Clinically Undiagnosed Diseases in Autopsies: Frequency and Risk Factors.

CONTEXT.­: Autopsies can reveal clinically undiagnosed diseases. However, the frequency of first diagnoses at autopsy and their association with clinically known risk factors are not well understood because of lack of systematic analyses addressing this topic. OBJECTIVE.­: To perform a large retrospective cohort analysis on the frequency of clinically undiagnosed postmortem findings and correlate these with patients' risk factors. DESIGN.­: Six hundred forty-eight consecutive and complete autopsies of adults (age >18 years), performed in the University Hospital Zurich, Switzerland, during a 3-year time period were retrospectively analyzed. Clinical diagnoses and postmortem findings were compared in order to identify clinically undiagnosed lesions and clarify their correlation with common risk factors. RESULTS.­: In 633 of 648 patients (98%), at least one clinically undiagnosed finding was identified at autopsy. The most common nonneoplastic entities were bronchopneumonia (198; 31%), coronary artery disease (155; 24%) and acute or subacute myocardial infarction (94; 15%), and the most common malignancies were prostate cancer in men (14; 2.2%), followed by kidney cancer (10; 1.5%), gastrointestinal stromal tumor (10; 1.5%), and lung carcinoma (9; 1.4%) in both genders. Clinically undiagnosed cardiac amyloidosis was demonstrated in 8% (52 of 648) of patients and was significantly associated with age, hypertension, chronic kidney disease, coronary artery disease, and hypertensive cardiomyopathy. CONCLUSIONS.­: Autopsy is a useful investigation for the detection of clinically undiagnosed entities. In our cohort, cardiac amyloidosis showed the highest number of underlying risk factors, but was clinically underdiagnosed. Our findings underline the necessity of improved clinical detection of cardiac amyloidosis, especially in light of emerging therapeutic options. Moreover, we characterize the most common entities prone to clinical underdiagnosis.

ERBB2-amplified lobular breast carcinoma exhibits concomitant CDK12 co-amplification associated with poor prognostic features.

Most invasive lobular breast carcinomas (ILBCs) are luminal-type carcinomas with an HER2-negative phenotype (ERBB2 or HER2 un-amplified) and CDH1 mutations. Rare variants include ERBB2-amplified subtypes associated with an unfavorable prognosis and less response to anti-HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2-amplified ILBC and compared these characteristics with ERBB2-unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin-embedded formalin-fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast-specific markers was tested by immunohistochemistry (IHC). Hybrid capture-based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2-amplified ILBC had higher tumor stage (p < 0.0001), more frequent positive nodal status (p = 0.00022), more distant metastases (p = 0.012), and higher histological grade (p < 0.0001), and were more often hormone receptor negative (p < 0.001) and more often SOX10 positive (p = 0.005). ERBB2 short variant sequence mutations were more often detected in ERBB2-unamplified tumors (6/10, p = 0.027), whereas CDH1 mutations/copy loss were frequently present in both subgroups (9/10 and 7/10, respectively). Amplification of pathogenic genes were more common in HER2-positive ILBC (p = 0.0009). CDK12 gene amplification (≥6 copies) was detected in 7 of 10 ERBB2-amplified ILBC (p = 0.018). There were no CDK12 gene amplifications reported in 44,293 invasive breast carcinomas in the FMI Insights CGP database. ERBB2-amplified ILBC is a distinct molecular subgroup with frequent coamplification of CDK12, whereas ERBB2 sequence mutations occur only in ERBB2-unamplified ILBC. CDK12/ERBB2 co-amplification may explain the poor prognosis and therapy resistance of ERBB2-amplified ILBC.

Long-Term Follow-Up of High-Risk Breast Lesions at Vacuum-Assisted Biopsy without Subsequent Surgical Resection.

