Neighboring macrophage-induced alteration in the phenotype of colorectal cancer cells in the tumor budding area.

BACKGROUND: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. METHODS: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor-stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. RESULTS: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 µm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. CONCLUSION: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.

Histological spatial analysis on the induction of PD-L1+ macrophages by CD8+ T cells at the marginal microenvironment of triple-negative breast cancer.

BACKGROUND: Programmed death-ligand 1 (PD-L1) plays important roles in the evasion of antitumor immunity. Because we observed the localization of PD-L1-positive (PD-L1+) cells in the marginal region of triple-negative breast cancer (TNBC) specimens, we hypothesized that the marginal microenvironment of TNBC would involve the induction of PD-L1+ cells. METHODS: One hundred and one TNBC surgical specimens were examined. We performed immunohistochemical (IHC) studies of PD-L1, CD68, CD8, and pan-cytokeratin in these specimens. We analyzed the localization of IHC-positive cells and the distance between these cells by histological spatial analysis. RESULTS: In 30.7% of TNBC specimens, PD-L1+ cells were located in the marginal region. Approximately three PD-L1+ cells accumulated around a single TNBC cell. Most PD-L1+ cells were located within 50 µm of TNBC cells. PD-L1+ cells were indicated to interact with TNBC cells in the marginal region. PD-L1+CD68+ cells were located in the marginal region, while CD68+ macrophages (MΦs) were observed either in the marginal region or the core region. PD-L1 expression in MΦs was induced in the marginal region. The colocalization of CD8+ T cells in the marginal region indicates that PD-L1 expression in MΦs would be induced by interaction with CD8+ T cells. Because CD8+ T cells are positive for CCL2, CCL2 may induce PD-L1 expression in MΦs. CONCLUSION: At the marginal microenvironment of TNBC, PD-L1 expression would be induced in MΦs by interaction with CD8+ T cells through CCL2. The interaction between PD-L1+ MΦs and TNBC cells would facilitate the growth of TNBC under antitumor immunity. These interactions would be potential targets for restoring antitumor immunity and suppressing TNBC progression.

Prognostic role of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography with an image-based harmonization technique: A multicenter retrospective study.

Objectives: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography-based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non-small cell lung cancer. Methods: We retrospectively examined 495 patients with clinical stage I non-small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Results: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Conclusions: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non-small cell lung cancers.

In vivo [18F]THK-5351 imaging detected reactive astrogliosis in argyrophilic grain disease with comorbid pathology: A clinicopathological study.

Quantification of in vivo reactive astrogliosis, which represents neural inflammation and remodeling in the brain, is an emerging methodology for the evaluation of patients with neurodegenerative diseases. [18F]THK-5351 is a positron emission tomography (PET) tracer for monoamine oxidase B (MAO-B), a molecular marker of reactive astrogliosis. We performed in vivo [18F]THK-5351 PET in a patient who at autopsy was found to have argyrophilic grain disease (AGD) with comorbid pathology to visualize reactive astrogliosis for the first time. We aimed to validate an imaging-pathology correlation using [18F]THK-5351 PET and the autopsy brain. The patient, a 78-year-old man, was pathologically diagnosed with AGD combined with limbic-predominant age-related transactive response DNA-binding protein of 43 kDa encephalopathy and Lewy body disease without Alzheimer disease-related neuropathological changes. Reactive astrogliosis in the postmortem brain was abundant in the inferior temporal gyrus, insular gyrus, entorhinal cortex, and ambient gyrus where premortem [18F]THK-5351 signals were high. We found a proportional correlation between the amount of reactive astrogliosis in the postmortem brain and the in vivo [18F]THK-5351 standardized uptake value ratio (r = 0.8535, p = 0.0004). These results indicated that reactive astrogliosis in AGD with comorbid pathology could be identified and quantified by in vivo MAO-B imaging.

Clinicopathological diversity of semantic dementia: Comparisons of patients with early-onset versus late-onset, left-sided versus right-sided temporal atrophy, and TDP-type A versus type C pathology.

