[Cystic pancreatic lesions-indications, timing and reasons for surveillance]. / Pankreaszysten ­ Indikationen, Zeitpunkt und Rationale für eine Surveillance.

BACKGROUND: Cystic pancreatic lesions are detected incidentally at an increasing rate. Often, the patients present asymptomatically. Hence, the resulting clinical consequences remain challenging and unsettling for both physicians and patients. OBJECTIVES: Status of current recommendations in handling cystic pancreatic lesions. MATERIALS AND METHODS: Selective literature search of PubMed while taking current guidelines into account. RESULTS: Correct diagnostic classification of the cystic lesion is crucial since further action depends on the type of cystic lesion. Resection is generally recommended for mucinous cystic neoplasms (MCN), solid pseudopapillary neoplasms (SPN), and intraductal papillary mucinous neoplasms (IPMN) with relevant risk criteria such as prominent main-duct dilation. Surveillance is recommended for IPMN without risk criteria, as long as comorbidities and life expectancy of the patient will allow preventive resection over the years. SCNs are benign and only symptomatic SCNs require resection. Inflammatory pancreatic cysts should only be treated under certain circumstances.

Digital single-operator pancreatoscopy for the treatment of symptomatic pancreatic duct stones: a prospective multicenter cohort trial.

BACKGROUND: Digital single-operator pancreatoscopy (DSOP)-guided lithotripsy is a novel treatment modality for pancreatic endotherapy, with demonstrated technical success in retrospective series of between 88 % and 100 %. The aim of this prospective multicenter trial was to systematically evaluate DSOP in patients with chronic pancreatitis and symptomatic pancreatic duct stones. METHODS: Patients with symptomatic chronic pancreatitis and three or fewer stones ≥ 5mm in the main pancreatic duct (MPD) of the pancreatic head or body were included. The primary end point was complete stone clearance (CSC) in three or fewer treatment sessions with DSOP. Current guidelines recommend extracorporeal shock wave lithotripsy (ESWL) for MPD stones > 5 mm. A performance goal was developed to show that the CSC rate of MPD stones using DSOP was above what has been previously reported for ESWL. Secondary end points were pain relief measured with the Izbicki pain score (IPS), number of interventions, and serious adverse events (SAEs). RESULTS: 40 chronic pancreatitis patients were included. CSC was achieved in 90 % of patients (36/40) on intention-to-treat analysis, after a mean (SD) of 1.36 (0.64) interventions (53 procedures in total). The mean (SD) baseline IPS decreased from 55.3 (46.2) to 10.9 (18.3). Overall pain relief was achieved in 82.4 % (28/34) after 6 months of follow-up, with complete pain relief in 61.8 % (21/34) and partial pain relief in 20.6 % (7/34). SAEs occurred in 12.5 % of patients (5/40), with all treated conservatively. CONCLUSION: DSOP-guided endotherapy is effective and safe for the treatment of symptomatic MPD stones in highly selected patients with chronic pancreatitis. It significantly reduces pain and could be considered as an alternative to standard ERCP techniques for MPD stone treatment in these patients.

Photochemical Internalization of Gemcitabine Is Safe and Effective in Locally Advanced Inoperable Cholangiocarcinoma.

