Publications by authors named "Tim Holland-Letz"

95 Publications

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

Eur J Cancer 2021 11 11;157:464-473. Epub 2021 Oct 11.

Digital Biomarkers for Oncology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: Lymph node status is a prognostic marker and strongly influences therapeutic decisions in colorectal cancer (CRC).

Objectives: The objective of the study is to investigate whether image features extracted by a deep learning model from routine histological slides and/or clinical data can be used to predict CRC lymph node metastasis (LNM).

Methods: Using histological whole slide images (WSIs) of primary tumours of 2431 patients in the DACHS cohort, we trained a convolutional neural network to predict LNM. In parallel, we used clinical data derived from the same cases in logistic regression analyses. Subsequently, the slide-based artificial intelligence predictor (SBAIP) score was included in the regression. WSIs and data from 582 patients of the TCGA cohort were used as the external test set.

Results: On the internal test set, the SBAIP achieved an area under receiver operating characteristic (AUROC) of 71.0%, the clinical classifier achieved an AUROC of 67.0% and a combination of the two classifiers yielded an improvement to 74.1%. Whereas the clinical classifier's performance remained stable on the TCGA set, performance of the SBAIP dropped to an AUROC of 61.2%. Performance of the clinical classifier depended strongly on the T stage.

Conclusion: Deep learning-based image analysis may help predict LNM of patients with CRC using routine histological slides. Combination with clinical data such as T stage might be useful. Strategies to increase performance of the SBAIP on external images should be investigated.
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http://dx.doi.org/10.1016/j.ejca.2021.08.039DOI Listing
November 2021

Efficacy and Safety of Checkpoint Inhibitor Treatment in Patients with Advanced Renal or Urothelial Cell Carcinoma and Concomitant Chronic Kidney Disease: A Retrospective Cohort Study.

Cancers (Basel) 2021 Apr 1;13(7). Epub 2021 Apr 1.

Department of Medical Oncology, National Center of Tumor Diseases (NCT), University Hospital Heidelberg, 69120 Heidelberg, Germany.

: Checkpoint inhibitors are a standard of care in the treatment of advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC). Patients with these tumors often suffer from concomitant chronic kidney disease (CKD). Limited data are available on the efficacy and toxicity of checkpoint inhibitors in patients with CKD. : We retrospectively analyzed 126 patients who received checkpoint inhibitors for RCC ( = 85) or UC ( = 41) and analyzed the frequency of treatment- and immune-related adverse events (AEs). We performed a multivariate analysis to determine progression-free survival (PFS) and overall survival (OS). : A total of 38.9% of patients had CKD. Frequencies of general AEs (49.0% in CKD vs. 48.1%, > 0.99999) and immune-related AEs (28.6 vs. 24.7%, ≥ 0.9999) did not significantly differ between the groups. There was no difference in PFS for patients with RCC or UC and CKD or without CKD (RCC: 6.81 vs. 7.54 months, HR 1.000 (95%CI 0.548-01.822), = 0.999; UC:2.33 vs. 3.67 months, HR 01.492 (95%CI 0.686-3.247), = 0.431). CKD appeared to be a potential effect modifier for OS in both RCC and UC (RCC: NR vs. 23.9 months, HR 0.502 (95%CI 0.219-1.152), = 0.104; UC:18.84 vs. 15.42 months, HR 0.656 (95%CI 0.296-1.454), = 0.299). : Checkpoint inhibitor treatment in our cohort of patients with CKD was as safe and efficient as in the cohort of patients without CKD.
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http://dx.doi.org/10.3390/cancers13071623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036307PMC
April 2021

Predicting the Risk of Metastases by PSMA-PET/CT-Evaluation of 335 Men with Treatment-Naïve Prostate Carcinoma.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Department of Nuclear Medicine, Heidelberg University Hospital, 69120 Heidelberg, Germany.

