HER2 mutations in advanced cervical neuroendocrine carcinoma: implications for trastuzumab deruxtecan therapy.

Recent clinical evidence shows that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) can successfully treat patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). We aimed to characterize HER2 mutations in cervical neuroendocrine carcinoma (NEC) among Taiwanese women to provide the rationale for exploring T-DXd as a tumor-agnostic targeted therapy option. We analyzed 12 archived primary cervical NEC samples from Taiwanese patients. Tumor-rich areas were marked for microdissection on 10 µm unstained sections. DNA was extracted, and HER2 hotspots were sequenced using a targeted panel on the Illumina MiSeq. HER2 missense mutations were identified in 5 of 12 cases (41.7%). Of the 5 cases with mutations, 2 patients (40%) had a single mutation, while 3 patients (60%) had double mutations. We detected 4 substitutions outside the tyrosine kinase domain (non-TKD), which were p.P1170A, p.S305C, p.I655V, and a novel T328K alteration. No mutations were found within the tyrosine kinase domain (TKD). The 41.7% HER2 mutation rate warrants expanded screening and future clinical investigation of the T-DXd targeting HER2 mutations in cervical NEC patients. Overall, this study contributes to the molecular understanding of cervical NEC and lays the groundwork for developing more effective treatment strategies.

Update on Regulation of Regenerative Medicine in Taiwan.

Due to rapid development of biotechnology in recent years, the field of regenerative medicine has attracted considerable attention. Regenerative medicine-related regulations have been established in several countries to ensure the quality, safety, and efficacy of innovative treatments. Considering the diversity of regenerative medicine, the regulatory framework in Taiwan has been adjusted in response to global trend and local demand. Before 2010, cell and gene therapies were regarded as "new medical practice" under the "Medical Care Act." Along with the establishment of Taiwan Food and Drug Administration (TFDA) in 2010, regenerative medicine was regulated as "medicinal products" under the "Pharmaceutical Affairs Act." Then, the Ministry of Health and Welfare (MOHW) established a new dual-track regulatory pathway for regenerative medicine in 2016. The dual-track pathway divided regenerative medicine into medical practices and medicinal products, aiming to improve the accessibility of new treatments to patients and maintain the flexibility for clinical operations. In order to refine the regulation, the MOHW proposed two draft Acts for regenerative medicine in 2022. The two draft Acts are currently under legislative process. It is expected that the research and development of regenerative medicine can be further accelerated, thus providing early access to innovative therapies for patients in the future.

Generalizable Natural Language Processing Framework for Migraine Reporting from Social Media.

Migraine is a highly prevalent and disabling neurological disorder. However, information about migraine management in real-world settings is limited to traditional health information sources. In this paper, we (i) verify that there is substantial migraine-related chatter available on social media (Twitter and Reddit), self-reported by those with migraine; (ii) develop a platform-independent text classification system for automatically detecting self-reported migraine-related posts, and (iii) conduct analyses of the self-reported posts to assess the utility of social media for studying this problem. We manually annotated 5750 Twitter posts and 302 Reddit posts, and used them for training and evaluating supervised machine learning methods. Our best system achieved an F1 score of 0.90 on Twitter and 0.93 on Reddit. Analysis of information posted by our 'migraine cohort' revealed the presence of a plethora of relevant information about migraine therapies and sentiments associated with them. Our study forms the foundation for conducting an in-depth analysis of migraine-related information using social media data.

Ling Zhi-8, a fungal immunomodulatory protein in Ganoderma lucidum, alleviates CPT-11-induced intestinal injury via restoring claudin-1 expression.

CPT-11 (Irinotecan) remains an important chemotherapeutic agent against various solid tumors nowadays. Potential adverse effects, especially gastrointestinal toxicities, are the main limiting factor for its clinical utility. Ling Zhi-8 (LZ-8), a fungal immunomodulatory protein in Ganoderma lucidum mycelia, has potential for drug development due to its multiple bioactivities and functions. This study aimed to explore the influence of LZ-8 on CPT-11-treated IEC-6 cells in vitro and on mice with CPT-11-induced intestinal injury in vivo. The mechanism through which LZ-8 exerted its protective effects was also investigated. In the in vitro study, the viability and claudin-1 expression of IEC-6 cells decreased gradually with increasing concentrations of CPT-11, but LZ-8 treatment had no obvious influence on their viability, morphology, and claudin-1 expression. Pretreatment of LZ-8 significantly improved CPT-11-decreased cell viability and claudin-1 expression in IEC-6 cells. In mice with CPT-11-induced intestinal injury, LZ-8 treatment could ameliorate symptoms and mitigate intestinal damage. Meanwhile, LZ-8 restored claudin-1 expression in the intestinal membranes in CPT-11-treated mice. Collectively, our results demonstrated the protective effects of LZ-8 against CPT-11 damage in both IEC-6 cells and mice. LZ-8 can restore claudin-1 expression in intestinal cells following CPT-11 treatment, suggesting the role of claudin-1 in the scenario.

