The WERA cancer center matrix: Strategic management of patient access to precision oncology in a large and mostly rural area of Germany.

PURPOSE: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. METHODS: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. RESULTS: The WERA matrix overlooked an active screening area of 821 postal code areas - representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity - with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog - characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. CONCLUSIONS: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.

First-line immunotherapy for lung cancer with MET exon 14 skipping and the relevance of TP53 mutations.

BACKGROUND: The efficacy of checkpoint inhibitors for non-small cell lung cancer (NSCLC) with MET exon 14 skipping (METΔ14ex) remains controversial. MATERIALS AND METHODS: 110 consecutive METΔ14ex NSCLC patients receiving first-line chemotherapy (CHT) and/or immunotherapy (IO) in 10 German centers between 2016-2022 were analyzed. RESULTS: Combined CHT-IO was given to 35/110 (32%) patients, IO alone to 43/110 (39%), and CHT to 32/110 (29%) upfront. Compared to CHT, CHT-IO showed longer progression-free survival (median PFS 6 vs. 2.5 months, p = 0.004), more objective responses (ORR 49% vs. 28%, p = 0.086) and numerically longer overall survival (OS 16 vs. 10 months, p = 0.240). For IO monotherapy, OS (14 vs. 16 months) and duration of response (26 vs. 22 months) were comparable to those of CHT-IO. Primary progressive disease (PD) was more frequent with IO compared to CHT-IO (13/43 vs. 3/35, p = 0.018), particularly for never-smokers (p = 0.041). Higher PD-L1 TPS were not associated with better IO outcomes, but TP53 mutated tumors showed numerically improved ORR (56% vs. 32%, p = 0.088) and PFS (6 vs. 3 months, p = 0.160), as well as longer OS in multivariable analysis (HR=0.54, p = 0.034) compared to their wild-type counterparts. Any second-line treatment was administered to 35/75 (47%) patients, with longer survival for capmatinib or tepotinib compared to crizotinib (PFS 10 vs. 3 months, p = 0.013; OS 16 vs. 13 months, p = 0.270). CONCLUSION: CHT-IO is superior to CHT, and IO alone also effective for METΔ14ex NSCLC, especially in the presence of TP53 mutations and independent of PD-L1 expression, but never-smokers are at higher risk of primary PD.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

BACKGROUND: Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. CASE PRESENTATION: A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. CONCLUSION: This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.

[NGS-based molecular genetics of leukemia-a powerful and decentralized approach]. / NGS-basierte Molekulargenetik der Leukämie ­ ein leistungsfähiger und dezentraler Lösungsansatz.

The diagnosis of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), originally based on morphological assessment alone, has to bring together more and more disciplines. Today, modern AML/MDS diagnostics rely on cytomorphology, cytochemistry, immunophenotyping, cytogenetics, and molecular genetics. Only the integration of all these methods allows a comprehensive and complementary characterization of each case, which is a prerequisite for optimal AML/MDS diagnosis and treatment. In the following, we present why multidisciplinary and local diagnosis is essential today and will become even more important in the future, especially in the context of precision medicine. We present our idea and strategy implemented at Augsburg University Hospital, which has realized multidisciplinary diagnostics in AML/MDS in an interdisciplinary and decentralized approach. In particular, this includes the recent technical advances that molecular genetics provides with modern methods. The enormous amount of data generated by these techniques represents a major challenge, but also a unique opportunity. We will reflect on how this increase in knowledge can be integrated into routine practice to lead the way for personalized medicine in AML/MDS to improve patient care.

Quantitative multiorgan proteomics of fatal COVID-19 uncovers tissue-specific effects beyond inflammation.

SARS-CoV-2 may directly and indirectly damage lung tissue and other host organs, but there are few system-wide, untargeted studies of these effects on the human body. Here, we developed a parallelized mass spectrometry (MS) proteomics workflow enabling the rapid, quantitative analysis of hundreds of virus-infected FFPE tissues. The first layer of response to SARS-CoV-2 in all tissues was dominated by circulating inflammatory molecules. Beyond systemic inflammation, we differentiated between systemic and true tissue-specific effects to reflect distinct COVID-19-associated damage patterns. Proteomic changes in the lungs resembled those of diffuse alveolar damage (DAD) in non-COVID-19 patients. Extensive organ-specific changes were also evident in the kidneys, liver, and lymphatic and vascular systems. Secondary inflammatory effects in the brain were related to rearrangements in neurotransmitter receptors and myelin degradation. These MS-proteomics-derived results contribute substantially to our understanding of COVID-19 pathomechanisms and suggest strategies for organ-specific therapeutic interventions.

