Invasive Adenocarcinoma Research Articles

Colloid Pattern of Salivary Mucinous Adenocarcinomas With Recurrent BRAF V600E Mutations.

The relationship between various patterns of mucin-producing salivary adenocarcinomas, including invasive salivary adenocarcinomas with mucinous differentiation, such as colloid and papillary carcinomas, remains unclear. Herein, we aimed to describe the clinicopathologic characteristics, immunophenotypes, molecular underpinnings, and clinical behavior of salivary mucinous adenocarcinomas (MA) to clarify their classification. We described a broad series of colloid and papillary patterns of MAs, indicating that papillary pattern presented papillary cystic proliferation of mucinous columnar cells as salivary intraductal papillary mucinous neoplasms with recurrent AKT1 E17K mutations, whereas colloid adenocarcinomas containing large mucinous pools or lakes around the malignant epithelial nests or islands harbored BRAF V600E mutations with worse prognosis. Typical morphologic structures, CK7(+), CK20(-), CDX2(-), p63(-), p40(-), MAML2 fluorescence in situ hybridization (-), AR(-), TTF-1(-), S100(-), mammaglobin(-), or S100/mammaglobin(+) with ETV6 fluorescence in situ hybridization (-) immunophenotype, and recurrent AKT1 E17K or BRAF V600E mutations may be defined. To our knowledge, this small series represents the first genetic study on a typical colloid pattern of MA, and our study with the spectrum documentation for MA in clinicopathologic characteristics, histologic and immunophenotypes, molecular features, and clinical behavior will allow for a better understanding of these rare but distinctive tumors.

Clinical characteristics and progression of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET rearrangements: a retrospective cohort study.

Patients harboring anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangements are usually diagnosed at a relatively late stage with nodal and distant metastasis, and rapid progression course of ALK/RET fusion-positive lung cancer were well-known. However, clinical characteristics and course of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET fusions are poorly described. Identifying patients with gene fusions at early stage may offer surgical options that could cure those patients. We retrospectively included patients with surgically resected pre-/minimally invasive lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations or ALK/RET rearrangements, and further compared the patient clinical characteristics, nodule natural course, and survival outcomes. Radiological characteristics including ground-glass component, cystic airspace, pleural attachment, etc. were specially assessed for this study. EGFR (exons 18-22) was detected by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the ALK/RET rearrangements. Lung cancer-specific survival (LCSS), relapse-free survival (RFS), and overall survival (OS) were all evaluated. Of 238 patients with pre-/minimally invasive lung adenocarcinomas, 226 patients had EGFR mutations, 7 patients had ALK fusions, and 5 patients had RET fusions. Average age at surgery was 45.3 years for ALK/RET-positive group and 52.6 years for EGFR-positive group (P=0.049). Radiologically, among the 12 patients with ALK/RET fusions, the majority of lesions (10/12) manifested as mixed ground-glass opacities (mGGOs), which was significantly more prevalent when compared with patients with EGFR mutations (83.4% vs. 24.3%, P<0.001). Moreover, a substantial proportion of cystic airspace was found in ALK/RET-positive group but not in EGFR-positive group (66.7% vs. 14.2%, P<0.001). Among four patients with ALK/RET fusions undergoing surveillance over 1 year before surgery, two of them developed rapid radiologic progression. The 5-year LCSS and RFS were 100%, 100% for ALK/RET-positive group, and 100%, 100% for EGFR-positive group, respectively. ALK/RET-positive pre-/minimally invasive lung adenocarcinomas were mostly characterized as mGGOs with cystic airspace developing rapid nodule progression, and no recurrence occurred during long-term follow-up after resection. This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.

