Intratumoral metabolic heterogeneity of colorectal cancer.

Although the metabolic phenotype within tumors is known to differ significantly from that of the surrounding normal tissue, the importance of this heterogeneity is just becoming widely recognized. Colorectal cancer (CRC) is often classified as the Warburg phenotype, a metabolic type in which the glycolytic system is predominant over oxidative phosphorylation (OXPHOS) in mitochondria for energy production. However, this dichotomy (glycolysis vs. OXPHOS) may be too simplistic and not accurately represent the metabolic characteristics of CRC. Therefore, in this review, we decompose metabolic phenomena into factors based on their source/origin and reclassify them into two categories: extrinsic and intrinsic. In the CRC context, extrinsic factors include those based on the environment, such as hypoxia, nutrient deprivation, and the tumor microenvironment, whereas intrinsic factors include those based on subpopulations, such as pathological subtypes and cancer stem cells. These factors form multiple layers inside and outside the tumor, affecting them additively, dominantly, or mutually exclusively. Consequently, the metabolic phenotype is a heterogeneous and fluid phenomenon reflecting the spatial distribution and temporal continuity of these factors. This allowed us to redefine the characteristics of specific metabolism-related factors in CRC and summarize and update our accumulated knowledge of their heterogeneity. Furthermore, we positioned tumor budding in CRC as an intrinsic factor and a novel form of metabolic heterogeneity, and predicted its metabolic dynamics, noting its similarity to circulating tumor cells and epithelial-mesenchymal transition. Finally, the possibilities and limitations of using human tumor tissue as research material to investigate and assess metabolic heterogeneity are discussed.

The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer.

BACKGROUND: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA). METHODS: A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months. RESULTS: FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases. CONCLUSIONS: Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.

Tertiary lymphoid structure and neutrophil-lymphocyte ratio coordinately predict outcome of pembrolizumab.

Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.

Examination of nailfold videocapillaroscopy findings in ANCA-associated vasculitis.

OBJECTIVE: The objective of this study was to evaluate nailfold videocapillaroscopy (NVC) as a useful tool for assessing the disease activity of ANCA-associated vasculitis (AAV). METHODS: This study enrolled 51 patients with AAV and 21 healthy controls. We scored NVC findings semiquantitatively, and compared them between AAV patients and controls. We examined the association of NVC findings with disease activity indicators, histopathological findings of skin biopsies, and high-resolution CT (HRCT) scores in AAV. Additionally, we repeatedly rated the NVC findings 3 months after immunosuppressive therapy. RESULTS: Of the 51 enrolled patients, 36 (70.6%) showed a microangiopathy pattern and 4 (7.8%) showed a scleroderma pattern in AAV. The scores for microhaemorrhage, capillary loss, neoangiogenesis, and tortuosity were significantly higher in the AAV group than in the control group. NVC abnormalities correlated with the severity of skin, lung and kidney involvement. The scores of giant capillaries significantly correlated with the total BVAS and the chest BVAS; the scores of capillary loss correlated with the chest BVAS and the renal BVAS. The scores of microhaemorrhage significantly correlated with perivascular inflammatory cell infiltrations in the upper dermis of the purpura and tended to correlate with the total ground-glass opacity and consolidation scores on HRCT. In addition, capillary loss scores had a significant positive correlation with serum creatinine levels. Additionally, the microhaemorrhage scores were significantly reduced after 3 months of immunosuppressive therapy. CONCLUSION: In AAV patients, NVC abnormalities are significantly associated with disease severity. This result suggests that NVC is a useful tool for assessing the disease activity and treatment response in AAV.

A glucocorticoid-receptor agonist ameliorates bleomycin-induced alveolar simplification in newborn rats.