Challenges of the eighth edition of the American Joint Committee on Cancer staging system for pathologists focusing on early stage lung adenocarcinoma.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer adopts new criteria for tumor size, and for determining pTis, pT1a(mi), and pT1a. The latter is based on the size of stromal invasion. It is quite challenging for lung pathologists. METHODS: All patients who had undergone surgical resection for pulmonary adenocarcinoma (ADC) at Chung Shan Medical University Hospital between January 2014 and April 2018 were reviewed, and restaged according to the eighth AJCC staging system. The clinical characteristics and survival of patients with tumor stage 0 (pTis), I or II were analyzed. RESULTS: In total, 376 patients were analyzed. None of the pTis, pT1a(mi), or pT1a tumors recurred during the follow-up period up to 5 years, but pT1b, pT1c, pT2a, and pT2b tumors all had a few tumor recurrences (p < 0.0001). In addition, 95.2%, 100%, and 77.5% of pTis, pT1a(mi), and pT1a tumors, respectively, had tumor sizes ≤1.0 cm by gross examination. All pTis, pT1a(mi), and pT1a tumors exhibited only lepidic, acinar, or papillary patterns histologically. CONCLUSIONS: This study demonstrated excellent survival for lung ADC patients with pTis, pT1a(mi), and pT1a tumors when completely excised. To reduce the inconsistencies between pathologists, staging lung ADC with tumors of ≤1 cm in size grossly as pTis, pT1a(mi), or pT1a may not be necessary when the tumors exhibit only lepidic, acinar, or papillary histological patterns. A larger cohort study with sufficient follow-up data is necessary to support this proposal.

Alterations of mesenchymal stem cells on regulating Th17 and Treg differentiation in severe aplastic anemia.

Immune-mediated hematopoietic destruction is a key factor in idiopathic severe aplastic anemia (SAA). With great immunomodulatory functions, mesenchymal stem cells (MSCs) are important for bone marrow niche. While the underlying etiology of immunologic changes in SAA bone marrow remains unknown, dysfunctional MSCs are implicated as a major cause. To provide evidence for their defects in immunomodulation, alterations of SAA MSCs in regulating T cell differentiation were determined. During differentiation from CD4+ T cells into T helper 17 (Th17) cells under polarization conditions, impaired inhibition on IL-17 and IL-1ß production was noted when cocultured with SAA MSCs compared to control MSCs (P < 0.05). After stimulation of Th17 activation, the percentage of IL-17-secreting cells was significantly increased in the SAA group (9.1 ± 1.5% vs 6.6 ± 0.4%, P < 0.01). Under regulatory T (Treg) polarization, a higher percentage of CD4+CD25+FoxP3+ Treg cells was detected when cocultured with SAA MSCs compared to control MSCs (8.1 ± 0.5% vs 5.8 ± 0.8%, P < 0.01). Inconsistently, transforming growth factor-ß (TGF-ß) concentrations in the culture supernatant were decreased and IL-1ß concentrations were elevated in the SAA group. Our data indicated impaired inhibition of SAA MSCs on Th17 activation and aberrant regulation of SAA MSCs on Treg differentiation. Increased IL-17 and IL-1ß levels with decreased TGF-ß levels in the supernatant suggested the potential of SAA MSCs for triggering a hyperinflammatory environment. Dysfunctional MSCs could contribute to the lack of immunoprotection in the bone marrow, which may be associated with SAA.

The straightforward synthesis of N-coordinated ruthenium 4-aryl-1,2,3-triazolato complexes by [3 + 2] cycloaddition reactions of a ruthenium azido complex with terminal phenylacetylenes and non-covalent aromatic interactions in structures.

