FK228 suppress the growth of human malignant pleural mesothelioma tumor independent to epithelioid or non-epithelioid histology.

Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.

Trismus in head and neck cancer: translation and validation of the Chinese version of the Gothenburg Trismus Questionnaire-2 (C-GTQ-2).

OBJECTIVES: Trismus, marked by restricted mouth opening, significantly affects patients with temporomandibular disorder (TMD) and head and neck cancer (HNC). Despite its prevalence, specialized questionnaires for trismus assessment are scarce. This study aims to fill this gap by translating and validating the Gothenburg Trismus Questionnaire version 2 (GTQ-2) into Chinese (C-GTQ-2), enhancing the evaluation of trismus in HNC and TMD patients. MATERIALS AND METHODS: The study involved 78 HNC patients, 75 TMD patients, and a control group of 150 individuals without trismus symptoms. Participants were asked to complete the C-GTQ-2 and other health-related quality of life (HRQL) instruments. A subset of 30 individuals retook the questionnaire within two weeks to assess test-retest reliability. RESULTS: The C-GTQ-2 demonstrated remarkable reliability, with Cronbach's alpha values exceeding 0.70 in three of the four domains, indicating high internal consistency. The instrument also showcased high intra-class correlations in the test-retest, affirming its reliability. Furthermore, it exhibited strong convergent validity, aligning well with other HRQL instruments, and effectively discriminated between patients with and without trismus, establishing its discriminant validity. CONCLUSIONS: The C-GTQ-2 emerges as a valid and reliable tool for assessing trismus in HNC and TMD patients, promising to significantly enhance both clinical and research approaches to managing trismus-related complications in the Chinese-speaking demographic. CLINICAL RELEVANCE: C-GTQ-2 proves effective for trismus assessment in head and neck cancer and temporomandibular disorder patients, offering enhanced clinical and research utility.

Pulmonary invasive mucinous adenocarcinoma.

Invasive mucinous adenocarcinoma (IMA) is a relatively rare subtype of lung adenocarcinoma, composed of goblet and/or columnar tumour cells containing abundant intracytoplasmic mucin vacuoles. While a majority of IMAs are driven by KRAS mutations, recent studies have identified distinct genomic alterations, such as NRG1 and ERBB2 fusions. IMAs also more frequently present as a pneumonic-like pattern with multifocal and multilobar involvement, and comparative genomic profiling predominantly shows a clonal relationship, suggesting intrapulmonary metastases rather than synchronous primary tumours. Accordingly, these unique features require different therapeutic approaches when compared to nonmucinous adenocarcinomas in general. In this article, we review recent updates on the histopathological, clinical, and molecular features of IMAs, and also highlight some unresolved issues for future studies.

Rapid On-Site AI-Assisted Grading for Lung Surgery Based on Optical Coherence Tomography.

The determination of resection extent traditionally relies on the microscopic invasiveness of frozen sections (FSs) and is crucial for surgery of early lung cancer with preoperatively unknown histology. While previous research has shown the value of optical coherence tomography (OCT) for instant lung cancer diagnosis, tumor grading through OCT remains challenging. Therefore, this study proposes an interactive human-machine interface (HMI) that integrates a mobile OCT system, deep learning algorithms, and attention mechanisms. The system is designed to mark the lesion's location on the image smartly and perform tumor grading in real time, potentially facilitating clinical decision making. Twelve patients with a preoperatively unknown tumor but a final diagnosis of adenocarcinoma underwent thoracoscopic resection, and the artificial intelligence (AI)-designed system mentioned above was used to measure fresh specimens. Results were compared to FSs benchmarked on permanent pathologic reports. Current results show better differentiating power among minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (IA), and normal tissue, with an overall accuracy of 84.9%, compared to 20% for FSs. Additionally, the sensitivity and specificity, the sensitivity and specificity were 89% and 82.7% for MIA and 94% and 80.6% for IA, respectively. The results suggest that this AI system can potentially produce rapid and efficient diagnoses and ultimately improve patient outcomes.

Impact of Perineural Invasion and Preexisting Type 2 Diabetes on Patients with Esophageal Squamous Cell Carcinoma Receiving Neoadjuvant Chemoradiotherapy.

Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the cornerstone treatment strategy in locally advanced esophageal squamous cell carcinoma (ESCC). Despite this high- intensity multimodality therapy, most patients still experience recurrences and metastases, especially those who do not achieve a pathological complete response (pCR) after neoCRT. Here, we focused on identifying poor prognostic factors. In this retrospective cohort study; we enrolled 140 patients who completed neoCRT plus surgery treatment sequence with no interval metastasis. Overall, 45 of 140 patients (32.1%) achieved a pCR. The overall survival, disease-free survival (DFS), and metastasis-free survival was significantly better in patients with a pCR than in patients with a non-pCR. In the non-pCR subgroup, the presence of perineural invasion (PNI) and preexisting type 2 diabetes (T2DM) were two factors adversely affecting DFS. After adjusting for other factors, multivariate analysis showed that the hazard ratio (HR) was 2.354 (95% confidence interval [CI] 1.240-4.467, p = 0.009) for the presence of PNI and 2.368 (95% CI 1.351-4.150, p = 0.003) for preexisting T2DM. Patients with a combination of both factors had the worst survival. In conclusion, PNI and preexisting T2DM may adversely affect the prognosis of patients with ESCC receiving neoadjuvant chemoradiotherapy.

Deep exploration of immune function in EGFR wild-type and mutated lung adenocarcinomas by gene expression profiling: role of TRAIL-R2 (TNFRSF10B) in patient treatment and outcome.

The tumor microenvironment is important in the initiation and progression of lung adenocarcinoma (LUAD). In this study, we aim to analyze the expression profile of immune-related genes in LUADs, examine the differential expression of immune-related genes in epidermal growth factor receptor (EGFR) wild-type and mutant LUADs, and the clinicopathologic significance of these differentially expressed genes. We used the NanoString PanCancer Immune Profiling Panel to examine 34 cases of LUADs (18 EGFR wild-type, 16 EGFR mutant). In EGFR wild-type LUADs, the macrophage and neutrophil signatures are significantly higher, and significantly higher expression of chemokines, interleukins, leukocyte, macrophage, natural killer cell, pathogen defense, Tumor necrosis factor superfamily, and transporter function signatures are also observed. TNFRSF10B mRNA was preferentially expressed in EGFR wild-type LUADs (P = 6.15e-6, adjusted P = .0244). Immunohistochemical staining for TRAIL-R2 (encoded by TNFRSF10B) on 134 tissue microarray LUAD cases demonstrated strong, moderate, and weak staining in 75 (56.0%), 46 (34.3%), and 13 (9.7%) cases, respectively. Strong TRAIL-R2 expression was significantly associated with poor overall survival (OS) in all stages and EGFR wild-type LUADs, but not in EGFR-mutant tumors. Furthermore, strong TRAIL-R2 expression (P = .004) was an independent risk factor for poor OS. In summary, TNFRSF10B mRNA revealed significantly higher expression in EGFR wild-type LUADs, and strong TRAIL-R2 expression predicts an unfavorable prognosis for these tumors. These patients may benefit from additional treatment with TRAIL-R2-targeted therapies.

Comparison of Different Hepatocyte Nuclear Factor 4α Clones for Invasive Mucinous Adenocarcinoma of the Lung.

Invasive mucinous adenocarcinoma (IMA) is a rare variant of adenocarcinoma that comprises mucinous epithelial cells. The expression of hepatocyte nuclear factor 4α (HNF4α) has been previously reported as a marker for IMA, but controversy remains regarding whether HNF4α is a reliable marker for lung IMAs. In the present study, we compared HNF4α expression levels between IMA and nonmucinous adenocarcinoma (NMA) cases using 2 different HNF4α clones. We used 2 HNF4α antibody clones, H1 and H1415, to examine HNF4α expression in 36 IMA and 40 NMA cases, which comprised the control group. HNF4α immunostaining intensity (range, 0 to 3) and percentage of intensity (range, 0% to 100%) were evaluated by 3 pathologists and ImageJ software, and average H-scores were calculated for each case. Interobserver agreement was assessed using intraclass correlation coefficient. Receiver-operating characteristic curve was used to analyze sensitivity and specificity of the clones. The mean H-score was higher in the IMA group than in the NMA group for both the H1415 (141.3 vs. 9.3) and H1 (67.3 vs. 3.4) clones. The intraclass correlation coefficient for agreement among the 4 observers was good (0.806 and 0.711). The H1415 clone exhibited comparable sensitivity (83.3% vs. 83.3%) with higher specificity (97.5% vs. 92.5%) compared with the H1 clone when using cutoff values of 36.2 (H1415) and 9.5 (H1), respectively. Our analyses suggest that HNF4α should be considered as a reliable marker for primary IMA of the lung. The H1415 clone should be preferred for use in clinical practice.