Incidental precancerous and cancerous neoplasms in routine cholecystectomy specimens – A fascinating series of cases in a tertiary care center

Laparoscopic cholecystectomy is one of the most commonly performed surgeries for benign gall bladder pathologies. Pre-cancerous and malignant gall bladder neoplasms often have overlapping non-specific clinical manifestation in their early stages. Radiological findings are also non-specific in the early stages with the presence of cholelithiasis in a significant proportion of cases. Cholelithiasis is said to be one of the important comorbid risk factors for gall bladder carcinoma (GBC) as a source of constant irritation to biliary mucosa. In such cases, cholecystectomy done for benign indications may lead to a histopathological diagnosis of incidental gall bladder carcinomas. Pancreaticobiliary type of adenocarcinoma is the most common subtype of GBC with two described cases in this series. Invasive foci need to be ruled out in. All cases of high-grade biliary intraepithelial neoplasia as were seen in the third case. Intracholecystic papillary neoplasm is a recently described entity with one reported case in this series that was associated with invasive adenocarcinoma. Signet ring adenocarcinoma is a rarely encountered adenocarcinoma in gall bladder with worse outcome. One such case has been described here where the patient has succumbed to death within 3 months of surgery and during the course of adjuvant therapy.

Lung microwave ablation: Post-procedure imaging features and evolution of pulmonary ground-glass nodule-like lung cancer.

To retrospectively examine the imaging characteristics of chest-computed tomography (CT) following percutaneous microwave ablation (MWA) of the ground-glass nodule (GGN)-like lung cancer and its dynamic evolution over time. From June 2020 to May 2021, 147 patients with 152 GGNs (51 pure GGNs and 101 mixed GGNs, mean size 15.0 ± 6.3 mm) were enrolled in this study. One hundred and forty-seven patients underwent MWA procedures. The imaging characteristics were evaluated at predetermined time intervals: immediately after the procedure, 24-48 h, 1, 3, 6, 12, and ≥18 months (47 GGNs). This study population included 147 patients with 152 GGNs, as indicated by the results: 43.5% (66/152) adenocarcinoma in situ, 41.4% (63/152) minimally invasive adenocarcinoma, and 15.1% (23/152) invasive adenocarcinoma. Immediate post-procedure tumor-level analysis revealed that the most common CT features were ground-glass opacities (93.4%, 142/152), hyperdensity within the nodule (90.7%, 138/152), and fried egg sign or reversed halo sign (46.7%, 71/152). Subsequently, 24-48 h post-procedure, ground-glass attenuations, hyperdensity, and the fried egg sign remained the most frequent CT findings, with incidence rates of 75.0% (114/152), 71.0% (108/152), and 54.0% (82/152), respectively. Cavitation, pleural thickening, and consolidation were less frequent findings. At 1 month after the procedure, consolidation of the ablation region was the most common imaging feature. From 3 to 12 months after the procedure, the most common imaging characteristics were consolidation, involutional parenchymal bands and pleural thickening. At ≥18 months after the procedure, imaging features of the ablation zone revealed three changes: involuting fibrosis (80.8%, 38/47), consolidation nodules (12.8%, 6/47), and disappearance (6.4%, 3/47). This study outlined the anticipated CT imaging characteristics of GGN-like lung cancer following MWA. Diagnostic and interventional radiologists should be familiar with the expected imaging characteristics and dynamic evolution post-MWA in order to interpret imaging changes with a reference image.

Clinicopathological and computed tomography features associated with recurrence-free survival of patients with small-sized peripheral invasive lung adenocarcinoma after sublobectomy.

Sublobar resection is gradually becoming a standard treatment for small-sized (≤2 cm) peripheral non-small cell lung cancer (NSCLC), with lung adenocarcinoma (LADC) being the most frequent histologic subtype. However, the prognostic predictors for preoperatively determining whether sublobectomy is feasible for patients with early LADC have not yet been well identified. Therefore, this study aimed to investigate the clinicopathological and computed tomography (CT) features associated with the recurrence-free survival (RFS) of patients with small-sized invasive LADC (SILADC) after sublobar resection. This retrospective cohort study analyzed 107 patients with SILADC who underwent preoperative chest CT scan and sublobar resection from December 2012 to March 2019. The Kaplan-Meier survival was used to analyze the relationship between clinicopathological characteristics, preoperative chest CT findings, and RFS. The Cox proportional hazards regression was used to identify independent prognostic factors of poor RFS. For clinicopathological characteristics, RFS was shorter in patients aged ≥70 years, smokers, and those with micropapillary/solid-predominant adenocarcinomas (all P values <0.05). For preoperative CT features, RFS was shorter in patients with tumor size ≥1.4 cm, solid component size ≥1.1 cm, proportion of solid component ≥72%, solid density, spiculation, vascular convergence sign, peripheral fibrosis, and type II pleural tag (all P values <0.05). Multivariate analysis showed proportion of solid component ≥72% [hazard ratio (HR): 5.920; P=0.006; 95% confidence interval (CI): 1.686-20.794], spiculation (HR: 5.026; P=0.001; 95% CI: 2.008-12.581), and type II pleural tag (HR: 4.638; P=0.002; 95% CI: 1.773-12.136) were independent risk factors for poor prognosis in patients with SILADC after sub-lobectomy. Clinicopathological and CT characteristics are helpful for predicting the RFS of patients with SILADC after sublobar resection and can be used as an auxiliary tool for thoracic surgeons to choose the best surgical mode.

