Background
The purpose of this study was to comprehensively characterize head and neck squamous cell carcinoma (HNSCC) arising in young patients (<45 years old).
Methods
We performed ...immunohistochemistry, silver, and fluorescence in situ hybridization using samples obtained from 396 radically resected cases among 1787 HNSCCs.
Results
Young age HNSCCs occurred in 10.9% (194/1787) and were most common in the oral tongue (50.5%). They revealed distinctively lower frequency of p16 positivity, high c‐MET expression, MET copy number gain, and lower pan‐Trk expression. PD‐L1 positivity in tumor cells and ICOS+ tumor infiltrating lymphocytes (TILs) were higher in the young age. Perineural invasion, PD‐L1 positivity, and higher ratio of CD163+ tumor infiltrating macrophages to CD8 + TILs were determined to be independent factors for poor progression‐free survival.
Conclusion
Characterizing these features of young age HNSCC may help to identify the underlying pathogenesis and to improve patient outcome through different treatment strategies.
Salivary duct carcinoma (SDC) is an aggressive carcinoma with poor prognosis. Although anti-HER2 therapy is a potential treatment option for HER2-positive SDC, other potential therapeutic targets are ...not known, in particular for HER2-negative cases. In this study, the recently identified receptors tyrosine kinases MET and tropomyosin-receptor kinase (Trk) were investigated as potential therapeutic targets. A total of 28 consecutive, surgically resected, de novo SDC cases were selected after evaluating histology and immunohistochemical expression of androgen receptor. Immunohistochemical expression of c-erb2, TrkA, TrkB, TrkC, and c-MET was analyzed, and the genetic status of the HER2 and MET genes was investigated through dual-color silver in situ hybridization. High expression of c-MET or Trk was defined as that above the median value. Among the 28 SDC cases, 64.3% (18/28) were HER2-positive. c-MET expression varied, with a median H-score of 65 (range, 0 to 200). Copy number gain and amplification of MET were noted in 57.1% (16/28) and 10.7% (3/28) of cases, respectively. TrkA was variably expressed, with a median H-score of 100 (range, 0 to250). High TrkA expression was significantly related to an inferior overall survival rate in HER2-negative SDC. High expression of TrkA and c-MET and MET copy number gain/amplification were frequent events in SDC, and high expression of TrkA revealed the tendency to be related to poor prognosis in HER2-negative SDC. TrkA and MET may be possible therapeutic targets in SDC, especially in HER2-negative SDC.
•Salivary duct carcinoma (SDC) is an aggressive carcinoma•High expression of TrkA and c-MET and MET gene copy number gain/amplification are frequent events in SDC.•High expression of TrkA reveals the tendency to be related to poor prognosis in HER2-negative de novo SDC.•TrkA and MET may be possible targets in SDC and in HER2-negative SDC.
•Different combustion characteristics in two coal-fired boilers of same design were assessed.•CFD for individual windboxes determined the air flow distribution between burners.•Swirl strength of ...burners had a linear relationship with the gap of air register vanes.•Predicted temperature and heat transfer rates reasonably agreed well with the operating data.•Detailed data for heat flux and flow path can be used for combustion optimization.
In a large coal-fired power plant, it is common for the multiple boilers to be of an identical design in order to reduce construction and operating costs. Despite the design and operating conditions being the same, the boilers often exhibit different combustion characteristics after being in operation for an extended period. Using computational fluid dynamics (CFD), this study diagnosed the combustion in two identical coal-fired boilers with a capacity of 500 MWe, but which exhibited different trends in their temperature and heat distribution. Based on a survey on the detailed operation parameters, individual windboxes with different damper settings were analyzed to determine the air flow distribution between the burners and the overfire air ports. Then, the swirl burners were investigated in an attempt to identify a correlation with the swirl strength for a range of vane angles and air flow rates. The results were introduced into the CFD simulations for the boilers, for which we adopted advanced models for the coal devolatilization and char conversion. The predicted temperatures and heat transfer rates were in reasonable agreement with the measured data. The main reason for the higher gas temperatures and heat transfer rates in boiler A was found to be the higher air flow rate in the burner zone. Individual burners produced different gas flow paths and, therefore, the low-O2 pockets downstream could be traced to particular burners. Those burners with narrower vane gaps produced stronger swirls in the secondary air, which led to wider-angled flames closer to the burners, together with strong internal recirculation zones. This increased the heat flux on the adjacent wall. This study shows that CFD simulations for existing boilers require careful consideration of the operating parameters that may lead to significant differences in the combustion characteristics.