Semantic dementia (SD) is a unique clinicopathological entity associated with TDP-type C pathology. We present four cases of SD that illustrate the clinicopathological diversity of TDP-43 pathology, including early-onset cases of TDP-type C with corticospinal tract (CST) and motor neuron pathology and late-onset cases of TDP-type A with combined pathology. Case 1 was a 62-year-old man with semantic variant of primary progressive aphasia (svPPA) with left-predominant temporal atrophy and TDP-type C pathology with low Alzheimer's disease neuropathologic changes (ADNC). Case 2 was a 63-year-old woman with right-predominant temporal atrophy and TDP-type C pathology who had prosopagnosia and personality changes. Phosphorylated(p)-TDP-43-positive long dystrophic neurites (DNs) were observed throughout the cerebral cortex; they were more abundant in the relatively spared cortices and less so in the severely degenerated cortices. We observed CST degeneration with TDP-43 pathology in the upper and lower motor neurons, without apparent motor symptoms, in SD with TDP-type C pathology. Case 3 was a 76-year-old man who had svPPA and personality changes, with left-predominant temporal atrophy and TDP-type A pathology with high ADNC and argyrophilic grain (AG) stage 3. Case 4 was an 82-year-old man who had prosopagnosia and later developed symptoms of dementia with Lewy bodies (DLB) with right-predominant temporal atrophy and TDP-type A pathology with high ADNC, DLB of diffuse neocortical type, and AG stage 3. The distribution of p-TDP-43-positive NCIs and short DNs was localized in the anterior and inferior temporal cortices. An inverse relationship between the extent of TDP pathology and neuronal loss was also observed in SD with TDP-type A pathology. In contrast, the extent of AD, DLB, and AG pathology was greater in severely degenerated regions. CST degeneration was either absent or very mild in SD with TDP-type A. Understanding the clinicopathological diversity of SD will help improve its diagnosis and treatment.

Presence of a Ground-Glass Opacity Component Is the True Prognostic Determinant in Clinical Stage I NSCLC.

Introduction: Recent studies have suggested that including presence or absence of ground-glass opacity (GGO) may improve the tumor descriptor (T descriptor) classification in clinical stage I NSCLC. In this study, we analyzed prognostic implications of presence or absence of GGO, size of the solid component, and predominant histology to identify the true prognostic determinant for early-stage NSCLC. Methods: We retrospectively examined 384 patients with clinical stage I NSCLC (solid: 242, part solid: 142) who underwent complete resection between 2009 and 2013. Results: Survival curves of the whole cohort revealed good separation using the current TNM classification. Nevertheless, the part-solid group had a favorable prognosis irrespective of solid component size. Conversely, patients in the solid tumor group with tumors between 3 and 4 cm had a worse prognosis than patients whose tumors were less than or equal to 3 cm. Thus, we propose the following novel T descriptor classification: IA, part-solid tumors; IB, solid tumors less than or equal to 3 cm; and IC, solid tumors between 3 and 4 cm. This novel classification system stratified patient prognosis better than the current classification. On pathologic evaluation, the part-solid group always had better prognoses than the solid group in each subgroup divided by pathologic grade. Conclusions: These results suggest that presence of GGO is the true prognostic determinant of stage I NSCLC, irrespective of the size of the solid component. Our novel T descriptor classification system could more accurately predict prognoses of clinical stage I NSCLC cases.

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis.

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH-RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH-RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH-RA group. The percentage of distorted GCs was 13.3% in FTH-RA group and 3.25% in FTH associated with MG (FTH-MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH-RA group. Positive indices of CD27+ cells and PD-1+ cells per GC in FTH-RA group were significantly higher than those in FTH-MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α-SMA, tenascin-C, and l-caldesmon expression, was significantly increased in the FTH-RA group compared with the FTH-MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH-RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

A surgical case of pediatric spinal medulloepithelioma.

Embryonal tumor with multilayered rosettes (ETMR), C19MC-altered was introduced to the World Health Organization classification of central nervous system tumors in 2016. It is characterized by amplification or fusion of the chromosome 19 microRNA cluster (C19MC) locus at 19q13.42. Medulloepithelioma also an ETMR but lacks C19MC alteration. We report a rare case of spinal medulloepithelioma in a 2-year-old boy and review the literature.

Video-Assisted Thoracoscopic Segmentectomy for Deep and Peripheral Small Lung Cancer.

BACKGROUND: We aimed to retrospectively compare the long-term prognosis and recurrence after segmentectomy between nonsmall cell lung cancer (NSCLC) patients with deep and peripheral lesions. METHODS: Data were extracted for 85 lobectomy-tolerable NSCLC patients with tumors measuring ≤2 cm, who underwent video-assisted thoracoscopic segmentectomy with curative intent during January 2006 to December 2014. Tumor location was determined by the surgeon using thin-slice (1 mm) and three-dimensional computed tomography. Overall and recurrence-free survival was compared between patients with peripheral and deep lesions using univariate and multivariate Cox proportional hazard models. The indications for segmentectomy included NSCLC measuring ≤2 cm and consolidation/tumor ratio ≤20%, solid NSCLC ≤1 cm, and indeterminate nodule ≤1.5 cm. RESULTS: No recurrence of peripheral and deep lesions was noted. The 5-year overall survival was 96.4% for all patients, and 100 and 95.3% for patients with deep and peripheral lesions, respectively. There was no significant difference between the overall survival rates associated with the deep and peripheral lesions (95% confidence interval [CI], 89.5-98.8, nonsignificant, 86.4-98.4, respectively; p = 0.189). In a multivariate analysis, the American Society of Anesthesiologists score (hazard ratio [HR], 13.30; 95% CI, 1.31-210.36; p = 0.028) and histology (HR, 0.03; 95% CI, 0.00-0.32; p = 0.037) were independent prognostic factors for overall survival; tumor location was not a prognostic factor. CONCLUSIONS: When video-assisted thoracoscopic segmentectomy with curative intent was performed with sufficient surgical margins, the location of small NSCLC did not affect recurrence risk and prognosis. Video-assisted thoracoscopic segmentectomy for small NSCLC is acceptable, regardless of the tumor location.

