Ultrasound point shear wave elastography of the pancreas: comparison of patients with type 1 diabetes and healthy volunteers - results from a pilot study.

BACKGROUND: The aims of this study were to establish shear wave elastography of the pancreas by comparing measurements in patients with type 1 diabetes (T1D) and healthy volunteers and to consider whether this method could contribute to the screening or prevention of T1D. METHODS: This pilot study included 15 patients with T1D (10 men, 5 women) and 15 healthy volunteers (10 men, 5 women) as controls. Measurements were performed with a Siemens Acuson S3000 (Siemens Healthcare, Erlangen, Germany) using a 6C1 convex transducer and the Virtual Touch™ tissue quantification (VTQ) method. RESULTS: The mean shear wave velocity of the head of the pancreas was 1.0 ± 0.2 m/s (median: 1.1 m/s) for the study group and likewise 1.0 ± 0.2 m/s (median: 0.9 m/s) for the control group. Velocities of 1.2 ± 0.2 m/s (median: 1.2 m/s) were measured in the body of the pancreas in both groups. There was a significant difference between the values obtained in the tail of the pancreas: patients 1.1 ± 0.1 m/s (median: 1.0 m/s) versus controls 0.9 ± 0.1 m/s (median: 0.8 m/s) (p = 0.0474). The mean value in the whole pancreas of the study group was not significantly above that of the control group: 1.1 ± 0.1 m/s (median: 1.0 m/s) versus 1.0 ± 0.1 m/s (median: 1.0 m/s) (p = 0.2453). CONCLUSIONS: Sonoelastography of the pancreas revealed no overall difference between patients with T1D and healthy volunteers. Patients with T1D showed higher values only in the tail segment. Future studies need to determine whether specific regional differences can be found in a larger study population.

From Phantoms to Patients: Improved Fusion and Voxel-Wise Analysis of Diffusion-Weighted Imaging and FDG-Positron Emission Tomography in Positron Emission Tomography/Magnetic Resonance Imaging for Combined Metabolic-Diffusivity Index (cDMI).

Hybrid positron emission tomography/magnetic resonance imaging (PET/MR) opens new possibilities in multimodal multiparametric (m2p) image analyses. But even the simultaneous acquisition of positron emission tomography (PET) and magnetic resonance imaging (MRI) does not guarantee perfect voxel-by-voxel co-registration due to organs and distortions, especially in diffusion-weighted imaging (DWI), which would be, however, crucial to derive biologically meaningful information. Thus, our aim was to optimize fusion and voxel-wise analyses of DWI and standardized uptake values (SUVs) using a novel software for m2p analyses. Using research software, we evaluated the precision of image co-registration and voxel-wise analyses including the rigid and elastic 3D registration of DWI and [18F]-Fluorodeoxyglucose (FDG)-PET from an integrated PET/MR system. We analyzed DWI distortions with a volume-preserving constraint in three different 3D-printed phantom models. A total of 12 PET/MR-DWI clinical datasets (bronchial carcinoma patients) were referenced to the T1 weighted-DIXON sequence. Back mapping of scatterplots and voxel-wise registration was performed and compared to the non-optimized datasets. Fusion was rated using a 5-point Likert scale. Using the 3D-elastic co-registration algorithm, geometric shapes were restored in phantom measurements; the measured ADC values did not change significantly (F = 1.12, p = 0.34). Reader assessment showed a significant improvement in fusion precision for DWI and morphological landmarks in the 3D-registered datasets (4.3 ± 0.2 vs. 4.6 ± 0.2, p = 0.009). Most pronounced differences were noted for the chest wall (p = 0.006), tumor (p = 0.007), and skin contour (p = 0.014). Co-registration increased the number of plausible ADC and SUV combinations by 25%. The volume-preserving elastic 3D registration of DWI significantly improved the precision of fusion with anatomical sequences in phantom and clinical datasets. The research software allowed for a voxel-wise analysis and visualization of [18F]FDG-PET/MR data as a "combined diffusivity-metabolic index" (cDMI). The clinical value of the optimized PET/MR biomarker can thus be tested in future PET/MR studies.

Leishmania major parasite stage-dependent host cell invasion and immune evasion.