Alterations in Natural Killer Cells in Colorectal Cancer Patients with Stroma AReactive Invasion Front Areas (SARIFA).

BACKGROUND: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct tumor biology. Considering it is already known that peripheral immune cells are altered in colorectal cancer (CRC) patients, this study aims to investigate the changes in lymphocyte subsets in SARIFA-positive cases and correlate these changes with the local immune response. METHODS: Flow cytometry was performed to analyze B, T, and natural killer (NK) cells in the peripheral blood (PB) of 45 CRC patients. Consecutively, lymphocytes in PB, tumor-infiltrating lymphocytes (TILs), and CD56+ and CD57+ lymphocytes at the invasion front and the tumor center were compared between patients with SARIFA-positive and SARIFA-negative CRCs. RESULTS: Whereas no differences could be observed regarding most PB lymphocyte populations as well as TILs, NK cells were dramatically reduced in the PB of SARIFA-positive cases. Moreover, CD56 and CD57 immunohistochemistry suggested SARIFA-status-dependent changes regarding NK cells and NK-like lymphocytes in the tumor microenvironment. CONCLUSION: This study proves that our newly introduced biomarker, SARIFA, comes along with distinct immunologic alterations, especially regarding NK cells.

All-Body-Cavity (ABC)-scopy-An approach for a feasible method of minimally invasive autopsy to allow for postmortem tissue sampling in cases where a conventional autopsy is denied.

OBJECTIVES: The decreasing autopsy numbers in many western countries have been partially attributed to the invasiveness of the autopsy, which causes relatives to decline postmortem examination. This issue has been addressed by developing methods of minimally or non-invasive autopsy, which could be shown to increase acceptance for autopsies. The aim of this study is to compare the All-Body-Cavity-scopy (ABC-scopy) to conventional autopsies for diagnostic accuracy. METHODS: The ABC-scopy is an endoscopic approach for minimally invasive autopsy involving laparoscopic and thoracoscopic evaluation of the accessible organs, followed by excision biopsies of relevant organs and conspicuous findings. The method was performed in 10 cases on deceased patients scheduled for autopsy, each followed by a conventional autopsy. RESULTS: The results gathered from ABC-scopy through observation and histopathological evaluation provided an acceptable diagnostic accuracy in 9 out of 10 autopsies when compared to those of the conventional autopsy for diagnostic findings. CONCLUSIONS: The ABC-scopy is a feasible approach for minimally invasive autopsy that provides acceptable diagnostic value. Despite its minimally invasive nature, the procedure enables representative histology through providing large size excision biopsies from intraabdominal and thoracic organs, which is especially useful for examining disseminated diseases such as metastasized tumors.

Fatal cases after Omicron BA.1 and BA.2 infection: Results of an autopsy study.

OBJECTIVES: Omicron lineages BA.1/2 are considered to cause mild clinical courses. Nevertheless, fatal cases after those infections are recognized but little is known about risk factors. METHODS: A total of 23 full and three partial autopsies in deceased with known Omicron BA.1/2 infections have been consecutively performed. The investigations included histology, blood analyses, and molecular virus detection. RESULTS: COVID-19-associated diffuse alveolar damage was found in only eight cases (31%). This rate is significantly lower compared with previous studies, including non-Omicron variants, where rates between 69% and 92% were observed. Neither vaccination nor known risk factors were significantly associated with a direct cause of death by COVID-19. Only those patients who were admitted to the clinic because of COVID-19 but not for other reasons had a significant association with a direct COVID-19 -caused death (P >0.001). CONCLUSION: Diffuse alveolar damage still occurred in the Omicron BA.1/BA.2 era but at a considerably lower frequency than seen with previous variants of concern. None of the known risk factors discriminated the cases with COVID-19-caused death from those that died because of a different disease. Therefore, the host's genomics might play a key role in this regard. Further studies should elucidate the existence of such a genomic risk factor.

Concurrent loss of MLH1, PMS2 and MSH6 immunoexpression in digestive system cancers indicating a widespread dysregulation in DNA repair processes.