Introduction: B3-lesions of the breast are a heterogeneous group of neoplasms, associated with a higher risk of breast cancer. Recent studies show a low upgrade rate into malignancy after subsequent open surgical excision (OE) of most B3-lesions when proven by vacuum-assisted biopsy (VAB). However, there is a lack of long-term follow-up data after VAB of high-risk lesions. The primary aim of this study was to demonstrate whether follow-up of B3 lesions is a beneficial and reliable alternative to OE in terms of long-term outcome. The secondary aim was to identify patient and lesion characteristics of B3 lesions for which OE is still necessary. Methods: This retrospective multicenter study was conducted at 8 Swiss breast centers between 2010 and 2019. A total of 278 women (mean age: 53.5 ± 10.7 years) with 286 B3-lesions who had observation only and who had at least 24 months of follow-up were included. Any event during follow-up (ductal carcinoma in situ [DCIS], invasive cancer, new B3-lesion) was systematically recorded. Data from women who had an event during follow-up were compared with those who did not. The results for the different B3 lesions were analyzed using the t test and Fisher's exact test. A p value of <0.05 was considered statistically significant. Results: The median follow-up interval was 59 months (range: 24-143 months) with 52% (148/286) having a follow-up of more than 5 years. During follow-up, in 42 women, 44 suspicious lesions occurred, with 36.4% (16/44) being invasive cancer and 6.8% (3/44) being DCIS. Thus, 6.6% (19/286) of all women developed malignancy during follow-up after a median follow-up interval of 6.5 years (range: 31-119 months). The initial histology of the B3 lesion influenced the subsequent occurrence of a malignant lesion during follow-up (p < 0.038). The highest malignancy-developing rate was observed in atypical ductal hyperplasia (ADH) (24%, 19/79), while all other B3-lesions had malignant findings ipsi- and contralateral between 0% and 6%. The results were not influenced by the VAB method (Mx-, US-, magnetic resonance imaging-guided), the radiological characteristics of the lesion, or the age or menopausal status of the patient (p > 0.12). Conclusion: With a low risk of <6% of developing malignancy, VAB followed by long-term follow-up is a safe alternative to OE for most B3-lesions. A higher malignancy rate only occurred in ADH (24%). Based on our results, radiological follow-up should be bilateral, preferable using the technique of initial diagnosis. As we observed a late peak (6-7 years) of breast malignancies after B3-lesions, follow-up should be continued for a longer period (>10 years). Knowledge of these long-term outcome results will be helpful in making treatment decisions and determining the optimal radiological follow-up interval.

EUSOMA quality indicators for non-metastatic breast cancer: An update.

INTRODUCTION: Quality care in breast cancer is higher if patients are treated in a Breast Center with a dedicated and specialized multidisciplinary team. Quality control is an essential activity to ensure quality care, which has to be based on the monitoring of specific quality indicators. Eusoma has proceeded with the up-dating of the 2017 Quality indicators for non-metastatic breast cancer based on the new diagnostic, locoregional and systemic treatment modalities. METHODS: To proceed with the updating, EUSOMA setup a multidisciplinary working group of BC experts and patients' representatives. It is a comprehensive set of QIs for early breast cancer care, which are classified as mandatory, recommended, or observational. For the first time patient reported outcomes (PROMs) have been included. As used in the 2017 EUSOMA QIs, evidence levels were based on the short version of the US Agency for Healthcare Research and Quality. RESULTS: This is a set of quality indicators representative for the different steps of the patient pathway in non-metastatic setting, which allow Breast Centres to monitor their performance with referring standards, i.e minimum standard and target. CONCLUSIONS: Monitoring these Quality Indicators, within the Eusoma datacentre will allow to have a state of the art picture at European Breast Centres level and the development of challenging research projects.

European guidelines for the diagnosis, treatment and follow-up of breast lesions with uncertain malignant potential (B3 lesions) developed jointly by EUSOMA, EUSOBI, ESP (BWG) and ESSO.

