VHL-dependence of EHHADH Expression in a Human Renal Cell Carcinoma Cell Line.

The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in up to 90% of clear cell renal cell carcinoma (ccRCC) cases, thus playing a key role in ccRCC pathogenesis. ccRCC can be classified as a metabolic disease in which alterations in fatty acid metabolism facilitate cancer cell proliferation. Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH) is an enzyme involved in peroxisomal fatty acid degradation. It is primarily expressed in renal proximal tubule cells, presumably the origin of ccRCC. Although EHHADH is still a relatively unexplored gene, it is known to be differentially expressed in several tumors. In this study, analysis of several databases revealed that EHHADH expression is downregulated in ccRCC samples compared to healthy kidney samples. Moreover, cell culture experiments were performed to investigate the relationship between EHHADH and VHL at the gene and protein level. qPCR and Western blot analyses using the human ccRCC cell line RCC4 revealed that EHHADH is expressed in a VHL-dependent manner. RCC4 cells reconstituted with VHL show significantly higher EHHADH mRNA and protein levels than VHL-deficient RCC4 control cells. These results indicate that the downregulation of EHHADH in ccRCC reported may be due to the loss of VHL function. This study is the first to molecularly characterize EHHADH, a key enzyme in peroxisomal ß-oxidation, in relation to VHL, suggesting a potential pathogenic interaction that is worthy of further investigation.

Impact of [18F]FDG PET/CT in the Assessment of Immunotherapy-Induced Arterial Wall Inflammation in Melanoma Patients Receiving Immune Checkpoint Inhibitors.

We aimed to investigate the role of [18F]FDG positron emission tomography/computed tomography (PET/CT) in the early detection of arterial wall inflammation (AWI) in melanoma patients receiving immune checkpoint inhibitors (ICIs). Our retrospective study enrolled 95 melanoma patients who had received ICIs. Inclusion criteria were ICI therapy for at least six months and at least three [18F]FDG PET/CTs, including one pretreatment session plus two scans three and six months after treatment initiation. AWI was assessed using quantitative and qualitative methods in the subclavian artery, thoracic aorta, and abdominal aorta. We found three patients with AWI visual suspicion in the baseline scan, which increased to five in the second and twelve in the third session. Most of these patients' treatments were terminated due to either immune-related adverse events (irAEs) or disease progression. In the overall population, the ratio of arterial-wall maximum standardized uptake value (SUVmax)/liver-SUVmax was significantly higher three months after treatment than the pretreatment scan in the thoracic aorta (0.83 ± 0.12 vs. 0.79 ± 0.10; p-value = 0.01) and subclavian artery (0.67 ± 0.13 vs. 0.63 ± 0.12; p-value = 0.01), and it remained steady in the six-month follow-up. None of our patients were diagnosed with definite clinical vasculitis on the dermatology follow-up reports. To conclude, our study showed [18F]FDG PET/CT's potential to visualise immunotherapy-induced subclinical inflammation in large vessels. This may lead to more accurate prediction of irAEs and better patient management.

Increasing incidence of Trichophyton tonsurans in Munich-A single-centre observation.

BACKGROUND: Tinea capitis and tinea corporis are highly prevalent fungal skin infections, which globally are mainly caused by Microsporum canis and Trichophyton rubrum, respectively. While in the United States and Great Britain Trichophyton tonsurans is widely prevalent as a causative pathogen, it so far only plays a minor role in Germany. OBJECTIVES: Since the frequency of pathogenic species varies regionally and temporally, this study assesses the proportion of Trichophyton tonsurans infections in the dermatology department of a large university hospital in Germany from 2019 to 2022 and thoroughly characterises the affected patient population. PATIENTS/METHODS: This retrospective study at the Technical University of Munich analyses mycological culture results regarding the identified dermatophyte and infection site. Detailed patient and disease-related information on Trichophyton tonsurans positive patients was obtained. RESULTS: In 2022, 23 patients of 111 dermatophyte culture-positive patients tested positive for Trichophyton tonsurans. This accounted for 20.7% and represented a tenfold increase from 2.1% in 2019. Contact sports were only practiced by 21.7% of patients, and no common hotspot or other linkage could be identified between the cases. Additionally, 47.8% of the patients received a systemic treatment, with 30.4% visiting the clinic more than three times. In 2022, 21.7% were diagnosed with a simultaneous infection of the capillitium and body, whereas this was only observed in 7.1% of cases in 2019 to 2021. CONCLUSIONS: This study suggests an increase of Trichophyton tonsurans infections via several routes of transmission.

