Influence of Lymphatic, Microvascular and Perineural Invasion on Oncological Outcome in Patients with Neuroendocrine Tumors of the Small Intestine.

For the histopathological work-up of resected neuroendocrine tumors of the small intestine (siNET), the determination of lymphatic (LI), microvascular (VI) and perineural (PnI) invasion is recommended. Their association with poorer prognosis has already been demonstrated in many tumor entities. However, the influence of LI, VI and PnI in siNET has not been sufficiently described yet. A retrospective analysis of all patients treated for siNET at the ENETS Center of Excellence Charité-Universitätsmedizin Berlin, from 2010 to 2020 was performed (n = 510). Patients who did not undergo primary resection or had G3 tumors were excluded. In the entire cohort (n = 161), patients with LI, VI and PnI status had more distant metastases (48.0% vs. 71.4%, p = 0.005; 47.1% vs. 84.4%, p < 0.001; 34.2% vs. 84.7%, p < 0.001) and had lower rates of curative surgery (58.0% vs. 21.0%, p < 0.001; 48.3% vs. 16.7%, p < 0.001; 68.4% vs. 14.3%, p < 0.001). Progression-free survival was significantly reduced in patients with LI, VI or PnI compared to patients without. This was also demonstrated in patients who underwent curative surgery. Lymphatic, vascular and perineural invasion were associated with disease progression and recurrence in patients with siNET, and these should therefore be included in postoperative treatment considerations.

Discovering Process Dynamics for Scalable Perovskite Solar Cell Manufacturing with Explainable AI.

Large-area processing of perovskite semiconductor thin-films is complex and evokes unexplained variance in quality, posing a major hurdle for the commercialization of perovskite photovoltaics. Advances in scalable fabrication processes are currently limited to gradual and arbitrary trial-and-error procedures. While the in situ acquisition of photoluminescence (PL) videos has the potential to reveal important variations in the thin-film formation process, the high dimensionality of the data quickly surpasses the limits of human analysis. In response, this study leverages deep learning (DL) and explainable artificial intelligence (XAI) to discover relationships between sensor information acquired during the perovskite thin-film formation process and the resulting solar cell performance indicators, while rendering these relationships humanly understandable. The study further shows how gained insights can be distilled into actionable recommendations for perovskite thin-film processing, advancing toward industrial-scale solar cell manufacturing. This study demonstrates that XAI methods will play a critical role in accelerating energy materials science.

A community-endorsed open-source lexicon for contrast agent-based perfusion MRI: A consensus guidelines report from the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

This manuscript describes the ISMRM OSIPI (Open Science Initiative for Perfusion Imaging) lexicon for dynamic contrast-enhanced and dynamic susceptibility-contrast MRI. The lexicon was developed by Taskforce 4.2 of OSIPI to provide standardized definitions of commonly used quantities, models, and analysis processes with the aim of reducing reporting variability. The taskforce was established in February 2020 and consists of medical physicists, engineers, clinicians, data and computer scientists, and DICOM (Digital Imaging and Communications in Medicine) standard experts. Members of the taskforce collaborated via a slack channel and quarterly virtual meetings. Members participated by defining lexicon items and reporting formats that were reviewed by at least two other members of the taskforce. Version 1.0.0 of the lexicon was subject to open review from the wider perfusion imaging community between January and March 2022, and endorsed by the Perfusion Study Group of the ISMRM in the summer of 2022. The initial scope of the lexicon was set by the taskforce and defined such that it contained a basic set of quantities, processes, and models to enable users to report an end-to-end analysis pipeline including kinetic model fitting. We also provide guidance on how to easily incorporate lexicon items and definitions into free-text descriptions (e.g., in manuscripts and other documentation) and introduce an XML-based pipeline encoding format to encode analyses using lexicon definitions in standardized and extensible machine-readable code. The lexicon is designed to be open-source and extendable, enabling ongoing expansion of its content. We hope that widespread adoption of lexicon terminology and reporting formats described herein will increase reproducibility within the field.

RNA contact prediction by data efficient deep learning.