BACKGROUND: Photochemical internalization (PCI) is a novel technology for light-induced enhancement of the local therapeutic effect of cancer drugs, utilizing a specially designed photosensitizing molecule (fimaporfin). The photosensitizing molecules are trapped in endosomes along with macromolecules or drugs. Photoactivation of fimaporfin disrupts the endosomal membranes so that drug molecules are released from endosomes inside cells and can reach their therapeutic target in the cell cytosol or nucleus. Compared with photodynamic therapy, the main cytotoxic effect with PCI is disruption of the endosomal membrane resulting in delivery of chemotherapy drug, and not to the photochemical reactions per se. In this study we investigated the effect of PCI with gemcitabine in patients with inoperable perihilar cholangiocarcinoma (CCA). METHODS: The in vitro cytotoxic effect of PCI with gemcitabine was studied on two CCA-derived cell lines. In a fimaporfin dose-escalation phase I clinical study, we administered PCI with gemcitabine in patients with perihilar CCA (n = 16) to establish a safe and tolerable fimaporfin dose and to get early signals of efficacy. The patients enrolled in the study had tumors in which the whole length of the tumor could be illuminated from the inside of the bile duct, using an optical fiber inserted via an endoscope (Fig. 1). Fimaporfin was administered intravenously at day 0; gemcitabine (i.v.) and intraluminal biliary endoscopic laser light application on day 4; followed by standard gemcitabine/cisplatin chemotherapy. RESULTS: Preclinical experiments showed that PCI enhanced the effect of gemcitabine. In patients with CCA, PCI with gemcitabine was well tolerated with no dose-limiting toxicities, and no unexpected safety signals. Disease control was achieved in 10 of 11 evaluable patients, with a clearly superior effect in the two highest dose groups. The objective response rate (ORR) was 42%, including two complete responses, while ORR at the highest dose was 60%. Progression-free survival at 6 months was 75%, and median overall survival (mOS) was 15.4 months, with 22.8 months at the highest fimaporfin dose. CONCLUSION: Photochemical internalization with gemcitabine was found to be safe and resulted in encouraging response and survival rates in patients with unresectable perihilar CCA.

Impact of tumor size and location on endoscopic ultrasound-guided sampling of pancreatic neuroendocrine tumors: A recursive partitioning analysis.

BACKGROUND: Current guidelines provide weak recommendations to treat small (<2 cm) non-functional pancreatic neuroendocrine tumors with low Ki-67 proliferation index either by resection or clinical follow-up. However, there is a lack of consensus regarding the minimal size of pNET, which allows EUS-guided biopsy with high enough diagnostic accuracy for stratification. METHODS: We conducted a retrospective, bicentric analysis of patients who had undergone EUS-guided pNET sampling in two tertiary care Endoscopy Units in Germany and Poland. Using a recursive partitioning of the tree-aided model, we aimed to stratify the probability of successful EUS-guided biopsy of pNET lesions according to their size and location. RESULTS: In our pNET cohort, successful histological confirmation of a pNET diagnosis was achieved in 59/69 (85.5%) cases at the initial EUS-guided biopsy. In 41 patients with a pNET size less than 18.5 mm, the EUS-guided first biopsy was successful in 90.2%. In 16 of these patients with smaller lesions, EUS-guided sampling was 100% in very small (less than 11 mm) and extremely small lesions (less than 8 mm). The biopsy success rate was 100% in tail lesions in the size range between ≥5.95 and <8.1 mm but only 33.3% independent of the investigator in pancreatic head or body, with an error rate of 11.2% CONCLUSION: Using a recursive partitioning of the tree-aided stratification model, we demonstrate for the first time that in balancing risks and benefits, very small pNETs (<1 cm) in the tail of the pancreas should be sampled under EUS-guidance.

Differential expression of gut miRNAs in idiopathic Parkinson's disease.

OBJECTIVE: In the present work, we aimed to investigate the expression of microRNAs (miRNAs) in routine colonic biopsies obtained from patients with idiopathic Parkinson's disease (PD) and to address their value as a diagnostic biomarker for PD and their mechanistic contribution to PD onset and progression. METHODS: Patients with PD (n = 13) and healthy controls (n = 17) were prospectively recruited to undergo routine colonic biopsies for cancer screening. Total RNA was extracted from the biopsy material and the expression of miRNAs was quantified by Illumina High-Throughput Sequencing. RESULTS: Statistical analysis revealed a significant submucosal enrichment of the miRNA hsa-miR-486-5p in colonic biopsies from PD patients compared to the control subjects. The expression of miR-486-5p correlated with age and disease severity as measured by the UPDRS and Hoehn & Yahr scale. miRNA gene target analysis identified 301 gene targets that are affected by miR-486-5p. A follow-up associated target identification and pathway enrichment analysis further determined their role in distinct biological processes in the enteric nervous system (ENS). INTERPRETATION: Our work demonstrates an enrichment of submucosal miR-486-5p in routine colonic biopsies from PD patients. Our results will support the examination of miR-486-5p as a PD biomarker and help to understand the significance of the miR-486-5p gene targets for PD onset and progression. In addition, our data will support the investigation of the molecular and cellular mechanisms of GI dysfunction in PD.

Endoscopic and percutaneous biliary interventions in patients with altered upper gastrointestinal anatomy-the Munich Multicenter Experience.