Abstract B127: Novel anti-CD147 antibody DS-1471a exerts antitumor effect in hepatocellular carcinoma Patient Derived Xenograft models and its efficacy correlates with the expression of CD147

Abstract Background: CD147 is an immunoglobulin-like receptor that is highly expressed in various cancers and involved in the growth, metastasis, and activation of inflammatory pathways via interactions with various functional molecules, such as integrins, CD44, and monocarboxylate transporters. Through screening of CD147-targeting antibodies with antitumor efficacy, we developed a novel humanized IgG4-formatted monoclonal anti-CD147 antibody, DS-1471a. Our previous studies revealed this antibody showed potent antitumor efficacy superior to standard of care drugs in various cell line xenograft mouse models such as hepatocellular carcinoma (HCC), pancreatic invasive ductal adenocarcinoma, and chronic myelogenous leukemia. In this study, we further examined antitumor efficacy and biomarker expression in 18 patient derived xenograft (PDX) models established from HCC patients. Methods: DS-1471a or vehicle was administered intravenously once per week at 10 mg/kg doses in HCC-PDX models and tumor volumes were measured every 2 or 3 days. After tumors were harvested, samples were analyzed by simple western blotting (sWB, capillary based western blotting system) and immunohistochemistry (IHC). H-scores were calculated from IHC results and correlation between H-score, protein expression by sWB, and tumor growth inhibition (TGI) ratio were examined. Results: Seven out of 18 PDX models showed over 50% TGI with DS-1471a treatment in comparison to vehicle, regardless of gender, tumor grade, and hepatitis virus type. Protein expression analysis by sWB showed good correlation of several biomarker candidates with efficacy of DS-1471a. Among the biomarker candidates tested, CD147, the DS-1471a target molecule, showed the strongest correlation with efficacy (r = 0.78). SMAD4, which regulates the downstream signaling of the CD147 complex, and FBXO22, reported to contribute to CD147 degradation, also showed good correlation with DS-1471a efficacy (r = 0.66 and r = 0.77, respectively). By both sWB and IHC analysis, all PDX models showed negative or weak KLF5 expression, another biomarker candidate for DS-1471a that is known to be a suppressor for SMAD signaling pathway. A clear correlation between CD147 H-score and TGI was observed (r= 0.74) in these patient derived PDX models. Correlation between CD147 H-score and protein expression levels by sWB was also observed (r = 0.71). Of note, all PDX models showed moderate to high expression of CD147. Conclusion: These pre-clinical study results suggest DS-1471a may be potentially beneficial for HCC treatment. In addition, our results show correlation of DS-1471a efficacy with expression of CD147. Further studies are needed to further understand the full potential benefit of DS-1471a in clinical trials. Citation Format: Hiroshi Yuita, Ryuichi Nakamura, Jun Tsukada, Hideo Yukinaga, Huynh The Hung, Keisuke Fukuchi. Novel anti-CD147 antibody DS-1471a exerts antitumor effect in hepatocellular carcinoma Patient Derived Xenograft models and its efficacy correlates with the expression of CD147 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B127.

