Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression.

Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.

Adjuvant chemoradiotherapy plus pembrolizumab for locally advanced esophageal squamous cell carcinoma with high risk of recurrence following neoadjuvant chemoradiotherapy: a single-arm phase II study.

BACKGROUND: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear. METHODS: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate. RESULTS: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7-33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0-19.5) and 21.6 (95% CI: 0.0-45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab. CONCLUSIONS: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267).

CT-Based Deep-Learning Model for Spread-Through-Air-Spaces Prediction in Ground Glass-Predominant Lung Adenocarcinoma.

BACKGROUND: Sublobar resection is strongly associated with poor prognosis in early-stage lung adenocarcinoma, with the presence of tumor spread through air spaces (STAS). Thus, preoperative prediction of STAS is important for surgical planning. This study aimed to develop a STAS deep-learning (STAS-DL) prediction model in lung adenocarcinoma with tumor smaller than 3 cm and a consolidation-to-tumor (C/T) ratio less than 0.5. METHODS: The study retrospectively enrolled of 581 patients from two institutions between 2015 and 2019. The STAS-DL model was developed to extract the feature of solid components through solid components gated (SCG) for predicting STAS. The STAS-DL model was assessed with external validation in the testing sets and compared with the deep-learning model without SCG (STAS-DLwoSCG), the radiomics-based model, the C/T ratio, and five thoracic surgeons. The performance of the models was evaluated using area under the curve (AUC), accuracy and standardized net benefit of the decision curve analysis. RESULTS: The study evaluated 458 patients (institute 1) in the training set and 123 patients (institute 2) in the testing set. The proposed STAS-DL yielded the best performance compared with the other methods in the testing set, with an AUC of 0.82 and an accuracy of 74%, outperformed the STAS-DLwoSCG with an accuracy of 70%, and was superior to the physicians with an AUC of 0.68. Moreover, STAS-DL achieved the highest standardized net benefit compared with the other methods. CONCLUSION: The proposed STAS-DL model has great potential for the preoperative prediction of STAS and may support decision-making for surgical planning in early-stage, ground glass-predominant lung adenocarcinoma.

Deep-learning model to improve histological grading and predict upstaging of atypical ductal hyperplasia / ductal carcinoma in situ on breast biopsy.

AIMS: Risk stratification of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), diagnosed using breast biopsy, has great clinical significance. Clinical trials are currently exploring the possibility of active surveillance for low-risk lesions, whereas axillary lymph node staging may be considered during surgical planning for high-risk lesions. We aimed to develop a machine-learning algorithm based on whole-slide images of breast biopsy specimens and clinical information to predict the risk of upstaging to invasive breast cancer after wide excision. METHODS AND RESULTS: Patients diagnosed with ADH/DCIS on breast biopsy were included in this study, comprising 592 (740 slides) and 141 (198 slides) patients in the development and independent testing cohorts, respectively. Histological grading of the lesions was independently evaluated by two pathologists. Clinical information, including biopsy method, lesion size, and Breast Imaging Reporting and Data System (BI-RADS) classification of ultrasound and mammograms, were collected. Deep DCIS consisted of three deep neural networks to evaluate nuclear grade, necrosis, and stromal reactivity. Deep DCIS output comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. Deep DCIS highly correlated with the pathologists' evaluations of both slide- and patient-level labels. All five parameters of Deep DCIS were significantly associated with upstaging to invasive carcinoma in subsequent wide excisional specimens. Using multivariate logistic regression, Deep DCIS predicted upstaging to invasive carcinoma with an area under the curve (AUC) of 0.81, outperforming pathologists' evaluation (AUC, 0.71 and 0.69). After including clinical and hormone receptor status information, performance further improved (AUC, 0.87). This combined model retained its predictive power in two subgroup analyses: the first subgroup included unequivocal DCIS (excluding cases of ADH and DCIS suspicious for microinvasion) (AUC, 0.83), while the second excluded cases of high-grade DCIS (AUC, 0.81). The model was validated in an independent testing cohort (AUC, 0.81). CONCLUSION: This study demonstrated that deep-learning models can refine histological evaluation of ADH and DCIS on breast biopsies, which may help guide future treatment planning.