Men diagnosed with aggressive prostate cancer are at high risk of local relapse or systemic progression after definitive treatment. Treatment intensification is highly needed for that patient cohort; however, no relevant stratification tool has been implemented into the clinical work routine so far. Therefore, the aim of the current study was to analyze the role of initial PSMA-PET/CT as a prediction tool for metastases. In total, 335 men with biopsy-proven prostate carcinoma and PSMA-PET/CT for primary staging were enrolled in the present, retrospective study. The number and site of metastases were analyzed and correlated with the maximum standardized uptake value (SUVmax) of the intraprostatic, malignant lesion. Receiver operating characteristic (ROC) curves were used to determine sensitivity and specificity and a model was created using multiple logistic regression. PSMA-PET/CT detected 171 metastases with PSMA-uptake in 82 patients. A statistically significant higher SUVmax was found for men with metastatic disease than for the cohort without distant metastases (median 16.1 vs. 11.2; < 0.001). The area under the curve (AUC) in regard to predicting the presence of any metastases was 0.65. Choosing a cut-off value of 11.9 for SUVmax, a sensitivity and specificity (factor 1:1) of 76.0% and 58.4% was obtained. The current study confirms, that initial PSMA-PET/CT is able to detect a relatively high number of treatment-naïve men with metastatic prostate carcinoma. Intraprostatic SUVmax seems to be a promising parameter for the prediction of distant disease and could be used for treatment stratification-aspects which should be verified within prospective trials.
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http://dx.doi.org/10.3390/cancers13071508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037082PMC
March 2021

Performance of [Ga]Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer after prostatectomy-a multi-centre evaluation of 2533 patients.

Eur J Nucl Med Mol Imaging 2021 08 4;48(9):2925-2934. Epub 2021 Feb 4.

Department of Nuclear Medicine, Technical University of Munich, Munich, Germany.

Purpose: To evaluate the performance of [Ga]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 [Ga]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 (PSA), PSA velocity (PSA), 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, PSA and PSA were not associated with a higher probability of a pathological scan.

Conclusion: [Ga]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 [Ga]Ga-PSMA-11 PET/CT and age, amount of injected tracer, PSA or PSA.
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http://dx.doi.org/10.1007/s00259-021-05189-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263399PMC
August 2021

Potential therapeutic effect of low-dose paclitaxel in melanoma patients resistant to immune checkpoint blockade: A pilot study.

Cell Immunol 2021 02 28;360:104274. Epub 2020 Dec 28.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cellimm.2020.104274DOI Listing
February 2021

The design heatmap: A simple visualization of -optimality design problems.

Biom J 2020 Oct 14. Epub 2020 Oct 14.

German Cancer Research Center, Division of Biostatistics, Heidelberg, Germany.

Optimal experimental designs are often formal and specific, and not intuitively plausible to practical experimenters. However, even in theory, there often are many different possible design points providing identical or nearly identical information compared to the design points of a strictly optimal design. In practical applications, this can be used to find designs that are a compromise between mathematical optimality and practical requirements, including preferences of experimenters. For this purpose, we propose a derivative-based two-dimensional graphical representation of the design space that, given any optimal design is already known, will show which areas of the design space are relevant for good designs and how these areas relate to each other. While existing equivalence theorems already allow such an illustration in regard to the relevance of design points only, our approach also shows whether different design points contribute the same kind of information, and thus allows tweaking of designs for practical applications, especially in regard to the splitting and combining of design points. We demonstrate the approach on a toxicological trial where a -optimal design for a dose-response experiment modeled by a four-parameter log-logistic function was requested. As these designs require a prior estimate of the relevant parameters, which is difficult to obtain in a practical situation, we also discuss an adaption of our representations to the criterion of Bayesian -optimality. While we focus on -optimality, the approach is in principle applicable to different optimality criteria as well. However, much of the computational and graphical simplicity will be lost.
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http://dx.doi.org/10.1002/bimj.202000087DOI Listing
October 2020

Drawing statistical conclusions from experiments with multiple quantitative measurements per subject.

Radiother Oncol 2020 11 20;152:30-33. Epub 2020 Aug 20.

Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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.
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http://dx.doi.org/10.1016/j.radonc.2020.08.009DOI Listing
November 2020

Diagnostic Accuracy of F-PSMA-1007 PET/CT Imaging for Lymph Node Staging of Prostate Carcinoma in Primary and Biochemical Recurrence.

J Nucl Med 2021 02 17;62(2):208-213. Epub 2020 Aug 17.

Department of Nuclear Medicine, University Hospital, Heidelberg, Germany

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, F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Ninety-six patients with prostate cancer underwent 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. Of the patients, 90.6% received 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. 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. F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.
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http://dx.doi.org/10.2967/jnumed.120.246363DOI Listing
February 2021

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

Front Med (Lausanne) 2020 2;7:233. Epub 2020 Jun 2.

Division of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.

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. 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. 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. The vast majority of participants exhibited a positive attitude toward the use of artificial intelligence in melanoma diagnostics, especially as an assistance system.
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http://dx.doi.org/10.3389/fmed.2020.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326111PMC
June 2020

Clinical outcome of PSMA-guided radiotherapy for patients with oligorecurrent prostate cancer.

Eur J Nucl Med Mol Imaging 2021 01 13;48(1):143-151. Epub 2020 May 13.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.

Purpose: First-line treatment of patients with recurrent, metastatic prostate cancer involves hormone therapy with or without additional systemic therapies. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) allows the detection of oligometastatic disease that may be amenable to image-guided radiotherapy. The current study classifies the type and localization of metastases and the clinical outcome of PSMA-PET/CT-guided radiotherapy to selected metastases.

Materials And Methods: Between 2011 and 2019, 86 patients with recurrent, oligometastatic prostate carcinoma were identified by PSMA-PET/CT and were treated with image-guided radiotherapy of their metastases. Sites of relapse were characterized, and the primary endpoint overall survival (OS), biochemical progression-free survival (bPFS), and androgen deprivation therapy (ADT)-free survival were tabulated.

Results: In total, 37% of the metastases were bone metastases, 48% were pelvic nodal metastases, and 15% were nodal metastases outside of the pelvis. After PSMA-guided radiotherapy, a biochemical response was detected in 83% of the cohort. A statistically significant decrease in the standard uptake value (SUV) was seen in irradiated metastases. After a median follow-up of 26 months, the 3-year OS and bPFS were 84% and 55%, respectively. The median time of ADT-free survival was 13.5 months. A better clinical outcome was observed for patients receiving concomitant ADT or more than 24 fractions of radiation.

Conclusion: PSMA-guided radiotherapy is a promising therapeutic approach with excellent infield control for men with oligorecurrent prostate carcinoma. However, prospective, randomized trials are necessary to determine if this approach confers a survival advantage.
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http://dx.doi.org/10.1007/s00259-020-04777-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835298PMC
January 2021

Multiplex quantitation of 270 plasma protein markers to identify a signature for early detection of colorectal cancer.

Eur J Cancer 2020 03 21;127:30-40. Epub 2020 Jan 21.

Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumour Diseases (NCT), Heidelberg, Germany; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejca.2019.11.021DOI Listing
March 2020

Tumor microenvironment-derived S100A8/A9 is a novel prognostic biomarker for advanced melanoma patients and during immunotherapy with anti-PD-1 antibodies.

J Immunother Cancer 2019 12 5;7(1):343. Epub 2019 Dec 5.

Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Predicting metastasis in melanoma patients is important for disease management and could help to identify those who might benefit from adjuvant treatment. The aim of this study was to investigate whether the tumor microenvironment-derived protein S100A8/A9 qualifies as prognostic marker for melanoma patients, also in the setting of immunotherapy.

Methods: S100A8/A9 gene and protein expression were analyzed on melanocytic nevi, primary melanomas and metastases using a cDNA library and three independent tissue-microarrays (TMA). Serum levels of S100A8/A9 were measured using a specific ELISA in two independent cohorts of 354 stage III and stage IV melanoma patients as well as in two independent cohorts of patients treated with the PD-1 antibody pembrolizumab.