Metronomic doses and drug schematic combination response tested within chambered coverslips for the treatment of breast cancer cells (JIMT-1).

Low-dose metronomic (LDM) chemotherapy is an alternative to conventional chemotherapy and is the most frequently used approach in low dose chemotherapy regimens. The selection of patients, drug dosages, and dosing intervals in LDM is empirical. In this study, we systematically examined the schedule-dependent interaction of drugs on a breast cancer cell line (BCC) cultured in chambered coverslips. The LDM studies were combined with cell staining in order to better characterize different cell states and cell death modes, including caspase-dependent apoptosis, caspase-independent cell death and autophagy-dependent cell death. Microscope images were examined using the Fiji Trainable Weka Segmentation plugin to analyse cell area in 7500 images showing different modes of cell death. Paclitaxel combined with LDM chemotherapy demonstrated a reduction in the area covered by live cells. In contrast, there was an induction of high levels of cell death due to caspase-dependent apoptosis.

Molecular Imaging in Primary Staging of Prostate Cancer Patients: Current Aspects and Future Trends.

Accurate primary staging is the cornerstone in all malignancies. Different morphological imaging modalities are employed in the evaluation of prostate cancer (PCa). Regardless of all developments in imaging, invasive histopathologic evaluation is still the standard method for the detection and staging of the primary PCa. Magnetic resonance imaging (MRI) and computed tomography (CT) play crucial roles; however, functional imaging provides additional valuable information, and it is gaining ever-growing acceptance in the management of PCa. Targeted imaging with different radiotracers has remarkably evolved in the past two decades. [111In]In-capromab pendetide scintigraphy was a new approach in the management of PCa. Afterwards, positron emission tomography (PET) tracers such as [11C/18F]choline and [11C]acetate were developed. Nevertheless, none found a role in the primary staging. By introduction of the highly sensitive small molecule prostate-specific membrane antigen (PSMA) PET/CT, as well as recent developments in MRI and hybrid PET/MRI systems, non-invasive staging of PCa is being contemplated. Several studies investigated the role of these sophisticated modalities in the primary staging of PCa, showing promising results. Here, we recapitulate the role of targeted functional imaging. We briefly mention the most popular radiotracers, their diagnostic accuracy in the primary staging of PCa, and impact on patient management.

Obesity in Humans Is Characterized by Gut Inflammation as Shown by Pro-Inflammatory Intestinal Macrophage Accumulation.

Chronic low-grade inflammation is a hallmark of obesity and associated with cardiovascular complications. However, it remains unclear where this inflammation starts. As the gut is constantly exposed to food, gut microbiota, and metabolites, we hypothesized that mucosal immunity triggers an innate inflammatory response in obesity. We characterized five distinct macrophage subpopulations (P1-P5) along the gastrointestinal tract and blood monocyte subpopulations (classical, non-classical, intermediate), which replenish intestinal macrophages, in non-obese (BMI<27kg/m2) and obese individuals (BMI>32kg/m2). To elucidate factors that potentially trigger gut inflammation, we correlated these subpopulations with cardiovascular risk factors and lifestyle behaviors. In obese individuals, we found higher pro-inflammatory macrophages in the stomach, duodenum, and colon. Intermediate blood monocytes were also increased in obesity, suggesting enhanced recruitment to the gut. We identified unhealthy lifestyle habits as potential triggers of gut and systemic inflammation (i.e., low vegetable intake, high processed meat consumption, sedentary lifestyle). Cardiovascular risk factors other than body weight did not affect the innate immune response. Thus, obesity in humans is characterized by gut inflammation as shown by accumulation of pro-inflammatory intestinal macrophages, potentially via recruited blood monocytes. Understanding gut innate immunity in human obesity might open up new targets for immune-modulatory treatments in metabolic disease.

Feasibility of equivalent performance of 3D TOF [18F]-FDG PET/CT with reduced acquisition time using clinical and semiquantitative parameters.