Feasibility of new-generation endocytoscopy for the real-time diagnosis of ampullary lesions: A pilot study (with video).

BACKGROUND AND AIM: An early and accurate diagnosis of ampullary neoplasia is crucial; however, sampling bias is still a major concern. New-generation endocytoscopy enables real-time visualization of cellular structures and enables an accurate pathological prediction; however, its feasibility for small ampullary lesions has never been investigated. METHODS: We developed a novel endocytoscopic (EC) classification system for ampullary lesions after an expert review and agreement from five experienced endoscopists and one pathologist. We then consecutively enrolled a total of 43 patients with an enlarged ampulla (< 3 cm), all of whom received an endocytoscopic examination. The feasibility of endocytoscopy was evaluated, and the performance of the EC classification system was then correlated with the final histopathology. RESULTS: In five cases (11.6%), the endocytoscope could not approach the ampulla, and these cases were defined as technical failure. Among the remaining 38 patients, 8 had histopathology-confirmed adenocarcinoma, 15 had adenoma, and 15 had non-neoplastic lesions. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the EC classification system to diagnose ampullary neoplasias were 95.7%, 86.7%, 91.7%, 92.9%, and 92.1%, respectively. Moreover, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the EC classification to diagnose ampullary cancer were 62.5%, 100%, 100%, 90.9%, and 92.1%, respectively. One case with intra-ampullary papillary-tubular carcinoma was classified as having a non-neoplastic lesion by endocytoscopy. CONCLUSIONS: Endocytoscopy and the novel EC classification system demonstrated good feasibility to discriminate ampullary neoplasias from non-neoplastic lesions and may be useful for optical biopsies of clinically suspicious ampullary lesions.

Sequential development of diffuse panbronchiolitis and myasthenia gravis after thymectomy for thymic neoplasm: a case report.

BACKGROUND: Myasthenia gravis (MG) is the most common paraneoplastic disorder associated with thymic neoplasms. MG can develop after thymectomy, and this condition is referred to post-thymectomy myasthenia gravis (PTMG). Diffuse panbronchiolitis (DPB), is a rare form of bronchiolitis and is largely restricted to East Asia, has been reported in association with thymic neoplasms. Only three cases of combined MG and DPB have been reported in the literature. CASE PRESENTATION: A 45-year-old Taiwanese woman presented to our hospital with productive cough, rhinorrhea, anosmia, ear fullness, shortness of breath, and weight loss. She had a history of thymoma, and she underwent thymectomy with adjuvant radiotherapy 7 years ago. Chest computed tomography scan revealed diffuse bronchitis and bronchiolitis. DPB was confirmed after video-assisted thoracoscopic surgery lung biopsy, and repeated sputum cultures grew Pseudomonas aeruginosa. She has been on long-term oral azithromycin therapy thereafter. Intravenous antipseudomonal antibiotics, inhaled amikacin, as well as oral levofloxacin were administered. Three months after DPB diagnosis, she developed ptosis, muscle weakness, and hypercapnia requiring the use of noninvasive positive pressure ventilation. MG was diagnosed based on the acetylcholine receptor antibody and repetitive stimulation test results. Her muscle weakness gradually improved after pyridostigmine and corticosteroid therapies. Oral corticosteroids could be tapered off ten months after the diagnosis of MG. She is currently maintained on azithromycin, pyridostigmine, and inhaled amikacin therapies, with intravenous antibiotics administered occasionally during hospitalizations for respiratory infections. CONCLUSIONS: To our knowledge, this might be the first case report of sequential development of DPB followed by PTMG. The coexistence of these two disorders poses a therapeutic challenge for balancing infection control for DPB and immunosuppressant therapies for MG.

Constant p.L424H Mutation in GTF2I in Micronodular Thymomas With Lymphoid Stroma: Evidence Supporting Close Relationship With Type A and AB Thymomas.

Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I.

