identical effects on model performance independently of the type of risk prediction. An ensemble of all survival curve-based models exhibited a more robust performance, as did a similar ensemble based on binary risk prediction. Patients could be further stratified within clinical risk groups. However, performance still varied across cohorts, indicating limited generalization of all investigated image analysis pipelines, whereas models using clinical data performed robustly on all cohorts., (© 2023. The Author(s).)

In vitro experiments have shown that the E2 protein of human papillomaviruses (HPV) binds to the upstream regulatory region (URR) of the viral genome and modulates transcription. Additionally, it seems to be a necessary component for viral DNA replication together with E1. We have developed a transgenic mouse model containing the URR region of the low-risk virus HPV11 that regulates the expression of the lacZ reporter gene. Most interestingly, in these mice, the transgene was exclusively expressed in the bulge region of the hair follicle but not in any other tissues. Further experimental data indicate that in double transgenic mice that also express the HPV11-E2 protein under the control of the Ubiquitin C-promoter, the transcription of the reporter gene is modulated. When E2 is present, the expression of the reporter gene also occurs exclusively in the bulge region of the hair follicles as it does in the single transgenic mice, but the expression of the lacZ driven by the URR is increased and the statistical spread is greater. Even if the expression of the reporter gene occurs in the hair follicles of the dorsal skin of an animal uniform, E2 obviously has the capacity for both to induce and to repress the URR activity in vivo., (© 2023. The Author(s).)

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs., (© 2022. The Author(s).)

Respiratory tract infections are among the deadliest communicable diseases worldwide. Severe cases of viral lung infections are often associated with a cytokine storm and alternating platelet numbers. We report that hematopoietic stem and progenitor cells (HSPCs) sense a non-systemic influenza A virus (IAV) infection via inflammatory cytokines. Irrespective of antiviral treatment or vaccination, at a certain threshold of IAV titer in the lung, CD41-positive hematopoietic stem cells (HSCs) enter the cell cycle while endothelial protein C receptor-positive CD41-negative HSCs remain quiescent. Active CD41-positive HSCs represent the source of megakaryocytes, while their multi-lineage reconstitution potential is reduced. This emergency megakaryopoiesis is thrombopoietin independent and attenuated in IAV-infected interleukin-1 receptor-deficient mice. Newly produced platelets during IAV infection are immature and hyper-reactive. After viral clearance, HSC quiescence is re-established. Our study reveals that non-systemic viral respiratory infection has an acute impact on HSCs via inflammatory cytokines to counteract IAV-induced thrombocytopenia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlying resistance mechanisms and to find ways to overcome the resistance, preclinical models that became resistant to SMO inhibition are needed., Methods: To induce SMO inhibitor resistant tumors, we have treated a patient-derived xenograft (PDX) model of SHH medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg Sonidegib using an intermitted treatment schedule. Vehicle-treated and resistant models were subjected to whole-genome and RNA sequencing for molecular characterization and target engagement. In vitro drug screens (76 drugs) were performed using Sonidegib-sensitive and -resistant lines to find other drugs to target the resistant lines. One of the top hits was then validated in vivo ., Results: Nine independent Sonidegib-resistant PDX lines were generated. Molecular characterization of the resistant models showed that eight models developed missense mutations in SMO and one gained an inactivating point mutation in MEGF8, which acts downstream of SMO as a repressor in the SHH pathway. The in vitro drug screen with Sonidegib-sensitive and -resistant lines identified good efficacy for Selinexor in the resistant line. Indeed, in vivo treatment with Selinexor revealed that it is more effective in resistant than in sensitive models., Conclusions: We report the first human SMO inhibitor resistant medulloblastoma PDX models, which can be used for further preclinical experiments to develop the best strategies to overcome the resistance to SMO inhibitors in patients., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Prostate-specific membrane antigen (PSMA)-ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, 18 F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Methods: Ninety-six patients with prostate cancer underwent 18 F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET-positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Results: Of the patients, 90.6% received 18 F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. 18 F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. Conclusion: 18 F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

In experiments with multiple quantitative measurements per subject, for example measurements on multiple lesions per patient, the additional measurements on the same patient provide limited additional information. Treating these measurements as independent observations will produce biased estimators for standard deviations and confidence intervals, and increases the risk of false positives in statistical tests. The problem can be remedied in a simple way by first taking the average of all observations of each specific patient, and then doing all further calculations only on the list of these patient means. A more sophisticated statistical modeling of the experiment, for example in a linear mixed model, is only required if (i) there is a large imbalance in the number of observations per patient or (ii) there is a specific interest in actually identifying the various sources of variation in the experiment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Jutzi, Krieghoff-Henning, Holland-Letz, Utikal, Hauschild, Schadendorf, Sondermann, Fröhling, Hekler, Schmitt, Maron and Brinker.)

