Purpose: To determine oncological and functional outcomes and side effects after focal therapy of prostate cancer (PCa) with high-intensity focused ultrasound (HIFU). Methods: This retrospective ...single-center study included 57 consecutive patients with localised PCa. Aged 18–80 with ≤2 suspicious lesions on mpMRI (PIRADS ≥ 3), PSA of ≤15 ng/mL, and an ISUP GG of ≤2. HIFU was performed between November 2014 and September 2018. All men had an MRI/US fusion-guided targeted biopsy (TB) combined with a TRUS-guided 10-core systematic biopsy (SB) prior to focal therapy. HIFU treatment was performed as focal, partial, or hemiablative, depending on the prior histopathology. Follow-up included Questionnaires (IIEF-5, ICIQ, and IPSS), prostate-specific antigen (PSA) measurement, follow-up mpMRI, and follow-up biopsies. Results: The median age of the cohort was 72 years (IQR 64–76), and the median PSA value before HIFU was 7.3 ng/mL (IQR 5.75–10.39 ng/mL). The median follow-up was 27.5 (IQR 23–41) months. At the time of the follow-up, the median PSA value was 2.5 ng/mL (IQR 0.94–4.96 ng/mL), which shows a significant decrease (p < 0.001). In 17 (29.8%) men, mpMRI revealed a suspicious lesion, and 19 (33.3%) men had a positive biopsy result. Only IIEF values significantly decreased from 16 (IQR 10.75–20.25) to 11.5 (IQR 4.5–17) (p < 0.001). The rate of post-HIFU complications was low, at 19.3% (11 patients). The limitation of this study is the lack of long-term follow-up. Conclusions: HIFU as a therapy option for nonmetastatic, significant prostate cancer is effective in the short term for carefully selected patients and shows a low risk of adverse events and side effects.
Objective
Cervical lymph node metastasis (CLNM) is one of the most relevant influencing factors for the oncological outcome of patients with oral squamous cell carcinoma (OSCC). Several studies ...showed that the tumors depth of invasion (DOI) influences the risk for CLNM, however varying across the oral subsites. The aim of this study is to investigate the role of DOI and other risk factors in OSCC of the tongue in relation to the occurrence of occult CLNM.
Materials and methods
In this retrospective study,
n
= 139 patients with primary OSCC of the tongue, treated by complete surgical resection (R0) with curative intention between 2013 and 2021, were included. For data analysis, epidemiologic data as well as preoperative tumor staging, surgical therapy including neck management, histopathological tumor data and follow-up were considered. Uni- and multivariate logistic regression were used to determine association between histopathological risk factors and the occurrence of occult CLNM.
Results
The rate of occult cervical metastasis was 19.4%. T-staging, cervical nodal disease (pN+) and lymphatic invasion were significantly associated with reduced OS and RFS. While DOI had no relevant influence on the OS and RFS (
p
= 0.88 and
p
= 0.91 respectively), there was significant correlation between DOI and the occurrence of occult CLNM (OR: 1.17, 95%CI: 1.05–1.30;
p
< 0.01). The optimal cutoff in predicting occult CLNM was 6 mm (Sensitivity: 84.2%, Specificity: 73.5%, AUC: 0.75).
Conclusions
The DOI is a helpful risk parameter to predict the occurrence of occult nodal disease in OSCC of the tongue. Given the critical decision cutoff between 2 and 4 mm DOI for performing elective neck dissection in the current guidelines, our data suggests that in these cases, surgical de-escalation could be feasible with close follow-up.
Clinical relevance
This study highlights the relevance of DOI as a risk parameter in the prediction of CLNM with the aim to specify the individual patient risk and to deescalate surgical therapy in order to decrease comorbidities while improving the oncological prognosis.