Results: cDNA analysis revealed an upregulation of S100A8 and S100A9 gene expression in melanoma metastases compared to primary melanomas. Significantly higher numbers of infiltrating S100A8/A9 positive cells were found in tissue samples of metastasizing primary melanomas compared to non-metastasizing melanomas (P < .0001) and in melanomas of short-term survivors compared to long-term survivors (P < .0001). Serum S100A8/A9 levels > 5.5 mg/l were associated with impaired overall survival in two independent cohorts (both P < .0001). Importantly, patients with serum elevated S100A8/A9 treated with pembrolizumab showed significantly impaired survival compared to patients with lower S100A8/A9 levels (cohort 1: P = .0051; cohort 2: P < .0001).

Conclusions: The tumor microenvironment-associated protein S100A8/A9 serves as a novel prognostic marker for metastasis and survival of metastatic melanoma patients and predicts response to immunotherapy with pembrolizumab. These data underscore the significance of tumor microenvironment-derived factors as suitable biomarkers for melanoma.
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http://dx.doi.org/10.1186/s40425-019-0828-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896585PMC
December 2019

Modeling dose-response functions for combination treatments with log-logistic or Weibull functions.

Arch Toxicol 2020 01 30;94(1):197-204. Epub 2019 Nov 30.

German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1007/s00204-019-02631-2DOI Listing
January 2020

Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer-a modified protocol compared with the common protocol.

Eur J Nucl Med Mol Imaging 2020 03 1;47(3):624-631. Epub 2019 Nov 1.

Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Purpose: Ga-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 Ga-PSMA-11 PET/CT with a modified protocol.

Methods: In 2017, we used the following scanning protocol for Ga-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.
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http://dx.doi.org/10.1007/s00259-019-04548-5DOI Listing
March 2020

Response Prediction of Lu-PSMA-617 Radioligand Therapy Using Prostate-Specific Antigen, Chromogranin A, and Lactate Dehydrogenase.

J Nucl Med 2020 05 25;61(5):689-695. Epub 2019 Oct 25.

Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.

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 Lu-prostate-specific membrane antigen 617 (PSMA) radioligand therapy (RLT) in comparison with the established tumor markers. 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. 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. 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.
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http://dx.doi.org/10.2967/jnumed.119.231431DOI Listing
May 2020

Superior skin cancer classification by the combination of human and artificial intelligence.

Eur J Cancer 2019 10 10;120:114-121. Epub 2019 Sep 10.

National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany; Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Background: In recent studies, convolutional neural networks (CNNs) outperformed dermatologists in distinguishing dermoscopic images of melanoma and nevi. In these studies, dermatologists and artificial intelligence were considered as opponents. However, the combination of classifiers frequently yields superior results, both in machine learning and among humans. In this study, we investigated the potential benefit of combining human and artificial intelligence for skin cancer classification.

Methods: Using 11,444 dermoscopic images, which were divided into five diagnostic categories, novel deep learning techniques were used to train a single CNN. Then, both 112 dermatologists of 13 German university hospitals and the trained CNN independently classified a set of 300 biopsy-verified skin lesions into those five classes. Taking into account the certainty of the decisions, the two independently determined diagnoses were combined to a new classifier with the help of a gradient boosting method. The primary end-point of the study was the correct classification of the images into five designated categories, whereas the secondary end-point was the correct classification of lesions as either benign or malignant (binary classification).

Findings: Regarding the multiclass task, the combination of man and machine achieved an accuracy of 82.95%. This was 1.36% higher than the best of the two individual classifiers (81.59% achieved by the CNN). Owing to the class imbalance in the binary problem, sensitivity, but not accuracy, was examined and demonstrated to be superior (89%) to the best individual classifier (CNN with 86.1%). The specificity in the combined classifier decreased from 89.2% to 84%. However, at an equal sensitivity of 89%, the CNN achieved a specificity of only 81.5% INTERPRETATION: Our findings indicate that the combination of human and artificial intelligence achieves superior results over the independent results of both of these systems.
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http://dx.doi.org/10.1016/j.ejca.2019.07.019DOI Listing
October 2019

Systematic outperformance of 112 dermatologists in multiclass skin cancer image classification by convolutional neural networks.