Neuroendocrinelike transdifferentiation of prostate cancer adenocarcinomas correlates with serum levels of chromogranin A (CgA) and drives treatment resistance. The aim of this work was to evaluate whether CgA can serve as a response predictor for 177 Lu-prostate-specific membrane antigen 617 (PSMA) radioligand therapy (RLT) in comparison with the established tumor markers. Methods: One hundred consecutive patients with metastasized castration-resistant prostate cancer scheduled for PSMA RLT were evaluated for prostate-specific antigen (PSA), lactate dehydrogenase (LDH), and CgA at baseline and in follow-up of PSMA RLT. Tumor uptake of PSMA ligand, a known predictive marker for response, was assessed as a control variable. Results: From the 100 evaluated patients, 35 had partial remission, 16 stable disease, 15 mixed response, and 36 progression of disease. Tumor uptake above salivary gland uptake translated into partial remission, with an odds ratio (OR) of 60.265 (95% confidence interval [CI], 5.038-720.922). Elevated LDH implied a reduced chance for partial remission, with an OR of 0.094 (95% CI, 0.017-0.518), but increased the frequency of progressive disease (OR, 2.717; 95% CI, 1.391-5.304). All patients who achieved partial remission had a normal baseline LDH. Factor-2 elevation of CgA increased the risk for progression, with an OR of 3.089 (95% CI, 1.302-7.332). Baseline PSA had no prognostic value for response prediction. Conclusion: In our cohort, baseline PSA had no prognostic value for response prediction. LDH was the marker with the strongest prognostic value, and elevated LDH increased the risk for progression of disease under PSMA RLT. Elevated CgA demonstrated a moderate impact as a negative prognostic marker in general but was explicitly related to the presence of liver metastases. Well in line with the literature, sufficient tumor uptake is a prerequisite to achieve tumor response., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Dose-response curves of new substances in toxicology and related areas are commonly fitted using log-logistic functions. In more advanced studies, an additional interest is often how these substances will behave when applied in combination with a second substance. Here, an essential question for both design and analysis of these combination experiments is whether the resulting dose-response function will still be a member of the class of log-logistic functions, and, if so, what function parameters will result for the combined substances. Different scenarios might be considered in regard to whether a true interaction between the substances is expected, or whether the combination will simply be additive. In this paper, it is shown that the resulting function will in general not be a log-logistic function, but can be approximated very closely with one. Parameters for this approximation can be predicted from the parameters of both ingredients. Furthermore, some simple interaction structures can still be represented with a single log-logistic function. The approach can also be applied to Weibull-type dose-response functions, and similar results are obtained. Finally, the results were applied to a real data set obtained from cell culture experiments involving two cancer treatments, and the dose-response curve of a combination treatment was predicted from the properties of the singular substances.