BACKGROUND: In patients with altered upper gastrointestinal anatomy, conventional endoscopic retrograde cholangiography is often not possible and different techniques, like enteroscopy-assisted or percutaneous approaches are required. Aim of this study was to analyze success and complication rates of these techniques in a large collective of patients in the daily clinical practice in a pre-endosonographic biliary drainage era. PATIENTS AND METHODS: Patients with altered upper gastrointestinal anatomy with biliary interventions between March 1st, 2006, and June 30th, 2014 in four tertiary endoscopic centers in Munich, Germany were retrospectively analyzed. RESULTS: At least one endoscopic-assisted biliary intervention was successful in 234/411 patients (56.9%)-in 192 patients in the first, in 34 patients in the second and in 8 patients in the third attempt. Success rates for Billroth-II/Whipple-/Roux-en-Y reconstruction were 70.5%/56.7%/49.5%. Complication rates for these reconstructions were 9.3%/6.5%/6.3%, the overall complication rate was 7.1%. Success rates were highest in patients with Billroth-II reconstruction where use of a duodenoscope was possible, complication rates were also highest in this scenario. Success rates were lowest in longer-limb anatomy like Roux-en-Y reconstruction. Percutaneous biliary drainages (PTBD) were inserted 268 times with substantially higher success (90.7%) as well as complication rates (11.6%) compared to the endoscopic approach. Compared to patients treated endoscopically, patients with PTBD had a lower performance status, more severe cholestasis and a significant higher rate of malignant underlying disease. CONCLUSION: In patients with altered upper gastrointestinal anatomy, success rates of endoscopic-assisted biliary interventions are lower compared to PTBD. Still, due to the beneficial complication rates of the endoscopic approach, this technique should be preferred whenever possible and in selected patients who still need to be defined in detail, repeated endoscopic attempts are useful to help achieve the desired result.

Prolonged time to treatment initiation in advanced pancreatic cancer patients has no major effect on treatment outcome: a retrospective cohort study controlled for lead time bias and waiting time paradox.

PURPOSE: A prolonged time to treatment initiation (TTI) correlates with an adverse prognosis in different cancer types including resectable pancreatic cancer (PC). Only limited evidence on the correlation between TTI and prognosis in advanced PC exists. METHODS: Consecutive PC patients (n = 368) who were diagnosed or treated at our high-volume comprehensive cancer center were included in a prospectively maintained database. We retrospectively analyzed time from first imaging showing advanced PC to initiation of palliative first-line chemotherapy. Lead time bias and waiting time paradox were addressed by landmark analysis and correlation of tumor burden with TTI. RESULTS: Two hundred and ninety-seven patients met the pre-specified in- and exclusion criteria of our study. Median TTI was 29 days (range: 1-124 days). Most common reasons for prolonged TTI (> 21 days) were referral from an external treatment center (39%) and a second biopsy (31%). A TTI above the median-, 75th or 90th percentile (43 or 60 days, respectively) had no impact on overall survival. Furthermore, no correlation between levels of carbohydrate antigen 19-9 (CA 19-9) at time of treatment initiation and TTI was observed. CONCLUSION: While a timely work-up of advanced PC patients remains important, delays in treatment initiation due to repeated biopsies, inclusion in a clinical study or transfer to a specialized cancer center appear to be justified in light of the absence of a strong adverse effect of prolonged TTI on prognosis in advanced PC patients.

Management Algorithm for Cystic Pancreatic Lesions.

Cystic pancreatic lesions are common findings in an aging society due to an increasing availability of high-resolution cross-sectional imaging. Although the overall prevalence of malignancy and the rate of malignant conversion are low, especially mucinous pancreatic cystic lesions such as intraductal papillary mucinous neoplasm and mucinous cystic neoplasm harbor significant malignant potential depending on their morphology and size. Recently updated guidelines recommend sophisticated algorithms for initial workup and surveillance based on individual characteristics of the cystic lesion and the patient, thus weighing the lifetime risk for malignancy against the adverse event rate of potentially curative surgery in the light of number and location of cystic lesions, age of the patient, comorbidities, and the resulting life expectancy as well as the effect of repeated follow-up examinations on the patient's quality of life. This article summarizes recommendations from available guidelines and proposes a pragmatic approach to the clinical management of pancreatic cystic lesions.