BACKGROUND: High-performance time-of-flight (TOF) positron emission tomography (PET) systems have the capability for rapid data acquisition while preserving diagnostic image quality. However, determining a reliable and clinically applicable cut-off of the acquisition time plays an important role in routine practice. This study aimed to assess the diagnostic equivalence of short acquisition time of 57 with routine 75 seconds per bed position (s/BP) of [18F]-fluoro-deoxy-glucose (FDG) PET. Phantom studies applying EARL criteria suggested the feasibility of shortened acquisition time in routine clinical imaging by 3D TOF PET/CT scanners. Ninety-six patients with melanoma, lung or head and neck cancer underwent a standard whole-body, skull base-to-thigh or vertex-to-thigh [18F]-FDG PET/CT examination using the 3D TOF Ingenuity TF PET/CT system (Philips, Cleveland, OH). The [18F]-FDG activity applied was equal to 4MBq per kg body weight. Retrospectively, PET list-mode data were used to calculate a second PET study per patient with a reduced acquisition time of 57 s instead of routine 75 s/BP. PET/CT data were reconstructed using a 3D OSEM TOF algorithm. Blinded patient data were analysed by two nuclear medicine physicians. The number of [18F]-FDG-avid lesions per body region (head&neck, thorax, abdomen, bone, extremity) and image quality (grade 1-5) were evaluated. Semiquantitative analyses were performed by standardized uptake value (SUV) measurements using 3D volume of interests (VOI). The visual and semiquantitative diagnostic equivalence of 214 [18F]-FDG-avid lesions were analysed in the routine standard (75 s/BP) as well as the calculated PET/CT studies with short acquisition time. Statistical analyses were performed by equivalence testing and Bland-Altman plots. RESULTS: Lesion detection rate per patient's body region agreed in > 98% comparing 57 s/BP and 75 s/BP datasets. Overall image quality was determined as equal or superior to 75 s in 80% and 69%, respectively. In the semiquantitative lesion-based analyses, a significant equivalence was found between the 75 s/BP and 57 s/BP PET/CT images both for SUVmax (p = 0.004) and SUVmean (p = 0.003). CONCLUSION: The results of this study demonstrate significant clinical and semiquantitative equivalence between short acquisition time of 57 s/BP and standard 75 s/BP 3D TOF [18F]-FDG PET/CT scanning, which may improve the patient's workflow in routine practice.

Alicaforsen, an Antisense Inhibitor of Intercellular Adhesion Molecule-1, in the Treatment for Left-Sided Ulcerative Colitis and Ulcerative Proctitis.

BACKGROUND: Data on the efficacy of intercellular adhesion molecule-1 antisense oligonucleotide alicaforsen in ulcerative colitis (UC) is inconsistent. METHODS: All patients, who had received at least one dose of alicaforsen, were analyzed retrospectively. Alicaforsen's efficacy was assessed in patients treated for left-sided UC and proctitis by comparing clinical and (if applicable) endoscopic disease activity before/after treatment. RESULTS: Twelve patients were treated for left-sided UC or proctitis. Eleven patients received a 6-week course of a once-daily 240 mg alicaforsen enema formulation. In 1 patient, treatment was discontinued, because it was found to be inefficient. Disease activity measured by the partial Mayo score and 6-point symptom score was significantly reduced after treatment (6.0 vs. 2.4, p = 0.011 and 3.7 vs. 1.4, p = 0.008). Faecal calprotectin showed a trend towards reduction (484.4 vs. 179.5 µg/g, p = 0.063). Clinical improvement was achieved in 10 patients (83.3%). In 7 patients, a relapse occurred (70%). Median duration of clinical improvement was 18.0 weeks (range 1-112). Three patients showed an ongoing improvement of >9 months. No adverse events were reported. CONCLUSIONS: A 6-week course of alicaforsen seemed to be safe and efficacious in inducing clinical improvement in patients with left-sided UC and proctitis. Prolonged clinical improvement was observed in many but not all patients.

Littoral cell angioma in main and accessory intrapancreatic spleen presenting as splenic rupture.

We report the incidental finding of a nodular mass in the pancreatic tail on a contrast-enhanced computed tomography scan preinterventional to emergency laparotomy for splenic rupture. Because of the past surgical history and radiologic appearance, differential diagnosis included atypical lymphoma in the spleen and regional lymph node, pancreatic adenocarcinoma with splenic metastasis, and intrapancreatic metastase of malignant melanoma; the patient underwent both splenectomy and pancreatic tail resection. A diagnosis of littoral cell angioma in main and accessory intrapancreatic spleen was made. To our knowledge, this is the first description of littoral cell angioma of the spleen involving both main and accessory organ presenting as splenic rupture.