On the path to full understanding of the structure-function relationship or even design of RNA, structure prediction would offer an intriguing complement to experimental efforts. Any deep learning on RNA structure, however, is hampered by the sparsity of labeled training data. Utilizing the limited data available, we here focus on predicting spatial adjacencies ("contact maps") as a proxy for 3D structure. Our model, BARNACLE, combines the utilization of unlabeled data through self-supervised pre-training and efficient use of the sparse labeled data through an XGBoost classifier. BARNACLE shows a considerable improvement over both the established classical baseline and a deep neural network. In order to demonstrate that our approach can be applied to tasks with similar data constraints, we show that our findings generalize to the related setting of accessible surface area prediction.

The impact of tumor metabolic activity assessed by 18F-FET amino acid PET imaging in particle radiotherapy of high-grade glioma patients.

Background: Selective uptake of (18)F-fluoro-ethyl-tyrosine (18F-FET) is used in high-grade glioma (HGG) to assess tumor metabolic activity via positron emission tomography (PET). We aim to investigate its value for target volume definition, as a prognosticator, and associations with whole-blood transcriptome liquid biopsy (WBT lbx) for which we recently reported feasibility to mirror tumor characteristics and response to particle irradiation in recurrent HGG (rHGG). Methods: 18F-FET-PET data from n = 43 patients with primary glioblastoma (pGBM) and n = 33 patients with rHGG were assessed. pGBM patients were irradiated with photons and sequential proton/carbon boost, and rHGG patients were treated with carbon re-irradiation (CIR). WBT (Illumina HumanHT-12 Expression BeadChips) lbx was available for n = 9 patients from the rHGG cohort. PET isocontours (40%-70% SUVmax, 10% steps) and MRI-based treatment volumes (MRIvol) were compared using the conformity index (CI) (pGBM, n = 16; rHGG, n = 27). Associations with WBT lbx data were tested on gene expression level and inferred pathways activity scores (PROGENy) and from transcriptome estimated cell fractions (CIBERSORT, xCell). Results: In pGBM, median SUVmax was higher in PET acquired pre-radiotherapy (4.1, range (R) 1.5-7.8; n = 20) vs. during radiotherapy (3.3, R 1.5-5.7, n = 23; p = 0.03) and in non-resected (4.7, R 2.9-7.9; n = 11) vs. resected tumors (3.3, R 1.5-7.8, n = 32; p = 0.01). In rHGG, a trend toward higher SUVmax values in grade IV tumors was observed (p = 0.13). Median MRIvol was 32.34 (R 8.75-108.77) cm3 in pGBM (n = 16) and 20.77 (R 0.63-128.44) cm3 in rHGG patients (n = 27). The highest median CI was observed for 40% (pGBM, 0.31) and 50% (rHGG, 0.43, all tumors) isodose, with 70% (40%) isodose in grade III (IV) rHGG tumors (median CI, 0.38 and 0.49). High SUVmax was linked to shorter survival in pGBM (>3.3, p = 0.001, OR 6.0 [2.1-17.4]) and rHGG (>2.8, p = 0.02, OR 4.1 [1.2-13.9]). SUVmax showed associations with inferred monocyte fractions, hypoxia, and TGFbeta pathway activity and links to immune checkpoint gene expression from WBT lbx. Conclusion: The benefits of 18F-FET-PET imaging on gross tumor volume (GTV) definition for particle radiotherapy warrant further evaluation. SUVmax might assist in prognostic stratification of HGG patients for particle radiotherapy, highlights heterogeneity in rHGG, and is positively associated with unfavorable signatures in peripheral whole-blood transcriptomes.

[Robot-assisted Distal Pancreatectomy with En Bloc Celiac Axis Resection (Modified Appleby Procedure) after Neoadjuvant Therapy]. / Robotisch assistierte Resektion eines zentralen neoadjuvant behandelten Pankreaskarzinoms mit En-bloc-Resektion des Truncus coeliacus (modifizierte Appleby-Operation).

