Background: MRI-guided prostate biopsies from visible tumor-specific lesions (TBx) can be used to diagnose clinically significant carcinomas (csPCa) requiring treatment more selectively than conventional systematic biopsies (SBx). Ex vivo fluorescence confocal microscopy (FCM) is a novel technique that can be used to examine TBx prior to conventional histologic workup. Methods: TBx from 150 patients were examined with FCM on the day of collection. Preliminary findings were reported within 2 h of collection. The results were statistically compared with the final histology. Results: 27/40 (68%) of the csPCa were already recognized in the intraday FCM in accordance with the results of conventional histology. Even non-significant carcinomas (cisPCa) of the intermediate and high-risk groups (serum prostate-specific antigen (PSA) > 10 or 20 ng/mL) according to conventional risk stratifications were reliably detectable. In contrast, small foci of cisPCa were often not detected or were difficult to distinguish from reactive changes. Conclusion: The rapid reporting of preliminary FCM findings helps to reduce the psychological stress on patients, and can improve the clinical management of csPCa. Additional SBx can be avoided in individual cases, leading to lower rates of complications and scarring in the future surgical area. Additional staging examinations can be arranged without losing time. FCM represents a promising basis for future AI-based diagnostic algorithms.

The standard procedure for the diagnosis of prostate carcinoma involves the collection of 10-12 systematic biopsies (SBx) from both lobes. MRI-guided targeted biopsies (TBx) from suspicious foci increase the detection rates of clinically significant (cs) PCa. We investigated the extent to which the results of the TBx predicted the tumor board treatment decisions. SBx and TBx were acquired from 150 patients. Risk stratifications and recommendations for interventional therapy (prostatectomy and radiotherapy) or active surveillance were established by interdisciplinary tumor boards. We analyzed how often TBx alone were enough to correctly classify the tumors as well as to indicate interventional therapy and how often the findings of SBx were crucial for therapy decisions. A total of 28/39 (72%) favorable risk tumors were detected in TBx, of which 11/26 (42%) very-low-risk tumors were not detected and 8/13 (62%) low-risk tumors were undergraded. A total of 36/44 (82%) intermediate-risk PCa were present in TBx, of which 4 (9%) were underdiagnosed as a favorable risk tumor. A total of 12/13 (92%) high-risk carcinomas were detected and correctly grouped in TBx. The majority of csPCa were identified by the sampling of TBx alone. The tumor size was underestimated in a proportion of ISUP grade 1 tumors. Systematic biopsy sampling is therefore indicated for the next AS follow-up in these cases.

Abstract Staphylococcus aureus bacteriuria (SABU) can occur in patients with S. aureus bacteremia (SAB). However, little is known on the (molecular) pathomechanisms of the renal passage of S. aureus. This review discusses the epidemiology and pathogenesis of SABU in patients with SAB and identifies knowledge gaps. The literature search was restricted to the English language. The prevalence of SABU in patients with SAB is 7.8%–39% depending on the study design. The main risk factor for SABU is urinary tract catheterization. SABU in SAB patients is associated with increased mortality. Given present evidence, hematogenous seeding—as seen in animal models—and the development of micro-abscesses best describe the translocation of S. aureus from blood to urine. Virulence factors that might be involved are adhesion factors, sortase A, and coagulase, among others. Other potential routes of bacterial translocation (eg, transcytosis, paracytosis, translocation via “Trojan horses”) were identified as knowledge gaps.

Objective The objective of this study was to characterize patients with extracranial giant cell arteritis with intracranial involvement. Methods In a multicenter retrospective study, we included 31 patients with systemic giant cell arteritis (GCA) with intracranial involvement. Clinical characteristics, pattern of arterial involvement, and cytokine profiles were assessed. Patients with GCA without intracranial involvement (n = 17), and with intracranial atherosclerosis (n = 25) served as controls. Results Erythrocyte sedimentation rate (ESR) was elevated in 18 patients (69.2%) with and in 16 patients (100%) without intracranial involvement ( p = 0.02). Headache was complained by 15 patients (50.0%) with and 13 patients (76.5%) without intracranial involvement ( p = 0.03). Posterior circulation arteries were affected in 26 patients (83.9%), anterior circulation arteries in 17 patients (54.8%), and both territories in 12 patients (38.7%). Patients with GCA had vertebral artery stenosis proximal and, in contrast, patients with atherosclerosis distal to the origin of posterior inferior cerebellar artery (PICA). Among patients with GCA with intracranial involvement, 11 patients (37.9%) had a rapid progressive disease course characterized by short‐term recurrent ischemic events. The median modified Rankin Scale (mRS) at follow‐up in these patients was 4 (interquartile range [IQR] = 2.0–6.0) and 4 patients (36.4%) died. Vessel wall expression of IL‐6 and IL‐17 was significantly increased in patients with rapid progressive course. Interpretation Typical characteristics of GCA, headache, and an elevated ESR, are frequently absent in patients with intracranial involvement. However, differentiation of intracranial GCA from atherosclerosis can be facilitated by the typical pattern of vertebral artery stenosis. About one‐third of patients with intracranial GCA had a rapid progressive course with poor outcome. IL‐17 and IL‐6 may represent potential future treatment targets. ANN NEUROL 2021;90:118–129