EGFR Q787Q Polymorphism Is a Germline Variant and a Prognostic Factor for Lung Cancer Treated With TKIs.

The prevalence and impact of epidermal growth factor receptor (EGFR) Q787Q polymorphism on the treatment of lung adenocarcinoma remains unclear. We retrospectively analyzed patients with stage IV lung adenocarcinoma to evaluate the prevalence of the EGFR Q787Q polymorphism and its influence on effects of tyrosine kinase inhibitor (TKI) treatment. A total of 333 patients were included in this study. The prevalence of the EGFR Q787Q polymorphism was 38%, 42%, and 35% in the total patients, EGFR mutation negative, and EGFR mutation positive groups, respectively. The prevalence of EGFR Q787Q polymorphism was significantly higher in EGFR wild-type patients than in the general non-cancerous population from Taiwan Biobank and 1000 Genome Project databases, respectively. EGFR Q787Q polymorphism had significant protective effects on the overall survival of EGFR-mutant lung adenocarcinoma treated with EGFR TKIs (aHR =0.61, p=0.03). Our study demonstrated that EGFR Q787Q polymorphism is a germline variant in the general population. It is a protective predictor of overall survival in patients with stage IV EGFR-mutated lung adenocarcinoma treated with TKIs.

Increased risk of secondary lung cancer in patients with tuberculosis: A nationwide, population-based cohort study.

BACKGROUND: Tuberculosis (TB) presents a global threat in the world and the lung is the frequent site of metastatic focus. A previous study demonstrated that TB might increase primary lung cancer risk by two-fold for more than 20 years after the TB diagnosis. However, no large-scale study has evaluated the risk of TB and secondary lung cancer. Thus, we evaluated the risk of secondary lung cancer in patients with or without tuberculosis (TB) using a nationwide population-based dataset. METHODS: In a cohort study of 1,936,512 individuals, we selected 6934 patients among patients with primary cancer and TB infection, based on the International Classification of Disease (ICD-p-CM) codes 010-011 from 2000 to 2015. The control cohort comprised 13,868 randomly selected, propensity-matched patients (by age, gender, and index date) without TB exposure. Using this adjusted date, a possible association between TB and the risk of developing secondary lung cancer was estimated using a Cox proportional hazards regression model. RESULTS: During the follow-up period, secondary lung cancer was diagnosed in 761 (10.97%) patients with TB and 1263 (9.11%) patients without TB. After adjusting for covariates, the risk of secondary lung cancer was 1.67 times greater among primary cancer in the cohort with TB than in the cohort without TB. Stratification revealed that every comorbidity (including diabetes, hypertension, cirrhosis, congestive heart failure, cardiovascular accident, chronic kidney disease, chronic obstructive pulmonary disease) significantly increased the risk of secondary lung cancer when comparing the TB cohort with the non-TB cohort. Moreover, the primary cancer types (including head and neck, colorectal cancer, soft tissue sarcoma, breast, kidney, and thyroid cancer) had a more significant risk of becoming secondary lung cancer. CONCLUSION: A significant association exists between TB and the subsequent risk for metastasis among primary cancers and comorbidities. Therefore, TB patients should be evaluated for the subsequent risk of secondary lung cancer.

Magnifying endoscopy with narrow-band image for diagnosing diffuse type of gastric antral vascular ectasia in cirrhotic patients.

OBJECTIVE: Gastric antral vascular ectasia (GAVE) and portal hypertensive gastropathy (PHG) can cause gastrointestinal bleeding in cirrhotic patients. Distinguishing diffuse-type GAVE and severe PHG is important but difficult by conventional endoscopy and endoscopic biopsy. The aim of this study is to evaluate the value of magnifying endoscopy with narrow-band image for diagnosing diffuse-type GAVE in cirrhotic patients. METHODS: From January 2010 to December 2013, cirrhotic patients with diffuse red spots of stomach in suspicion of diffuse-type GAVE on conventional endoscopy in a tertiary medical center were included. The detection of diffuse red spots on magnifying endoscopy with narrow-band image (NBI) was classified into ring-pattern which suggested GAVE and mosaic-pattern which suggested non-GAVE. The golden diagnosis of GAVE was based on histological criteria of GAVE score ≥3 by any one of two endoscopic sessions. RESULTS: Total 27 cirrhotic patients were included. Twenty-two patients reached the diagnosis of GAVE and five patients were diagnosed of non-GAVE by histology. The diagnostic rate of conventional endoscopy was 81.5% (22/27). The positive rate of initial endoscopic biopsy was 77.2%. On magnifying endoscopy with NBI, the sensitivity, specificity, positive, negative predicted rate and accuracy of ring-pattern for the diagnosis of GAVE were 100, 90, 96.4, 100 and 97.3%. Kappa coefficient of inter-observer agreement for differentiating the ring and mosaic-pattern was 0.92. CONCLUSIONS: The efficacy and accuracy of magnifying endoscopy with NBI for diagnosing diffuse-type GAVE in cirrhotic patients have been demonstrated. It can avoid repeated endoscopy to confirm diagnosis and obviate the invasive biopsy in cirrhotic patients.