Immunohistochemical analysis of mismatch repair (MMR) protein expression is widely used to identify tumors with a deficient MMR (dMMR). MMR proteins (MLH1/PMS2 and MSH2/MSH6) work as functional heterodimers, which usually leads to the loss of expression in only one functional MMR heterodimer. Recently, there have been studies showing the simultaneous loss of immunoexpression in proteins of both heterodimers. Yet, this phenomenon has been rarely investigated. In this study, we retrospectively considered cases of different digestive system cancers (gastric cancer, ampullary cancer, small bowel cancer, colorectal cancer), which were immunohistochemically tested for dMMR within a 4-year period at our university hospital (n=352). Of the 103 cases showing dMMR, 5 cases (1.4% of all, 5.1% of dMMR cases) showed a concurrent loss of MLH1, PMS2 and MSH6 immunoexpression, whereas in the other 98 dMMR cases only one MMR heterodimer was affected. MLH1-/PMS2-/MSH6- cancer cases almost arose throughout the entire digestive tract: from the gastric antrum to the left colic flexur. To provide a comprehensive molecular characterization of this MLH1-/PMS2-/MSH6- immunophenotype, tumors were analyzed for microsatellite instability, MLH1 promotor hypermethylation and BRAF exon 15 status. Furthermore, we performed next-generation sequencing focusing on genes related to DNA repair. Here, we could detect pathogenic germline variants as well as multiple sporadic mutations in different genes involved in MMR and homologous recombination repair (HRR) respectively. The affected MMR/HRR-related genes were: ATM, BARD1, BRCA1, CDK12, CHEK1, CHEK2, FANCA, MLH1, MSH6, PALB2, TP53. Considering the biologic function of HRR/MMR proteins as potential drug targets and the low frequency of most of these mutations in digestive system cancers in general, their common occurrence in our MLH1-/PMS2-/MSH6- cases seems to be even more noteworthy, highlighting the need for recognition, awareness and further investigation of this unusual IHC staining pattern.

Identification of Disparities in Personalized Cancer Care-A Joint Approach of the German WERA Consortium.

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots-regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.

Molecular Assessment of Staphylococcus Aureus Strains in STAT3 Hyper-IgE Syndrome Patients.

Hyper-IgE syndromes (HIES) are a group of inborn errors of immunity (IEI) caused by monogenic defects such as in the gene STAT3 (STAT3-HIES). Patients suffering from HIES show an increased susceptibility to Staphylococcus aureus (S. aureus) including skin abscesses and pulmonary infections. To assess if the underlying immune defect of STAT3-HIES patients influences the resistance patterns, pathogenicity factors or strain types of S. aureus. We characterized eleven S. aureus strains isolated from STAT3-HIES patients (n = 4) by whole genome sequencing (WGS) to determine presence of resistance and virulence genes. Additionally, we used multi-locus sequence typing (MLST) and protein A (spa) typing to classify these isolates. Bacterial isolates collected from this cohort of STAT3-HIES patients were identified as common spa types in Germany. Only one of the isolates was classified as methicillin-resistant S. aureus (MRSA). For one STAT3 patient WGS illustrated that infection and colonization occurred with different S. aureus isolates rather than one particular clone. The identified S. aureus carriage profile on a molecular level suggests that S. aureus strain type in STAT3-HIES patients is determined by local epidemiology rather than the underlying immune defect highlighting the importance of microbiological assessment prior to antibiotic treatment.

The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions.

BACKGROUND: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. PATIENTS AND METHODS: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. RESULTS: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8+ and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. CONCLUSIONS: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival.

High viral loads: what drives fatal cases of COVID-19 in vaccinees? - an autopsy study.