CD34+ fibroblasts are constitutive stromal components of virtually all organs, including the mammary stroma, being involved in matrix synthesis, antigen presentation, and tumor-associated stromal remodeling. The most common subtype of invasive breast carcinoma, invasive carcinoma of no special type (IBC-NST), is known for its stromal loss of CD34+ fibroblasts while acquiring alpha smooth muscle actin-positive (α-SMA+) myofibroblasts, i.e., cancer-associated fibroblasts (CAF), whereas invasive lobular carcinoma (ILC) displays partial preservation of CD34+ fibroblasts. The aim of this study was to evaluate the prognostic relevance of stromal CD34+ fibroblasts and α-SMA+ myofibroblasts in an extended collection of ILC. A total of 133 cases of ILC, primarily resected between 1996 and 2004 at University Hospital Marburg, were examined semiquantitatively for stromal content of CD34+ fibroblasts and α-SMA+ myofibroblasts. Partial preservation of CD34+ fibroblasts in the tumor stroma of ILC was confirmed. Absence of CD34+ fibroblasts in the tumor stroma significantly correlated with the presence of α-SMA+ myofibroblasts (p = 0.010), positive lymph node status (p = 0.004), and pN stage (p = 0.006). Stromal loss of CD34+ fibroblasts was significantly associated with lower overall and disease-free survival rates (p = 0.012 and 0.013, respectively). Multivariate analysis adjusted for pT and pN stage revealed stromal loss of CD34+ fibroblasts as independent prognostic parameter (p = 0.05). To our knowledge, this is the first report defining prognostically relevant stromal subtypes of ILC with long-term follow-up. Future research targeting the potential diagnostic and therapeutic implications of CD34+ fibroblasts and CAF in breast cancer, especially ILC, is a promising field of interest.

INTRODUCTION:Besides invasive or non-invasive ventilation, treatment of severe forms of interstitial lung diseases (ILD) includes immunosuppressive medication. In case of refractory organ- or life-threatening courses of disease, cyclophosphamide pulse therapy can serve as a rescue treatment option.OBJECTIVES:To investigate therapeutic and prognostic effects of cyclophosphamide for the treatment of severe forms of ILD on intensive care unit (ICU) we performed this analysis.METHODS:Between 2009 and 2017 we identified 14 patients, who were treated on intensive care unit (ICU) with severe forms of ILD. Retrospectively, clinical, radiologic and prognostic data were collected and evaluated.RESULTS:Our analysis demonstrated a prognostic impact of cyclophosphamide on the ILD in general. Whereas pulmonary manifestations of both systemic sclerosis (SSc) and ANCA-associated vasculitis had an improved outcome, a reduced overall survival was found for Goodpasture syndrome (GPS), dermatomyositis (DM), cryptogenic organizing pneumonia (COP) and drug reaction with eosinophilia and systemic symptoms (DRESS; p=0.040, logrank test). Besides, additional plasmapheresis and initiation of cyclophosphamide within ten days following initial diagnosis of ILD were associated with improved prognosis.CONCLUSION:Positive prognostic effects of cyclophosphamide pulse therapy in ICU treated patients suffering from severe respiratory failure due to pulmonary manifestations of both SSc and ANCA-associated-vasculitis were observed. Further prognostic and therapeutic data are needed for cyclophosphamide for this indication in order to prevent patients from its toxic side-effects, who most likely will not benefit from its application.