Eur J Cancer 2019 09 14;119:57-65. Epub 2019 Aug 14.

National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany; Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Background: Recently, convolutional neural networks (CNNs) systematically outperformed dermatologists in distinguishing dermoscopic melanoma and nevi images. However, such a binary classification does not reflect the clinical reality of skin cancer screenings in which multiple diagnoses need to be taken into account.

Methods: Using 11,444 dermoscopic images, which covered dermatologic diagnoses comprising the majority of commonly pigmented skin lesions commonly faced in skin cancer screenings, a CNN was trained through novel deep learning techniques. A test set of 300 biopsy-verified images was used to compare the classifier's performance with that of 112 dermatologists from 13 German university hospitals. The primary end-point was the correct classification of the different lesions into benign and malignant. The secondary end-point was the correct classification of the images into one of the five diagnostic categories.

Findings: Sensitivity and specificity of dermatologists for the primary end-point were 74.4% (95% confidence interval [CI]: 67.0-81.8%) and 59.8% (95% CI: 49.8-69.8%), respectively. At equal sensitivity, the algorithm achieved a specificity of 91.3% (95% CI: 85.5-97.1%). For the secondary end-point, the mean sensitivity and specificity of the dermatologists were at 56.5% (95% CI: 42.8-70.2%) and 89.2% (95% CI: 85.0-93.3%), respectively. At equal sensitivity, the algorithm achieved a specificity of 98.8%. Two-sided McNemar tests revealed significance for the primary end-point (p < 0.001). For the secondary end-point, outperformance (p < 0.001) was achieved except for basal cell carcinoma (on-par performance).

Interpretation: Our findings show that automated classification of dermoscopic melanoma and nevi images is extendable to a multiclass classification problem, thus better reflecting clinical differential diagnoses, while still outperforming dermatologists at a significant level (p < 0.001).
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http://dx.doi.org/10.1016/j.ejca.2019.06.013DOI Listing
September 2019

Deep neural networks are superior to dermatologists in melanoma image classification.

Eur J Cancer 2019 09 8;119:11-17. Epub 2019 Aug 8.

Department of Dermatology, Heidelberg University, Mannheim, Germany; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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).
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http://dx.doi.org/10.1016/j.ejca.2019.05.023DOI Listing
September 2019

Comparison of PSMA-ligand PET/CT and multiparametric MRI for the detection of recurrent prostate cancer in the pelvis.

Eur J Nucl Med Mol Imaging 2019 Oct 27;46(11):2289-2297. Epub 2019 Jul 27.

Department of Radiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

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.
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http://dx.doi.org/10.1007/s00259-019-04438-wDOI Listing
October 2019

Lymph Node Involvement in Treatment-Naïve Prostate Cancer Patients: Correlation of PSMA PET/CT Imaging and Roach Formula in 280 Men in Radiotherapeutic Management.

J Nucl Med 2020 01 13;61(1):46-50. Epub 2019 Jul 13.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

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. 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. 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. 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.
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http://dx.doi.org/10.2967/jnumed.119.227637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954455PMC
January 2020

Pathologist-level classification of histopathological melanoma images with deep neural networks.

Eur J Cancer 2019 07 23;115:79-83. Epub 2019 May 23.

National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany; Department of Dermatology, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Background: 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.

Methods: 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.

Findings: 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%).

Interpretation: 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.
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http://dx.doi.org/10.1016/j.ejca.2019.04.021DOI Listing
July 2019

Deep learning outperformed 136 of 157 dermatologists in a head-to-head dermoscopic melanoma image classification task.

Eur J Cancer 2019 05 10;113:47-54. Epub 2019 Apr 10.

National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.