Pancreatic carcinoma in the body and on the left side of the mesentericoportal axis is often only detected in late stages owing to unspecific or even missing clinical symptoms. In approximately 20% of the cases, there is already infiltration of the tumour into the surrounding arteries or veins. Despite locally advanced growth, 30% of patients do not have distant metastases and would potentially qualify for local resection. Arterial resections and vascular reconstruction are associated with an almost 9-fold increase in postoperative mortality compared with resections without vascular reconstruction. The Appleby procedure is a complex surgical technique originally developed for advanced gastric cancer. The technique has been further developed for patients with advanced pancreatic body and tail tumours with infiltration of the coeliac trunk (modified Appleby procedure). The advantage of the procedure is that technically, no reconstruction of the resected arteries is required. This is because a natural internal anastomosis in the pancreatic head between the A. mesenterica superior and the A. hepatica via branches of the A. gastroduodenalis is used to maintain liver perfusion and gastric blood flow. However, the surgical procedure is also associated with high morbidity and mortality, with comparably poor oncological results (R0 rates of approximately 60%). Therefore, the procedure was not recommended until a few years ago, and patients were considered inoperable. With developments in neoadjuvant therapy for pancreatic carcinoma, the Appleby procedure is being performed more frequently, with the goal of improving oncological outcomes in the context of multimodal treatment. With developments in robotics in visceral surgery, the previous limitations of minimally invasive pancreatic surgery can be overcome, and significantly more patients may benefit from the advantages of this minimally invasive surgery, such as faster convalescence. The use of robotic surgical techniques allows the extension of minimally invasive techniques into the field of complex vessel resection and reconstruction. In this video contribution, we describe a robot-assisted modified Appleby procedure using the Da Vinci Xi Surgical System in a patient with advanced pancreatic carcinoma of the pancreatic body, after neoadjuvant therapy.

[Evidence in minimally invasive surgery of the pancreas]. / Evidenz in der minimal-invasiven Pankreaschirurgie.

Minimally invasive pancreatic surgery lags behind the development of other fields of application of minimally invasive surgery. After a very slow development over the last two decades minimally invasive pancreatic surgery has currently gained wider acceptance especially in centers. This is due if nothing else, to the increasing availability of robotic assistance systems, which provide maneuverable instruments as well as a 3­dimensional and enlarged view. Meanwhile, the technical feasibility for even complex pancreatic resections has been shown. This gives rise to the question whether laparoscopic or robotic techniques can generate equal or better results (evidence) with respect to perioperative morbidity, survival after oncological resection and the quality of life. As with all innovative techniques, which are implemented in surgery, the transferability to a wider audience, teaching methods and cost-effectiveness have to be evaluated. This article presents the current scientific evidence for laparoscopic and robotic pancreatic head and left-sided pancreatic surgery.

[Indications for Surgical Therapy in Chronic Pancreatitis]. / Operationsindikationen bei der chronischen Pankreatitis.

Chronic pancreatitis is a recurrent disease with repeating exacerbations of inflammation of the pancreatic gland - associated with belt-like back pain. Without treatment, recurrent chronic pancreatitis leads to development of opioid-dependent pain. The chronic pancreatitis leads to recurrent hospital stays for the affected patient and socioeconomic challenges. In progress it can lead to local complications of chronic pancreatitis, such as formation of pseudocysts, biliary duct obstruction, duodenal obstruction or portal hypertension. The aim of this article is a detailed description of the indication for surgical therapy in chronic pancreatitis. The underlying analysis was a systematic literature research and evaluation, the formulation of key questions according to the PICO system and the evaluation of indications and key statements and questions, as implemented in a three level Delphi process among the members of the pancreas research group and the indications for the surgery group of the German Society of General and Visceral Surgery (DGAV). Surgical resection of the inflammatory pancreatic head pseudotumour, after initial conservative therapy, is a highly efficient therapy for the control of pain and the avoidance of complications in chronic pancreatitis. For this purpose, well evaluated surgical strategies are available. Delay in surgical therapy can lead to chronic pain, kachexia and malnutrition and increase complications of surgical therapy.