Abstract Background Epithelial‐to‐mesenchymal transition (EMT) is a crucial step in lung cancer pathogenesis. Among others, cancer‐associated fibroblasts (CAFs) are reported to regulate this process. Objectives To investigate the prognostic and clinical impact, we analyzed CD34+ and SMA+ CAFs in non‐small cell lung cancer (NSCLC). Methods Retrospectively, immunohistochemistry was performed to study stromal protein expression of both CD34 and SMA in 304 NSCLC patients with pTNM stage I‐III disease. All tissue samples were embedded on tissue microarrays (TMAs). Results Our analysis revealed an association for CD34+ CAFs with G1/2 tumors and adenocarcinoma histology. Moreover CD34+ CAFs were identified as an independent prognostic factor (both for progression free survival [PFS] and overall survival [OS] in stage I‐III NSCLC). Besides, SMA+ expression correlated with higher pTNM‐tumor stages and lymphatic spread (pN stage). In turn, SMA‐negativity was associated with improved PFS, but no prognostic impact was found on OS. Of interest, neither CD34+ CAFs nor SMA+ CAFs were associated with the primary tumor size, localization and depth of infiltration (pT stage). Conclusions CD34 was identified as an independent prognostic marker in pTNM stage I‐III NSCLC. Moreover, loss of CD34+ CAFs might influence the dedifferentiation of the NSCLC tumor from its cell origin. Finally, SMA+ CAFs are more prevalent in NSCLC tumors of higher stages and lymphonodal positive NSCLC. Key points Expression of CD34 on cancer associated fibroblasts (CAFs) is an independent prognostic factor in stage I‐III NSCLC. SMA+ cancer associated fibroblasts are associated with higher tumor stages in NSCLC and might contribute to tumor progression in NSCLC.

Background Crohn’s Disease (CD) is typically characterized by abdominal symptoms, however, besides gastrointestinal symptoms, CD patients may suffer from extraintestinal manifestations which are far less common and medical treatment can be challenging. Case presentation We report about a 34-year-old Crohn’s Disease (CD) patient in clinical remission under adalimumab therapy who presented in the clinic for Cranio-Maxillo Surgery due to severe pain in the mandibular area. Ulcerative lesions of the buccal-side mucosa of the right mandible were detected. To rule out malignancy, a biopsy was obtained and revealed ulcerative stomatitis with noncaseating granulomas consistent with oral CD. Shortening the adalimumab administration interval to weekly injections resulted in a complete healing of the oral CD lesions without residual inflammation. Conclusion The case presented here demonstrates that gastroenterologists should evaluate and consider oral CD lesions as a possible marker of disease activity in patients despite having quiescent intestinal CD.

Multispectral optoacoustic tomography (MSOT) represents a new in vivo imaging technique with high resolution (~250 μm) and tissue penetration (>1 cm) using the photoacoustic effect. While ultrasound contains anatomical information for lesion detection, MSOT provides functional information based on intrinsic tissue chromophores. We aimed to evaluate the feasibility of combined ultrasound/MSOT imaging of breast cancer in patients compared to healthy volunteers.

Chromogranin A (CgA) is a well-established marker for diagnosis and follow up of patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Recently, it has been shown that plasma levels of CgA correlate with tumor load and predict survival of patients with NEN of the small bowel. It is assumed that this is as well valid for NEN of the colon and rectum, however, this is not supported by data. To evaluate this assumption, we analyzed 62 patients with NEN of the colon and rectum listed in the Marburg GEP-NEN registry for clinicopathological characteristics, expression and plasma levels of CgA. The present study demonstrates that immunohistochemical CgA and synaptophysin are good markers for histological diagnosis in patients with NEN of the colon and rectum. However, plasma CgA is a poor marker to follow-up these patients because only a minority exhibited increased levels which did not increase significantly during tumor progression. In contrast to NEN of the small bowel, there is no correlation of CgA plasma levels with tumor burden or survival. Patients with NEN of the colon and rectum displayed a relatively good prognosis resulting in a median survival of 8.5 years. However, a subset of patients affected by G3 neoplasms, exhibited a poorer prognosis with a median survival of 2.5 years. Taken together, CgA is a valuable marker for immunohistochemical diagnosis, but CgA plasma concentration is not suitable to mirror tumor burden or prognosis in patients with NEN of the colon and rectum.