Discrimination of invasive lung adenocarcinoma from Lung-RADS category 2 nonsolid nodules through visual assessment: a retrospective study.

OBJECTIVES: Invasive adenocarcinomas (IADs) have been identified among nonsolid nodules (NSNs) assigned as Lung Imaging Reporting and Data System (Lung-RADS) category 2. This study used visual assessment for differentiating IADs from noninvasive lesions (NILs) in this category. METHODS: This retrospective study included 222 patients with 242 NSNs, which were resected after preoperative computed tomography (CT)-guided dye localization. Visual assessment was performed by using the lung and bone window (BW) settings to classify NSNs into BW-visible (BWV) and BW-invisible (BWI) NSNs. In addition, nodule size, shape, border, CT attenuation, and location were evaluated and correlated with histopathological results. Logistic regression was performed for multivariate analysis. A p value of < 0.05 was considered statistically significant. RESULTS: A total of 242 NSNs (mean diameter, 7.6 ± 2.8 mm), including 166 (68.6%) BWV and 76 (31.4%) BWI NSNs, were included. IADs accounted for 31% (75) of the nodules. Only 4 (5.3%) IADs were identified in the BWI group and belonged to the lepidic-predominant (n = 3) and acinar-predominant (n = 1) subtypes. In univariate analysis for differentiating IADs from NILs, the nodule size, shape, CT attenuation, and visual classification exhibited statistical significance. Nodule size and visual classification were the significant predictors for IAD in multivariate analysis with logistic regression (p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value of visual classification in IAD prediction were 94.7%, 43.1%, 42.8%, and 94.7%, respectively. CONCLUSIONS: The window-based visual classification of NSNs is a simple and objective method to discriminate IADs from NILs. CLINICAL RELEVANCE STATEMENT: The present study shows that using the bone window to classify nonsolid nodules helps discriminate invasive adenocarcinoma from noninvasive lesions. KEY POINTS: • Evidence has shown the presence of lung adenocarcinoma in Lung-RADS category 2 nonsolid nodules. • Nonsolid nodules are classified into the bone window-visible and the bone window-invisible nonsolid nodules, and this classification differentiates invasive adenocarcinoma from noninvasive lesions. • The Lung-RADS category 2 nonsolid nodules are unlikely invasive adenocarcinoma if they show nonvisualization in the bone window.

Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract.

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.

Solid Attenuation Components Attention Deep Learning Model to Predict Micropapillary and Solid Patterns in Lung Adenocarcinomas on Computed Tomography.

BACKGROUND: High-grade adenocarcinoma subtypes (micropapillary and solid) treated with sublobar resection have an unfavorable prognosis compared with those treated with lobectomy. We investigated the potential of incorporating solid attenuation component masks with deep learning in the prediction of high-grade components to optimize surgical strategy preoperatively. METHODS: A total of 502 patients with pathologically confirmed high-grade adenocarcinomas were retrospectively enrolled between 2016 and 2020. The SACs attention DL model was developed to apply solid-attenuation-component-like subregion masks (tumor area ≥ - 190 HU) to guide the DL model for predicting high-grade subtypes. The SACA-DL was assessed using 5-fold cross-validation and external validation in the training and testing sets, respectively. The performance, which was evaluated using the area under the curve (AUC), was compared between SACA-DL and the DL model without SACs attention (DLwoSACs), the prior radiomics model, or the model based on the consolidation/tumor (C/T) diameter ratio. RESULTS: We classified 313 and 189 patients into training and testing cohorts, respectively. The SACA-DL achieved an AUC of 0.91 for the cross-validation, which was significantly superior to those of the DLwoSACs (AUC = 0.88; P = 0.02), prior radiomics model (AUC = 0.85; P = 0.004), and C/T ratio (AUC = 0.84; P = 0.002). An AUC of 0.93 was achieved for external validation in the SACA-DL and was significantly better than those of the DLwoSACs (AUC = 0.89; P = 0.04), prior radiomics model (AUC = 0.85; P < 0.001), and C/T ratio (AUC = 0.85; P < 0.001). CONCLUSIONS: The combination of solid-attenuation-component-like subregion masks with the DL model is a promising approach for the preoperative prediction of high-grade adenocarcinoma subtypes.