[Indications for Surgery in Pancreatic Ductal Adenocarcinoma - Consensus Recommendations by the German Society for General and Visceral Surgery]. / Von der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie konsentierte Operationsindikationen beim duktalen Pankreasadenokarzinom.

BACKGROUND: Surgery for pancreatic cancer in Germany is increasing due to the climbing incidence of this cancer in the population. This review presents a summary of modern evidence-based indications for surgery in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The German Society for General and Visceral Surgery (DGAV) authorised a task force to define evidence based indications for surgery in patients with PDAC. A systematic literature search in Medline and Cochrane Library databases (1989 - 2019) was performed. Recommendations were summarised on the basis of the most relevant and recent guidelines and clinical studies and then voted by members of the Working Group on Hepato-Biliary and Pancreatic Diseases (CALGP) in a Delphi procedure. RESULTS: Indications for surgery in patients with PDAC should be set by experienced pancreatic surgeons within a tumour board. Decisions should consider the guidelines as well as the individual patient characteristics. Large vessel infiltration, metastatic disease and severe comorbidities are the most common contraindications for surgery. Borderline-resectable, primary resectable oligometastatic and secondary resectable PDAC should be preferably managed at high-volume centres as a part of clinical studies. Centralisation of pancreatic surgery reduces mortality and improves survival. Palliative bypass surgery as well as staging laparoscopy are still indicated in a large proportion of patients with PDAC. CONCLUSION: Irrespective of the recent development of multimodal therapeutic concepts, surgical resection remains the sole chance of long-term cure for patients with PDAC. Due to the significant proportion of patients in advanced stages of the disease, palliative surgery still plays an important role in the complex management of this cancer.

[Indications for the Surgical Management of Pancreatic Neuroendocrine Neoplasms]. / Operationsindikationen bei neuroendokrinen Neoplasien des Pankreas.

Neuroendocrine neoplasms of the pancreas (pNEN) have an increasing incidence and prevalence. Thus, this entity is of increasing clinical significance. Patients with pNEN become clinically apparent due to different and unspecific symptoms. Some tumours secrete hormones and peptides and become clinically symptomatic. In general, these tumours can metastasise early and even small tumours lead to distant metastases. Nonetheless, primary tumour size and grading are important prognostic factors. On the basis of a systematic literature research and the formulation of key issues according to the PICO system, therapeutic concepts were established. These concepts were evaluated with a Delphi process among the members of the pancreas research group and the indications for surgery group of the German Society of General and Visceral Surgery. Thus this article gives an overview of the surgical treatment modalities and indications for the treatment of pNEN. Surgery is still the gold standard in treatment and the only potential chance of cure. Surgery is indicated for sporadic as well as hereditary pNEN > 2 cm independent of the functional activity. A so called "wait and see" strategy might be indicated in smaller pNEN; however, there is little evidence for this approach. In this respect, pNEN of 1 - 2 cm represent a surgical indication. The treatment of hereditary pNEN is challenging and should be interdisciplinary. Even in the case of distant metastases, a curative approach might be feasible and multimodal treatment is indicated.

[Indications for Surgical and Interventional Therapy of Acute Pancreatitis]. / Indikationen zur chirurgischen und interventionellen Behandlung der akuten Pankreatitis.