Objectives Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is a clinical and research standard for evaluating malignant tumors and lymph node metastasis. However, quantitative analysis of ...nodal status is limited to measurement of short axis diameter (SAD), and metastatic lymph nodes below 10 mm in SAD are often not detected. The purpose of this study was to evaluate the value of multifrequency magnetic resonance elastography (MRE) when added to RECIST 1.1 for detection of lymph node metastasis. Materials and Methods Twenty-five benign and 82 metastatic lymph nodes were prospectively examined by multifrequency MRE at 1.5 T using tomoelastography postprocessing at 30, 40, 50, and 60 Hz (total scan time of 4 minutes). Shear wave speed as a surrogate of soft tissue stiffness was provided in m/s. Positron emission tomography–computed tomography was used as reference standard for identification of abdominal lymph node metastasis from histologically confirmed primary tumors. The diagnostic performance of MRE was compared with that of SAD according to RECIST 1.1 and evaluated by receiver operating characteristic curve analysis using generalized linear mixed models and binary logistic mixed models. Sensitivity, specificity, and predictive values were calculated for different cutoffs. Results Metastatic lymph nodes (1.90 ± 0.57 m/s) were stiffer than benign lymph nodes (0.98 ± 0.20 m/s, P < 0.001). An area under the curve of 0.95 for a cutoff of 1.32 m/s was calculated. Using a conservative approach with 1.0 specificity, we found sensitivity (SAD/MRE/MRE + SAD, 0.56/0.84/0.88), negative predictive values (0.41/0.66/0.71), and overall accuracy (0.66/0.88/0.91) to be improved using MRE and even higher for combined MRE and SAD. Conclusions Multifrequency MRE improves metastatic abdominal lymph node detection by 25% based on higher tissue stiffness—even for lymph nodes with an SAD ≤10 mm. Stiffness information is quick to obtain and would be a promising supplement to RECIST.
The regularization of derivative expectation operator (RODEO) approach developed by Laferty and Wasserman (2008) is a regularization technique designed for a wide range of nonparametric kernel ...smoothers. The approach applies regularization by penalizing the bias reduction associated with a bandwidth reduction along a smooth path of decreasing bandwidth parameter values in order to avoid overftting. Dimensions with small local variation are efectively smoothed out, thus implicitly carrying out variable selection. Under certain conditions, faster rates of converges of convergence for the mean integrated square error can be achieved, which makes the approach attractive for applications in high dimensions. In this paper we apply the RODEO approach to local polynomial density estimation. We implemented the approach in the R package lpderodeo. We apply our implementation to a few examples, and evaluate its performance in a comparative study using a sample of eight other approaches for nonparametric density estimation. Our fndings suggest that the approach does not work well in comparison to the other considered approaches with regard to the applied performance metrics. Furthermore, our implementation sufers from long computation time due to a naive query. Our main fnding, however, concerns the fact that the theoretical framework proposed by Liu, Laferty, and Wasserman (2007) has severe shortcomings. In fact, we demonstrate that a simple rotation of the data makes the algorithm fail in practice.
Post-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been ...well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.
In this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3-8, 9-16, and 17-20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.
Patients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.
Our findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.
C. S. was supported by a grant from the Weidenhammer-Zoebele Foundation. F. K. was supported by the Volkswagen Foundation.
Coronavirus disease 2019 (COVID-19) and non-COVID-19 community-acquired pneumonia (NC-CAP) often result in hospitalization with considerable risks of mortality, ICU treatment, and long-term ...morbidity. A comparative analysis of clinical outcomes in COVID-19 CAP (C-CAP) and NC-CAP may improve clinical management.
Using prospectively collected CAPNETZ study data (January 2017 to June 2021, 35 study centers), we conducted a comprehensive analysis of clinical outcomes including in-hospital death, ICU treatment, length of hospital stay (LOHS), 180-day survival, and post-discharge re-hospitalization rate. Logistic regression models were used to examine group differences between C-CAP and NC-CAP patients and associations with patient demography, recruitment period, comorbidity, and treatment.
Among 1368 patients (C-CAP: n = 344; NC-CAP: n = 1024), C-CAP showed elevated adjusted probabilities for in-hospital death (aOR 4.48 95% CI 2.38-8.53) and ICU treatment (aOR 8.08 95% CI 5.31-12.52) compared to NC-CAP. C-CAP patients were at increased risk of LOHS over seven days (aOR 1.88 95% CI 1.47-2.42). Although ICU patients had similar in-hospital mortality risk, C-CAP was associated with length of ICU stay over seven days (aOR 3.59 95% CI 1.65-8.38). Recruitment period influenced outcomes in C-CAP but not in NC-CAP. During follow-up, C-CAP was linked to a reduced risk of re-hospitalization and mortality post-discharge (aOR 0.43 95% CI 0.27-0.70).