The straightforward preparation of N-coordinated ruthenium triazolato complexes by [3 + 2] cycloaddition reactions of a ruthenium azido complex [Ru]-N3 (1, [Ru] = (η5-C5H5)(dppe)Ru, dppe = Ph2PCH2CH2PPh2) with a series of terminal phenylacetylenes is reported. The reaction products, N(2)-bound ruthenium 4-aryl-1,2,3-triazolato complexes such as [Ru]N3C2H(4-C6H4CN) (2), [Ru]N3C2H(4-C6H4CHO) (3), [Ru]N3C2H(4-C6H4F) (4), [Ru]N3C2H(Ph) (5) and [Ru]N3C2H(4-C6H4CH3) (6) were produced from 4-ethynylbenzonitrile, 4-ethynylbenzaldehyde, 1-ethynyl-4-fluorobenzene, phenylacetylene and 4-ethynyltoluene, respectively, at 80 °C or above under an atmosphere of air. To the best of our knowledge, this is the first example of the preparation of N-coordinated ruthenium aryl-substituted 1,2,3-triazolato complexes by the [3 + 2] cycloaddition of a metal-coordinated azido ligand and a terminal aryl acetylene, less electron-deficient terminal aryl alkynes. All of the compounds have been fully characterized and the structures of complexes 2, 3, 5 and 6 were confirmed by single-crystal X-ray diffraction analysis. Each compound participates in non-covalent aromatic interactions in the solid-state structure which can be favorable in the binding of DNA/biomolecular targets and has shown great potential in the development of biologically active anticancer drugs.

Immunomodulation of Mesenchymal Stem Cells in Acute Lung Injury: From Preclinical Animal Models to Treatment of Severe COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a major public health challenge worldwide. Owing to the emergence of novel viral variants, the risks of reinfections and vaccine breakthrough infections has increased considerably despite a mass of vaccination. The formation of cytokine storm, which subsequently leads to acute respiratory distress syndrome, is the major cause of mortality in patients with COVID-19. Based on results of preclinical animal models and clinical trials of acute lung injury and acute respiratory distress syndrome, the immunomodulatory, tissue repair, and antiviral properties of MSCs highlight their potential to treat COVID-19. This review article summarizes the potential mechanisms and outcomes of MSC therapy in COVID-19, along with the pathogenesis of the SARS-CoV-2 infection. The properties of MSCs and lessons from preclinical animal models of acute lung injury are mentioned ahead. Important issues related to the use of MSCs in COVID-19 are discussed finally.

Primary malignant peritoneal mesothelioma mimicking tuberculous peritonitis: A case report.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignancy arising in mesothelial cells in the peritoneum. It can be mistaken for many other diseases, such as peritoneal carcinomatosis and tuberculous peritonitis (TBP), because its clinical manifestations are often nonspecific. Therefore, the diagnosis of MPM is often challenging and delayed. CASE SUMMARY: A 42-year-old man was referred to our hospital with lower abdominal pain for 1 wk and ascites observed under abdominal sonography. His laboratory findings revealed an isolated elevated tumor marker of carcinoma antigen 125 (167.4 U/mL; normal, < 35 U/mL), and contrast enhanced computed tomography showed peritoneal thickening. Thus, differential diagnoses of TBP, carcinomatosis of an unknown nature, and primary peritoneal malignancy were considered. After both esophagogastroduodenoscopy and colonoscopy produced negative findings, laparoscopic intervention was performed. The histopathological results revealed mesothelioma invasion into soft tissue composed of a papillary, tubular, single-cell arrangement of epithelioid cells. In addition, immunohistochemical staining was positive for mesothelioma markers and negative for adenocarcinoma markers. Based on the above findings, TBP was excluded, and the patient was diagnosed with MPM. CONCLUSION: It is important to distinguish MPM from TBP because they have similar symptoms and blood test findings.

Immunomodulation via MyD88-NFκB Signaling Pathway from Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury.

Excess inflammatory processes play a key detrimental role in the pathophysiology of acute lung injury (ALI). Mesenchymal stem cells (MSCs) were reported to be beneficial to ALI, but the underlying mechanisms have not been completely understood. The present study aimed to examine the involvement of MyD88−NFκB signaling in the immunomodulation of MSCs in mice with lipopolysaccharides (LPS)-induced ALI. We found that serum concentrations of IL-6, TNF-α, MCP-1, IL-1ß, and IL-8 were significantly decreased at 6 h after LPS-induced ALI in the MSC group (p < 0.05). For each of the five cytokines, the serum concentration of each individual mouse in either group declined to a similar level at 48 h. The intensity of lung injury lessened in the MSC group, as shown by histopathology and lung injury scores (p < 0.001). The expressions of MyD88 and phospho-NFκB in the lung tissue were significantly decreased in mice receiving MSCs as measured by Western blotting and immunohistochemistry. Our data demonstrated that human umbilical cord-derived MSCs could effectively alleviate the cytokine storm in mice after LPS-induced ALI and attenuated lung injury. Firstly, we documented the correlation between the down-regulation of MyD88−NFκB signaling and immunomodulatory effects of MSCs in the situation of ALI.

Orphan drug development: The impact of regulatory and reimbursement frameworks.