The importance of prostate-specific membrane antigen (PSMA) PET/CT for primary staging of treatment-naïve prostate cancer patients is still under debate. Therefore, the present study aimed to evaluate the role of PSMA PET/CT in detecting nodal metastases in a large cohort of men and compare imaging results with the risk of lymph node involvement based on the Roach formula. Methods: In total, 280 men with newly diagnosed prostate carcinoma were included in the present study. For all patients, PSMA PET/CT was performed for primary staging. Median age was 67 y (range, 38-84 y), and 84% of all patients were classified as high-risk according to the d'Amico criteria. The risk of lymph node involvement was calculated using the Roach formula and compared with the PSMA PET/CT results. Results: PSMA-positive nodes were detected in 90 of 280 men (32.1%). Although most nodal metastases occurred within the pelvis, 36.0% were in extrapelvic sites. In 9 patients (3.2%), nodal metastases occurred in the Virchow node. After comparison of PSMA data with the results of the Roach formula, an area under the curve of 0.781 was obtained for the Roach predictions. Conclusion: For treatment-naïve prostate cancer patients, PSMA PET/CT is well suited for the detection of nodal metastases. However, the original Roach formula can still be used for a quick assessment of potential lymphatic spread in daily clinical routine., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

The present study analyzed the impact of Gallium-68 ( 68 Ga)-labeled prostate-specific membrane antigen-HBED-CC ( 68 Ga-PSMA-11) positron-emission tomography (PET)/computed tomography (CT) on radiotherapeutic management in a large cohort of men with primary or recurrent disease. Methods: This study investigated 121 men with carcinoma of the prostate who underwent 68 Ga-PSMA-11 PET/CT as well as conventional imaging. 50 patients were treatment naive, 11 had persistent prostate-specific antigen (PSA) soon after surgery and 60 presented with recurrent PSA following definitive therapy. Changes in TNM classification of malignant tumors (TNM) stage and radiotherapeutic management after 68 Ga-PSMA-11 imaging were compared to results achieved with conventional imaging. Results: In total, a change in TNM stage and radiotherapeutic management was observed for 49 patients (40.5%) and 62 patients (51.2%), respectively. In treatment naïve patients, a change in TNM stage and radiotheraeutic plan occurred in 26.0% and 44.0% of the cohort respectively. For patients with PSA persistence or recurrence, TNM and radiotherapeutic management changed in 50.7% and 56.3% respectively. Conclusion: 68 Ga-PSMA-11 PET/CT may shortly become an indispensable tool for detecting prostate cancer lesions in treatment-naïve patients as well as in men with recurrent disease or persistent PSA and seems to be very helpful in personalizing radiotherapeutic management to the individual patients' distribution of disease., (Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The objective of this study was to evaluate the rate of detection of bone metastases obtained with the prostate-specific membrane antigen (PSMA)-targeting tracer 99m Tc-MIP-1427, as opposed to conventional bone scanning with 99m Tc-methylene diphosphonate ( 99m Tc-MDP), in a collective of patients with known advanced-stage osseous metastasized prostate cancer. Methods: Twenty-one patients with known metastatic disease were staged with both conventional bone scanning and PSMA ligand scintigraphy within a time frame of less than 10 d. Imaging included planar whole-body scanning and SPECT or SPECT/CT with 2 bed positions 3 h after injection of either 500-750 MBq of 99m Tc-MIP-1427 or 600-750 MBq of 99m Tc-MDP. Lesions were scored as typical tumor, equivocal (benign/malignant), or normal within a standard reporting schema divided into defined anatomic regions. Masked and consensus readings were performed with sequential unmasking: planar scans first, then SPECT/CT, the best evaluable comparator (including MRI), PET/CT, and follow-up examinations. Results: Eleven patients had PSMA-positive visceral metastases that were predictably not diagnosed with conventional bone scanning. However, SPECT/CT was required to distinguish between soft-tissue uptake and overlapping bone. Four patients had extensive 99m Tc-MDP-negative bone marrow lesions. Seven patients had superscan characteristics on bone scans; in contrast, the extent of red marrow involvement was more evident on PSMA scans. Only 3 patients had equivalent results on bone scans and PSMA