BACKGROUND: 15 to 20% of patients with acute pancreatitis develop necrosis of the pancreatic parenchyma or extrapancreatic tissue. The disease is associated with a mortality rate of up to 20%. The mainstays of treatment consist of intensive medical care and surgical and interventional therapy. METHODS: A systematic literature search focused on indications for surgical and interventional therapy of necrotising pancreatitis. 85 articles were analysed for this review. By using the Delphi method, the results were presented to the quality committee for pancreas diseases of the German Society for General and Visceral Surgery and to expert pancreatologists in an interactive conference using plenary voting during the visceral medicine congress 2019 in Wiesbaden. For the finalised recommendations, an agreement of 84% of participants was achieved. RESULTS: Documented or clinical suspicion of infected, necrotising pancreatitis are indications for surgical and interventional therapy (recommendation grade: strong; evidence grade; low). Sterile necrosis is a less common indication for intervention due to late complications or persistent severe pancreatitis. Invasive interventions should be delayed when possible until four weeks after onset of pancreatitis. Optimal treatment strategy consists of a "step-up approach" (evidence grade: high; recommendation grade: strong). The first step is catheter drainage, followed, if necessary, by minimally invasive surgical or interventional necrosectomy. If minimally invasive techniques do not result in clinical improvement, open necrosectomy is necessary. 35 to 50% of patients are successfully treated with drainage alone. Indications for emergency intervention are bowel perforation, bowel ischemia and bleeding. Surgical decompression of abdominal compartment syndrome is indicated if the patient is refractory to medical treatment and percutaneous drainage. Abscesses and symptomatic pseudocysts are indications for interventional drainage. Early cholecystectomy during index admission is recommended for patients with mild biliary pancreatitis. Cholecystectomy should be delayed after severe, biliary pancreatitis. CONCLUSION: The recommendations for surgical an interventional therapy of necrotising pancreatitis address the basis of current indications in literature. They should serve in daily practice as a reference standard for decision making in multidisciplinary teams.

[Indications for the Surgical Management of Pancreatic Cystic Lesions]. / Operationsindikationen bei zystischen Tumoren des Pankreas.

A steady improvement in modern imaging as well as increasing age in society have led to an increasing number of cystic pancreatic tumours being detected. Pancreatic cysts are a clinically challenging entity because they span a broad biological spectrum and their differentiation is often difficult, especially in small tumours. Therefore, they require a differentiated indication for indication of surgery. To determine recommendations for the surgical indication in cystic tumours of the pancreas, a quality committee for pancreatic diseases of the German Society for General and Visceral Surgery performed a systematic literature search and created this review. Based on the current evidence, signs of malignancy and high-risk criteria (icterus due to cystic pancreatic duct obstruction in the bile duct, enhancing mural nodules ≥ 5 mm or solid components in the cyst or pancreatic duct ≥ 10 mm), as well as symptoms, are a surgical indication, independently of the cyst entity (except pseudocysts). If the entity of the pancreatic cyst is detectable by diagnostic imaging, all main duct IPMN and IPMN of the mixed type, all MCN > 4 cm and all SPN should be resected. SCN and branch-duct IPMN without worrisome features do not constitute an indication for surgery. The indication of operation in branch-duct IPMN with relative risk criteria and MCN < 4 cm is the subject of current discussions and should be individualised. By defining indication recommendations, the present work aims to improve the indication quality in cystic pancreatic tumours. However, the surgical indication should always be individualised, taking into account age, comorbidities and the patient's wishes.

[Robot-assisted Pancreatic Surgery]. / Robotergestützte Bauchspeicheldrüsenchirurgie.

INTRODUCTION: The use of robots in minimally invasive surgery has become increasingly common in recent years. Robot-assisted pancreatoduodenectomy is more frequent than the laparoscopic procedure especially due to the greater flexibility of instruments and therefore better handling and better angulation. Furthermore, there are benefits from enhanced 3D visibility, software-based tremor control and reduction in the physical exertion of the surgeon. METHODS AND RESULTS: This review delivers a point-by-point approach to the setup of a robotic pancreatic programme and a detailed approach to robot-assisted pancreatoduodenectomy. RESULTS: In our standardised SOP approach, we use 5 trocars, 4 robotic trocars and one assist trocar. We prefer the position of the robot ports to be in a straight horizontal line with a distance of 20 cm away from the operational field. The operation is dissected in 11 standardised procedural steps, namely 1. Access to the pancreas and visualisation, 2. extended Kocher manoeuvre, 3. lower rim and mesenterico-portal axis, 4. upper rim and hepato-duodenal ligament, 5. dissection of the pancreatic neck, 6. mesenteric root and pars IV duodeni, 7. mesopancreas, 8. pancreatic anastomosis reconstruction, 9. bilio-enteric anastomosis, 10. dudenojejunal anastomosis, 11. drainage and closure. The set up of the pancreas program and the structured approach to complex pancreatic resections are elucidated. SUMMARY: In summary, this review describes the approach to robotic pancreatic surgery in a high-volume pancreas centre at a structural and procedural level, in order to support establishment of such programs at other locations.