The enactment of orphan drug-specific legislation pioneered by the USA was subsequently followed by many regions, including the European Union (EU), Australia, Japan, and Taiwan. Here, we discuss the associated regulations established and their impacts in the aforementioned regions, which are among the first with frameworks specific for orphan drugs. Varied scopes of rare diseases or orphan drugs, diverse incentives, and heterogeneous types of reimbursement systems imply the prioritization of the agencies concerned. The numbers of designated and approved drugs reflect the impact of the regulatory and reimbursement frameworks. A comparison of the frameworks and their impact in the respective regions could provide valuable information for developing and improving related frameworks for countries worldwide.

Comparing the 2017 ASCO/CAP guideline for gastroesophageal adenocarcinoma surgical specimen to the 2018 ASCO/CAP guideline for breast cancer in assessing the HER2 status in primary mucinous ovarian carcinoma.

The successful experiences of HER2 inhibitors in patients with HER2 ( +) breast cancer (BC) and advanced gastroesophageal adenocarcinoma (GEA) have encouraged us to continuously explore the HER2 status and its potential as a therapeutic target in primary mucinous ovarian carcinoma (mOC). Using 49 primary mOC samples, we compared the assay characteristics of HER2 status between both 2017 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) for GEA and 2018 ASCO/CAP for BC guideline recommendations. We demonstrated moderate to strong agreement between their HER2 IHC results (Weighted Kappa = 0.78) and perfect agreement between their HER2 FISH results (Kappa = 1.00). The overall concordance of non-equivocal HER2 IHC and HER2 FISH results was 97.56% (kappa = 0.93) by 2017 ASCO/CAP for GEA criteria and 100% (kappa = 1.00) by 2018 ASCO/CAP for BC criteria. The number (n = 8; 16.32%) of HER2 IHC equivocal (score + 2) by 2017 ASCO/CAP for GEA criteria was twofold higher than that (n = 4; 8.16%) by 2018 ASCO/CAP for BC criteria. Additionally, we identified one false-positive (FP) case (n = 1; 2.04%) that was HER2 IHC positive (score + 3), but HER2 FISH non-amplified result by the 2017 ASCO/CAP for GEA criteria. In conclusion, owing to the absence of FP/ FN and fewer equivocal cases of HER2 IHC, we recommend that the 2018 ASCO/CAP for BC are more appropriate than 2017 ASCO/CAP for GEA criteria in appraising the HER2 status in mOC and justifying the inclusion of eligible subjects for basket clinical trials of the newly developmental anti-HER2 treatments.

High frequency of BRAF mutations in primary mucinous ovarian carcinoma of Taiwanese patients.

OBJECTIVE: Considering the clinical evidence of BRAF inhibitors that can treat melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups. MATERIALS AND METHODS: 20 archived primary MOC samples were analyzed. The BRAF mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with Sanger sequencing method. Additionally, we extended our prior reported data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation. RESULTS: Of them (n = 20), 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n=1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), T599I/S602F (n = 1). The BRAF S602F is novel. The prevalence of BRAF mutation is significantly higher than either HER2 mutation (80% vs. 35%; p = 0.022) or HER2 amplification (80% vs. 35%; p = 0.022). However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289). CONCLUSION: Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation.

High Expression of MTA1 Predicts Unfavorable Survival in Patients With Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Metastasis-associated protein 1 (MTA1) plays a role in ATP-dependent nucleosome disruption activity and histone deacetylase activity and may indicate DNA methylation activity. MTA1 may also be involved in the progression of oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: MTA1 immunoreactivity was analyzed using immunohistochemical (IHC) staining analysis in specimens from 281 OSCC patients. Kaplan-Meier analysis was used to determine the prognostic value of MTA1 for overall survival. RESULTS: High MTA1 expression was significantly associated with female gender and lymph node metastasis. Multivariate analyses showed the independent prognostic role of high MTA1 expression in patients with OSCC of poorer mean survival. CONCLUSION: MTA1 expression, detected by IHC staining, could be an independent prognostic marker for patients of OSCC.

Progress of Indirect Estimation Methods for Mechanical Property of Articular Cartilage / 医用生物力学

With extraordinary mechanical properties, articular cartilage is one of the most critical factors in human movement and load transmission. With the increase of sports participation and population aging, more and more patients suffer from cartilage injury and related diseases. Accurate acquisition of mechanical properties for articular cartilage is the key process of cartilage injury and functional evaluation. In this paper, the research progress of indirect estimation for mechanical properties of articular cartilage was summarized. Furthermore, some new perspectives were prospected on mechanical characterization of articular cartilage.