Photodynamic therapy for cholangiocarcinoma using low dose mTHPC (Foscan(®)).

BACKGROUND: Photodynamic therapy (PDT) combined with stenting is an effective treatment modality for palliation of nonresectable cholangiocarcinoma (CC). A drawback of standard PDT using Photofrin(®) as photosensitizer is the long lasting skin photosensitivity of up to 3 months. The aim of this study was to show the outcome of PDT of CC, potential side effects and to determine the best drug light interval (DLI) using mTHPC (Foscan(®)) at a low dose. METHODS: 13 patients with nonresectable CC were treated with stenting and PDT (3mg Foscan(®) per treatment, 0.032-0.063 mg/kg body weight, 652 nm, 50 J/cm). Fluorescence measurements were performed with a single bare fiber for 5/13 patients prior to PDT at the tumor site to determine the fluorescence contrast. For another 7/13 patients, long-term fluorescence-kinetics were measured on the oral mucosa to determine the time of maximal relative fluorescence intensity. RESULTS: The results so far indicate a median survival time of 13 months. Side effects such as perforations or skin phototoxicity could not be observed. Foscan(®) fluorescence within the tumor site was clearly detectable but a significant fluorescence contrast of tumor to adjacent healthy tissue could not be found. The fluorescence kinetics measured in the oral mucosa showed a maximum at 3.85 days (median) after drug administration. CONCLUSION: Combined stenting and PDT performed with a low Foscan(®) dose results in equal and potentially longer survival times compared to standard Photofrin(®) PDT, while lowering the risk of side effects strongly. Thus it may improve the quality of life.

In silico design of optimal ratio for co-administration of pramlintide and insulin in type 1 diabetes.

BACKGROUND: The ability to simulate in silico experiments is crucial for fast and cost-effective preliminary studies prior to clinical trials. We present an in silico approach to the design of optimal pramlintide-to-insulin (P/I) ratios, using our computer simulator of the human metabolic system, with a population of virtual adult type 1 diabetes mellitus patients and with individual parameters modified to account for the dynamic effects of pramlintide. MATERIALS AND METHODS: A model of pramlintide action on gastric emptying was built using data of 15 type 1 diabetes mellitus subjects studied twice with a standardized dual-tracer meal on placebo and pramlintide, which was incorporated in our type 1 diabetes simulator. Extensive in silico experiments on 100 virtual subjects were performed to optimize the co-administration of pramlintide and insulin prior to its submission to clinical trials; several P/I ratios were tested in terms of efficacy, in attenuating postprandial hyperglycemia, and in hypoglycemia safety. RESULTS: In silico experiments estimated the optimal P/I ratio to be 9 µg of pramlintide per unit (U) of insulin. Additional simulations narrowing the investigated range indicated that P/I ratios of 8 and 10 µg/U would achieve similar performance. Moreover, simulation results suggested that in clinical trials, insulin boluses should be reduced by approximately 21% at a P/I ratio of 9 µg/U to account for the effects of pramlintide and avoid postprandial hypoglycemia. CONCLUSIONS: We can assert that a valid simulation model of pramlintide action was developed, leading to in silico estimation of optimal pramlintide:insulin co-administration ratio. Clinical trials will confirm (or adjust) this initial estimation.

Magnetic resonance colonography for the detection of colorectal neoplasia in asymptomatic adults.