SMARCB1(INI1)-deficient sinonasal adenocarcinoma: Report of a case previously diagnosed as high-grade non-intestinal-type sinonasal adenocarcinoma.

SMARCB1(INI1)-deficient sinonasal carcinoma is a recently recognized entity with wide histomorphologic spectrum. The classification of sinonasal adenocarcinoma (SNAC) is complex and yet to be redefined, especially the category of high-grade non-intestinal-type SNAC. Recently SMARCB1(INI1)-deficient SNACs with an unique oncocytoid/rhabdoid cytomorphology and variable degrees of glandular formation have been reported. Here we described a rare case of SMARCB1(INI1)-deficient SNAC composed of mainly oncocytoid/rhabdoid cells with mixed solid and cribriform patterns. This case was originally diagnosed as non-intestinal-type SNAC and was reclassified due to complete loss expression of SMARCB1(INI1) by immunohistochemistry (IHC). The SMARCB1(INI1) stain provides a valuable tool for identification of this specific type of SNAC. We compared this case with other SNACs diagnosed in our department and reviewed relevant literature for this specific type of SNAC.

The efficacy of incorporating ultrasound-guided core biopsy into the clinical workflow of indeterminate thyroid tumors.

BACKGROUND: Ultrasound-guided core biopsy (USCB) is a minimally invasive sampling procedure which may help to confirm the diagnoses of the thyroid tumors with indeterminate results of ultrasound-guided fine-needle aspiration (USFNA). Although with potential advantages, the working protocol of introducing USCB in the routine practice has not been established yet. This study aims to evaluate the efficacy of USCB when it is included in the clinical workflow of assessing the thyroid tumors with indeterminate USFNA results after a long-term follow up. METHODS: Between 2009 and 2016, consecutive patients receiving thyroid USFNA were reviewed retrospectively in the tertiary referral hospital. The patients, who finally received USCB for their thyroid tumors after repeated indeterminate USFNA results, were recruited. The important sonographic features in facilitating specific diagnoses by USCB, differentiating malignancy from benignity, and confirming origins of thyroid tumors were analyzed and the role of USCB was investigated. RESULTS: Thirty-nine patients met the inclusion criteria were analyzed. The specific diagnoses were confirmed in 23 patients (59%) by USCB. Taller than wide, ill-defined margin and hypoechogenicity helped in differentiating malignant tumors and the latter two features were pertinent to the success of applying USCB for specific diagnosis. No sonographic features were able to differentiate the thyroid malignancy from extra-thyroid origins exclusively. Thyroid USCB facilitated clinical decision making in 37 of the 39 patients (94.9%) with indeterminate USFNA results. CONCLUSION: The USCB is a cost-effective sampling procedure for confirming the diagnosis of indeterminate thyroid tumors and their clinical management, especially for those malignancies from extra-thyroid origins.

DEK-AFF2 fusion-associated papillary squamous cell carcinoma of the sinonasal tract: clinicopathologic characterization of seven cases with deceptively bland morphology.