INTRODUCTION: Breast lesions of uncertain malignant potential (B3) include atypical ductal and lobular hyperplasias, lobular carcinoma in situ, flat epithelial atypia, papillary lesions, radial scars and fibroepithelial lesions as well as other rare miscellaneous lesions. They are challenging to categorise histologically, requiring specialist training and multidisciplinary input. They may coexist with in situ or invasive breast cancer (BC) and increase the risk of subsequent BC development. Management should focus on adequate classification and management whilst avoiding overtreatment. The aim of these guidelines is to provide updated information regarding the diagnosis and management of B3 lesions, according to updated literature review evidence. METHODS: These guidelines provide practical recommendations which can be applied in clinical practice which include recommendation grade and level of evidence. All sections were written according to an updated literature review and discussed at a consensus meeting. Critical appraisal by the expert writing committee adhered to the 23 items in the international Appraisal of Guidelines, Research and Evaluation (AGREE) tool. RESULTS: Recommendations for further management after core-needle biopsy (CNB) or vacuum-assisted biopsy (VAB) diagnosis of a B3 lesion reported in this guideline, vary depending on the presence of atypia, size of lesion, sampling size, and patient preferences. After CNB or VAB, the option of vacuum-assisted excision or surgical excision should be evaluated by a multidisciplinary team and shared decision-making with the patient is crucial for personalizing further treatment. De-escalation of surgical intervention for B3 breast lesions is ongoing, and the inclusion of vacuum-assisted excision (VAE) will decrease the need for surgical intervention in further approaches. Communication with patients may be different according to histological diagnosis, presence or absence of atypia, or risk of upgrade due to discordant imaging. Written information resources to help patients understand these issues alongside with verbal communication is recommended. Lifestyle interventions have a significant impact on BC incidence so lifestyle interventions need to be suggested to women at increased BC risk as a result of a diagnosis of a B3 lesion. CONCLUSIONS: These guidelines provide a state-of-the-art overview of the diagnosis, management and prognosis of B3 lesions in modern multidisciplinary breast practice.

Data-Driven Gradient Regularization for Quasi-Newton Optimization in Iterative Grating Interferometry CT Reconstruction.

Grating interferometry CT (GI-CT) is a promising technology that could play an important role in future breast cancer imaging. Thanks to its sensitivity to refraction and small-angle scattering, GI-CT could augment the diagnostic content of conventional absorption-based CT. However, reconstructing GI-CT tomographies is a complex task because of ill problem conditioning and high noise amplitudes. It has previously been shown that combining data-driven regularization with iterative reconstruction is promising for tackling challenging inverse problems in medical imaging. In this work, we present an algorithm that allows seamless combination of data-driven regularization with quasi-Newton solvers, which can better deal with ill-conditioned problems compared to gradient descent-based optimization algorithms. Contrary to most available algorithms, our method applies regularization in the gradient domain rather than in the image domain. This comes with a crucial advantage when applied in conjunction with quasi-Newton solvers: the Hessian is approximated solely based on denoised data. We apply the proposed method, which we call GradReg, to both conventional breast CT and GI-CT and show that both significantly benefit from our approach in terms of dose efficiency. Moreover, our results suggest that thanks to its sharper gradients that carry more high spatial-frequency content, GI-CT can benefit more from GradReg compared to conventional breast CT. Crucially, GradReg can be applied to any image reconstruction task which relies on gradient-based updates.

Molecular pathology in breast disease: diagnostic, prognostic, and therapeutic tools.

Molecular testing in breast cancer gained increasing attention and importance as specific molecular results can tailor not only oncological decisions on systemic adjuvant or neoadjuvant or in metastatic setting, but increasingly serve in diagnostic routine histopathological services to differentiate between morphologically overlapping or ambiguous histological pictures. Diagnostic tools involve in most cases a broad spectrum of immunohistochemical panels, followed by entity-specific in situ hybridization probes and in given cases NGS-based sequencing. Workflow of which methodology is applied and in which order depends on the specific entity resp. on the given differential diagnosis in question. Regarding prognostic/predictive molecular testing, the choice of assay and the workflow are based on clinical algorithms and on the evidence of targeted therapies following the molecular alterations. In this review paper, we aim to address the use of molecular technics in [1] the histological diagnostic setting (such as subtyping of invasive carcinomas/malignant spindle cell tumors and sarcomas and some B3 lesions) and [2] in the context of adjuvant or neoadjuvant or other clinical settings with special focus of targeted therapies.

Higher parental education was associated with good cognitive outcomes in infants with hypoxic-ischaemic encephalopathy.