Thoracoscopic anatomical individual basilar segmentectomy.

OBJECTIVES: Thoracoscopic anatomical single or combined anatomical individual basilar segmentectomy, including subsegmentectomy, is technically challenging due to variations and the deep location of vessels and bronchi in the parenchyma. However, the long-term perioperative outcomes of various anatomical subsegmentectomy approaches have not been reported. Thus, we investigated the effectiveness of thoracoscopic basilar segmentectomy. METHODS: We evaluated the records of 119 patients who underwent thoracoscopic single or complex basilar segmentectomy between January 2005 and December 2020 and compared the fissure and non-fissure approach for S9 and/or S10. RESULTS: A total of 29 patients underwent single segmentectomy, and 90 patients underwent various combined anatomical segmentectomies via video-assisted thoracoscopic surgery and planning using three-dimensional simulation. There were 39 cases of S9 and/or S10 segmentectomy. The median chest tube in-dwell duration and postoperative hospital stay were 1 and 4 days, respectively. The postoperative morbidity (Clavien-Dindo grade II/IIIa) rate was 5.9% without perioperative mortality. Pathological examination revealed 83 cases of lung cancer, 21 cases of metastasis and 15 cases of benign lesions. The postoperative hospitalization duration showed significant differences in the perioperative outcomes between the fissure and non-fissure approaches for S9 and/or S10. CONCLUSIONS: Thoracoscopic anatomical basilar individual segmentectomy has emerged as a safe and feasible procedure. The non-fissure approach enabled anatomic resection of a single segment or combined basal segments, helped avoid dissection of an incomplete fissure and facilitated surgical outcomes similar to the fissure approach.

Clinicopathological heterogeneity of Alzheimer's disease with pure Alzheimer's disease pathology: Cases associated with dementia with Lewy bodies, very early-onset dementia, and primary progressive aphasia.

We report four cases depicting the heterogeneity of Alzheimer's disease (AD) associated with pure AD pathology. Case 1 was a 77-year-old man with a false positive diagnosis of dementia with Lewy bodies with reduced dopamine transporter uptake activity of the striatum but no Lewy body pathology. There were tau deposits in the large neurons in the putamen, which may be related to the development of parkinsonism. Case 2 was an AD patient in his early 30s who presented with a psychotic episode and a cognitive decline, and later developed myoclonus and seizures. He demonstrated considerable amyloid-beta deposits in the cerebral cortex, including cotton wool plaques, basal ganglia, and cerebellum. Tau deposits were also abundant in the cerebral neocortex, hippocampus, basal ganglia, and brain stem. Case 3 was a 60-year-old woman who exhibited typical symptoms characteristic of the logopenic variant of primary progressive aphasia (lvPPA). Case 4 was a 68-year-old man who exhibited the semantic variant of primary progressive aphasia (svPPA) plus repetition impairment, a rare case associated with AD pathology. In addition to tau pathology, astrocytic pathology was prominent in the white matter and cortical layers of the left temporoparietal cortices. While the main AD lesion in case 4 was evaluated by tau accumulation and astrogliosis in the left temporal lobe, that in case 3 in was evaluated by the same points in the left parietal lobe. Within the spectrum of lvPPA, case 4 may be regarded as a temporal variant of lvPPA presenting svPPA. The pathology of PPA associated with AD may have broader clinical manifestations than that in previously described cases. Case 4 also showed pathological features characteristic of cerebral amyloid angiopathy throughout the cerebral cortex. The distribution of tau and astrocytic pathologies in the cerebral cortex, basal ganglia, brain stem, and cerebellum may explain the various symptoms of atypical pure AD patients.

[Two-year remission of a relapsed primary gastric peripheral T-cell lymphoma treated with total gastrectomy followed by adjuvant chemotherapy].

A 67-year-old man was diagnosed with a submucosal primary gastric T-cell lymphoma (PGTL) via upper gastroenteroscopy following an annual health check-up. He received six cycles of CHOP and achieved a complete remission. However, the patient relapsed 4 months post therapy. A second remission, which was maintained for years, was achieved after surgical gastrectomy followed by adjuvant chemotherapies. Prior reports have shown that surgery combined with chemotherapies was curative for patients with newly-diagnosed PGTL. In this report, surgery combined with chemotherapies was successfully applied for early-relapsed PGTL.