BACKGROUND: Glucocorticoids (GCs) are highly effective yet problematic agents against bronchopulmonary dysplasia (BPD). The dimeric trans-activation of GCs induces unfavorable effects, while monomeric trans-repression suppresses inflammation-related genes. Recently, non-steroidal-selective glucocorticoid-receptor agonists and modulators (SEGRAMs) with only the trans-repressive action have been designed. METHODS: Using a bleomycin (Bleo)-induced alveolar simplification newborn rat model (recapitulating arrested alveolarization during BPD), we evaluated the therapeutic effects of compound-A (CpdA), a SEGRAM. Sprague-Dawley rats were administered Bleo from postnatal day (PD) 0 to 10 and treated with dexamethasone (Dex) or CpdA from PD 0 to 13. The morphological changes and mRNA expression of inflammatory mediators, including interleukin (IL)-1ß, C-X-C motif chemokine ligand 1 (CXCL1), and C-C motif chemokine 2 (CCL2) were investigated. RESULTS: Similar to the effects of Dex, CpdA exerted protective effects on morphological derangements and inhibited macrophage infiltration and production of pro-inflammatory mediators in Bleo-treated animals. The effects of CpdA were probably mediated by GC receptor (GR)-dependent trans-repression, because unlike the Dex-treated group, anti-inflammatory genes specifically induced by GR-dependent trans-activation (such as "glucocorticoid-induced leucine zipper, GILZ") were not upregulated. CONCLUSIONS: CpdA improved lung inflammation, inhibited the arrest of alveolar maturation, and restored histological and biochemical changes in a Bleo-induced alveolar simplification model. IMPACT: SEGRAMs have attracted widespread attention because they are expected to not exhibit unfavorable effects of GCs. Compound A, one of the SEGRAMs, improved lung morphometric changes and decreased lung inflammation in a bleomycin-induced arrested alveolarization, a newborn rat model representing one of the main features of BPD pathology. Compound A did not elicit bleomycin-induced poor weight gain, in contrast to dexamethasone treatment. SEGRAMs, including compound A, may be promising candidates for the therapy of BPD with less adverse effects compared with GCs.

Clinicopathological characteristics of four major histological types of high-grade parotid carcinoma.

OBJECTIVE: High-grade parotid carcinoma generally has a poor prognosis, and the histological type is mucoepidermoid carcinoma (MEC), salivary duct carcinoma (SDC), carcinoma ex pleomorphic adenoma (CEPA), or adenoid cystic carcinoma (AdCC) in the majority of cases. METHODS: During the 23-year period from September 1999 to December 2022, 250 patients with parotid carcinoma underwent initial treatment and had the histopathological type of their carcinoma. Retrospective study evaluated 111 MEC, SDC, CEPA, or AdCC cases among 134 patients with high-grade parotid carcinoma. We examined pathological and clinical features and prognosis, evaluated factors associated with recurrence, and performed immunohistological examinations. RESULTS: Pathological and clinical features and factors associated with recurrence were different for each histological type. The 10-year disease-free survival rates were as follows: MEC, 34.9%; SDC, 22.6%; CEPA, 47.1%; and AdCC, 56.3%. Human epidermal growth factor receptor type-2 and androgen receptor were positive in 48% and 56% of patients with SDC, respectively, 38% and 25% of those with CEPA. CONCLUSION: Each histological type has its own pathological and clinical features, recurrence types, and tumor activities, suggesting that differentiating between high-grade parotid carcinomas according to histological type will improve diagnosis, and thus prognosis.

CCL2 produced by CD68+/CD163+ macrophages as a promising clinical biomarker of microscopic polyangiitis-interstitial lung disease.

OBJECTIVES: Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance. METHODS: We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining. RESULTS: Initial serum C-C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs. CONCLUSION: CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD.

A novel clinically-oriented classification of fine-needle aspiration cytology for salivary gland tumors: a 20-year retrospective analysis of 1175 patients.

BACKGROUND: When determining treatment strategy for a salivary gland tumor, assessing histology and malignancy grade before surgery is essential. Several new diagnostic classification systems for salivary gland cytology have recently been proposed. However, none incorporate histology and grade of malignancy. METHODS: We developed a new cytology classification system that incorporates histology and grade of malignancy of salivary gland tumors (OMC classification), consisting of 11 categories. Our OMC classification was applied to 1175 patients who had preoperative cytology and confirmed final pathological diagnosis available from the past 20 years at our hospital (benign tumor: 981 patients, malignant tumor: 194 patients). RESULTS: Based on the cytology, 729 patients (62.0%) had benign histology (Category 4-1), and 87 patients (7.4%) were diagnosed with grade of malignancy (Category 6-3 + 6-4). Based on the final pathological diagnosis, the accuracy rate of Category 4-1 and Category 6-3 + 6-4 of our classification system was 93.4% and 88.5%, respectively. CONCLUSION: Based on the correct diagnosis rate, the inclusion of histology and grade of malignancy in the salivary gland cytology classification was considered feasible. Thus, the OMC classification system is considered a useful tool when determining the treatment strategy for a salivary gland tumor.

Effective surgical management of anterior tumors of the parotid gland: Main trunk method vs. peripheral Smethod.