A novel DEK-AFF2 fusion has been recently identified in four cases of basaloid to nonkeratinizing squamous cell carcinoma (SCC) in the sinonasal tract and middle ear with high-grade morphology. The exceptional response to immune checkpoint inhibitor in the first reported case highlights the potential clinical importance of identifying tumors with DEK-AFF2 fusions. We herein reported the first series of seven cases of DEK-AFF2 fusion-associated sinonasal SCC with deceptively bland morphology, including four cases of low-grade papillary Schneiderian carcinoma, which is a recently described tumor type with unknown molecular underpinnings. The DEK gene rearrangement was confirmed by DEK break-apart fluorescence in situ hybridization and DEK-AFF2 fusion transcripts were detected by reverse transcription polymerase chain reaction. In contrast to the previously reported DEK-AFF2 fusion-positive high-grade carcinomas, these tumors had a monotonous and bland morphology and were all initially diagnosed as sinonasal papilloma (SP) of various types, with or without dysplasia or carcinoma in situ. The tumor was characterized by mixed exophytic and inverted patterns, broad papillary fronds, acantholytic change, cellular monotony, dense neutrophilic infiltrates, and peripheral palisading. All tumors were diffusely positive for p40 or p63 and negative for NUT and p16. Molecular drivers associated with SP, including EGFR and KRAS mutations and both high and low-risk human papillomavirus infection, were negative in all cases. Although there was no overt stromal invasion or desmoplastic reaction in the initial specimens, these tumors tended to progress locoregionally through a prolonged clinical course and occasionally develop lymph node metastases, high-grade transformation, or extensively local destruction eventually leading to death. These justify more aggressive clinical management. Therefore, we propose the new terminology "DEK-AFF2 fusion-associated papillary SCC of the sinonasal tract" to better describe this clinicopathologically and molecularly distinct entity.

Thoracoscopic Wedge Resection Versus Segmentectomy for cT1N0 Lung Adenocarcinoma.

BACKGROUND: The choice between wedge resection and segmentectomy as a sublobar resection method for patients with cT1N0 lung cancer remains debatable. This study aimed to evaluate the clinical outcomes after wedge resection and segmentectomy for patients with cT1N0 lung adenocarcinoma. METHODS: The study enrolled 1002 consecutive patients with cT1N0 lung adenocarcinoma who underwent sublobar resection at the authors' institution between 2011 and 2017. A propensity score-matching analysis was used to compared the clinical outcomes between the wedge resection and segmentectomy groups. RESULTS: Wedge resection was performed for 810 patients (80.8%), and segmentectomy was performed for 192 patients (19.2%). Wedge resection resulted in better perioperative outcomes than segmentectomy. The multivariate analysis showed that the significant risk factors for poor disease-free survival (DFS) were elevated preoperative serum carcinoembryonic antigen levels, total tumor diameter greater than 2 cm, and a consolidation-to-tumor (C/T) ratio higher than 50%. After propensity-matching, no differences in overall survival or DFS were noted between the two matched groups. However, subgroup analysis showed that segmentectomy was associated with better DFS than wedge resection (p = 0.039) for the patients with a tumor diameter greater than 2 cm and a C/T ratio higher than 50%. CONCLUSION: Segmentectomy is the appropriate surgical method for sublobar resection in cT1N0 lung adenocarcinoma patients with a tumor diameter greater than 2 cm and a C/T ratio higher than 50%. Wedge resection may be a safe and feasible sublobar resection method for patients with a tumor diameter of 2 cm or smaller or a C/T ratio of 50% or lower.

Prediction of micropapillary and solid pattern in lung adenocarcinoma using radiomic values extracted from near-pure histopathological subtypes.

OBJECTIVES: Near-pure lung adenocarcinoma (ADC) subtypes demonstrate strong stratification of radiomic values, providing basic information for pathological subtyping. We sought to predict the presence of high-grade (micropapillary and solid) components in lung ADCs using quantitative image analysis with near-pure radiomic values. METHODS: Overall, 103 patients with lung ADCs of various histological subtypes were enrolled for 10-repetition, 3-fold cross-validation (cohort 1); 55 were enrolled for testing (cohort 2). Histogram and textural features on computed tomography (CT) images were assessed based on the "near-pure" pathological subtype data. Patch-wise high-grade likelihood prediction was performed for each voxel within the tumour region. The presence of high-grade components was then determined based on a volume percentage threshold of the high-grade likelihood area. To compare with quantitative approaches, consolidation/tumour (C/T) ratio was evaluated on CT images; we applied radiological invasiveness (C/T ratio > 0.5) for the prediction. RESULTS: In cohort 1, patch-wise prediction, combined model (C/T ratio and patch-wise prediction), whole-lesion-based prediction (using only the "near-pure"-based prediction model), and radiological invasiveness achieved a sensitivity and specificity of 88.00 ± 2.33% and 75.75 ± 2.82%, 90.00 ± 0.00%, and 77.12 ± 2.67%, 66.67% and 90.41%, and 90.00% and 45.21%, respectively. The sensitivity and specificity, respectively, for cohort 2 were 100.0% and 95.35% using patch-wise prediction, 100.0% and 95.35% using combined model, 75.00% and 95.35% using whole-lesion-based prediction, and 100.0% and 69.77% using radiological invasiveness. CONCLUSION: Using near-pure radiomic features and patch-wise image analysis demonstrated high levels of sensitivity and moderate levels of specificity for high-grade ADC subtype-detecting. KEY POINTS: • The radiomic values extracted from lung adenocarcinoma with "near-pure" histological subtypes provide useful information for high-grade (micropapillary and solid) components detection. • Using near-pure radiomic features and patch-wise image analysis, high-grade components of lung adenocarcinoma can be predicted with high sensitivity and moderate specificity. • Using near-pure radiomic features and patch-wise image analysis has potential role in facilitating the prediction of the presence of high-grade components in lung adenocarcinoma prior to surgical resection.