Colon Capsule Endoscopy compared to Conventional Colonoscopy under routine screening conditions.

BACKGROUND: Colonoscopy (CSPY) for colorectal cancer screening has several limitations. Colon Capsule Endoscopy (PillCam Colon, CCE) was compared to CSPY under routine screening conditions. METHODS: We performed a prospective, single-center pilot study at a University Hospital. Data were obtained from November 2007 until May 2008. Patients underwent CCE on Day 1 and CSPY on Day 2. Outcomes were evaluated regarding sensitivity and specificity of polyp detection rate, with a significance level set at >5 mm. RESULTS: 59 individuals were included in this study, the results were evaluable in 56 patients (males 34, females 22; median age 59). CCE was complete in 36 subjects. Polyp detection rate for significant polyps was 11% on CSPY and 27% on CCE.6/56 (11%) patients had polyps on CSPY not detected on CCE (miss rate).Overall sensitivity was 79% (95% confidence interval [CI], 61 to 90), specificity was 54% (95% CI, 35 to 70), positive predictive value (PPV) was 63% and negative predictive value (NPV) was 71%. Adjusted to significance of findings, sensitivity was 50% (95% CI, 19 to 81), specificity was 76% (95% CI, 63 to 86), PPV was 20% and NPV was 93%. CONCLUSION: In comparison to the gold standard, the sensitivity of CCE for detection of relevant polyps is low, however, the high NPV supports its role as a possible screening tool. TRIAL REGISTRATION: NCT00991003.

Meta-analysis shows colon capsule endoscopy is effective in detecting colorectal polyps.

BACKGROUND & AIMS: Colon capsule endoscopy (CCE) is a noninvasive and painless technique used to explore the colon without sedation or air insufflation. We performed a systematic review and meta-analysis to assess the accuracy of CCE in detecting colorectal polyps. METHODS: The MEDLINE, EMBASE, and SCOPUS databases were searched, from 2006 to 2009, for the terms "colon capsule" and "Pillcam colon"; searches included abstracts. Studies were included that focused on detecting colorectal polyps with CCE and that were verified using within-subject reference colonoscopy. The risk of bias within each study was ascertained according to Quality Assessment of Diagnostic Accuracy in Systematic Reviews recommendations. The per-patient sensitivity and specificity were calculated for polyps of any size and for significant findings (polyps, > or =6 mm in size or >3 in number). Forest plots were produced based on random-effect models. The risk of bias across studies was assessed using the interstudy heterogeneity statistic, meta-regression, and the Egger test. RESULTS: Eight studies provided data on 837 patients; the prevalences of polyps and significant findings were 57% and 27.4%, respectively. CCE sensitivity for polyps of any size and significant findings were 71% and 68%, respectively. CCE specificity for polyps of any size and significant findings were 75% and 82%, respectively. High levels of heterogeneity (interstudy heterogeneity, >75%) were not detected. Moderate heterogeneity partially was explained by the different design of individual studies. CCE identified 16 of the 21 cancerous lesions detected by colonoscopy (pooled sensitivity, 76%). CONCLUSIONS: CCE sensitivity for polyps and significant findings compares favorably with other noninvasive colorectal cancer screening strategies. CCE specificity is likely to be underestimated because reference colonoscopy examination results are blinded.

In vitro sensitivity of Plasmodium falciparum to lumefantrine in north-western Thailand.

Lumefantrine (benflumetol) belongs to the class-2 blood schizontocidal compounds. In combination with artemether it serves as an alternative drug for treating chloroquine-resistant infections with Plasmodium falciparum. In view of activity correlations with mefloquine, it is important to monitor the parasite's intrinsic sensitivity to lumefantrine in areas with multi-drug resistant P. falciparum, the objective of this study. The observations were carried out in 2002 at Mae Sot, northwestern Thailand, near the border to Myanmar. The 41 successfully in-vitro tested parasite isolates yielded a geometric mean cut-off concentration of schizont maturation of 237.54 nM, and EC50, EC90 and EC90 values of 15.13 nM, 86.71 nM and 359.97 nM, respectively. As compared to the findings of 1998 and 1999, the susceptibility to lumefantrine has increased, possibly due to the improved therapeutic response of mefloquine-resistant P. falciparum infections to combined treatment with artesunate + mefloquine. The EC9o and EC99 data of 2002 for lumefantrine in the study area suggest fully curative clinical-parasitological efficacy.