OBJECTIVE: Several surgical procedures have been proposed for tumors in the anterior parotid gland. Although the standard approach to other parotid tumors is generally also used for anterior tumors, handling of the facial nerve has not been addressed in any previous reports. METHODS: A total of 654 patients with benign parotid tumors who underwent surgery in our department were classified into anterior (AT), middle (MT), and posterior tumor (PT) groups according to tumor location. Clinical characteristics, histopathological types, and frequency of postoperative transient facial palsy were examined. In the AT group, two surgical methods were compared, which were the main trunk method (MTM) and the peripheral method (PM). RESULTS: 172 patients were included in the AT group, 175 in the MT group, and 307 in the PT group. The AT group showed significant female predominance and a higher percentage of deep lobe tumors than the PT group. There was no significant difference in the rate of postoperative transient facial palsy among the AT (MTM), MT, and PT groups. The PM had a significantly shorter operating time and lower rate of transient facial palsy than the MTM. CONCLUSION: The PM for AT was considered a useful surgical method from the standpoints of postoperative complications and operating time. In the PM, a wide operating field made identification of the facial nerve easier.

PD-L1 and PD-L2 expression in the tumor microenvironment including peritumoral tissue in primary central nervous system lymphoma.

BACKGROUND: The prevalence of programmed death-ligand 1 (PD-L1) and PD-L2 expression on tumor cells and tumor-infiltrating immune cells in primary central nervous system lymphoma (PCNSL) remains unclear. In the present study, we analyzed needle biopsy and craniotomy specimens of patients with PCNSL to compare the PD-L1 and PD-L2 levels in the tumor and surrounding (peritumoral) tissue. We also assessed the correlation between biological factors and the prognostic significance of PD-L1 and PD-L2 expression. METHODS: We retrospectively analyzed the cases of 70 patients histologically diagnosed with PCNSL (diffuse large B-cell lymphoma). Immunohistochemistry for CD20, CD68, PD-L1, and PD-L2 was performed. In cases with specimens taken by craniotomy, the percentages of PD-L1- and PD-L2-positive macrophages were evaluated in both tumor and peritumoral tissue. The Kaplan-Meier method with log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS: The tumor cells expressed little or no PD-L1 and PD-L2, but macrophages expressed PD-L1 and PD-L2 in most of the patients. The median percentage of PD-L2-positive cells was significantly higher among peritumoral macrophages (32.5%; 95% CI: 0-94.6) than intratumoral macrophages (27.5%; 95% CI: 0-81.1, p = 0.0014). There was a significant correlation between the percentages of PD-L2-positive intratumoral macrophages and PD-L2-positive peritumoral macrophages (p = 0.0429), with very low coefficient correlation (ρ = 0.098535). PD-L1 expression on macrophages was significantly associated with biological factors (intratumoral macrophages: better KPS, p = 0.0008; better MSKCC score, p = 0.0103; peritumoral macrophages: low proportion of LDH elevation, p = 0.0064) and longer OS (for intratumoral macrophages: high PD-L1 = 60 months, 95% CI = 30-132.6; low PD-L1 = 24 months, 95% CI = 11-48; p = 0.032; for peritumoral macrophages: high PD-L1 = 60 months, 95% CI = 30.7-NR; low PD-L1 = 14 months, 95% CI = 3-26). PD-L1 expression on peritumoral macrophages was strongly predictive of a favorable outcome (HR = 0.30, 95% CI = 0.12-0.77, p = 0.0129). CONCLUSIONS: Macrophages in intratumoral and peritumoral tissue expressed PD-L1 and PD-L2 at a higher rate than tumor cells. PD-L1 expression, especially on peritumoral macrophages, seems to be an important prognostic factor in PCNSL. Future comprehensive analysis of checkpoint molecules in the tumor microenvironment, including the peritumoral tissue, is warranted.

Endoscopic Evaluation of Neoadjuvant Chemotherapeutic Efficacy in Gastric Cancer before Gastrectomy Might be as Useful as Histological Assessment after Gastrectomy.