Leishmania pathogenesis is primarily studied using the disease-inducing promastigote stage of Leishmania major. Despite many efforts, all attempts so far have failed to culture the disease-relevant multiplying amastigote stage of L. major. Here, we established a stably growing axenic L. major amastigote culture system that was characterized genetically, morphologically, and by stage-specific DsRed protein expression. We found parasite stage-specific disease development in resistant C57BL/6 mice. Human neutrophils, as first host cells for promastigotes, do not take up amastigotes. In human macrophages, we observed an amastigote-specific complement receptor 3-mediated, endocytotic entry mechanism, whereas promastigotes are taken up by complement receptor 1-mediated phagocytosis. Promastigote infection of macrophages induced the inflammatory mediators TNF, CCL3, and CCL4, whereas amastigote infection was silent and resulted in significantly increased parasite numbers: from 7.1 ± 1.4 (after 3 h) to 20.1 ± 7.9 parasites/cell (after 96 h). Our study identifies Leishmania stage-specific disease development, host cell preference, entry mechanism, and immune evasion. Since the amastigote stage is the disease-propagating form found in the infected mammalian host, the newly developed L. major axenic cultures will serve as an important tool in better understanding the amastigote-driven immune response in leishmaniasis.

Diagnostic, Structured Classification and Therapeutic Approach in Cystic Pancreatic Lesions: Systematic Findings with Regard to the European Guidelines.

Due to the increasing use of cross-sectional imaging techniques and new technical possibilities, the number of incidentally detected cystic lesions of the pancreas is rapidly increasing in everyday radiological routines. Precise and rapid classification, including targeted therapeutic considerations, is of essential importance. The new European guideline should also support this. This review article provides information on the spectrum of cystic pancreatic lesions, their appearance, and a comparison of morphologic and histologic characteristics. This is done in the context of current literature and clinical value. The recommendations of the European guidelines include statements on conservative management as well as relative and absolute indications for surgery in cystic lesions of the pancreas. The guidelines suggest surgical resection for mucinous cystic neoplasm (MCN) ≥ 40 mm; furthermore, for symptomatic MCN or imaging signs of malignancy, this is recommended independent of its size (grade IB recommendation). For main duct IPMNs (intraductal papillary mucinous neoplasms), surgical therapy is always recommended; for branch duct IPMNs, a number of different risk criteria are applicable to evaluate absolute or relative indications for surgery. Based on imaging characteristics of the most common cystic pancreatic lesions, a precise diagnostic classification of the tumor, as well as guidance for further treatment, is possible through radiology.

Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer of the elderly, with high metastatic potential and poor prognosis. In particular, the primary resistance to immune checkpoint inhibitors (ICI) in metastatic (m)MCC patients represents a challenge not yet met by any efficient treatment modality. Herein, we describe a novel therapeutic concept with short-interval, low-dose 177Lutetium (Lu)-high affinity (HA)-DOTATATE [177Lu]Lu-HA-DOTATATE peptide receptor radionuclide therapy (SILD-PRRT) in combination with PD-1 ICI to induce remission in patients with ICI-resistant mMCC. We report on the initial refractory response of two immunocompromised mMCC patients to the PD-L1 inhibitor avelumab. After confirming the expression of somatostatin receptors (SSTR) on tumor cells by [68Ga]Ga-HA-DOTATATE-PET/CT (PET/CT), we employed low-dose PRRT (up to six treatments, mean activity 3.5 GBq per cycle) at 3-6 weeks intervals in combination with the PD-1 inhibitor pembrolizumab to restore responsiveness to ICI. This combination enabled the synergistic application of PD-1 checkpoint immunotherapy with low-dose PRRT at more frequent intervals, and was very well tolerated by both patients. PET/CTs demonstrated remarkable responses at all metastatic sites (lymph nodes, distant skin, and bones), which were maintained for 3.6 and 4.8 months, respectively. Both patients eventually succumbed with progressive disease after 7.7 and 8 months, respectively, from the start of treatment with SILD-PRRT and pembrolizumab. We demonstrate that SILD-PRRT in combination with pembrolizumab is safe and well-tolerated, even in elderly, immunocompromised mMCC patients. The restoration of clinical responses in ICI-refractory patients as proposed here could potentially be used not only for patients with mMCC, but many other cancer types currently treated with PD-1/PD-L1 inhibitors.

Coincidence of Intra-Abdominal Splenosis in a Patient with Advanced Ovarian Cancer: Case Report and Review of the Literature.

