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Frozen section is a standard of care procedure during thoracic surgery when an immediate diagnosis is needed. An alternative procedure is intraoperative cytology. Video-assisted thoracic surgery is currently widely used for thoracic surgical procedures. The aim of this study was to assess intraoperative cytology together with frozen section for accuracy, turnaround time, and total response time during video-assisted thoracic surgery. We included patients having video-assisted thoracic surgery between August 2018 and February 2019 at our institution. A cytopathologist and a surgical pathologist independently performed intraoperative cytology and frozen sections, respectively. Final histologic diagnosis was the reference standard. Intraoperative cytology, frozen section turnaround, and total response times were analyzed. A total of 52 specimens from 27 patients were included. The intraoperative cytology correlated with final histology in 98% of cases. Frozen section correlated with final histology in 100% of cases. Intraoperative cytology turnaround and total response times were equal (mean, 4.35 minutes; range, 2-15 minutes). Mean frozen section turnaround and response times were 26.2 minutes (range, 9-61 minutes) and 36.7 minutes (range, 16-90 minutes), respectively. We found a statistically significant difference between intraoperative cytology and frozen section turnaround time and total response times (P <.001). This study highlights that intraoperative cytology could be as accurate as frozen section and considerably faster during video-assisted thoracic surgery (P <.001). Total response time could potentially be used as a quality metric for video-assisted thoracic surgery. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to analyze the medical history, with regards to previous remote depression, in patients with neuropathologically verified Alzheimer''s disease (AD), vascular dementia (VaD) and mixed AD/VaD. The 201 patients included (115 AD, 44 VaD and 42 mixed AD/VaD) had been referred to the Psychogeriatric/Psychiatric Department, Lund University Hospital, for psychogeriatric investigation and were followed-up with clinical records and detailed information on psychiatric history prior to the onset of dementia. Depression was considered to exist when the patient had consulted a psychiatrist or physician and had been diagnosed with a “depressive episode” or “depression” and when anti-depressants and/or other specific treatments had been prescribed. Twenty patients (10%) had suffered from depression earlier in life well before the onset of dementia. Eight of the 9 AD patients with a previous diagnosis of depression had suffered from only one depressive episode and all had responded well to treatment, with complete recovery. In the VaD group, 8 out of 9 patients suffered two or more depressive episodes and only two recovered completely. Events with a possible significant relationship to depression were seen in 8 of the 9 AD patients but in only 1 of the 9 VaD patients. Psychotic symptoms were more common in VaD than in the AD group. The treatment modality of depression was similar in the groups. In conclusion, a history of depression prior to dementia is more common and more therapy-resistant in VaD than in AD. [Copyright &y& Elsevier]

Objective: The overall aim was to evaluate to what extent the diagnosis of dementia subtypes, obtained by three clinical rating scales, concurred with postmortem neuro-pathologic (NP) diagnosis of Alzheimer disease (AD), frontotemporal dementia (FID), vascular dementia (VaD) and mixed AD/VaD. Design: A prospective longitudinal clinical work-up with postmortem NP examination. Participants: Two hundred nine patients with dementia referred for clinical evaluation and follow-up. Methods: The diagnostic scores in a set of three short clinical rating scales for AD, FTD, and VaD were evaluated against NP diagnoses. Results: The sensitivity and specificity of the AD scale were 0.80 and 0.87, respectively, of the FTD scale 0.93 and 0.92, respectively, and of the Hachinski Ischemic Score (HIS, VaD diagnosis) 0.69 and 0.92, respectively. Cases with mixed AD/VaD generally presented a combination of high AD and ischemic scores. A preferred cutoff score of six was identified for both the AD and FTD scales. Conclusions: All three clinical rating scales showed a high sensitivity and specificity, in close agreement with final NP diagnosis--for the HIS a moderate sensitivity. These scales may thus be considered good diagnostic tools and are recommended for clinical and research center settings. (Am J Geriatr Psychiatry 2010; 18:810-820) [ABSTRACT FROM AUTHOR]