BACKGROUND: Neoadjuvant chemotherapy for advanced gastric cancer is expected to improve prognoses. However, as there is no method to evaluate neoadjuvant chemotherapeutic efficacy before gastrectomy, some patients at high risk for a poor prognosis undergo gastrectomy. The aim of the present study was to investigate whether endoscopy could be useful for assessing the efficacy of neoadjuvant chemotherapy. METHODS: In this retrospective study, we analyzed the data of 41 patients who received neoadjuvant chemotherapy followed by gastrectomy at our institution to investigate whether responsiveness to neoadjuvant chemotherapy, as assessed with endoscopy, can serve as a surrogate marker for histological grades 1b or higher in the Japanese Classification of Gastric Carcinoma (JCGC) scheme. RESULTS: There were 32 (78.0%) responders and 9 (22.0%) nonresponders to neoadjuvant chemotherapy, as observed in endoscopic evaluations. Among the endoscopic responders, 24 (75.0%) had cancer of histological grade 1b or higher, and 15 (46.9%) had cancer of grade 2 or higher. Among the endoscopic nonresponders, 1 (11.1%) patient had histological grade 1b cancer. Compared with endoscopic nonresponders, endoscopic responders were more likely to show a histological response (chi-square test: p = 0.0005 for JCGC grade 1b or higher; p = 0.0099 for JCGC grade 2 or higher). CONCLUSIONS: Most endoscopic responders showed JCGC histological responses. Evaluation of neoadjuvant chemotherapeutic efficacy by endoscopy in gastric cancer may be useful before gastrectomy. As this was a retrospective study, further investigations are required. The protocol was approved by the ethics review committee at Osaka Medical College (No. 2422) and was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000033088).

Challenges with preoperative diagnosis of low/intermediate-grade carcinoma of the parotid gland: single-center study of 112 patients.

BACKGROUND: The malignancy of parotid carcinoma varies, and accurate preoperative assessment of malignancy is important for selecting the appropriate treatment. However, the preoperative diagnosis of low/intermediate-grade carcinoma is difficult, and surgery may sometimes be performed without any prior knowledge of malignancy. METHODS: The results of fine-needle aspiration cytology (FNA), imaging studies (MRI and US), physical examination, and frozen section biopsy (FSB) were evaluated in 112 patients with low/intermediate-grade parotid carcinoma. RESULTS: The result of FNA was benign/inadequate specimen in 44.6% of the patients. In addition, the tumor was diagnosed as benign by MRI/US in 21.4% of the patients and 37.5% had no symptoms/signs of malignancy on physical examination. The rate of misdiagnosis as benign decreased when FNA was combined with imaging and physical findings. However, malignancy could not be diagnosed by FNA and FSB in 12.5% of the patients who were only found to have malignant tumors by the final pathological examination. CONCLUSION: FNA shows a high misdiagnosis rate of malignancy in patients with low/intermediate-grade cancer. Therefore, it is necessary to carefully evaluate the findings of imaging studies and physical examination, and FSB should be conducted if such findings suggest the possibility of malignancy.

Clinical characteristics of acinic cell carcinoma and secretory carcinoma of the parotid gland.

PURPOSE: Mammary analogue secretory carcinoma (SC) of the parotid gland is a relatively uncommon cancer associated with the ETV6-NTRK3 fusion product similar to breast cancer. The clinical characteristics and outcome of treatment were reviewed for patients with this tumor at our hospital. METHODS: In this retrospective case series, 24 patients with a diagnosis of acinic cell carcinoma (AcCC) of the parotid gland were classified as having either SC or AcCC based on analysis of the ETV6-NTRK3 fusion gene. These two groups were compared with respect to their clinical and imaging characteristics (MRI/US), cytologic findings, accuracy of fine-needle aspiration cytology and frozen section, treatment outcomes, and immunohistochemical findings. RESULTS: Based on re-classification by ETV6-NTRK3 fusion gene analysis, the diagnosis was SC in 14 patients and AcCC in 10 patients. The SC group had a significantly higher proportion of male patients and was also significantly younger than the AcCC group. Imaging studies revealed that SC was significantly more likely to show internal heterogeneity. Correct grading of both tumors was comparable by fine needle aspiration, with the rate being 60% for AcCC and 50% for SC. Diagnosis by frozen section biopsy diagnosis obtained the correct grade in 90% of the AcCC group and 93% of the SC group. CONCLUSIONS: In 24 patients previously diagnosed with AcCC, re-analysis of the ETV6-NTRK3 fusion product indicated that 14 patients actually had SC. Although AcCC and SC show similarities of their biological aggressiveness and prognosis, patients with SC were significantly more likely to be male and younger.

IgG4-Positive Plasmacytic Infiltration in Aortic Wall and Aortic Valve Surgical Samples and Its Relation to Preoperative Serum IgG4 Levels.