Surgical resection of brain metastases prolongs overall survival in non-small-cell lung cancer.

It remains unclear whether surgical resection of brain metastases prolongs overall survival in patients with non-small-cell lung cancer (NSCLC). A retrospective study was designed to evaluate the benefits of surgical resection for 296 patients with NSCLC and brain metastases. Patients were grouped into those who underwent craniotomy (brain surgery group) and those who did not (non-surgery group). Characteristics, survival, and EGFR mutation status were compared between the two groups. We found that the clinical characteristics were similar between the two groups. However, patients in the brain surgery group had metastases of larger diameters (3.67 cm vs. 2.06 cm, P<0.001) and a lower rate of extracranial metastasis (8.7% vs. 45.5%, P=0.001). Overall survival was significantly longer for those who underwent brain surgery (40.3 months vs. 8.4 months, P<0.001). The adjusted hazard ratio of craniotomy was 0.30 (95% confidence interval [CI], 0.15-0.62). The survival benefit of brain surgery was observed in both EGFR mutation-positive and EGFR mutation-negative sub-populations; the adjusted hazard ratios [aHRs] were 0.34 [95% CI, 0.11-1.00] and 0.26 [95% CI, 0.09-0.73] for EGFR mutation-positive and mutation-negative sub-populations, respectively. We concluded that for patients with NSCLC and brain metastases, surgical resection of brain metastases improved overall survival. This survival benefit was particularly evident in cases with large-sized metastases limited to the brain.

TAZ negatively regulates the novel tumor suppressor ANKRD52 and promotes PAK1 dephosphorylation in lung adenocarcinomas.

Lung cancer is the leading cause of cancer death, and therefore the discovery of novel therapeutic targets is crucial. P21-activated kinase (PAK1) is an important oncogene involved in the signaling of actin cytoskeleton organization. Although PAK1 inhibition has been shown to suppress cancer progression, specific PAK1 inhibitors are not available due to the complex structure and insufficient understanding of this kinase. The Hippo signaling effector TAZ is known to be elevated in multiple human cancers and to promote cancer metastasis. This study aimed to explore the role of TAZ in regulating the tumor suppressor ankyrin repeat domain 52 (ANKRD52) and PAK1 activity. A negative correlation between TAZ and ANKRD52 was observed, with knockdown of TAZ leading to enhanced ANKRD52 promoter activity and increased mRNA levels. Moreover, reduced ANKRD52 levels were associated with late-stage lung cancer. Knockdowns of ANKRD52 resulted in elevated cell mobility, while forced ANKRD52 expression attenuated cell mobility. ANKRD52 is a subunit of the protein phosphatase 6 (PP6) holoenzyme. Mass spectrometry analysis revealed the interaction between PAK1 and the ANKRD52-PP6 complex. Knockdown of ANKRD52 or PP6c resulted in upregulated PAK1 phosphorylation. Our study demonstrates that the novel tumor suppressor protein ANKRD52 is transcriptionally inhibited by TAZ, regulating cell mobility through interactions with PP6c and dephosphorylation of PAK1.

Mucinous adenocarcinoma arising in congenital pulmonary airway malformation: clinicopathological analysis of 37 cases.