AIM: Predicting neurodevelopmental outcomes in hypoxic-ischaemic encephalopathy (HIE) remains imprecise, despite advanced imaging and neurophysiological tests. We explored the predictive value of socio-economic status (SES). METHODS: The cohort comprised 93 infants (59% male) with HIE, who had received therapeutic hypothermia. Patients underwent magnetic resonance imaging, and brain injuries were quantified using the Barkovich scoring system. Family SES was self-reported using a questionnaire. Adverse outcomes were defined as mild to severely delayed development with a score of ≤85 in any domain at 2 years of age, based on the Bayley Scales of Infant Development, Second Edition. Data are presented as odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Multiple regression modelling revealed that higher parental education was strongly associated with good cognitive development, when adjusted for gestational age, serum lactate and brain injuries (OR 2.20, 95% CI 1.16-4.36). The effect size of parental education (ß = 0.786) was higher than one score for any brain injury using the Barkovich scoring system (ß = -0.356). The literacy environment had a significant effect on cognitive development in the 21 infants who had brain injuries (OR 40, 95% CI 3.70-1352). CONCLUSION: Parental education and the literacy environment influenced cognitive outcomes in patients with HIE.

Synthesis and biochemical evaluation of 17-N-beta-aminoalkyl-4,5α-epoxynormorphinans.

Opiate alkaloids and their synthetic derivatives are still widely used in pain management, drug addiction, and abuse. To avoid serious side effects, compounds with properly designed pharmacological profiles at the opioid receptor subtypes are long needed. Here a series of 17-N-substituted derivatives of normorphine and noroxymorphone analogues with five- and six-membered ring substituents have been synthesized for structure-activity study. Some compounds showed nanomolar affinity to MOR, DOR and KOR in in vitro competition binding experiments with selective agonists [3H]DAMGO, [3H]Ile5,6-deltorphin II and [3H]HS665, respectively. Pharmacological characterization of the compounds in G-protein signaling was determined by [35S]GTPγS binding assays. The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH substituent resulted in a shift in the pharmacological profiles in the agonist > partial agonist > antagonist direction compared to the parent compounds. A molecular docking-based in silico method was also applied to estimate the pharmacological profile of the compounds. Docking energies and the patterns of the interacting receptor atoms, obtained with experimentally determined active and inactive states of MOR, were used to explain the observed pharmacological features of the compounds.

1,1,6-Trimethyl-1,2-dihydronaphthalene Content of Riesling Wines in Hungary.

1,1,6-Trimethyl-1,2-dihydronaphthalene (TDN) is known to give a petrol note when smelling and tasting wine, which is most pronounced in Riesling varieties. Its increasing concentration has been linked to climate change. In the present work, a gas chromatographic method was used to quantify free TDN in "Italian Riesling", "Rhine Riesling", and "Kéknyelu" wines from Hungary. From the vintages 2010 to 2020, 39 bottles of wine from different wine regions were evaluated by instrumental analysis and sensory evaluation. Our aim is to determine the extent to which the Riesling wines in Hungary show a petrol character. The other objective was a comparison of sorts to see if there is a difference in TDN production potential between Italian Riesling and Rhine Riesling. We also aimed to clarify the question whether the Hungarian variety Kéknyelu is also capable of developing a petrol character. The wines we tested were corked and screw-locked. This allowed us to compare the difference in TDN concentration variation over time between the two closure methods.

Stable organization of the early lexical-semantic network in 18- and 24-month-old preterm and full-term infants: an eye-tracker study.