The rate of SARS-CoV-2 infections in vaccinees has become a relevant serious issue. This study aimed to determine the causes of death, histological organ alteration, and viral spread in relation to demographic, clinical-pathological, viral variants, and vaccine types for deceased individuals with proven SARS-CoV-2 infection after vaccination who died between January and November 2021. Twenty-nine consecutively collected cases were analyzed and compared to 141 nonvaccinated control cases. Autopsies were performed on 16 partially and 13 fully vaccinated individuals. Most patients were elderly and suffered from several relevant comorbidities. Real-time RT-PCR (RT-qPCR) identified a significantly increased rate of generalized viral dissemination within organ systems in vaccinated cases versus nonvaccinated cases (45% vs. 16%, respectively; P = 0.008) mainly with Ct-values of higher than 25 in non-respiratory samples. However, vaccinated cases also showed high viral loads, reaching Ct-values below 10, especially in the upper airways and lungs. This was accompanied by high rates of pulmonal bacterial or mycotic superinfections and the occurrence of immunocompromising factors, such as malignancies, immunosuppressive drug intake, or decreased immunoglobulin levels. All these findings were particularly accentuated in partially vaccinated patients compared to fully vaccinated individuals. The virus dissemination observed in our case study may indicate that patients with an impaired immune system have a decreased ability to eliminate the virus. However, the potential role of antibody-dependent enhancement must also be ruled out in future studies. Fatal cases of COVID-19 in vaccinees were rare and often associated with severe comorbidities or other immunosuppressive conditions.

ALK, NUT, and TRK Do Not Play Relevant Roles in Gastric Cancer-Results of an Immunohistochemical Study in a Large Series.

ALK, NUT, and TRK are rare molecular aberrations that are pathognomonic for specific rare tumors. In low frequencies, however, they are found in a wide range of other tumor entities. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of the immunohistochemical expressions of ALK, NUT, and TRK in 477 adenocarcinomas of the stomach and gastroesophageal junction. Seven cases (1.5%) showed an expression of TRK. In NGS, no NTRK fusion was confirmed. No case with ALK or NUT expression was detected. ALK, NUT, and NTRK expression does not seem to play an important role in gastric carcinomas.

Contamination of personal protective equipment during COVID-19 autopsies.

Confronted with an emerging infectious disease at the beginning of the COVID-19 pandemic, the medical community faced concerns regarding the safety of autopsies on those who died of the disease. This attitude has changed, and autopsies are now recognized as indispensable tools for understanding COVID-19, but the true risk of infection to autopsy staff is nevertheless still debated. To clarify the rate of SARS-CoV-2 contamination in personal protective equipment (PPE), swabs were taken at nine points in the PPE of one physician and one assistant after each of 11 full autopsies performed at four centers. Swabs were also obtained from three minimally invasive autopsies (MIAs) conducted at a fifth center. Lung/bronchus swabs of the deceased served as positive controls, and SARS-CoV-2 RNA was detected by real-time RT-PCR. In 9 of 11 full autopsies, PPE samples tested RNA positive through PCR, accounting for 41 of the 198 PPE samples taken (21%). The main contaminated items of the PPE were gloves (64% positive), aprons (50% positive), and the tops of shoes (36% positive) while the fronts of safety goggles, for example, were positive in only 4.5% of the samples, and all the face masks were negative. In MIAs, viral RNA was observed in one sample from a glove but not in other swabs. Infectious virus isolation in cell culture was performed on RNA-positive swabs from the full autopsies. Of all the RNA-positive PPE samples, 21% of the glove samples, taken in 3 of 11 full autopsies, tested positive for infectious virus. In conclusion, PPE was contaminated with viral RNA in 82% of autopsies. In 27% of autopsies, PPE was found to be contaminated even with infectious virus, representing a potential risk of infection to autopsy staff. Adequate PPE and hygiene measures, including appropriate waste deposition, are therefore essential to ensure a safe work environment.

Stroma AReactive Invasion Front Areas (SARIFA) - a new prognostic biomarker in gastric cancer related to tumor-promoting adipocytes.