AIMS: Mucinous adenocarcinoma arising in congenital pulmonary airway malformation (CPAM) is a rare complication, with little being known about its natural course. The aims of this article are to describe a series of mucinous adenocarcinomas arising from CPAMs, and present their clinicopathological features, genetics, and clinical outcome. METHODS AND RESULTS: Thirty-seven cases were collected within a 34-year period, and the subtype of adenocarcinoma and CPAM, tumour location, stage, growth patterns, molecular data and follow-up were recorded. The cohort comprised CPAM type 1 (n = 33) and CPAM type 2 (n = 4). Morphologically, 34 cases were mucinous adenocarcinomas (21 in situ; 13 invasive), and three were mixed mucinous and non-mucinous adenocarcinoma. Seventeen cases showed purely extracystic (intra-alveolar) adenocarcinoma, 15 were mixed intracystic and extracystic, and five showed purely intracystic proliferation. Genetically, nine of 10 cases tested positive for KRAS mutations, four with exon 2 G12V mutation and five with exon 2 G12D mutation. Residual disease on completion lobectomy was observed in two cases, and three cases recurred 7, 15 and 32 years after the original diagnosis. Two patients died of metastatic invasive mucinous adenocarcinoma. CONCLUSIONS: Most adenocarcinoma that arise in type 1 CPAMs, are purely mucinous, and are early-stage disease. Intracystic proliferation is associated with lepidic growth, an absence of invasion, and indolent behaviour, whereas extracystic proliferation may be associated with more aggressive behaviour and advanced stage. Most cases are cured by lobectomy, and recurrence/residual disease seems to be associated with limited surgery. Long-term follow-up is needed, as recurrence can occur decades later.

Downregulation of Jumonji-C domain-containing protein 5 inhibits proliferation by silibinin in the oral cancer PDTX model.

Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.

Prognostic Impact of Histopathologic Features in Pulmonary Invasive Mucinous Adenocarcinomas.

OBJECTIVES: The prognostic significance of pathologic features and invasive size has not been well studied for invasive mucinous adenocarcinoma (IMA). This study evaluates the significance of pathologic features and invasive size in relation to clinical outcome. METHODS: We reviewed the pathologic features in 84 IMAs, including histologic pattern, nuclear atypia, mitosis, necrosis, and lymphovascular invasion. The invasive size was calculated from the total size using the percentage of invasive components. Cases were subdivided into two pathologic grades based on five pathologic features, and the pathologic grade and adjusted T (aT) stage were correlated with disease-free and overall survival (OS). RESULTS: Necrosis and N stage were significantly associated with aT stage, and a significant association was noted between OS and aT stage. Nuclear atypia, mitosis, and lymphovascular and pleural invasion also showed a significant association with OS. High-grade tumors showing a significantly worse OS compared with low-grade tumors, as well as pathologic grade (hazard ratio [HR], 2.337; P = .043) and aT stage (HR, 1.875; P = .003), were independent prognostic factors in multivariate analysis. CONCLUSIONS: The pathologic grading system stratified IMAs into high- and low-grade tumors with significant differences in OS. Invasive size may provide a better prognostic stratification for OS.

Ex vivo full-field cellular-resolution optical coherence tomography of basal cell carcinomas: A pilot study of quality and feasibility of images and diagnostic accuracy in subtypes.

BACKGROUND: Studies have reported the application of conventional optical coherence tomography (OCT) in the diagnosis of basal cell carcinoma (BCC). The new OCT provides cellular details similar to those in pathology slides and may reduce user learning time. This study aimed to demonstrate the quality of ex vivo full-field cellular-resolution OCT images and compare the diagnostic accuracy between physicians with varying pathology experience. MATERIALS AND METHODS: Sixty histologically confirmed BCCs were selected. Tissue samples were sectioned and scanned using OCT, and their features were compared with those of hematoxylin and eosin (H&E)-stained sections. Thirty images were selected for the test administered to dermatology residents, dermatopathology fellows, and board-certified general pathologists without any OCT experience. The pretest learning included a 3-min instruction and 10-min self-study of four BCC variants. RESULTS: Histopathological BCC and normal histological features were clearly recognizable on the OCT images. The pathological BCC features observed in the OCT images correlated with those found in the H&E-stained sections. Seven participants completed the test. The correct answer rates of the residents, fellows, and pathologists were 71%, 68%, and 83% for BCC and 44%, 57%, and 57% for the BCC subtypes, respectively. CONCLUSION: All the participants identified BCC in >70% cases with a learning time of only 13 minutes. The results indicated that cellular-resolution OCT provided high-quality images similar to the conventional pathology slides. Pathology experience did reflect the diagnostic accuracy. However, a longer training time is still needed at all levels to recognize the BCC subtypes correctly.

Pretreatment body mass index as a prognostic predictor in patients with oral squamous cell carcinoma.