Preoperative 2-[18F]FDG PET-CT aids in the prognostic stratification for patients with primary ampullary carcinoma.

OBJECTIVES: We sought to investigate whether preoperative dual-phase 2-[18F]FDG PET-CT identify predictors for poor survival in patients with ampullary carcinoma receiving pancreaticoduodenectomy. METHODS: The preoperative PET-CT images of patients with resected ampullary carcinoma from June 2007 to July 2017 were analyzed. Survival curves were analyzed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard model was used to identify potential prognostic factors associated with disease-free survival (DFS) and overall survival (OS). RESULTS: Fifty-four subjects (26 men, 28 women) were enrolled with a median tumor size of 20 mm. All patients were followed for a median period of 36.9 months with 3- and 5-year DFS of 50.3% and 44.2%, and OS of 77.0% and 68.2%, respectively. Parameters associated with DFS in multivariate analysis were lymphovascular invasion (hazard ratio [HR]: 9.45, p < 0.001), involved margin in pathology (HR: 7.67, p < 0.001), and tumor retention index (RI) from the dual-phase PET (HR: 2.41, p = 0.03), whereas involved margin (HR: 13.14, p < 0.001), post-recurrence chemotherapy (HR: 0.10, p < 0.001), and metabolic tumor volume (MTV) (HR: 4.62, p = 0.009) emerged as independent prognostic factors for OS. CONCLUSIONS: Preoperative 2-[18F]FDG PET-CT offered independent prognostic biomarkers in patients with ampullary carcinoma receiving standard surgical resection. KEY POINTS: • 2-[18F]FDG PET-CT offers good survival prediction before operation in primary malignant neoplasms at ampulla of Vater. • Dual-phase PET scan with bowel distention can better delineate Ampulla of Vater and characterize tumor physiology. • Preoperative risk stratification might aid in better treatment planning.

Propensity-Matched Analysis Comparing Survival After Sublobar Resection and Lobectomy for cT1N0 Lung Adenocarcinoma.

BACKGROUND: The optimal surgical method for cT1N0 lung adenocarcinoma remains controversial. OBJECTIVE: The aim of this study was to evaluate the differences in clinical outcomes of sublobar resection and lobectomy for cT1N0 lung adenocarcinoma patients. METHODS: We included 1035 consecutive patients with cT1N0 lung adenocarcinoma who underwent surgery at our institute from January 2011 to December 2016. The surgical approach, either sublobar resection or lobectomy, was determined at the discretion of each surgeon. A propensity-matched analysis incorporating total tumor diameter, solid component diameter, consolidation-to-tumor (C/T) ratio, and performance status was used to compare the clinical outcomes of the sublobar resection and lobectomy groups. RESULTS: Sublobar resection and lobectomy were performed for 604 (58.4%; wedge resection/segmentectomy: 470/134) and 431 (41.6%) patients, respectively. Patients in the sublobar resection group had smaller total tumor diameters, smaller solid component diameters, lower C/T ratios, and better performance status. More lymph nodes were dissected in the lobectomy group. Patients in the sublobar resection group had better perioperative outcomes. A multivariable analysis revealed that the solid component diameter and serum carcinoembryonic antigen level are independent risk factors for tumor recurrence. After propensity matching, 284 paired patients in each group were included. No differences in overall survival (OS; p = 0.424) or disease-free survival (DFS; p = 0.296) were noted between the two matched groups. CONCLUSIONS: Sublobar resection is not inferior to lobectomy regarding both DFS and OS for cT1N0 lung adenocarcinoma patients. Sublobar resection may be a feasible surgical method for cT1N0 lung adenocarcinoma.