Splenosis is a rare disease, which is often discovered incidentally years after surgical procedures on the spleen or traumatic splenic lesions. Through injury of the splenic capsule, splenic cells are able to spread and autoimplant in a fashion similar to the process of metastatic cancer. Here we present the case of a 62-year-old female patient with a palpable tumor of the lower abdomen. Her medical history was unremarkable, except for splenectomy after traumatic splenic lesion in her childhood. Clinical examination and diagnostic imaging raised the suspicion of advanced ovarian cancer, which was further substantiated by the typical presentation of adnexal masses and disseminated peritoneal metastases during the following staging laparotomy. Surprisingly, we also found peritoneal implants macroscopically similar to splenic tissue. Microscopic examination of tissue specimens by intrasurgical frozen section confirmed the diagnosis of intra-abdominal splenosis. The patient then underwent cytoreductive surgery with complete resection of all cancer manifestations, sparing the remaining foci of splenosis to avoid further morbidity. This case demonstrates the rare coincidence of intra-abdominal carcinoma and splenosis, which could lead to intraoperative difficulties by misinterpreting benign splenic tissue. Therefore, splenosis should be considered in patients with medical history of splenic lesions and further diagnostic imaging like Tc-99m-tagged heat-damaged RBC scan could be used for presurgical distinguishing between tumor spread in the abdominal cavity and disseminated splenosis. The presented case report should not only raise awareness for the rare disease splenosis, but also emphasize the need to consider the possibility of simultaneous incidence of benign and malignant intra-abdominal lesions, as to our knowledge this is the first published case of simultaneous peritoneal carcinomatosis and splenosis.

Computed Tomography-Based Tumor Heterogeneity Analysis Reveals Differences in a Cohort with Advanced Pancreatic Carcinoma under Palliative Chemotherapy.

PURPOSE: Imaging in pancreatic cancer is a challenge, especially regarding therapy response evaluation. Tumor size, attenuation, and perfusion are widely used as parameters for computed tomography (CT) examinations, but are often limited due to blurry tumor borders and missing qualitative parameters. To improve monitoring of therapy response, we tested a new CT-based approach of tumor heterogeneity feature analysis. METHODS: A total of 13 patients with pancreatic adenocarcinoma undergoing abdominal CT according to standard as baseline imaging with clinical follow-up and imaging (median time span 64 days) under systematic therapy (FOLFIRINOX/gemcitabine) were retrospectively analyzed. Progression was defined as new lesions and local tumor spread. Tumor heterogeneity analysis was performed using mintLesion®. Seven different image features referring to image heterogeneity were analyzed. Statistical analysis was performed with Spearman's rank correlation and Mann-Whitney U test. RESULTS: During follow-up, tumor volume did not significantly change between our groups with overall progression (local and systemic) and progression-free patients (p = 0.661). Mean positivity of pixel values were significantly higher in patients without progression compared to patients with progression (p = 0.030). There was a significant negative correlation between changes in kurtosis and time to local tumor spread (p = 0.008) or systemic progression (p = 0.017). CONCLUSIONS: Results suggest that analysis of tumor heterogeneity might provide valuable information from routine-acquired images regarding therapy response evaluation. This might help adjusting therapy regimes and could be easily integrated in clinical workflows. Furthermore, this procedure might possibly predict therapy response and, hence could lead the way to find a potential marker for progression-free survival.

First Experiences with 177Lu-PSMA Therapy in Combination with Pembrolizumab or After Pretreatment with Olaparib in Single Patients.

Synergistic effects of immunotherapy with pembrolizumab or drugs targeting DNA damage, such as olaparib, might be used to overcome the limitations of radioligand therapy (RLT) with 177Lu-prostate-specific membrane antigen (PSMA) in metastasized castration-resistant prostate cancer. Here, we present 2 patients receiving such combination or sequential therapies. Methods: RLT was performed at 6- to 8-wk intervals after the patients either exhausted or were considered unfit for all approved conventional treatments. Patient 1 was on pembrolizumab for his squamous cell carcinoma of the skin, whereas patient 2 received RLT sequentially 4 wk after 3 mo of monotherapy with olaparib. Results: Both patients tolerated RLT without any significant hematotoxicity. Patient 2 showed a radiologic and biochemical response, whereas patient 1 achieved prostate-specific antigen stabilization after 3 therapy cycles. Conclusion: These cases indicate that RLT in combination with pembrolizumab or sequentially after olaparib might be well tolerated in single patients.