Nodal histiocytic sarcoma with prominent eosinophilic infiltration: expression of eotaxin-2 on tumor cells.

BACKGROUND: Histiocytic sarcoma (HS) is a rare neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. We report a patient with nodal HS exhibiting prominent reactive eosinophilic infiltration. CASE PRESENTATION: A 68-year-old man presented with intermittent left lower abdominal pain and weight loss over 3 months. A computed tomography scan revealed multiple abdominal nodules. Open biopsy of the mesenteric tumors was performed for definitive diagnosis. Histologically, the tumor was comprised of a diffuse noncohesive proliferation of pleomorphic large cells, including multinucleated cells. Neoplastic cells were positive for histiocytic markers (CD68, CD163, and LIGHT) and PD-L1 but lacked markers of Langerhans cells, follicular dendritic cells, and epithelial cells. Frequent reactive inflammatory cells were intermingled in the background. Interestingly, prominent eosinophilic infiltration was also noted. Spindle neoplastic cells were prone to be present around areas with little to no eosinophilic infiltration and exhibiting fibrosis and lymphatic vessel proliferation. Conversely, polygonal neoplastic cells were prone to be present around areas with relatively large amounts of eosinophilic infiltration without fibrosis or lymphatic vessel proliferation. Immunohistochemically, the tumor cells and reactive eosinophils expressed eotaxin-2 and eotaxin-3, respectively. CONCLUSION: We revealed that eotaxins induced the selective migration of eosinophils into tissues in this case. These eosinophils may affect the tumor remodeling and tumor biology characteristics of HS, such as fibrosis and lymphatic vessel proliferation.

Potential role of M2 TAMs around lymphatic vessels during lymphatic invasion in papillary thyroid carcinoma.

The aim of this study was to examine whether lymphatic invasion in papillary thyroid carcinoma (PTC) occurs when tumour-associated macrophages (TAMs) injure lymphatic vessels together with cancer cells. While there was no difference in the lymphatic vessel density in PTC and follicular thyroid carcinoma (FTC), the number of TAMs around the lymphatic vessels was increased in PTC compared to that in FTC. In particular, TAMs were observed together with cancer cells in lymphatic invasive lesions, and the number of M2 cells inside and outside the lymphatic vessels showed a significant correlation. MMP-2 mRNA was expressed in nonneoplastic stromal cells as well as cancer cells, and double immunofluorescence staining confirmed M2 positivity. Consequently, this study reveals that M2 TAMs around lymphatic vessels within the tumour border of PTC may be associated with the lymphatic invasion of cancer cells. This study represents a step forward in elucidating the mechanism of lymphatic invasion.

Comparative study of HO-1 expressing synovial lining cells between RA and OA.

OBJECTIVES: We aimed to clarify the characteristics of heme oxygenase (HO)-1 expressing cells in the synovium from rheumatoid arthritis (RA) and osteoarthritis (OA), and to investigate the co-expression of HO-1 and IgG-Fc/HLA-DR complex. METHODS: The characteristics of HO-1 expressing cells in the synovium were investigated by using immunohistochemistry. The co-expression of HO-1 and IgG-Fc/HLA-DR complex was examined by an in situ proximity ligation assay (PLA) with immunofluorescence. HO-1 mRNA was investigated by reverse transcription-polymerase chain reaction. RESULTS: The number of HO-1+ cells from the RA synovium is higher than that from OA synovium. The double positive cells of HO-1 and IgG-Fc/HLA-DR complex were detected by the in situ PLA with immunofluorescence in RA synovium. HO-1 mRNA was detected in both RA and OA synovium. CONCLUSION: A portion of HO-1+ cells with IgG-Fc/HLA-DR complex in lining layer of RA may be concluded as one of antigen presenting cells in RA and may be involved in production of RF.

Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders, Diffuse Large B-Cell Lymphoma Type, in a Patient with Behçet's Disease Treated with Cyclosporine A.

A 40-year-old man had been treated for Behçet's disease (BD) with cyclosporine A (CsA) for 14 years. He presented multiple lymphadenopathies with fever. Histological examination of surgical biopsy showed other iatrogenic immunodeficiency-associated lymphoproliferative disorders, diffuse large B-cell lymphoma type with positivity for Epstein-Barr virus encoding RNA-1 (EBER-1). BCL2-IgH, BCL6-IgH, and MYC-IgH translocations were not detected. CsA was stopped, and R-CHOP therapy was initiated. However, his lymphoma was chemotherapy resistant and rapidly progressed. To the best of our knowledge, this is the first case of diffuse large B-cell lymphoma that occurred in a BD patient treated with CsA reported in English. Both BD and CsA are associated with the pathogenesis of lymphoma. We also describe extremely rare cases in the form of a literature review.