Introduction: An organized mental lexicon determines new information acquisition by orienting attention during language processing. Adult-like lexical-semantic knowledge organization has already been demonstrated in 24-month-olds. However, the outcomes of earlier studies have been contradictory in terms of the organizational capacities of 18-month-olds, thus our aim was to examine lexical-semantic organization in this younger age group. In prematurely born infants, audiovisual integration deficits have been found alongside disruptions in language perception. By including late preterm infants with corrected ages in our study, we aimed to test whether maturational differences influence lexical-semantic organization when vocabulary is growing rapidly. Methods: We tested 47 late preterm and full-term 18- and 24-month-old infants by means of an infant-adapted target-absent task using a slightly modified version of the original visual world paradigm for eye tracker. Results: We found a longer fixation duration for the lexical and semantic distractors compared to the neutral pictures. Neither language proficiency nor age affected the looking time results. We found a dissociation by age between taxonomic and associative semantic relations. Maturational differences were detectable in the initial processing of taxonomic relations, as processing in the preterm group was slightly delayed and qualitatively different in the first half of the looking time. The size and composition of the expressive vocabulary differed only by age. Discussion: In general, our study demonstrated a stable lexical-semantic organization between 18 and 24 months of age, regardless of maturational differences.

Whole-Exome Sequencing Reveals High Mutational Concordance between Primary and Matched Recurrent Triple-Negative Breast Cancers.

PURPOSE: Triple-negative breast cancer (TNBC) is a molecularly complex and heterogeneous breast cancer subtype with distinct biological features and clinical behavior. Although TNBC is associated with an increased risk of metastasis and recurrence, the molecular mechanisms underlying TNBC metastasis remain unclear. We performed whole-exome sequencing (WES) analysis of primary TNBC and paired recurrent tumors to investigate the genetic profile of TNBC. METHODS: Genomic DNA extracted from 35 formalin-fixed paraffin-embedded tissue samples from 26 TNBC patients was subjected to WES. Of these, 15 were primary tumors that did not have recurrence, and 11 were primary tumors that had recurrence (nine paired primary and recurrent tumors). Tumors were analyzed for single-nucleotide variants and insertions/deletions. RESULTS: The tumor mutational burden (TMB) was 7.6 variants/megabase in primary tumors that recurred (n = 9); 8.2 variants/megabase in corresponding recurrent tumors (n = 9); and 7.3 variants/megabase in primary tumors that did not recur (n = 15). MUC3A was the most frequently mutated gene in all groups. Mutations in MAP3K1 and MUC16 were more common in our dataset. No alterations in PI3KCA were detected in our dataset. CONCLUSIONS: We found similar mutational profiles between primary and paired recurrent tumors, suggesting that genomic features may be retained during local recurrence.

Multielement Z-tag imaging by X-ray fluorescence microscopy for next-generation multiplex imaging.

Rapid, highly multiplexed, nondestructive imaging that spans the molecular to the supra-cellular scale would be a powerful tool for tissue analysis. However, the physical constraints of established imaging methods limit the simultaneous improvement of these parameters. Whole-organism to atomic-level imaging is possible with tissue-penetrant, picometer-wavelength X-rays. To enable highly multiplexed X-ray imaging, we developed multielement Z-tag X-ray fluorescence (MEZ-XRF) that can operate at kHz speeds when combined with signal amplification by exchange reaction (SABER)-amplified Z-tag reagents. We demonstrated parallel imaging of 20 Z-tag or SABER Z-tag reagents at subcellular resolution in cell lines and multiple human tissues. We benchmarked MEZ-XRF against imaging mass cytometry and demonstrated the nondestructive multiscale repeat imaging capabilities of MEZ-XRF with rapid tissue overview scans, followed by slower, more sensitive imaging of low-abundance markers such as immune checkpoint proteins. The unique multiscale, nondestructive nature of MEZ-XRF, combined with SABER Z-tags for high sensitivity or enhanced speed, enables highly multiplexed bioimaging across biological scales.

Mechanisms and clinical relevance of the bidirectional relationship of viral infections with metabolic diseases.

Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.

Third International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions).

The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH.

Bone marrow haematopoiesis in patients with COVID-19.