scans. In 16 patients, more suspect lesions were detected with PSMA scanning than with bone scanning. In 2 patients (10%), a PSMA-negative tumor phenotype was present. Conclusion: PSMA scanning provided a clear advantage over bone scanning by reducing the number of equivocal findings in most patients. SPECT/CT was pivotal for differentiating bone metastases from extraosseous tumor lesions., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Non-invasive blood-based molecular markers have been investigated for cancer diagnosis and prognosis. Circulating free or cell-free DNA (cfDNA) variables have been shown to be putative markers in breast cancer prognosis., Methods: Here, we investigated the potential prognostic ability of cfDNA concentration and cfDNA integrity (cfDI) in a study cohort of 268 patients by quantitative PCR. We compared cfDNA concentration and cfDI at baseline and after one cycle of therapy in metastatic breast cancer (MBC) patients., Results: A significantly increased cfDI (P = 1.21E-7 for ALU and P = 1.87E-3 for LINE1) and decreased cfDNA concentration (P = 1.17E-3 for ALU and P = 1.60E-2 for LINE1) in both repetitive DNA elements after one cycle of therapy was observed. A multiple Cox regression model indicated that cfDI and cfDNA concentration can serve as independent prognostic markers in patients at baseline with HR (95% CI) of 0.70 (0.48-1.01) for ALU cfDI, 0.63 (0.44-0.92) for LINE1 cfDI, 2.44 (1.68-3.53) for ALU cfDNA concentration, and 2.12 (1.47-3.06) for LINE1 cfDNA concentration and after one cycle of therapy with HR (95% CI) of 0.59 (0.42-0.84) for ALU cfDI, 0.51 (0.36-0.74) for LINE1 cfDI, 1.59 (1.31-1.92) for ALU cfDNA concentration, and 1.30 (1.17-1.45) for LINE1 cfDNA concentration, respectively. By comparing integrated prediction error of different models, cfDNA variables were shown to improve the prognostic power of the CTC status., Conclusions: We hereby show that cfDNA variables, especially in combination with other markers, can serve as attractive prognostic markers for MBC patients at baseline and during the systematic therapy.

68 Ga-prostate-specific membrane antigen (PSMA) PET/CT is a new method to detect early nodal metastases in patients with biochemical relapse of prostate cancer. In this retrospective investigation, the dimensions, volume, localization, and SUV max of nodes identified by 68 Ga-PSMA were correlated to their Gleason score (GS) at diagnosis. Methods: All PET/CT images were acquired 60 ± 10 min after intravenous injection of 68 Ga-PSMA (mean dose, 176 MBq). In 147 prostate cancer patients (mean age, 68 y; range, 44-87 y) with prostate-specific antigen relapse (mean prostate-specific antigen level, 5 ng/mL; range, 0.25-294 ng/mL), 362 68 Ga-PSMA PET-positive lymph nodes (LNs) were identified. These patients were classified on the basis of their histopathology at primary diagnosis into either low- (GS ≤ 6, well differentiated), intermediate- (GS = 7, moderately differentiated), or high-GS cohorts (GS ≥ 8, poorly differentiated prostate cancer). Using semiautomated LN segmentation software (Fraunhofer MEVIS), we measured node volume and short-axis dimensions (SADs) and long-axis dimensions based on CT and compared with the SUV max Nodes demonstrating uptake of 68 Ga-PSMA with an SUV max of 2.0 or more were considered PSMA-positive, and nodes with an SAD of 8 mm or more were considered positive by morphologic criteria. Results: Mean SUV max was 13.5 (95% confidence interval [CI], 10.9-16.1), 12.4 (95% CI, 9.9-14.9), and 17.8 (95% CI, 15.4-20.3) within the low-, intermediate-, and high-GS groups, respectively. The morphologic assessment of the 68 Ga-PSMA-positive LN demonstrated that the low-GS cohort presented with smaller 68 Ga-PSMA-positive LNs (mean SAD, 7.7 mm; n = 113), followed by intermediate- (mean SAD, 9.4 mm; n = 122) and high-GS cohorts (mean SAD, 9.5 mm; n = 127). On the basis of the CT morphology criteria, only 34% of low-GS patients, 56% of intermediate-GS patients, and 53% of high-GS patients were considered CT positive. Overall, 68 Ga-PSMA imaging led to a reclassification of stage in 90 patients (61%) from cN0 to cN1 over CT. Conclusion: 68 Ga-PSMA PET is a promising modality in biochemical recurrent prostate cancer patients for N staging. Conventional imaging underestimates LN involvement compared with PSMA molecular staging score in each GS cohort. The sensitivity of 68 Ga-PSMA PET/CT enables earlier detection of subcentimeter LN metastases in the biochemical recurrence setting., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.