We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue ...sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7-10.4). The common treatment-related adverse events of grades 3-4 included neutropenia (9 19.1%), elevated aspartate aminotransferase (7 14.9%), alanine aminotransferase (5 10.6%), and thrombocytopenia (4 8.5%). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20
B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10
) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20
B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.
Cutaneous melanoma, a melanocyte malignancy, can be divided into many clinical subtypes that differ in presentation, demographics, and genetic profile. In this study, we used next-generation ...sequencing (NGS) analysis to review genetic alterations in 47 primary cutaneous melanomas in the Korean population and compared them to alterations from melanomas in Western populations.
We retrospectively reviewed clinicopathologic and genetic features of 47 patients diagnosed with cutaneous melanomas between 2019-2021 at Severance Hospital, Yonsei University College of Medicine. NGS analysis was performed at diagnosis to evaluate single nucleotide variations (SNVs), copy number variations (CNVs), and genetic fusions. Genetic features in Western cohorts of melanoma were then compared with previous studies performed in the USA: Cohort 1 (n=556), Cohort 2 (n=79), and Cohort 3 (n=38).
The most common histological classification of melanoma was the acral lentiginous type (23/47, 48.9%). BRAF V600 mutation was most frequent (11/47, 23.4%), but was significantly lower compared to Cohort 1 (240/556, 43.2%) and Cohort 2 (34/79, 43.0%) (p=0.0300). CNV analysis identified amplifications in chromosomes 12q14.1-12q15 (11/47, 23.4%) including CDK4 and MDM2 genes and 11q13.3 (9/47, 19.2%) including CND1, FGF19, FGF3, and FGF4 genes more frequently in the present study population than Cohort 1 (p<0.0001).
These results clearly demonstrated differences in genetic alterations between melanomas in Asian and Western populations. Therefore, BRAF V600 mutation should be considered a significant signaling pathway explaining melanoma pathogenesis occurrence in both Asian and Western populations, whereas loss of chromosome 9p21.3 is unique to melanomas in Western populations.
Background
The differential diagnosis of intrahepatic cholangiocarcinomas (iCCAs) from metastatic adenocarcinomas from organs adjacent to the liver (gallbladder, pancreas, and stomach) is difficult ...due to histopathological similarity and a lack of specific markers. This study aimed to develop a method to differentiate iCCA and adenocarcinomas originated from extrahepatic organs adjacent to the liver.
Methods
We retrospectively enrolled surgically resected iCCA (
n
= 181) and adenocarcinomas from extrahepatic organs (
n
= 30,
n
= 28, and
n
= 38 from gallbladder, pancreas, and stomach, respectively) between 2007 and 2013. The albumin mRNA in situ hybridization (ISH) and immunohistochemistry (IHC) of filamin-A and cytokeratin 19 (CK19) were performed using tissue microarray. Using logistic regression analysis of three markers, iCCA-score was developed, and its diagnostic performance was evaluated.
Results
The iCCAs were more frequently positive for albumin ISH (23.2% vs. 0%), filamin-A IHC (47.5% vs. 12.5%) and CK19 (68.5% vs. 40.6%) than extrahepatic adenocarcinomas (
p
< 0.001 for all). The iCCA-score consisting of these three markers was developed, and it showed higher diagnostic performance (area under the curve AUC, 0.798 vs. 0.616,
p
< 0.001). Taking an iCCA-score of 2 or higher as the threshold for iCCA, the sensitivity was substantially higher than albumin ISH alone (45.9% and 23.2%, respectively;
p
< 0.001), but maintained high specificity (94.8% and 100%, respectively).