The prevalence and extent of immunoglobulin G4 (IgG4)-positive cell infiltration were investigated in 282 surgical samples of aortic wall and aortic valve. Tissue infiltration of IgG4-positive cells was observed in 24 (17.3%) of 139 aortic valve samples and 46 (32%) of 143 aortic wall samples, and the condition of IgG4-positive cell infiltration > 30/hpf together with IgG4/CD138 ratio > 40% was observed in 2 (1.4%) of aortic valve samples and 14 (9.8%) of aortic wall samples. Among 275 patients, preoperative serum IgG4 level was available in 48 patients (50 samples), and it was > 135 mg/dL in only one patient. Of these 48 patients with serum IgG4 measurement, 29 patients had aortic valve stenosis and 12 had aortic aneurysm. Compared with 23 aortic stenosis patients without tissue infiltration of IgG4-positive cells in the aortic valve, six patients with IgG4-positive cell infiltration had a more prevalent smoking history (26% versus 83%) and borderline significantly higher serum IgG4 (median, 24.5 mg/dL versus 55.5 mg/dL), although either preoperative peak pressure gradient between left ventriculum and aorta or aortic valve area did not differ significantly between groups. Compared with six aortic aneurysm patients without tissue infiltration of IgG4-positive cells in the aortic wall, six patients with IgG4-positive cell infiltration had borderline significantly higher serum IgG4 (median, 28.9 mg/dL versus 68.2 mg/dL). The current study showed that tissue IgG4-positive infiltration is not a rare occurrence in the aortic stenosis and aortic aneurysm. Clinical significance of tissue IgG4-postive cell infiltration in these patients requires further investigation.

Atrial Arrhythmias and Atrial Involvement in Cardiac Sarcoidosis.

Severe ventricular arrhythmias such as high-grade atrioventricular block and ventricular tachycardia may cause lethal conditions or sudden death in patients with cardiac sarcoidosis (CS). Physicians should examine patients carefully for these conditions and treat them appropriately. As arrhythmias are being better diagnosed and treated, physicians are increasingly aware of atrial arrhythmias, which have not been focused upon as CS-related conditions, in patients with CS. This article reports a case of atrial flutter in sarcoidosis, and discusses literature findings on atrial arrhythmias and atrial involvement of CS. It is highly likely that atrial arrhythmia and supraventricular conduction disorder associated with or caused by CS are more common than previously thought. Physicians should pay careful attention for these conditions in the diagnosis and treatment of CS.

A clinicopathological study of parotid carcinoma: 18-year review of 171 patients at a single institution.

BACKGROUND: This study investigated the clinical outcomes of patients with parotid carcinoma at a single institution during an 18-year period, with the focus on diagnosis, treatment, and survival. METHODS: The subjects were 171 patients with parotid carcinoma treated at our department during the 18-year period from September 1999 to August 2017. There were 19 patients in stage I, 65 patients in stage II, 22 patients in stage III, and 65 patients in stage IV. The symptoms, preoperative diagnosis, node metastasis, survival rate, prognostic factors, and immunohistological findings were investigated. RESULTS: Preoperative diagnosis of the histological grade by fine-needle aspiration cytology was only possible in 34% of the patients, while the histological grade was correctly determined by frozen section biopsy in 72%. The overall frequency of lymph node metastasis was 29%, with 59% in patients with high-grade carcinoma and only 6% in those with low-/intermediate-grade tumors. The disease-specific 5-year survival rate was 100% for patients in stage I, 95.2% in stage II, 70.4% in stage III, and 45.1% in stage IV. Multivariate analysis showed that the pathological grade was the most important prognostic factor. Immunohistological investigation showed patients with HER-2 or androgen receptor-positive tumors had a significantly worse prognosis. CONCLUSIONS: Although a high-grade tumor is the most important prognostic factor, preoperative diagnosis of the grade was not always accurate. Since advanced cancer has a poor prognosis with a limited response to surgery and radiation therapy, development of new treatment strategies, such as molecular-targeting therapies directed against HER-2 and AR, is required.

Eosinophilic granulomatosis with polyangiitis complicated by subarachnoid hemorrhage and coronary vasculitis: a case report and review of the literature.