Objective: Accurate distinction between dementia subtypes is important for patient care and pharmacological treatment. Continuing systematic comparisons of clinical and neuropathological dementia diagnoses may provide a basis for further improvement of the diagnostic procedure. The purpose of this study was to investigate concordance between clinical dementia diagnosis and neuropathological findings in the specialized dementia care.Methods: Inclusion required 1) a clinical dementia disorder diagnosed at a hospital-based memory clinic and 2) a neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1996-2006. A total of 176 consecutive patients fulfilled the criteria and were thus included. Clinical dementia diagnoses were obtained from the medical records and compared with the neuropathological findings.Results: The clinical and pathological dementia diagnoses were in full accordance in 86 (49%) of the patients (kappa 0.37). In an additional 24 (14%) cases, the clinical diagnosis corresponded with some but not all pathological components judged to contribute to the dementia disorder. Of the patients with clinical Alzheimer disease, 84% (46/55) had a significant Alzheimer component with or without other significant pathology at neuropathological examination. The corresponding figure for vascular dementia (VaD) was 59% (24/41), for frontotemporal dementia 74% (20/27), for combined Alzheimer and VaD 25% (4/16), and for dementia with Lewy bodies 67% (6/9).Conclusions: This study shows that clinical dementia diagnoses do not always correspond with neuropathological changes. It stresses the importance of neuropathological examination in research and in daily clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the distribution of neuropathologically defined dementia subtypes among individuals with dementia disorder. The neuropathological reports were studied on all patients (n =524; 55.3% females; median age 80, range 39–102 years) with clinically diagnosed dementia disorder who underwent complete autopsy including neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1974–2004. The neuropathological diagnosis was Alzheimer''s disease (AD) in 42.0% of the cases, vascular dementia (VaD) in 23.7%, dementia of combined Alzheimer and vascular pathology in 21.6%, and frontotemporal dementia in 4.0% of the patients. The remaining 8.8% of the patients had other dementia disorders, including combinations other than combined Alzheimer and vascular pathology. The registered prevalence of dementia subtypes depends on many variables, including referral habits, clinical and neuropathological judgments and diagnostic traditions, all of these variables potentially changing over time. This, however, does not seem to obscure the delineation of the major dementia subgroups. In this material of 30 years from Lund in the south of Sweden, AD by far dominated among dementia subtypes, while cerebrovascular pathology corresponded with the dementia disorder, either entirely or partly, in almost half of the demented patients. [Copyright &y& Elsevier]

The article presents a response to a letter to the editor in response to the article "Clinicopathological Concordance in Dementia Diagnostics," by H. Brunnström and E. Englund in an issue from 2009.

Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial immune phenotypes in the mutational and clinicopathological background of non–small cell lung cancer (NSCLC). We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs). CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg–B-cells, CD8-Eff–cancer cells and B-cells–CD4-Treg) demonstrated positive prognostic impact, whereas short M2–M1 distances were prognostically unfavourable. We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use. • Immune cells showed specific infiltration patterns within the tumour microenvironment. • Infiltration of lymphocytes and plasmacytoid dendritic cells are associated with good prognosis. • Distances of immune cells to each other or to tumour cells reveal an independent prognostic impact. [ABSTRACT FROM AUTHOR]

Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1 -amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response. In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1 -amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123. A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123. The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents. • FGFR1, a candidate drug target, is overexpressed in a subset of NSCLC. • NSCLC with high FGFR1 expression defines a distinct molecular and clinical subset. • High FGFR1 protein expression is associated with specific microRNAs and DNA hypomethylation. • A selective FGFR1 antagonist was active in PDX models with FGFR1 amplification and overexpression. [ABSTRACT FROM AUTHOR]

• NTRK fusions are extremely rare in non-small cell lung cancer. • High NTRK RNA and protein expression is present in a subgroup of NTRK fusion negative lung cancer cases. • A positive immunohistochemical assay should be confirmed by an independent molecular analysis. The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1–3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort. Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis. Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression. The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics. [ABSTRACT FROM AUTHOR]

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity. [ABSTRACT FROM AUTHOR]

Highlights • No technical bias between fresh frozen and FFPE samples. • A high fraction of adenocarcinoma patients with activating KRAS mutations. • Mutations in TP53, STK11 and SMARCA4 linked to poor prognosis in adenocarcinoma. • Mutations in CSMD3 linked to better prognosis in squamous cell carcinoma. • Co-mutations in TP53 or STK11 confer poor prognosis in KRAS positive patients. Abstract Objectives Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort. Materials and methods Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples. Results We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53 , STK11 or SMARCA4. In the adenocarcinoma KRAS -mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis. Conclusion Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS -positive adenocarcinoma subgroup. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a severe condition in interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-ILD, where the underlying mechanism is not well defined and with no curative treatments available. Serotonin (5-HT) signaling via the 5-HT 2B receptor has been recognized as a promising preclinical target for fibrosis. Despite this, the involvement of the 5-HT 2B receptor in fibrotic ILD is widely unexplored. This work highlights the spatial pulmonary distribution of the 5-HT 2B receptor in patients with IPF and systemic sclerosis-ILD. We show that the 5-HT 2B receptor is located in typical pathological structures e.g. honeycomb cysts and weakly in fibroblast foci. Together with immunohistochemistry and immunofluorescence stainings of patient derived distal lung tissues, we identified cell targets for 5-HT 2B receptor interference in type II alveolar epithelial cells, endothelial cells and M2 macrophages. Our results emphasize the role of 5-HT 2B receptor as a target in lung fibrosis, warranting further consideration in targeting fibrotic ILDs. [ABSTRACT FROM AUTHOR]