68 Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT represents an advanced method for the staging of primary prostate cancer (PCa) and diagnosis of recurrent or metastatic PCa. However, because of the narrow availability of 68 Ga the development of alternative tracers is of high interest. The objective of this study was to examine the value of the new PET tracer 18 F-PSMA-1007 for the staging of local disease by comparing it with multiparametric MRI (mpMRI) and radical prostatectomy (RP) histopathology. Methods: In 2016, 18 F-PSMA-1007 PET/CT was performed in 10 men with biopsy-confirmed high-risk PCa. Nine patients underwent mpMRI in the process of primary diagnosis. Consecutively, RP was performed in all 10 men. Agreement analysis was performed retrospectively. PSMA staining was added for representative sections in RP specimen slices. Localization and agreement analysis of 18 F-PSMA-1007 PET/CT, mpMRI, and RP specimens was performed by dividing the prostate into 38 sections as described in the prostate imaging reporting and data system (PI-RADS) (version 2). Sensitivity, specificity, positive predictive values, negative predictive values (NPVs), and accuracy were calculated for total and near-total agreement. Results: 18 F-PSMA-1007 PET/CT had an NPV of 68% and an accuracy of 75%, and mpMRI had an NPV of 88% and an accuracy of 73% for total agreement. Near-total agreement analysis resulted in an NPV of 91% and an accuracy of 93% for 18 F-PSMA-1007 PET/CT and 91% and 87% for mpMRI, respectively. Retrospective combination of mpMRI and PET/CT had an accuracy of 81% for total and 93% for near-total agreement. Conclusion: Comparison with RP histopathology demonstrates that 18 F-PSMA-1007 PET/CT is promising for accurate local staging of PCa., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Chromosomal instability is a hallmark of cancer and correlates with the presence of extra centrosomes, which originate from centriole overduplication. Overduplicated centrioles lead to the formation of centriole rosettes, which mature into supernumerary centrosomes in the subsequent cell cycle. While extra centrosomes promote chromosome missegregation by clustering into pseudo-bipolar spindles, the contribution of centriole rosettes to chromosome missegregation is unknown. We used multi-modal imaging of cells with conditional centriole overduplication to show that mitotic rosettes in bipolar spindles frequently harbor unequal centriole numbers, leading to biased chromosome capture that favors binding to the prominent pole. This results in chromosome missegregation and aneuploidy. Rosette mitoses lead to viable offspring and significantly contribute to progeny production. We further show that centrosome abnormalities in primary human malignancies frequently consist of centriole rosettes. As asymmetric centriole rosettes generate mitotic errors that can be propagated, rosette mitoses are sufficient to cause chromosome missegregation in cancer., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although PET/CT with 68 Ga-PSMA-11 in the diagnosis of prostate cancer (PCa) is routinely performed at 1 h after injection, later scans may be beneficial because most lesions present with higher uptake and contrast. This evaluation aimed to investigate the clinical impact of additional late 68 Ga-PSMA-11 PET/CT. Methods: Between 2011 and 2016, 112 patients with PCa who underwent early (at 1 h after injection) and late (at 3 h after injection) 68 Ga-PSMA-11 PET/CT scans were retrospectively evaluated. The late scans were conducted to clarify unclear findings in early scans or to increase the probability of tumor detection in the case of negative early scans. All patients were asked to drink 1 L of water between early and late scans. In addition, 20 patients received 20 mg of furosemide before late scans. Tumor detection and radioactivity concentration within the urinary bladder were analyzed in both scans. The SUV max and contrast of 149 tumor lesions were measured in 69 patients with pathologic findings. Results: Overall, 134 lesions characteristic for PCa in 57 patients clearly presented at 1 h after injection and 147 lesions in 68 patients at 3 h after injection. Forty-three patients showed no pathologic findings. Eight patients (7.1%) showed 1 unclear finding in early scans, which could be clarified as characteristic for PCa at 3 h after injection. Four patients (3.6%) presented with 1 lesion characteristic for PCa at 3 h after injection only. Twelve patients (10.7%) presented with 12 possible PCa lesions at 1 h after injection, which, however, could not be confirmed as PCa in late scans. Two patients presented with 1 lesion characteristic for PCa at 1 h after injection, which became invisible at 3 h after injection