Multi-classification model incorporating radiomics and clinic-radiological features for predicting invasiveness and differentiation of pulmonary adenocarcinoma nodules

PurposeTo develop a comprehensive multi-classification model that combines radiomics and clinic-radiological features to accurately predict the invasiveness and differentiation of pulmonary adenocarcinoma nodules.MethodsA retrospective analysis was conducted on a cohort comprising 500 patients diagnosed with lung adenocarcinoma between January 2020 and December 2022. The dataset included preoperative CT images and histological reports of adenocarcinoma in situ (AIS, n = 97), minimally invasive adenocarcinoma (MIA, n = 139), and invasive adenocarcinoma (IAC, n = 264) with well-differentiated (WIAC, n = 99), moderately differentiated (MIAC, n = 84), and poorly differentiated IAC (PIAC, n = 81). The patients were classified into two groups (IAC and non-IAC) for binary classification and further divided into three and five groups for multi-classification. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO) algorithm to identify the most informative radiomics and clinic-radiological features. Eight machine learning (ML) models were developed using these features, and their performance was evaluated using accuracy (ACC) and the area under the receiver-operating characteristic curve (AUC).ResultsThe combined model, utilizing the support vector machine (SVM) algorithm, demonstrated improved performance in the testing cohort, achieving an AUC of 0.942 and an ACC of 0.894 for the two-classification task. For the three- and five-classification tasks, the combined model employing the one versus one strategy of SVM (SVM-OVO) outperformed other models, with ACC values of 0.767 and 0.607, respectively. The AUC values for histological subtypes ranged from 0.787 to 0.929 in the testing cohort, while the Macro-AUC and Micro-AUC of the multi-classification models ranged from 0.858 to 0.896.ConclusionsA multi-classification radiomics model combined with clinic-radiological features, using the SVM-OVO algorithm, holds promise for accurately predicting the histological characteristics of pulmonary adenocarcinoma nodules, which contributes to personalized treatment strategies for patients with lung adenocarcinoma.

Invasive Pancreatic Adenocarcinoma with Squamous Differentiation Arising in an IOPN with Novel MDM2 Amplification

Abstract Introduction/Objective Intraductal oncocytic papillary neoplasms (IOPNs) are rare pancreatic tumors that are genetically distinct from intraductal papillary mucinous neoplasms (IPMNs). Morphologic and molecular characterization of invasive adenocarcinomas associated with IOPNs remains limited due to the rarity of this entity. Methods/Case Report We present a 68-year-old female who initially presented with abdominal pain and jaundice. MRI revealed a 2.6 cm mass in the pancreatic head with abutment of the superior mesenteric vein and dilation of the biliary and pancreatic duct. Biopsy revealed adenocarcinoma with mucinous features. The patient was started on gemcitabine and abraxane. Her treatment course was complicated by biliary and duodenal obstruction requiring common bile duct and duodenal stenting. Surgical management with pancreaticoduodenectomy was performed six months following initial diagnosis. Gross examination revealed a 2.5 cm ill-defined tumor surrounding the main pancreatic duct adjacent to the common bile duct. Microscopy revealed an IOPN arising within the pancreatic duct exhibiting a complex papillary growth pattern. There was an associated moderately to poorly differentiated invasive carcinoma with mucinous and squamous differentiation with lymph node metastasis. Molecular testing (FoundationOne®CDx) revealed ARID1A mutation and amplification of MDM2, CDK4, and ERBB3. Patient is alive and without radiologic evidence of disease recurrence at 6 months follow-up. Results (if a Case Study enter NA) NA Conclusion To our knowledge, our case is the first report of an invasive pancreatic adenocarcinoma with squamous differentiation arising in association with an IOPN. In addition, our case showed MDM2 amplification which has not been previously identified in pancreatic adenocarcinoma arising in IOPNs. Although recent literature demonstrated that less than 30% of IOPN showed invasive disease and even fewer cases with lymph node metastasis, our case showed extensive invasion with metastases to 2 lymph nodes. This may suggest that MDM2 amplification may play a role in more aggressive disease since it is implicated with poorer outcome in conventional pancreatic adenocarcinoma. Further molecular studies of IOPN may help to identify prognostic features of this entity.

