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Objective was to analyze the role of PD-L1 and its relation to demographic, patho-clinical and outcome parameters in salivary gland carcinoma (SGC) patients. Patients treated for salivary gland carcinomas between 1994 and 2010 were included. A retrospective chart review for baseline characteristics, pathohistological, clinical and outcome data was performed. Immunohistochemistry for PD-L1 was performed using tissue microarrays. PD-L1 expression was assessed in tumor cells and tumor-infiltrating immune cells (TIIC) and statistical analysis with regard to baseline and outcome data was performed. Expression of PD-L1 (by means ≥1% of the cells with PD-L1 positivity) was present in the salivary gland carcinoma cells of 17%, in the TIIC of 20% and in both tumor cells and TIIC of 10% the patients. PD-L1 expression in tumor cells and both tumor cells and TIIC was related to tumor grading (p = 0.035 and p = 0.031, respectively). A trend towards higher grading was also seen for PD-L1 expression in TIICs (p = 0.058). Patients with salivary duct carcinomas and PD-L1 expressing TIICs showed a significantly worse DFS and OS (p = 0.022 and p = 0.003, respectively), those with both tumor cells and TIIC expressing PD-L1 a significantly worse DFS (p = 0.030). PD-L1 expression is present in 17% and 20% of salivary gland carcinoma cells and TIIC. Ten percent of the patient showed a PD-L1 positivity in both tumor cells and TIIC. This is related to high tumor grading and therefore might be a negative prognostic factor.

Background. Invasive Mycobacterium chimaera infections were diagnosed in 2012 in 2 heart surgery patients on extracorporeal circulation. We launched an outbreak investigation to identify the source and extent of the potential outbreak and to implement preventive measures. Methods. We collected water samples from operating theaters, intensive care units, and wards, including air samples from operating theaters. Mycobacterium chimaera strains were characterized by randomly amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Case detection was performed based on archived histopathology samples and M. chimaera isolates since 2006, and the patient population at risk was prospectively surveyed. Results. We identified 6 male patients aged between 49 and 64 years with prosthetic valve endocarditis or vascular graft infection due to M. chimaera, which became clinically manifest with a latency of between 1.5 and 3.6 years after surgery. Mycobacterium chimaera was isolated from cardiac tissue specimens, blood cultures, or other biopsy specimens. We were able also to culture M. chimaera from water circuits of heater-cooler units connected to the cardiopulmonary bypass, and air samples collected when the units were in use. RAPD-PCR demonstrated identical patterns among M. chimaera strains from heater-cooler unit water circuits and air samples, and strains in 2 patient clusters. Conclusions. The epidemiological and microbiological features of this prolonged outbreak provided evidence for the airborne transmission of M. chimaera from contaminated heater-cooler unit water tanks to patients during open-heart surgery.

A 30‐year‐old male developed a PET‐positive left‐sided cervical lymphadenopathy that was suspected representing metastasis of a known right‐sided papillary thyroid cancer. First‐dose‐application of Spikevax three weeks ago was neither reflected, nor reported to the pathologists. Diagnostic lymphadenectomy was performed showing extrafollicular proliferation of B‐blasts, likely attributable to the vaccine application. The extrafollicular proliferation of B‐blast pattern seems to be recurrent in mRNA COVID‐19 vaccine‐induced lymphadenopathies and is one of the morphological correlates to PET‐imaging reactivity in respective instances. Generally, this type lymphadenopathy is observable as primary reaction to antigens and may represent a diagnostic pitfall to large cell lymphomas with scattered tumor cells.

The optical excitation of metals initially creates short-lived non-Fermi distributions of the electrons. The electrons and holes excited far above and below the Fermi level quickly relax to hot Fermi-distributions that subsequently cool via electron-phonon scattering. Here, we show that such non-thermal charge carriers beyond the Fermi-distribution speed up the prototypical first-order antiferromagnetic-to-ferromagnetic phase transition in FeRh. In ultrafast x-ray diffraction experiments, we vary the maximum electron temperature by increasing the pump pulse duration up to 10 ps. For direct optical excitation of FeRh, ferromagnetic domains nucleate within 8 ps as soon as the successively deposited energy surpasses the site-specific threshold energy. In contrast, suppressing the direct optical excitation by an optically opaque Pt layer leads to a nucleation on a 50 ps timescale driven by the near-equilibrium heat transport. These findings unambiguously identify the photo-excitation of non-thermal electrons and not electron-phonon non-equilibria to enable the rapid phase transition in FeRh. Distinguishing the effects of optically excited non-thermal electron distributions from hot electrons is difficult in many scientific contexts. By varying pump pulse duration and metal capping the authors show here that non-thermal electrons - as opposed to a simple electron-phonon nonequilibrium - are crucial for the non-equilibrium phase transition in FeRh.

Objectives Although there are many reports about risk factors for the development of BP-associated osteonecrosis of the jaws, the role of dental implants as a local risk factor is still discussed, especially in patients with oral BP treatment. Until now, a few case reports and surveys display a possible minor risk in patients with oral BP therapy, whereas the avoidance of implant placement is generally accepted in patients with intravenous BP therapy. Patient and methods In this study, the cases of 14 patients with osteonecrosis of the jaws in association with BP therapy and dental implant placement were analyzed carefully with a detailed literature review. Results Of 14 patients, nine had underlying malignant disease and five patients had osteoporosis. In ten patients, implants were placed either in the posterior mandible or maxilla; the mean interval between implant insertion and disease onset was 20.9 months. Pain ( n 12) and signs of infection ( n 10) were the most common symptoms. Histologically, signs of infection were found in nine of 11 analyzed patients with presence of Actinomyces in six patients. Two patients turned out to have infiltration of underlying malignant disease. Conclusions Posteriorly placed implants seem to be of higher risk of development of osteonecrosis of the jaws. Not only the implant placement but also the inserted implant itself seems to be a continuous risk factor. Clinical relevance The herein elaborated risk factors help dentists plan dental rehabilitation with implants in this high-risk group of patients and indicate careful and regular dental recall.