BACKGROUND & AIMS: Colonoscopy is the preferred screening test for colorectal neoplasia; the fecal occult blood test (FOBT) detects neoplasias with low levels of sensitivity. Computed tomographic colonography detects neoplasias with high levels of sensitivity but involves exposure to radiation. We investigated whether magnetic resonance colonography (MRC) can be used to screen for colorectal adenomas and cancers. METHODS: We analyzed data from 286 asymptomatic adults (40-82 years old) who underwent 3 Tesla MRC and colonoscopic examinations on the same day. FOBT was performed before bowel preparation. Colonoscopists were initially blinded to the findings on MRC and unblinded after withdrawal from the respective segments. Sensitivities for adenoma and per-patient sensitivities and specificities were calculated based on the unblinded results of colonoscopy. RESULTS: We detected 133 adenomas and 2 cancers in 86 patients; 37 adenomas were ≥6 mm, and 20 adenomas were advanced. Sensitivities of MRC and colonoscopy for adenomas ≥6 mm were 78.4% (95% confidence interval [CI], 61.8-90.2) and 97.3% (95% CI, 85.8-99.9); for advanced adenomas these values were 75% (95% CI, 50.9-91.3) and 100% (95% CI, 83.2-100.0), respectively. MRC identified 87.1% (95% CI, 70.2-96.4), colonoscopy 96.8% (95% CI, 83.3-99.9), and FOBT 10.0% (95% CI, 2.1-26.5) of individuals with adenomas ≥6 mm and 83.8% (95% CI, 58.6-96.4), 100% (95% CI, 81.5-100.0), and 17.6% (95% CI, 3.8-43.4) of individuals with advanced neoplasia. Specificities of MRC, colonoscopy, and FOBT for individuals with adenomas ≥6 mm were 95.3% (95% CI, 91.9-97.5), 96.9% (95% CI, 93.9-98.6), and 91.8% (95% CI, 87.6-94.9), respectively. CONCLUSIONS: 3 Tesla MRC detects colorectal adenomas ≥6 mm and advanced neoplasia with high levels of sensitivity and specificity. Although MRC detects colorectal neoplasia with lower levels of sensitivity than colonoscopy, it strongly outperforms one-time FOBT.

[Implants with 32P-foils for LDR-brachytherapy of benign stenosis in urology and gastroenterology]. / (32)P-haltige Folien als Implantate für die LDR-Brachytherapie gutartiger Stenosen in der Urologie und Gastroenterologie.

For LDR-brachytherapy, a limited number of implant geometries and materials are available. To avoid wound healing related hyper-proliferation (stenosis, keloids) a novel radioactive foil system was developed based on beta emitting (32)P, which can be easily integrated in existing implants such as urethral catheters or bile duct stents. As substrate material for these foils PEEK (polyetherethercetone) was chosen because of its radiation hardness during neutron activation of (32)P. The activity was determined by liquid scintillation counting and gamma spectroscopy, dose distributions were measured with scintillation detectors and radiochromic films. The correlation between activity and dose was checked by Monte-Carlo-simulations (Geant4). Prototypes of the (32)P-implants have shown in wash-out tests the required tightness for sealed radioactive sources. In animal tests on urethra and bile duct, the uncomplicated and save application of (32)P-foils mounted on standard implants has been demonstrated, which is almost unchanged due to the simple radiation protection with plexiglass. This concept of radioactive implants with integrated (32)P-foils could extend essentially the application possibilities of LDR-brachytherapy.

The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes.

In order to quantify the role of incretins in first- and second-phase insulin secretion (ISR) in type 2 diabetes mellitus (T2DM), a double-blind, randomized study with 12 T2DM subjects and 12 healthy subjects (HS) was conducted using the hyperglycemic clamp technique together with duodenal nutrition perfusion and intravenous infusion of the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9-39). Intravenous glucose alone resulted in a significantly greater first- and second-phase ISR in HS compared with T2DM subjects. Duodenal nutrition perfusion augmented both first- and second-phase ISR but first-phase ISR more in T2DM subjects (approximately eight- vs. twofold). Glucose-related stimulation of ISR contributed only 20% to overall ISR. Infusion with exendin(9-39) significantly reduced first- and second-phase ISR in both HS and T2DM subjects. Thus, both GLP-1 and non-GLP-1 incretins contribute to the incretin effect. In conclusion, both phases of ISR are impaired in T2DM. In particular, the responsiveness to glucose in first-phase ISR is blunted. GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions are unaltered. The absolute incretin effect is reduced in T2DM; its relative importance, however, appears to be increased, highlighting its role as an important amplifier of first-phase ISR in T2DM.

Assessment of colon motility using simultaneous manometric and functional cine-MRI analysis: preliminary results.