A clinical–radiological predictive model for solitary pulmonary nodules and the relationship between radiological features and pathological subtype

To develop a clinical-radiological model to predict the malignancy of solitary pulmonary nodules (SPNs) and to evaluate the accuracy of chest computed tomography imaging characteristics of SPN in diagnosing pathological type. The predictive model was developed using a retrospective cohort of 601 SPN patients (Group A) between July 2015 and July 2020. The established model was tested using a second retrospective cohort of 124 patients between August 2020 and August 2021 (Group B). The radiological characteristics of all adenocarcinomas in two groups were analysed to determine the correlation between radiological and pathological characteristics. Malignant nodules were found in 78.87% of cases and benign in 21.13%. Two clinical characteristics (age and gender) and four radiological characteristics (calcification, vascular convergence, pleural retraction sign, and density) were identified as independent predictors of malignancy in patients with SPN using logistic regression analysis. The area under the receiver operating characteristic curve (0.748) of the present model was greater than the other two reported models. Diameter, spiculation, lobulation, vascular convergence, and pleural retraction signs differed significantly among pre-invasive lesions, minimally invasive adenocarcinoma, and invasive adenocarcinoma. Only diameter and density were significantly different among invasive adenocarcinoma subtypes. Older age, male gender, no calcification, vascular convergence, pleural contraction sign, and lower density were independent malignancy predictors of SPNs. Furthermore, the pathological classification can be clarified based on the radiological characteristics of SPN, providing a new option for the prevention and treatment of early lung cancer.

Beta-Catenin Nuclear Expression in Squamoid Morules in Colorectal Adenomas: Clinicopathologic Study of Fifteen Cases

Abstract Introduction/Objective Squamoid morules are an intriguing finding rarely seen in colorectal adenomas, mimicking foci of microinvasion or neuroendocrine differentiation. Previous observations include mostly case reports and small series, with few examining the squamoid morules in detail. Methods/Case Report We identified fifteen colorectal adenomas with squamoid morules and collected clinicopathological data including age, sex, procedure, location, pathologic diagnosis, and size. A representative block was chosen for immunohistochemistry in each case. The expression of p40, p63, CK5/6, beta-catenin, synaptophysin, chromogranin, and Ki-67 in squamoid morules were examined immunohistochemically. Results (if a Case Study enter NA) The fifteen patients comprised thirteen males and two females ranging in age from 45 to 85 years (average: 60.6 years old). The adenomas were removed by endoscopic resection (n = 7) or surgical resection (n = 8). Nine adenomas were found in the rectosigmoid colon, one in the descending colon, and five in the right colon. Eleven adenomas were tubulovillous adenomas (average: 3.8 cm, ranging 1.0 to 6.0 cm) and four were tubular adenomas (average: 2.6 cm, ranging 1.6 to 3.0 cm). Seven adenomas contained invasive adenocarcinoma. Squamoid morules were randomly distributed in adenomas. All foci of squamoid morules showed beta-catenin nuclear positivity and most (more than 90 %) showed CK5/6 expression. Squamoid morules were focally positive for p63 in three adenomas and focally positive for p40 in one adenoma. In one adenoma squamoid morules are positive for both synaptophysin and chromogranin. In all fifteen adenomas squamoid morules were negative for Ki- 67. Conclusion Squamoid morules are characterized by strong male predominance, association with large adenoma size, beta-catenin nuclear positivity, CK5/6 expression, and no Ki-67 expression. Beta-catenin nuclear expression is helpful in distinguishing squamoid morules from foci of microinvasion.

Predicting visceral pleural invasion in lung adenocarcinoma presenting as part-solid density utilizing a nomogram model combined with radiomics and clinical features.

To develop and validate a preoperative nomogram model combining the radiomics signature and clinical features for preoperative prediction of visceral pleural invasion (VPI) in lung nodules presenting as part-solid density. We retrospectively reviewed 156 patients with pathologically confirmed invasive lung adenocarcinomas after surgery from January 2016 to August 2019. The patients were split into training and validation sets by a ratio of 7:3. The radiomic features were extracted with the aid of FeAture Explorer Pro (FAE). A CT-based radiomics model was constructed to predict the presence of VPI and internally validated. Multivariable regression analysis was conducted to construct a nomogram model, and the performance of the models were evaluated with the area under the receiver operating characteristic curve (AUC) and compared with each other. The enrolled patients were split into training (n = 109) and validation sets (n = 47). A total of 806 features were extracted and the selected 10 optimal features were used in the construction of the radiomics model among the 707 stable features. The AUC of the nomogram model was 0.888 (95% CI: 0.762-0.961), which was superior to the clinical model (0.787, 95% CI: 0.643-0.893; p = 0.049) and comparable to the radiomics model (0.879, 95% CI: 0.751-0.965; p > 0.05). The nomogram model achieved a sensitivity of 90.5% and a specificity of 76.9% in the validation dataset. The nomogram model could be considered as a noninvasive method to predict VPI with either highly sensitive or highly specific diagnoses depending on clinical needs.