Objectives/Hypothesis To analyze the impact of different types of perineural invasion (PNI) in squamous cell carcinoma (SCC) of the oral cavity on overall survival and recurrence rate, with a special focus on histologic subtypes and tumor stage. Study Design Retrospective case‐control study with clinicopathological analysis. Methods Seventeen patients who received primary surgical treatment for SCC of the oral cavity with PNI were matched to a control group. In a histologic review, PNI was classified into subtypes according to an adapted Liebig classification. The term type A was used to describe tumor invasion into the nerve, whereas type B was used to describe circumferential growth around the nerve. Clinical charts were reviewed, and a Kaplan‐Meier survival analysis was performed. Results The recurrence‐free survival rates were 47.1% versus 80.4% (PNI vs. matched control group, P < 0.05), 60.0% versus 94.1% (PNI in stage I and II disease vs. matched control group, P < 0.05) and 41.7% versus 73.5% (PNI in stage III and IV disease vs. matched control group, P < 0.05). In most cases (n = 9) of PNI, both histologic subtypes (type A and type B) were present. Five cases exclusively showed type A, and three cases exclusively showed type B. Conclusions Perineural invasion in early disease oral carcinoma has a particularly high impact on survival. Both histologic subtypes showed a significantly worse recurrence‐free survival rate when compared to the control group. Level of Evidence 3.

Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene deletion. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Up-regulation of p63 expression is required for ASPP2 Δᵉˣᵒⁿ³/⁺ BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear Rel/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB–mediated repression of p63.

Digital pathology (DP) is increasingly entering routine clinical pathology diagnostics. As digitization of the routine caseload advances, implementation of digital image analysis algorithms and artificial intelligence tools becomes not only attainable, but also desirable in daily sign out. The Swiss Digital Pathology Consortium (SDiPath) has initiated a Delphi process to generate best-practice recommendations for various phases of the process of digitization in pathology for the local Swiss environment, encompassing the following four topics: i) scanners, quality assurance, and validation of scans; ii) integration of scanners and systems into the pathology laboratory information system; iii) the digital workflow; and iv) digital image analysis (DIA)/artificial intelligence (AI). The current article focuses on the DIA-/AI-related recommendations generated and agreed upon by the working group and further verified by the Delphi process among the members of SDiPath. Importantly, they include the view and the currently perceived needs of practicing pathologists from multiple academic and cantonal hospitals as well as private practices.

The endothelium is one of the largest cellular compartments of the human body and has a high proliferative potential. However, angiosarcomas are among the rarest malignancies. Despite this interesting contradiction, data on growth and angiogenesis control mechanisms of angiosarcomas are scarce. In this study of 19 angiosarcomas and 10 benign vascular control lesions we investigated the sequence and expression of the p53 tumor suppressor gene and the expression of the mdm-2proto-oncogene, which is a negative regulator of p53 activity and of the vascular endothelial growth factor (VEGF), whose expression, among other factors, is regulated by the p53/MDM-2 pathway. Ten sarcomas (53%) exibited clear nuclear p53 protein accumulation. Two of these cases revealed mutations in the sequence-specific DNA binding domain of the p53gene. Thirteen angiosarcomas (68%) showed an increased amount of MDM-2 protein. Elevated expression of p53 and MDM-2 protein correlated with increased VEGF expression, which was found in nearly 80% of the angiosarcoma cases. Negative or clearly lower immunostaining was obtained in cases from the benign control collective. Only one case of a juvenile hemangioma reached the cutoff value of p53 positivity coincidentally with high VEGF expression. Our data suggest that the p53/MDM-2 pathway is impaired in about two-thirds (14/19) of the angiosarcomas. This may be a key event in the pathogenesis of human angiosarcomas. The increased VEGF expression observed supports this hypothesis.

The activating BRAF (V600) mutation is a well-established negative prognostic biomarker in metastatic colorectal carcinoma (CRC). A recently developed monoclonal mouse antibody (clone VE1) has been shown to detect reliably BRAF (V600E) mutated protein by immunohistochemistry (IHC). In this study, we aimed to compare the detection of BRAF (V600E) mutations by IHC, Sanger sequencing (SaS), and ultra-deep sequencing (UDS) in CRC. VE1-IHC was established in a cohort of 68 KRAS wild-type CRCs. The VE1-IHC was only positive in the three patients with a known BRAF (V600E) mutation as assessed by SaS and UDS. The test cohort consisted of 265 non-selected, consecutive CRC samples. Thirty-nine out of 265 cases (14.7%) were positive by VE1-IHC. SaS of 20 randomly selected IHC negative tumors showed BRAF wild-type (20/20). Twenty-four IHC-positive cases were confirmed by SaS (24/39; 61.5%) and 15 IHC-positive cases (15/39; 38.5%) showed a BRAF wild-type by SaS. UDS detected a BRAF (V600E) mutation in 13 of these 15 discordant cases. In one tumor, the mutation frequency was below our threshold for UDS positivity, while in another case, UDS could not be performed due to low DNA amount. Statistical analysis showed sensitivities of 100% and 63% and specificities of 95 and 100% for VE1-IHC and SaS, respectively, compared to combined results of SaS and UDS. Our data suggests that there is high concordance between UDS and IHC using the anti-BRAF(V600E) (VE1) antibody. Thus, VE1 immunohistochemistry is a highly sensitive and specific method in detecting BRAF (V600E) mutations in colorectal carcinoma.