OBJECTIVES: To evaluate whether low body mass index (BMI) is a potential adverse prognostic factor in patients with oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS: This cross-sectional study included 320 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The pretreatment BMI was measured as a common indicator of the pretreatment nutritional status to calculate the overall survival in Kaplan-Meier method. The adverse histopathological features of margin status, depth of invasion (DOI), lymphovascular invasion (LVSI), perineural invasion (PNI), and extranodal extension (ENE) were analyzed using the Cox regression model. RESULTS: Low BMI (underweight), DOI > 5 mm, and ENE were identified as detrimental prognostic factors. On multivariate Cox regression analysis, the low BMI group (odds ratio [OR] = 1.683; 95% confidence interval [95% CI] 1.116-2.539; P = 0.022), DOI > 5 mm (OR = 2.399; 95% CI 1.459-3.943; P = 0.001), and ENE (OR = 2.467; 95% CI 1.540-3.951; P = 0.000) yielded reduced survival rate. CONCLUSIONS: The lower BMI had an important and significant effect on the survival of patients with oral cancer and their surgical outcomes. In addition to the adverse histopathological features, a DOI > 5 mm and positive ENE were also identified as the most important prognostic factors. CLINICAL RELEVANCE: Underweight patients with low BMI, DOI of > 5 mm, and positive ENE should receive more intensive nutritional supplementation and postoperative adjuvant therapy.

A histopathological evaluation and potential prognostic implications of oral squamous cell carcinoma with adverse features.

OBJECTIVES: This study aimed to evaluate the adverse clinicopathologic features of oral squamous cell carcinoma (OSCC), including margin status, depth of invasion, lymphovascular invasion, perineural invasion, and extranodal extension that significantly affect survival outcomes. MATERIALS AND METHODS: This retrospective cross-sectional study included 341 patients with OSCC who underwent therapeutic surgical treatment in Taiwan. The Kaplan-Meier method was used to estimate survival outcomes. A multivariable Cox regression model was used to evaluate the associations of various clinicopathologic features with 5-year overall survival (OS) outcomes in patients with pN0 and pN+ tumors. RESULTS: Overall, the patients had 5-year OS and progression-free survival rates of 60.0 and 47.9%, respectively. In the pN0 group, the multivariate analysis identified a positive margin (odds ratio [OR] = 16.3, 95% confidence interval [95% CI]: 3.7-72.3; P = 0.001), depth of invasion >5 mm (OR = 2.1, 95% CI: 1.2-3.7; P = 0.012), presence of lymphovascular space invasion (OR = 5.4, 95% CI: 1.3-22.0; P = 0.018), and presence of perineural invasion (OR = 4.3, 95% CI: 1.7-11.1; P = 0.002) as independent and significant prognosticators of OS. In the pN+ group, only the presence of extranodal extension independently predicted OS (OR = 1.7, 95% CI: 1.1-2.7; P = 0.0026). CONCLUSIONS: When determining survival prognosis for patients with a pN0 status, we recommended including all adverse features. In contrast, extranodal extension was the most important prognostic factor for patients with a pN+ status.

Spindle Cell Tumors With RET Gene Fusions Exhibit a Morphologic Spectrum Akin to Tumors With NTRK Gene Fusions.

A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.

Decoy Receptor 3 Expression Is Associated With Wild-Type EGFR Status, Poor Differentiation of Tumor, and Unfavorable Patient Outcome.

OBJECTIVES: The role of decoy receptor 3 (DcR3) in lung cancer, particularly adenocarcinoma, has not been well studied. In this study, we aim to investigate the expression profile and the clinicopathologic implications of DcR3 expression in lung adenocarcinoma. METHODS: Immunohistochemistry was used to examine DcR3 expression in 461 lung adenocarcinomas. The differences in DcR3 expression among the various histopathologic patterns were analyzed. The relationship between DcR3 expression and clinicopathologic parameters, including epidermal growth factor receptor (EGFR) mutation, was also investigated. RESULTS: DcR3 expression was more frequently expressed in solid, micropapillary, and acinar patterns (P < .0001) and in tumors with wild-type EGFR status (P = .018). In addition, DcR3 expression portends a less favorable disease-free survival in stage I patients (P = .012). CONCLUSIONS: The expression of DcR3 might be involved in the differentiation and progression of lung adenocarcinoma. Therefore, DcR3 may be applied clinically for prediction of tumor progression in stage I lung adenocarcinoma.