[Robot-Assisted Upper Gastrointestinal and Hepato-Pancreato-Biliary Surgery: Implementation Using a Stepwise Approach and Analyses of the First 100 Surgical Procedures]. / Robotisch assistierte obere gastrointestinale und hepatopankreatobiliäre Chirurgie: Etablierung durch einen Stepwise Approach und eine Analyse der ersten 100 Operationen.

INTRODUCTION: Robot-assisted surgery is a promising technique for overcoming the limitations of laparoscopic surgery, especially for complex and advanced surgical procedures. We now describe the implementation of our robotic upper GI and HPB surgery program in our centre of excellence for minimally invasive surgery and the results of our first 100 surgical procedures. METHOD: Robot-assisted surgery was performed using the Da Vinci® Xi Surgical System™. Robot-assisted surgical procedures were performed by two surgeons specialising in minimally invasive surgery. Our robotic surgery program for upper GI and HPB surgery was established in three steps. Step 1: firstly, relatively easy surgical procedures were performed robotically, including cholecystectomies, minor gastric resections and fundoplications. Step 2: secondly, pancreatic left sided resections, adrenalectomies and small liver resection were performed, as procedures with moderate degree of difficulty. Step 3: finally, advanced and highly complex procedures were performed, including right hemihepatectomy, complex pancreatic resections, total gastrectomies and oesophagectomies. Data collected from July 2017 till October 2018 were analysed retrospectively with regard to conversion rate, morbidity (Clavien Dindo > 2) and 90-d-mortality. RESULTS: The first step of establishing our robotic surgical program included 26 procedures. Here, conversion rate, morbidity and mortality were 0%. In the second step of implementation, 23 procedures were performed. Conversion rate, morbidity and mortality were 28, 8 and 0% respectively. The last step included 51 advanced and highly complex procedures. These procedures had a morbidity of 41%, a mortality of 4% and a conversion rate of 43%. CONCLUSION: Our stepwise approach enables safe implementation of a robotic surgical program for upper GI and HPB surgery with comparable morbidity and mortality even for highly complex procedures. However, highly complex procedures in the learning curve required a high conversion rate.

Robot-Assisted Pancreatic Surgery: A Structured Approach to Standardization of a Program and of the Operation.

INTRODUCTION: The use of robots in minimal invasive surgery has become increasingly common in recent years. Robot-assisted pancreatoduodenectomy preponderates against a laparoscopic procedure especially due to the greater flexibility of instruments and therefore a better handling and a better angulation. Furthermore, there are benefits of enlarged 3-D visibility, software-based tremor control, and reduced physical exertion of the surgeon. METHODS AND RESULTS: This review delivers a point-by-point approach to the setup of a robot-assisted pancreatic program and a detailed approach to robot-assisted pancreatoduodenectomy. RESULTS: In our standardized standard operating procedure approach we use 5 trocars, i.e., 4 robotic trocars and 1 assist trocar. We prefer the position of the robot ports in a straight horizontal line with a distance of 20 cm from the operational field. The operation is dissected into 11 standardized procedural steps as follows: (1) access to the pancreas and visualization, (2) extended Kocher manoeuvre, (3) lower rim and mesentericoportal axis, (4) upper rim and hepatoduodenal ligament, (5) dissection of the pancreatic neck, (6) mesenteric root and pars IV duodeni, (7) mesopancreas, (8) pancreatic anastomosis reconstruction, (9) bilioenteric anastomosis, (10) dudenojejunal anastomosis, and (11) drainage and closure. The setup of the pancreas program and the structured approach to complex pancreatic resections are elucidated. SUMMARY: This review describes the approach to robot-assisted pancreatic surgery in a high-volume pancreas center on a structural and procedural level to support the establishment of such programs at other locations.