AIMS: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection broadly affects organ homeostasis, including the haematopoietic system. Autopsy studies are a crucial tool for investigation of organ-specific pathologies. Here we perform an in-depth analysis of the impact of severe coronavirus disease 2019 (COVID-19) on bone marrow haematopoiesis in correlation with clinical and laboratory parameters. METHODS AND RESULTS: Twenty-eight autopsy cases and five controls from two academic centres were included in the study. We performed a comprehensive analysis of bone marrow pathology and microenvironment features with clinical and laboratory parameters and assessed SARS-CoV-2 infection of the bone marrow by quantitative polymerase chain reaction (qPCR) analysis. In COVID-19 patients, bone marrow specimens showed a left-shifted myelopoiesis (19 of 28, 64%), increased myeloid-erythroid ratio (eight of 28, 28%), increased megakaryopoiesis (six of 28, 21%) and lymphocytosis (four of 28, 14%). Strikingly, a high proportion of COVID-19 specimens showed erythrophagocytosis (15 of 28, 54%) and the presence of siderophages (11 of 15, 73%) compared to control cases (none of five, 0%). Clinically, erythrophagocytosis correlated with lower haemoglobin levels and was more frequently observed in patients from the second wave. Analysis of the immune environment showed a strong increase in CD68+ macrophages (16 of 28, 57%) and a borderline lymphocytosis (five of 28, 18%). The stromal microenvironment showed oedema (two of 28, 7%) and severe capillary congestion (one of 28, 4%) in isolated cases. No stromal fibrosis or microvascular thrombosis was found. While all cases had confirmed positive testing of SARS-CoV-2 in the respiratory system, SARS-CoV-2 was not detected in the bone marrow by high-sensitivity PCR, suggesting that SARS-CoV-2 does not commonly replicate in the haematopoietic microenvironment. CONCLUSIONS: SARS-CoV-2 infection indirectly impacts the haematological compartment and the bone marrow immune environment. Erythrophagocytosis is frequent and associated with lower haemoglobin levels in patients with severe COVID-19.

[Thromboembolic complications associated to malignant diseases]. / A malignus betegségekhez társuló tromboembóliás szövodmények.

Cancers are known to increase the tendency for thrombosis, both on the venous and arterial side, which to this day is an important factor in the management of oncology patients. Malignant disease is an independent risk factor for developing venous thromboembolism (VTE). Thromboembolic complications in addition to the disease worsen prognosis and are accompanied by significant morbidity and mortality. VTE is the second most common cause of death in cancer after disease progression. Tumors are characterized by hypercoagulability, in addition to which venous stasis and endothelial damage also occur in cancer patients promoting increased clotting. Treatment of cancer-associated thrombosis is often complex; therefore, it is important to identify patients who benefit from primary thromboprophylaxis. The importance of cancer-associated thrombosis is indisputable in everyday oncology. We briefly summarize the frequency and characteristics of their occurrence, the underlying mechanisms, risk factors, clinical appearance, laboratory diagnostics, and the possibilities of prevention and treatment.

Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.

Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.

The impact of intraoperative frozen section in patients with clinically node-negative breast cancer (cN0/ycN0) who received neoadjuvant systemic therapy.

BACKGROUND: When surgical axillary staging reveals residual metastatic deposits in breast cancer (BC) patients who had received neoadjuvant chemotherapy (NACT), axillary lymphonodectomy is indicated. In this study, we investigate whether it is reasonable to perform intraoperative frozen section (FS) of the removed sentinel lymph nodes (SLNs) in cases where NACT had been administered in patients who had a clinically negative nodal status at the time of diagnosis. PATIENTS AND METHODS: We analyzed data from 101 BCE patients with 103 carcinomas who were diagnosed between 2014 and 2021 and met the above-mentioned criteria. RESULTS: In three cases (2.8% of the study group), histologically active tumor tissue was detected in the removed axillary LNs. Discontinuation of therapy/the use of a low-dose NACT regimen was a significant factor for positive LNs (p = 0.02) at the subsequent surgical procedure; tumor progression during therapy approached borderline significance (p = 0.058). Among patients who had completed NACT with the planned standard dose regimen, and in which the primary tumors showed a response to therapy (n = 94), only one case had histologically detected residual metastases in the SLNs. CONCLUSIONS: Certified breast centers aim to improve the outcome of the patients. However, these specialized centers should also focus on economic aspects. This means that diagnostic and therapeutic procedures should be continuously critically reviewed in order to avoid unnecessary expenses. In BC patients with clinically node negative disease who completed NACT as planned and in which the tumor showed a good response to therapy, time consuming and costly FS of the SLNs removed should be omitted.