Pathological diagnosis and immunohistochemical analysis of minute pulmonary meningothelial-like nodules: A case report

BACKGROUND Minute Pulmonary Meningothelial-like Nodules (MPMNs) are rare benign pulmonary nodules, which are more common in elderly women and have a higher detection rate in lung tissues of patients with lung malignant diseases. Its origin is not yet clear. At present, there are few reports on the diagnostic methods such as imaging and pathological manifestations of MPMNs. This article reports a 70-year-old female patient with pulmonary adenocarcinoma combined with MPMNs and reviews of the relevant literature. CASE SUMMARY A 70-year-old women was admitted to our institution with feeling sour in her back and occasional cough for more than 2 mo. Computerized electronic scanning scan and 3D reconstruction images in our institution showed there were multiple ground-glass nodules in both of her two lungs. The biggest one was in the apicoposterior segment of left upper lobe, about 2.5 mm × 9 mm in size. We performed thoracoscopic resection of the left upper lung apicoposterior segment of the patient, and the final pathological report was minimally invasive adenocarcinoma. Re-examination of high resolution computed tomography 21 mo after surgery showed multiple ground-glass nodules in both lungs, and a new ground-glass nodule was found in the superior segment of the right lower lobe. We took pathological biopsy of the right upper lung and right lower lung nodules for the patient under thoracoscopy. The histomorphology of the right lower lobe nodule showed multiple lesions in the lung tissue, and the small foci in the alveolar septum were distributed in mild form of the aggregation of short spindle cells. The immunohistochemistry showed that the lesion was epithelial membrane antigen (EMA) (+), somatostatin receptor 2a (SSTR2a) (+), S-100 (-), chromogranin A (-), Syn (-), cytokeratin (-) and HMB-45 (-). The final diagnosis was minimally invasive adenocarcinoma, accompanied by MPMNs. We recommend that patients continue to receive treatment after surgery and to do regular follow-up observations. CONCLUSION The imaging manifestations of MPMNs are atypical, histomorphology and immunohistochemistry can assist in its diagnosis. This article reviews the relevant literature of MPMNs immunohistochemistry and shows that MPMNs are positive for EMA, SSTR2a, and progesterone receptor.

Behind the Indolent Facade: Uncovering the Molecular Features and Malignancy Potential in Lung Minimally Invasive Adenocarcinoma by Single-Cell Transcriptomics.

The increased use of low-dose computed tomography screening has led to more frequent detection of early stage lung tumors, including minimally invasive adenocarcinoma (MIA). To unravel the intricacies of tumor cells and the immune microenvironment in MIA, this study performs a comprehensive single-cell transcriptomic analysis and profiles the transcriptomes of 156,447 cells from fresh paired MIA and invasive adenocarcinoma (IA) tumor samples, peripheral blood mononuclear cells, and adjacent normal tissue samples from three patients with synchronous multiple primary lung adenocarcinoma. This study highlights a connection and heterogeneity between the tumor ecosystem of MIA and IA. MIA tumor cells exhibited high expression of aquaporin-1 and angiotensin II receptor type 2 and a basal-like molecular character. Furthermore, it identifies that cathepsin B+ tumor-associated macrophages may over-activate CD8+ T cells in MIA, leading to an enrichment of granzyme K+ senescent CD8+ T cells, indicating the possibility of malignant progression behind the indolent appearance of MIA. These findings are further validated in 34 MIA and 35 IA samples by multiplexed immunofluorescence. These findings provide valuable insights into the mechanisms that maintain the indolent nature and prompt tumor progression of MIA and can be used to develop more effective therapeutic targets and strategies for MIA patients.

Pulmonary Low Malignant Potential Adenocarcinoma: A Validation of the Proposed Criteria for This Novel Subtype.