Compared to other malignancies, there is a lack of easy-to-evaluate biomarkers for gastric cancer, which is associated with an adverse clinical outcome in many cases. Here, we present Stroma AReactive Invasion Front Areas (SARIFA) as a new histological prognostic marker. We defined SARIFA as the direct contact between a cluster of tumor glands/cells comprising at least five tumor cells and inconspicuous surrounding adipose tissue at the invasion front. A total of 480 adenocarcinomas of the stomach and the gastroesophageal junction from two different collections were classified according to SARIFA. To understand the potential underlying mechanisms, a transcriptome analysis was conducted using digital spatial profiling (DSP). It was found that 20% of the tumors were SARIFA-positive. Kappa values between the three pathologists were good in both collections: 0.74 and 0.78. Patients who presented SARIFA-positive tumors had a significantly lower overall survival in Collections A (median: 20.0 versus 44.0 months; p = 0.014, n = 160) and B (median: 15.0 versus 41.0 months; p < 0.0001, n = 320). SARIFA positivity emerged as a negative independent prognostic factor for overall survival (HR 1.638, 95% CI 1.153-2.326, p = 0.006). Using DSP, the most upregulated genes in SARIFA-positive cases were those associated with triglyceride catabolism and endogenous sterols. COL15A1, FABP2, and FABP4 were differentially expressed in positive cases. At the protein level, the expression of proteins related to lipid metabolism was confirmed. SARIFA combines low inter-observer variability, minimal effort, and high prognostic relevance, and is therefore an extremely promising biomarker related to tumor-promoting adipocytes in gastric cancer. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Whole-genome analysis of SARS-CoV-2 samples indicate no tissue specific genetic adaptation of the virus in COVID-19 patients' upper and lower respiratory tract.

Sample panels of SARS-CoV-2 cases were retrospectively whole-genome sequenced. In three individuals, samples of upper and lower respiratory tract resulted in identical sequences suggesting virus stability including the spike protein cleavage site. In a fourth case, low-level intra-host genomic evolution and a unique 5-nucleotide deletion was observed.

Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas.

The SWI/SNF complex has important functions in the mobilization of nucleosomes and consequently influences gene expression. Numerous studies have demonstrated that mutations or deficiency of one or more subunits can have an oncogenic effect and influence the development, progression, and eventual therapy resistance of tumor diseases. Genes encoding subunits of the SWI/SNF complex are mutated in approximately 20% of all human tumors. This study aimed to investigate the frequency, association with clinicopathological characteristics, and prognosis of immunohistochemical expression of proteins of the SWI/SNF complexes, SMARCA2, SMARCA4 SMARCB1, ARID1A, ARID1B, and PBRM1 in 477 adenocarcinomas of the stomach and gastroesophageal junction. Additionally, the tumors were classified immunohistochemically in analogy to The Cancer Genome Atlas (TCGA) classification. Overall, 32% of cases demonstrated aberrant expression of the SWI/SNF complex. Complete loss of SMARCA4 was detected in three cases (0.6%) and was associated with adverse clinical characteristics. SWI/SNF aberration emerged as an independent negative prognostic factor for overall survival in genomically stable patients in analogy to TCGA. In conclusion, determination of SWI/SNF status could be suggested in routine diagnostics in genomically stable tumors to identify patients who might benefit from new therapeutic options.

Viral mapping in COVID-19 deceased in the Augsburg autopsy series of the first wave: A multiorgan and multimethodological approach.

BACKGROUND: COVID-19 is only partly understood, and the level of evidence available in terms of pathophysiology, epidemiology, therapy, and long-term outcome remains limited. During the early phase of the pandemic, it was necessary to effectively investigate all aspects of this new disease. Autopsy can be a valuable procedure to investigate the internal organs with special techniques to obtain information on the disease, especially the distribution and type of organ involvement. METHODS: During the first wave of COVID-19 in Germany, autopsies of 19 deceased patients were performed. Besides gross examination, the organs were analyzed with standard histology and polymerase-chain-reaction for SARS-CoV-2. Polymerase chain reaction positive localizations were further analyzed with immunohistochemistry and RNA-in situ hybridization for SARS-CoV-2. RESULTS: Eighteen of 19 patients were found to have died due to COVID-19. Clinically relevant histological changes were only observed in the lungs. Diffuse alveolar damage in considerably different degrees was noted in 18 cases. Other organs, including the central nervous system, did not show specific micromorphological alterations. In terms of SARS-CoV-2 detection, the focus remains on the upper airways and lungs. This is true for both the number of positive samples and the viral load. A highly significant inverse correlation between the stage of diffuse alveolar damage and viral load was found on a case and a sample basis. Mediastinal lymph nodes and fat were also affected by the virus at high frequencies. By contrast, other organs rarely exhibited a viral infection. Moderate to strong correlations between the methods for detecting SARS-CoV-2 were observed for the lungs and for other organs. CONCLUSIONS: The lung is the most affected organ in gross examination, histology and polymerase chain reaction. SARS-CoV-2 detection in other organs did not reveal relevant or specific histological changes. Moreover, we did not find CNS involvement.