144 Background: Recently developed 68Ga labeled prostate specific membrane antigen (PSMA) ligands were introduced as diagnostic tools to detect prostate cancer (PCa), PCa relapse and metastases with high accuracy. In this study we assessed the usability of preoperative PSMA-PET/CT information on congruency of spread of PCA compared with postoperative PCa-maps derived from radical prostatectomy (RPE) specimens. Methods: We referred 6 patients with biopsy proven high risk PCa to PSMA-PET/CT prior to RPE. Whole body PET/CT (Biograph mCT with 128 slice CT, Siemens) was performed 62±8 minutes after injection of 160±31 MBq [68Ga]-PSMA-HBED-CC (DKFZ-Ga-PSMA-11) as described by routine acquisition protocol. After RPE, prostate specimens were processed in the local pathology department. Topographical analysis of extension of PCa was reconstructed from representative slides on a schematic diagram resulting in a PCa-map of the prostate. After aligning the cutting planes of the PSMA-PET/CT to the PCa-map we defined 20 segments of the prostate and the seminal vesicles. We measured the maximum standard uptake value (SUV) of PSMA activity of the respective segments and compared the concordance of PSMA-positive and -negative areas with those of PCa and no PCa on the PCa-maps. We calculated sensitivity, specificity, positive and negative likelihood ratios (LR) taking available segments into account. Results: 106/112 segments were analyzed. 8 segments were excluded due to spillover of PSMA-activity in bladder urine. All but 3 segments with no PCa on the PCa-maps showed no uptake in PSMA-PET/CT (Specificity = 92%). The sensitivity of PSMA-PET/CT for showing PCa areas was equally 92%. The positive and negative LR for PSMA-PET/CT detecting or ruling out PCa was 11.5 and 0.09, respectively. Conclusions: This preliminary proof of concept study shows that prediction of later pathologic results in RPE-specimens could be estimated by preoperative PSMA-PET/CT. With optimized acquisition protocols it may be possible to improve our preliminary results. Perspectively PSMA-PET/CT may be helpful for identifying PCa suspicious lesions prior to prostate biopsy and support decision making prior to RPE or radiation therapy.

Systemic involvement is well known in patients with inflammatory bowel diseases (IBD), but there are only few data looking to Crohn's disease (CD) and ulcerative colitis (UC) separately instead of lumping together both entities to IBD. The frequency of bronchial involvement in UC is not yet exactly analysed but reported to be rare. We asked 100 patients with UC for bronchial complaints, and found in 13 patients a bronchial affection. From reports in the literature it is known that sometimes a bronchial involvement in patients with UC can affect the whole bronchial tree including small bronchi. The involvement of bronchial system in UC is obviously more prominent than previously thought and may fulfil the criteria for a separate syndrome. These relations may have consequences for pathogenetic understanding of UC as well as bronchitis and also consequences for treatment regimes.

BACKGROUND:Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies.METHODS:In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells.RESULTS:SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown.CONCLUSION:We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways.

BACKGROUND:To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone.PATIENTS AND METHODS:Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect.RESULTS:Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%).CONCLUSION:Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disease often manifesting with epistaxis, telangiectasia, and intraparenchymatous arteriovenous malformations. We report on the case of a 71-year-old man who was admitted to hospital due to a tricuspid valve insufficiency. During the following days, the patient developed liver and renal failure; the clinical condition worsened rapidly. Computed tomographic diagnostics revealed arteriovenous malformations in the lung and in the liver portal. Additionally, mucocutaneous telangiectasia in the mouth was found. Hereditary hemorrhagic telangiectasia was assumed; nevertheless, an effective treatment was impossible because of the patient's worse clinical state; he died a few days later. Autopsy affirmed the diagnosis of hereditary hemorrhagic telangiectasia; molecular genetic analysis revealed a heterozygous mutation in the ALK-1 gene. Despite its relatively high prevalence, hereditary hemorrhagic telangiectasia is not considered as a diagnosis as frequently as it should be, and clinicians need to be aware of the signs of hereditary hemorrhagic telangiectasia as well as the appropriate diagnostic workup.