Background: Recent studies have successfully demonstrated the use of deep-learning algorithms for dermatologist-level classification of suspicious lesions by the use of excessive proprietary image databases and limited numbers of dermatologists. For the first time, the performance of a deep-learning algorithm trained by open-source images exclusively is compared to a large number of dermatologists covering all levels within the clinical hierarchy.

Methods: We used methods from enhanced deep learning to train a convolutional neural network (CNN) with 12,378 open-source dermoscopic images. We used 100 images to compare the performance of the CNN to that of the 157 dermatologists from 12 university hospitals in Germany. Outperformance of dermatologists by the deep neural network was measured in terms of sensitivity, specificity and receiver operating characteristics.

Findings: The mean sensitivity and specificity achieved by the dermatologists with dermoscopic images was 74.1% (range 40.0%-100%) and 60% (range 21.3%-91.3%), respectively. At a mean sensitivity of 74.1%, the CNN exhibited a mean specificity of 86.5% (range 70.8%-91.3%). At a mean specificity of 60%, a mean sensitivity of 87.5% (range 80%-95%) was achieved by our algorithm. Among the dermatologists, the chief physicians showed the highest mean specificity of 69.2% at a mean sensitivity of 73.3%. With the same high specificity of 69.2%, the CNN had a mean sensitivity of 84.5%.

Interpretation: A CNN trained by open-source images exclusively outperformed 136 of the 157 dermatologists and all the different levels of experience (from junior to chief physicians) in terms of average specificity and sensitivity.
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http://dx.doi.org/10.1016/j.ejca.2019.04.001DOI Listing
May 2019

Impact of sialendoscopy on improving health related quality of life in patients suffering from radioiodineinduced xerostomia.

Nuklearmedizin 2018 Aug 20;57(4):160-167. Epub 2018 Aug 20.

Introduction: Xerostomia following radioiodine therapy (RIT) in patients suffering from differentiated thyroid cancer is a common side effect in 2 % to 67 % of patients treated with radioiodine (I-131). In order to evaluate the impact of sialendoscopy on health related quality of life (HRQOL) in patients suffering from therapy induced sialadenitis and xerostomia, we analyzed findings from two dedicated questionnaires (Xerostomy Questionnaire XQ and Xerostomy Inventory XI) in patients before and three months after sialendoscopy.

Procedures: In total, 12 patients suffering from differentiated thyroid carcinoma (10 women and 2 men) were evaluated. All patients had experienced conservative management. Patients were offered a sialendoscopy procedure if no major contradictions were present. Patients who denied the procedure formed the control group. Pre- and (three months) postoperative HRQOL was measured with the Patient Reported Outcome Measures (PROM) Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI), as well as by a pre- and post-interventional salivary gland scintigram. Patients were graded according to their sialendoscopical findings.

Results: Interventional group presented with significant improvements in HRQOL measurements regarding XQ and XI-scores three months postoperatively. Control group showed no significant changes in the XQ or the XI scores. Number of RIT and cumulative activity of I-131 did not correlate with higher disease grade in regards to sialendoscopical findings nor did it correlate with higher XQand XI scores. Pre- and post-interventional salivary gland scintigram stated that parotid glands are more severely damaged than submandibular glands (SMG), but no significant scintigraphically changes could be detected after sialendoscopy.

Conclusion: Sialendoscopy in patients suffering from therapy induced sialadenitis and xerostomia seems to be beneficial when evaluating the impact on HRQOL. Functional parameters measured by salivary gland scintigram did not show significant changes in post-interventional scintigrams.
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http://dx.doi.org/10.3413/Nukmed-0964-18-03DOI Listing
August 2018

Impact of long-term androgen deprivation therapy on PSMA ligand PET/CT in patients with castration-sensitive prostate cancer.

Eur J Nucl Med Mol Imaging 2018 11 7;45(12):2045-2054. Epub 2018 Jul 7.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.

Purpose: Since the introduction of PSMA PET/CT with Ga-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 Ga-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.
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http://dx.doi.org/10.1007/s00259-018-4079-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182397PMC
November 2018

Mapping Active Gene-Regulatory Regions in Human Repopulating Long-Term HSCs.