Impact of Single Dose Photons and Carbon Ions on Perfusion and Vascular Permeability: A Dynamic Contrast-Enhanced MRI Pilot Study in the Anaplastic Rat Prostate Tumor R3327-AT1.

We collected initial quantitative information on the effects of high-dose carbon (12C) ions compared to photons on vascular damage in anaplastic rat prostate tumors, with the goal of elucidating differences in response to high-LET radiation, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Syngeneic R3327-AT1 rat prostate tumors received a single dose of either 16 or 37 Gy 12C ions or 37 or 85 Gy 6 MV photons (iso-absorbed and iso-effective doses, respectively). The animals underwent DCE-MRI prior to, and on days 3, 7, 14 and 21 postirradiation. The extended Tofts model was used for pharmacokinetic analysis. At day 21, tumors were dissected and histologically examined. The results of this work showed the following: 1. 12C ions led to stronger vascular changes compared to photons, independent of dose; 2. Tumor growth was comparable for all radiation doses and modalities until day 21; 3. Nonirradiated, rapidly growing control tumors showed a decrease in all pharmacokinetic parameters (area under the curve, Ktrans, ve, vp) over time; 4. 12C-ion-irradiated tumors showed an earlier increase in area under the curve and Ktrans than photon-irradiated tumors; 5. 12C-ion irradiation resulted in more homogeneous parameter maps and histology compared to photons; and 6. 12C-ion irradiation led to an increased microvascular density and decreased proliferation activity in a largely dose-independent manner compared to photons. Postirradiation changes related to 12C ions and photons were detected using DCE-MRI, and correlated with histological parameters in an anaplastic experimental prostate tumor. In summary, this pilot study demonstrated that exposure to 12C ions increased the perfusion and/or permeability faster and led to larger changes in DCE-MRI parameters resulting in increased vessel density and presumably less hypoxia at the end of the observation period when compared to photons. Within this study no differences were found between curative and sub-curative doses in either modality.

MITK-ModelFit: A generic open-source framework for model fits and their exploration in medical imaging - design, implementation and application on the example of DCE-MRI.

BACKGROUND: Many medical imaging techniques utilize fitting approaches for quantitative parameter estimation and analysis. Common examples are pharmacokinetic modeling in dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI)/computed tomography (CT), apparent diffusion coefficient calculations and intravoxel incoherent motion modeling in diffusion-weighted MRI and Z-spectra analysis in chemical exchange saturation transfer MRI. Most available software tools are limited to a special purpose and do not allow for own developments and extensions. Furthermore, they are mostly designed as stand-alone solutions using external frameworks and thus cannot be easily incorporated natively in the analysis workflow. RESULTS: We present a framework for medical image fitting tasks that is included in the Medical Imaging Interaction Toolkit MITK, following a rigorous open-source, well-integrated and operating system independent policy. Software engineering-wise, the local models, the fitting infrastructure and the results representation are abstracted and thus can be easily adapted to any model fitting task on image data, independent of image modality or model. Several ready-to-use libraries for model fitting and use-cases, including fit evaluation and visualization, were implemented. Their embedding into MITK allows for easy data loading, pre- and post-processing and thus a natural inclusion of model fitting into an overarching workflow. As an example, we present a comprehensive set of plug-ins for the analysis of DCE MRI data, which we validated on existing and novel digital phantoms, yielding competitive deviations between fit and ground truth. CONCLUSIONS: Providing a very flexible environment, our software mainly addresses developers of medical imaging software that includes model fitting algorithms and tools. Additionally, the framework is of high interest to users in the domain of perfusion MRI, as it offers feature-rich, freely available, validated tools to perform pharmacokinetic analysis on DCE MRI data, with both interactive and automatized batch processing workflows.