Conclusion
Albumin ISH and IHC staining for filamin-A and CK19 showed distinct expression patterns between iCCA and extrahepatic adenocarcinomas from gallbladder, pancreas, and stomach. We developed iCCA-score that consisted of those three markers, and it showed better diagnostic performance than albumin ISH alone.
The International Society for Cutaneous Lymphoma (ISCL) proposes a diagnostic algorithm for early mycosis fungoides (MF) that includes clinical, histological, immunophenotypical, and molecular ...criteria. Here, we analyzed the immunologic markers and features of T-cell clonality in 38 early MF cases and 22 non-MF cases to validate the ISCL algorithm. We found that CD5 and CD7 expression differed significantly between early MF and non-MF cases, with epidermal discordance of CD7 expression more frequently identified in early MF. Notably, increasing the cut-off value for CD7 expression from 10% to 22.5% improved its sensitivity. Furthermore, TCR-γ and β chain rearrangements were more frequently detected in early MF than in non-MF cases. Based on these findings, we propose CD5 and CD7 deficiency as mandatory immunopathologic criteria and PCR-based testing for TCR-γ and β chains as required molecular/biologic criteria to improve the efficiency of early MF diagnosis using the ISCL algorithm.
(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many ...patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort,
= 48) and The Cancer Genome Atlas (TCGA,
= 9235). Secondly, we established the novel patient-derived preclinical models (
= 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.
...several studies have reported a subset of endocervical tumors with minimal to no evidence of stromal invasion manifesting as metastatic ovarian tumors.2,3 Distinguishing this metastatic disease ...from a primary ovarian tumor is difficult because ovarian lesions are typically large, unilateral, confined to the ovary, and well differentiated with mucinous or endometrioid-like histology, which are features consistent with a primary ovarian tumor.2 The metastatic nature of these lesions can be confirmed by comparing the human papillomavirus (HPV) type to that of the endocervical tumors.4 In this report, we demonstrate a case of endocervical AIS with no evidence of stromal invasion involving the unilateral ovary and simulating a primary ovarian tumor. The majority of cases with ovarian involvement occur in advanced-stage endoJournal Department of Pathology, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: +82-2-2228-1794, Fax: +82-2-362-0860, E-mail: hyunsookim@yuhs.ac Received: September 14, 2018 Revised: December 6, 2018 Accepted: December 16, 2018 cervical adenocarcinoma or in a primary lesion with extrauterine extension.6 However, there have been cases of early-stage disease, and even cases of noninvasive carcinoma, that involved the ovary.1,2,5,7 Most ovarian lesions show well-differentiated villoglandular and confluent glandular patterns, resembling those of primary ovarian borderline mucinous or endometrioid tumor.2 In a previous study, all cases examined were initially thought to represent independent primary ovarian epithelial tumors, including borderline tumors or grade 1 carcinomas of mucinous or endometrioid type.8 In cases with no stromal invasion in an endocervical adenocarcinoma, a borderline-appearing ovarian tumor could reasonably be interpreted as an independent primary ovarian tumor by the pathologist.7 In this situation, the presence of the identical HPV type in both the endocervical and ovarian tumors supports that the ovarian lesion is a metastatic endocervical adenocarcinoma rather than an independent primary ovarian tumor. Studies associating HPV and ovarian tumors have yielded almost universally negative results, suggesting that primary ovarian tumors are etiologically unrelated to HPV infection.7 In addition, p16 immunostaining may prove useful for distinguishing metastases from primary ovarian tumors. p16 immunoreactivity is a surrogate marker of high-risk HPV infection.9 Although p16 expression is absent or sporadically positive in ovarian mucinous and endometrioid carcinomas, HPV-related endocervical tumors typically display strong and diffuse nuclear p16 immunoreactivity.
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