Circulating Interleukin-6 is Associated with Prognosis and Genetic Polymorphisms of MIR608 in Patients with Esophageal Squamous Cell Carcinoma.

BACKGROUND: No effective targeted therapy exists for esophageal squamous cell carcinoma (ESCC), the major cell type of esophageal cancer. The pleiotropic cytokine interleukin (IL)-6 is associated with adverse prognosis of some cancers, and the open reading frame of IL-6 contains an miR-608 microRNA-targeted site. We investigated the correlation of circulating IL-6 levels with prognosis and with the mir608:rs4919510 genetic polymorphism in ESCC. METHODS: A total of 213 patients with primary ESCC were enrolled. Plasma IL-6 levels of ESCC patients were analyzed by enzyme-linked immunosorbent assay (ELISA). The patients' genotypes of mir608:rs4919510 were analyzed using the MassARRAY system, and functional assays were performed by transient overexpression in cells. The cytotoxicity of IL-6 signaling blockers in ESCC cells was analyzed by MTT assay. RESULTS: We found that plasma IL-6 levels significantly correlated with overall survival (p = 0.019), disease recurrence (p = 0.003), and postoperative complications (p =0.002). Patients with the GG genotype of mir608:rs4919510 had a 4.56-fold increased risk of high expression of IL-6 compared with patients with the CC genotype (odds ratio 4.56, 95% confidence interval 1.87-11.09; p =0.001). Transient overexpression of the miR-608 C (miR-608_C) and G variants (miR-608_G) in cancer cells revealed that the miR-608_G variant was less efficient in regulating the expression of IL-6 compared with miR-608_C. Finally, the IL-6 signaling blocker ruxolitinib exhibited effective cytotoxicity in ESCC cells. CONCLUSIONS: The results of this study provide a novel direction for a biomarker-based targeted therapy for ESCC.

CTNNB1 mutations in basal cell adenoma of the salivary gland.

BACKGROUND/PURPOSE: Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) are uncommon salivary gland tumors comprising proliferation of basaloid cells. Nuclear ß-catenin expression and mutations in its encoding gene (CTNNB1) are reported to be specific to BCA. PIK3CA mutations are only found in BCAC not in BCA. However, in previous studies the number of cases was relatively small. The present study analyzed 44 cases of basal cell neoplasms to identify the CTNNB1 and PIK3CA mutation profiles in this rare salivary gland tumor. METHODS: The basic clinical features and detailed histological patterns of 41 BCA and three BCAC cases were analyzed. All basal cell neoplasms and a tissue microarray of adenoid cystic carcinoma (AdCC) were tested for ß-catenin immunohistochemistry. CTNNB1, PIK3CA, and CYLD mutations were detected by PCR and Sanger sequencing in each case. RESULTS: Nuclear ß-catenin expression was present in 97.6% of BCA and 66.7% of BCAC cases but not in AdCC cases. CTNNB1 mutations were found in 60% of BCA but not in BCAC. None of the tested cases had PIK3CA mutations. CTNNB1 mutation trended to be more common in those cases having a predominant tubular or tubulotrabecular patterns (p = 0.059). CONCLUSION: ß-catenin immunohistochemistry is very useful for the differential diagnosis between BCA/BCAC and AdCC. CTNNB1 mutations are common in BCA, especially those with tubular or tubulotrabecular patterns.