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by necrotizing vasculitis of small-sized vessels with extravascular granulomas and eosinophilic infiltration. The case of a 48-year-old Japanese woman with EGPA, who presented concurrently with subarachnoid hemorrhage (SAH) and coronary vasculitis, is reported. She initially presented with bronchial asthma, and then 8 months later she developed various symptoms caused by systemic eosinophilic vasculitis and was admitted to our hospital. Three days after admission, she started oral corticosteroid therapy, and her 2009 Five-Factor Score (FFS) was 0. However, she developed an SAH, followed by coronary vasculitis 1 day later. With extensive treatment with a combination of betamethasone, cyclophosphamide, intravenous immunoglobulin, and rituximab, her systemic vasculitis improved dramatically. This seems to be the first case of EGPA with SAH and coronary vasculitis. In previous reports of EGPA with SAH, 4 of 11 cases developed SAH as an exacerbation of systemic vasculitis during remission induction therapy. The present patient also had SAH during remission induction therapy. However, the period between bronchial asthma and SAH was only 8 months. This is the shortest among case reports of EGPA with SAH. In addition, the present patient rapidly developed coronary vasculitis. These findings suggest that EGPA causes SAH and coronary vasculitis as early complications of systemic vasculitis. In EGPA, it is necessary to pay careful attention to rapid changes of disease activity, even when the FFS indicates a good prognosis.

Spontaneous Reduction in Abnormal Myocardial Uptake of Fluorine-18 Fluorodeoxygluose in a Patient with Cardiac Sarcoidosis.

Fluorine-18 fluorodeoxygluose (18F-FDG) positron emission tomography (PET) is a useful tool for evaluating disease activity in sarcoidosis including cardiac involvement. A 67-year-old patient who developed atrioventricular block requiring permanent pacemaker implantation was diagnosed with cardiac sarcoidosis. The patient did not undergo steroid or immunosuppressive therapy but underwent serial 18F-FDG PET examination, which showed spontaneous reduction in the myocardial FDG uptake, indicating the remission of immune-inflammatory activity. Although the global systolic function remained preserved, thinning of the septal wall emerged during the clinical course of follow-up, which is characteristic for cardiac sarcoidosis.

A Case of Aortic Stenosis with Serum IgG4 Elevation, and IgG4-Positive Plasmacytic Infiltration in the Aortic Valve, Epicardium, and Aortic Adventitia.

A 74-year-old man was admitted for preoperative screening of aortic stenosis. Five months before this admission, he was found to have elevated serum immunoglobulin G4 (IgG4; 2,010 mg/dL). Computed tomography (CT) showed a soft tissue mass surrounding the abdominal aorta, suggestive of IgG4-related periaortitis. CT coronary angiography showed perivascular thickening of the right coronary artery, and subsequent coronary angiography showed a multi-vessel disease. The patient underwent aortic valve replacement and coronary bypass surgery. Immunohistochemical analysis showed IgG4-positive plasmacytic infiltration in specimens from the aortic valve, epicardium, and aortic adventitia, suggestive of the possible role of IgG4-related immune inflammation for the pathogenesis.

IgG4-positive cell infiltration in various cardiovascular disorders - results from histopathological analysis of surgical samples.

BACKGROUND: The diagnosis of Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), in general, depends on serum IgG4 concentrations and histopathological findings; therefore, diagnosis of IgG4-RD in cardiovascular organs/tissues is often difficult owing to the risk of tissue sampling. METHODS: Prevalence of IgG4-positive lymphoplasmacytic infiltration in 103 consecutive cardiovascular surgical samples from 98 patients with various cardiovascular diseases was analyzed immunohistochemically. RESULTS: The diagnoses of the enrolled patients included aortic aneurysm (abdominal, n = 8; thoracic, n = 9); aortic dissection (n = 20); aortic stenosis (n = 24), aortic regurgitation (n = 10), and mitral stenosis/regurgitation (n = 17). In total, 10 (9.7%) of the 103 specimens showed IgG4-positive cell infiltration with various intensities; five of these were aortic valve specimens from aortic stenosis, and IgG4-positive cell infiltration was present at >10 /HPF in three of them. In one aortic wall sample from an abdominal aortic aneurysm, various histopathological features of IgG4-RD, such as IgG4-positive cell infiltration, obliterating phlebitis, and storiform fibrosis, were observed. CONCLUSIONS: IgG4-positive cell infiltration was observed in 9.7% of the surgical cardiovascular specimens, mainly in the aortic valve from aortic stenosis and in the aortic wall from aortic aneurysm. Whether IgG4-positive cell infiltration has pathophysiological importance in the development or progression of cardiovascular diseases should be investigated in future studies.