Cell Stem Cell 2018 Jul;23(1):132-146.e9

Department of Translational and Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Translational Medical Oncology, NCT-Dresden, University Hospital, Carl Gustav Carus, Technische Universität Dresden, Dresden and DKFZ, Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address:

Genes that regulate hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation are tightly controlled by regulatory regions. However, mapping such regions relies on surface markers and immunophenotypic definition of HSCs. Here, we use γ-retroviral integration sites (γRV ISs) from a gene therapy trial for 10 patients with Wiskott-Aldrich syndrome to mark active enhancers and promoters in functionally defined long-term repopulating HSCs. Integration site clusters showed the highest ATAC-seq signals at HSC-specific peaks and strongly correlated with hematopoietic risk variants. Tagged genes were significantly enriched for HSC gene sets. We were able to map over 3,000 HSC regulatory regions in late-contributing HSCs, and we used these data to identify miR-10a and miR-335 as two miRNAs regulating early hematopoiesis. In this study, we show that viral insertion sites can be used as molecular tags to assess chromatin conformation on functionally defined cell populations, thereby providing a genome-wide resource for regulatory regions in human repopulating long-term HSCs.
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http://dx.doi.org/10.1016/j.stem.2018.06.003DOI Listing
July 2018

Ga-PSMA-11 PET/CT in Primary and Recurrent Prostate Carcinoma: Implications for Radiotherapeutic Management in 121 Patients.

J Nucl Med 2019 02 5;60(2):234-240. Epub 2018 Jul 5.

University Hospital Heidelberg, Germany.

The present study analyzed the impact of Gallium-68 (Ga)-labeled prostate-specific membrane antigen-HBED-CC (Ga-PSMA-11) positron-emission tomography (PET)/computed tomography (CT) on radiotherapeutic management in a large cohort of men with primary or recurrent disease. This study investigated 121 men with carcinoma of the prostate who underwent 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 Ga-PSMA-11 imaging were compared to results achieved with conventional imaging. 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. 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.
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http://dx.doi.org/10.2967/jnumed.118.211086DOI Listing
February 2019

Impact of Computer-Aided CT and PET Analysis on Non-invasive T Staging in Patients with Lung Cancer and Atelectasis.

Mol Imaging Biol 2018 12;20(6):1044-1052

Department of Nuclear Medicine, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.

Purpose: Tumor delineation within an atelectasis in lung cancer patients is not always accurate. When T staging is done by integrated 2-deoxy-2-[F]fluoro-D-glucose ([F]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 [F]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 [F]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 [F]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 [F]FDG.
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http://dx.doi.org/10.1007/s11307-018-1196-9DOI Listing
December 2018

Evaluation of Promoter Methylation of RASSF1A and ATM in Peripheral Blood of Breast Cancer Patients and Healthy Control Individuals.

Int J Mol Sci 2018 Mar 19;19(3). Epub 2018 Mar 19.

Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg 69120, Germany.

Breast cancer (BC) is the most common cancer among women and has high mortality rates. Early detection is supposed to be critical for the patient's prognosis. In recent years, several studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop putative screening markers for cancer. However, most of the studies have not yet been validated. In our study, we analyzed the promoter methylation of and in peripheral blood DNA of 229 sporadic patients and 151 healthy controls by the MassARRAY EpiTYPER assay. There were no significant differences in DNA methylation levels of and between the sporadic BC cases and the healthy controls. Furthermore, we performed the Infinium HumanMethylation450 BeadChip (450K) array analysis using 48 sporadic BC cases and 48 healthy controls (cases and controls are the same from those of the MassARRAY EpiTYPER assay) and made a comparison with the published data. No significant differences were presented in DNA methylation levels of and between the sporadic BC cases and the healthy controls. So far, the evidence for powerful blood-based methylation markers is still limited and the identified markers need to be further validated.
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http://dx.doi.org/10.3390/ijms19030900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877761PMC
March 2018
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