Bolus arrival time estimation in dynamic contrast-enhanced magnetic resonance imaging of small animals based on spline models.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is used to quantify perfusion and vascular permeability. In most cases a bolus arrival time (BAT) delay exists between the arterial input function (AIF) and the contrast agent arrival in the tissue of interest which needs to be estimated. Existing methods for BAT estimation are tailored to tissue concentration curves, which have a fast upslope to the peak as frequently observed in patient data. However, they may give poor results for curves that do not have this characteristic shape such as tissue concentration curves of small animals. In this paper, we propose a method for BAT estimation of signals that do not have a fast upslope to their peak. The model is based on splines which are able to adapt to a large variety of concentration curves. Furthermore, the method estimates BATs on a continuous time scale. All relevant model parameters are automatically determined by generalized cross validation. We use simulated concentration curves of small animal and patient settings to assess the accuracy and robustness of our approach. The proposed method outperforms a state-of-the-art method for small animal data and it gives competitive results for patient data. Finally, it is tested on in vivo acquired rat data where accuracy of BAT estimation was also improved upon the state-of-the-art method. The results indicate that the proposed method is suitable for accurate BAT estimation of DCE-MRI data, especially for small animals.

Feasibility and robustness of dynamic 18F-FET PET based tracer kinetic models applied to patients with recurrent high-grade glioma prior to carbon ion irradiation.

The aim of this study was to analyze the robustness and diagnostic value of different compartment models for dynamic 18F-FET PET in recurrent high-grade glioma (HGG). Dynamic 18F-FET PET data of patients with recurrent WHO grade III (n:7) and WHO grade IV (n: 9) tumors undergoing re-irradiation with carbon ions were analyzed by voxelwise fitting of the time-activity curves with a simplified and an extended one-tissue compartment model (1TCM) and a two-tissue compartment model (2TCM), respectively. A simulation study was conducted to assess robustness and precision of the 2TCM. Parameter maps showed enhanced detail on tumor substructure. Neglecting the blood volume VB in the 1TCM yields insufficient results. Parameter K1 from both 1TCM and 2TCM showed correlation with overall patient survival after carbon ion irradiation (p = 0.043 and 0.036, respectively). The 2TCM yields realistic estimates for tumor blood volume, which was found to be significantly higher in WHO IV compared to WHO III (p = 0.031). Simulations on the 2TCM showed that K1 yields good accuracy and robustness while k2 showed lowest stability of all parameters. The 1TCM provides the best compromise between parameter stability and model accuracy; however application of the 2TCM is still feasible and provides a more accurate representation of tracer-kinetics at the cost of reduced robustness. Detailed tracer kinetic analysis of 18F-FET PET with compartment models holds valuable information on tumor substructures and provides additional diagnostic and prognostic value.

Impact of 18F-FET PET on Target Volume Definition and Tumor Progression of Recurrent High Grade Glioma Treated with Carbon-Ion Radiotherapy.

High-precision radiotherapy (HPR) of recurrent high grade glioma (HGG) requires accurate spatial allocation of these infiltrative tumors. We investigated the impact of 18F-FET PET on tumor delineation and progression of recurrent HGG after HPR with carbon ions. T1 contrast enhanced MRI and 18F-FET-PET scans of 26 HGG patients were fused with radiotherapy planning volumes. PET-positive (PET+) tumor volumes using different isocontours (I%) were systematically investigated and compared with MRI-derived gross tumor volumes (GTV). Standardized uptake ratios (SUR) were further correlated with GTV and tumor progression patterns. In grade IV glioma, SUR > 2.92 significantly correlated with poor median overall survival (6.5 vs 13.1 months, p = 0.00016). We found no reliable SUR cut-off criteria for definition of PET+ volumes. Overall conformity between PET and MRI-based contours was low, with maximum conformities between 0.42-0.51 at I40%. The maximum sensitivity and specificity for PET+ volumes outside of GTV predicting tumor progression were 0.16 (I40%) and 0.52 (I50%), respectively. In 75% of cases, FLAIR hyperintense area covered over 80% of PET+ volumes. 18F-FET-PET derived SUR has a prognostic impact in grade IV glioma. The value of substantial mismatches between MRI-based GTV and PET+ volumes to improve tumor delineation in radiotherapy awaits further validation in randomized prospective trials.