Expression of cytokine-regulated signal transducer and activator of transcription (STAT) proteins was histochemically assessed in patients diagnosed as having Hashimoto's disease or focal lymphocytic thyroiditis (n = 10). All surgical specimens showed histological features of lymphocytic thyroiditis, including a diffuse infiltration with mononuclear cells and an incomplete loss of thyroid follicles, resulting in the destruction of glandular tissue architecture. Immunohistochemical analysis demonstrated differential expression patterns of the various members of the STAT transcription factors examined, indicating that each member of this conserved protein family has its distinct functions in the development of the disease. Using an antibody that specifically recognized the phosphorylated tyrosine residue in position 701, we detected activated STAT1 dimers in numerous germinal macrophages and infiltrating lymphocytes as well as in oncocytes. In contrast, STAT3 expression was restricted to epithelial cells and showed a clear colocalization with the antiapoptotic protein Bcl-2. Moreover, expression of phospho-STAT3 was associated with low levels of stromal fibrosis, suggesting that STAT3 serves as a protective factor in the remodeling of the inflamed thyroid gland. Phospho-STAT5 immunoreactivity was detected in numerous infiltrating cells of hematopoietic origin and, additionally, in hyperplastic follicular epithelia. This tissue distribution demonstrated that activated STAT5 molecules participate in both lymphocytopoiesis and possibly also in the buildup of regenerating thyroid follicles. Taken together, the cell-type-specific expression patterns of STAT proteins in human lymphocytic thyroiditis reflect their distinct and partially antagonistic roles in orchestrating the balance between degenerating and regenerating processes within a changing cytokine environment.

BACKGROUND:Nowadays, the morphological assessment of samples obtained from living patients has a greater importance than the scientific knowledge which is gained by autopsy. Therefore, the aim of the study was a retrospective analysis of causes of death in patients with head and neck cancer.MATERIAL AND METHODS:The autopsy rate, clinical parameters of oncologic patients as well as autopsy findings like lethal complications, distant metastases and second primary tumors were retrospectively analyzed.RESULTS:From 1968 to 2007 in 91 patients with malignant tumors of the head and neck an autopsy was performed. In these 39 years an autopsy was performed in 45.9% of dead oncologic patients. Autopsy findings revealed distant metastases in 46.2% and second primary tumors in 17.6% of the patients. 49.5% of the patients died from pneumonia, 20.9% from tumor bleeding and 10% from progressive cachexia.CONCLUSION:The study confirms the global trend of a decline in autopsy numbers in the last 3 decades. However, as an important instrument of quality assurance autopsies continue to play an essential and indispensable role in medical research.

Regulatory T cells (Treg cells), which are lymphocyte subsets capable of suppressing immune responses, appear to play a crucial role in maintaining immune homeostasis and mediating peripheral tolerance. However, Treg cells also accumulate in cancer patients and have been implicated in tumor immune escape. The forkhead box P3 (FOXP3) transcription factor is currently regarded as the most specific and reliable marker for Treg cells in men. We investigated the frequency and characterized the distribution of FOXP3(+) cells in renal cell carcinoma (RCC) patients, focusing on the tumor microenvironment. FOXP3 expression was assessed in kidney tissue samples from 32 RCC patients by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Both conventional and quantitative RT-PCR disclosed higher FOXP3 expression levels in RCC than in adjacent normal renal tissue. Immunohistochemical staining of FOXP3-expressing cells confirmed the accumulation of FOXP3(+) cells in tumor tissue, particularly at the border between malignant and adjacent benign kidney tissues. Our findings indicate that Treg cells accumulate at the tumor invasion zone and could thus be part of an immune escape mechanism of RCC that promotes disease progression.

The structure of germinal centres (GCs) in human secondary lymphatic organs has not been thoroughly investigated until now. We stained follicular dendritic cells (FDCs) in serial sections of human hyperplastic tonsils and spleens to compare the morphology of GCs in fulminant immune reactions and quiescence. Detection of CD35, CD21, CD23 and the target of mAb CNA.42 confirmed that full-blown human tonsil GCs may consist of four regions, the dark zone, the basal and apical light zone and the outer zone. The outer zone was, however, not a constant feature of tonsillar GCs and existed only in a minority of follicles in most specimens. Thus, between 3 and 60% of tonsil GCs with a CD23(+) apical light zone exhibited an outer zone in individual specimens. FDCs in tonsil GCs appeared to be extremely sensitive to mechanical stress during surgery. In contrast to tonsils, seven of the eight adult spleens did not exhibit asymmetric polarized GCs, but only symmetric GCs without dark and light zones or follicles with few GC B cells. Some specimens apparently only contained primary follicles after conventional staining, but on closer inspection a homogenous hyaline extracellular material deposited among the FDCs indicated that a GC had been present. Our study demonstrates that the structure of GCs varies in different human secondary lymphatic organs most likely depending on the local antigenic challenge.