Distinct clinical trajectories of C-CAP and NC-CAP underscore the need for adapted management to avoid acute and long-term morbidity and mortality amid the evolving landscape of CAP pathogens.
Background: Post-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been ...well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear. Methods: In this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers. Findings: Patients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS. Interpretation: Our findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity. Funding: C. S. was supported by a grant from the Weidenhammer-Zoebele Foundation. F. K. was supported by the Volkswagen Foundation.
Janus kinase Tyk2 is implicated in cancer immune surveillance, but its role in solid tumors is not well defined. We used Tyk2 knockout mice (Tyk2
Δ/Δ
) and mice with conditional deletion of Tyk2 in ...hematopoietic (Tyk2
ΔHem
) or intestinal epithelial cells (Tyk2
ΔIEC
) to assess their cell type-specific functions in chemically induced colorectal cancer. All Tyk2-deficient mouse models showed a higher tumor burden after AOM-DSS treatment compared to their corresponding wild-type controls (Tyk2
+/+
and Tyk2
fl/fl
), demonstrating tumor-suppressive functions of Tyk2 in immune cells and epithelial cancer cells. However, specific deletion of Tyk2 in hematopoietic cells or in intestinal epithelial cells was insufficient to accelerate tumor progression, while deletion in both compartments promoted carcinoma formation. RNA-seq and proteomics revealed that tumors of Tyk2
Δ/Δ
and Tyk2
ΔIEC
mice were immunoedited in different ways with downregulated and upregulated IFNγ signatures, respectively. Accordingly, the IFNγ-regulated immune checkpoint Ido1 was downregulated in Tyk2
Δ/Δ
and upregulated in Tyk2
ΔIEC
tumors, although both showed reduced CD8
+
T cell infiltration. These data suggest that Tyk2
Δ/Δ
tumors are Ido1-independent and poorly immunoedited while Tyk2
ΔIEC
tumors require Ido1 for immune evasion. Our study shows that Tyk2 prevents Ido1 expression in CRC cells and promotes CRC immune surveillance in the tumor stroma. Both of these Tyk2-dependent mechanisms must work together to prevent CRC progression.
Abstract
Intestinal epithelial cells are covered by the brush border, which consists of densely packed microvilli. The Intermicrovillar Adhesion Complex (IMAC) links the microvilli and is required ...for proper brush border organization. Whether microvillus crosslinking is involved in the intestinal barrier function or colitis is currently unknown. We investigate the role of microvillus crosslinking in colitis in mice with deletion of the IMAC component CDHR5. Electron microscopy shows pronounced brush border defects in CDHR5‐deficient mice. The defects result in severe mucosal damage after exposure to the colitis‐inducing agent DSS. DSS increases the permeability of the mucus layer and brings bacteria in direct contact with the disorganized brush border of CDHR5‐deficient mice. This correlates with bacterial invasion into the epithelial cell layer which precedes epithelial apoptosis and inflammation. Single‐cell RNA sequencing data of patients with ulcerative colitis reveals downregulation of CDHR5 in enterocytes of diseased areas. Our results provide experimental evidence that a combination of microvillus crosslinking defects with increased permeability of the mucus layer sensitizes to inflammatory bowel disease.
Synopsis
image
Crosslinking of microvilli in the intestinal brush border mediated by CDHR5 represents an important barrier against invasion of luminal bacteria. A combination of reduced crosslinking with increased mucus layer permeability may sensitize to inflammatory bowel disease.
Deletion of CDHR5 leads to microvilli shortening and brush border disorganization in the small and large intestine of mice.
CDHR5 protects mice from DSS‐induced colitis, but not from hapten‐induced T cell‐mediated colitis.
Microvilli crosslinking prevents entry when the mucus layer becomes permeable and bacteria reach intestinal epithelia.
CDHR5 is downregulated in the inflamed epithelium compared to the non‐inflamed epithelium of ulcerative colitis patients.