because of low contrast. At 3 h after injection, 62.4% of the lesions demonstrated a higher SUV max and 65.1% a higher contrast than at 1 h after injection. Patients with furosemide presented with lower SUV and radioactivity concentration within the urinary bladder. Conclusion: 68 Ga-PSMA-11 PET/CT at 3 h after injection showed most lesions characteristic for PCa with a higher uptake and contrast. In addition, the radioactivity signal within the urinary bladder was lower at 3 h after injection, especially when furosemide was applied. Consequently, scans at 3 h after injection detected more tumor lesions than at 1 h after injection., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Dose-response modeling in areas such as toxicology is often conducted using a parametric approach. While estimation of parameters is usually one of the goals, often the main aim of the study is the estimation of quantities derived from the parameters, such as the ED50 dose. From the view of statistical optimal design theory such an objective corresponds to a c-optimal design criterion. Unfortunately, c-optimal designs often create practical problems, and furthermore commonly do not allow actual estimation of the parameters. It is therefore useful to consider alternative designs which show good c-performance, while still being applicable in practice and allowing reasonably good general parameter estimation. In effect, using optimal design terminology this means that a reasonable performance regarding the D-criterion is expected as well. In this article, we propose several approaches to the task of combining c- and D-efficient designs, such as using mixed information functions or setting minimum requirements regarding either c- or D-efficiency, and show how to algorithmically determine optimal designs in each case. We apply all approaches to a standard situation from toxicology, and obtain a much better balance between c- and D-performance. Next, we investigate how to adapt the designs to different parameter values. Finally, we show that the methodology used here is not just limited to the combination of c- and D-designs, but can also be used to handle more general constraint situations such as limits on the cost of an experiment., (© 2016, The International Biometric Society.)

In patients with lung cancer (LC), malignant melanoma (MM), gastroenteropancreatic neuroendocrine tumors (GEP NETs), and prostate cancer (PCA), lymph node (LN) staging is often performed by 18 F-FDG PET/CT (LC and MM), 68 Ga-DOTATOC PET/CT (GEP NET), and 68 Ga-labeled prostate-specific membrane antigen PET/CT (PCA) but is sometimes not accurate because of indeterminate PET findings. To better evaluate malignant LN infiltration, additional surrogate parameters, especially in cases with indeterminate PET findings, would be helpful. The purpose of this study was to evaluate whether SUV max in the PET examination might correlate with semiautomated density measurements of LNs in the CT component of the PET/CT examination., Methods: After approval by the institutional review board, 1,022 LNs in the PET/CT examinations of 148 patients were retrospectively analyzed (LC: 327 LNs of 40 patients; MM: 224 LNs of 33 patients; GEP NET: 217 LNs of 35 patients; and PCA: 254 LNs of 40 patients). PET/CT was performed before surgery, biopsy, chemotherapy, or internal or external radiation therapy, according to the clinical schedule; patients with prior chemotherapy or radiation therapy were excluded. SUV max analyses were based on uptake 60 min after tracer injection, and volumetric CT histogram analyses were based on the unenhanced CT images of the PET/CT scan., Results: PET findings were considered positive or negative on the basis of SUV max in the LN compared with that in the blood pool; histologic confirmation was not available. Of the 1,022 LNs, 331 were PET-positive (3 times the SUV max of the blood pool), 86 were PET-indeterminate (1-3 times the SUV max of the blood pool), and 605 were PET-negative (less than the SUV max of the blood pool). PET-positive LNs had significantly higher CT densities than PET-negative LNs, irrespective of the type of cancer., Conclusion: CT density measurements of LNs in patients with LC, MM, GEP NET, and PCA correlated with 18 F-FDG uptake, 68 Ga-DOTATOC uptake, and 68 Ga-PSMA uptake, respectively, and might therefore serve as an additional surrogate parameter for differentiating between malignant and benign LNs. The use of a 7.5-Hounsfield unit CT density threshold to differentiate between malignant and benign LN infiltration and 20 Hounsfield units to exclude benign LN processes might be possible in clinical routine and would be especially helpful for PET-indeterminate LNs., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)