PURPOSE: Gastrointestinal functional disorders are common symptoms. The evaluation of underlying colonic motility dysfunction is difficult due to lacking adequate examination techniques. Recently cine-magnetic resonance imaging (MRI) was introduced as imaging technique for visualizing colon motility. However, the correlation of MR-visible colonic-movements and real intraluminal movements was not demonstrated yet. Therefore, this feasibility study's purpose was to stimulate high amplitude propagated pressure waves (HAPPWs) by bisacodyl application under manometric control and to simultaneously identify them with cine-MRI. MATERIALS AND METHODS: Colonoscopically, a water-perfused 8-lumen-probe was placed in descending colon. Intraluminal pressure was recorded over time. After 90 min equilibration phase, MR exam at rest (HASTE-sequence, 1.5Tesla-Avanto(®), Siemens-Medical-Solutions) was performed. Consecutively, 10 mg bisacodyl were instilled via colonic probe to induce HAPPWs. Cine-MRI and manometry were performed simultaneously over 24 min. HAPPWs were defined as pressure waves with amplitude >50 mmHg and propagation over min. three side-holes. MRI was analyzed for corresponding luminal changes of the referring colonic segment propagated aborally. RESULTS: Ten healthy volunteers (age:19-62 years, 4 females, 6 males) were enrolled. Manometry identified 11 HAPPWs, most 9-16 min post-stimulation. All HAPPWs were identified on MRI with corresponding luminal changes (100% sensitivity). CONCLUSIONS: In accordance with our study group's previous publications, these results show that cine-MRI allows not only for reliable HAPPWs' visualization using pharmalogical stimuli, but visualized colonic movements have 100% correlation to intraluminal pressure changes in manometry (gold-standard). This may be a first step to introduce cine-MRI for non-invasive colon motility assessment in patients with functional gastro-intestinal disorders.

The physiological role of GLP-1 in human: incretin, ileal brake or more?

The proglucagon-derived peptide glucagon-like peptide-1 (GLP-1) is an intestinal signal peptide postprandially released from the L cells of the lower gut. Exogenously administered the synthetic hormone exerts a glucose-dependent insulinotropic effect at the pancreatic beta-cells and lowers plasma glucagon by an inhibitory effect against the alpha-cells. It delays gastric emptying by relaxation of the gastric fundus, inhibition of antral contractility, and stimulation of both the tonic and phasic motility of the pyloric sphincter. Enhancement of insulin, suppression of glucagon, and inhibition of gastric emptying are the main determinants controlling glucose homeostasis with GLP-1. Human studies employing the specific GLP-1 receptor antagonist exendin(9-39) show that endogenously released GLP-1 likewise controls fasting plasma glucagon, stimulates insulin, and influences all the motoric mechanisms known to control gastric emptying. Therefore, GLP-1 is discussed as an incretin hormone and as an enterogastrone in man. Synthetic GLP-1 also suppresses gastric acid and pancreatic enzyme secretion. The inhibitory effects on upper gastrointestinal functions are at least partly mediated by vagal-cholinergic inhibition and may involve interactions with vagal afferent pathways and/or circumventricular regions within the CNS. GLP-1 is a candidate humoral mediator of the 'ileal brake' exerting inhibition of upper gastrointestinal function preventing malabsorption and postprandial metabolic disturbances. As human studies indicate a central action of GLP-1 in reduction of food intake, it is uncertain if this is a consequence of induction of satiety or of transduction of visceral aversive stress signals.

[A 27-year-old patient with recurrent Fever]. / 27-jähriger Patient mit rezidivierendem Fieber.

BACKGROUND: In spite of a decreasing incidence of tuberculosis in highly industrialized countries, an obvious increase of the disease is observed worldwide. In times of progressing international migration, the early detection of tuberculosis is also becoming important in Germany. The diagnosis, however, is often impaired by unspecific symptomatology and ambiguous imaging results. CASE REPORT: A 27-year-old patient from Iraq presented with unclear recurring and antibiotic-resistant fever and inconspicuous thoracic X-ray. Only by thoracic computed tomography, markedly necrotizing mediastinal lymph nodes could be detected. Following lymph node biopsy and histologic investigation, the diagnosis of mediastinal lymph node tuberculosis could be ascertained. Test-adjusted antituberculotic combination treatment resulted in a normalization of body temperature and cessation of complaints. Starting from the case report presented, the importance of various investigative methods for the quick and secure diagnosis of tuberculosis and subsequent therapy are discussed. CONCLUSION: Unclear febrile disease even in young patients with an inconspicuous conventional thoracic X-ray may be caused by tuberculosis. In this situation, early extension of imaging diagnostics appears to be advantageous.