Adenocarcinoma (ADC) is the most common histologic type of lung cancer, including in situ (lepidic), minimally invasive, and invasive forms. While the former 2 types are associated with a favorable outcome, the latter includes tumors with variable behavior, often tumor stage-related. A recent study proposed strict morphologic criteria defining a new subgroup of resected stage I invasive ADC (16% of cases) with favorable outcomes (100% disease-specific survival), named "ADC of low malignant potential (LMP-ADC)." The following criteria were met: ≤3cm size, nonmucinous histotype, ≥15% lepidic growth, and the absence of the following: high-grade patterns, >1 mitosis/2mm 2 , necrosis, and vascular/pleural invasion. The aim of the present study was to validate the performance of such criteria to identify LMP-ADC in a series of 274 stage IA resected lung ADCs from a single institution. Thirty-four tumors (12.4%) met the proposed criteria for LMP-ADC, as confirmed by additional stains for mitotic figures, Ki67 index, and elastic fibers (helpful to assess alveolar wall invasion). Minor differences between the lepidic and invasive components were observed regarding cell atypia and proliferation. p53 was normally expressed by invasive tumor cells. Mutations occurred in known lung cancer genes (mostly KRAS and EGFR). Five patients (14.7%) developed disease progression and 2 of them (5.9%) died of the disease. In our series, the disease-specific survival was 94.1%. In conclusion, in resected invasive lung ADC, a subgroup presenting low-grade morphologic features and associated with favorable prognosis does exist. Morphologic criteria for LMP-ADC supported by ancillary techniques represent a valid tool to better define this novel subgroup and to refine the stratification of invasive lung ADC, possibly suggesting modified follow-up protocols, based on the observed indolent behavior in most cases.

An Innovative Non-Linear Prediction Model for Clinical Benefit in Women with Newly Diagnosed Breast Cancer Using Baseline FDG-PET/CT and Clinical Data.

Objectives: We aimed to develop a novel non-linear statistical model integrating primary tumor features on baseline [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), molecular subtype, and clinical data for treatment benefit prediction in women with newly diagnosed breast cancer using innovative statistical techniques, as opposed to conventional methodological approaches. Methods: In this single-center retrospective study, we conducted a comprehensive assessment of women newly diagnosed with breast cancer who had undergone a FDG-PET/CT scan for staging prior to treatment. Primary tumor (PT) volume, maximum and mean standardized uptake value (SUVmax and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured on PET/CT. Clinical data including clinical staging (TNM) but also PT anatomical site, histology, receptor status, proliferation index, and molecular subtype were obtained from the medical records. Overall survival (OS), progression-free survival (PFS), and clinical benefit (CB) were assessed as endpoints. A logistic generalized additive model was chosen as the statistical approach to assess the impact of all listed variables on CB. Results: 70 women with newly diagnosed breast cancer (mean age 63.3 ± 15.4 years) were included. The most common location of breast cancer was the upper outer quadrant (40.0%) in the left breast (52.9%). An invasive ductal adenocarcinoma (88.6%) with a high tumor proliferation index (mean ki-67 expression 35.1 ± 24.5%) and molecular subtype B (51.4%) was by far the most detected breast tumor. Most PTs displayed on hybrid imaging a greater volume (12.8 ± 30.4 cm3) with hypermetabolism (mean ± SD of PT maximum SUVmax, SUVmean, MTV, and TLG, respectively: 8.1 ± 7.2, 4.9 ± 4.4, 12.7 ± 30.4, and 47.4 ± 80.2). Higher PT volume (p < 0.01), SUVmax (p = 0.04), SUVmean (p = 0.03), and MTV (<0.01) significantly compromised CB. A considerable majority of patients survived throughout this period (92.8%), while five women died (7.2%). In fact, the OS was 31.7 ± 14.2 months and PFS was 30.2 ± 14.1 months. A multivariate prediction model for CB with excellent accuracy could be developed using age, body mass index (BMI), T, M, PT TLG, and PT volume as predictive parameters. PT volume and PT TLG demonstrated a significant influence on CB in lower ranges; however, beyond a specific cutoff value (respectively, 29.52 cm3 for PT volume and 161.95 cm3 for PT TLG), their impact on CB only reached negligible levels. Ultimately, the absence of distant metastasis M displayed a strong positive impact on CB far ahead of the tumor size T (standardized average estimate 0.88 vs. 0.4). Conclusions: Our results emphasized the pivotal role played by FDG-PET/CT prior to treatment in forecasting treatment outcomes in women newly diagnosed with breast cancer. Nevertheless, careful consideration is required when selecting the methodological approach, as our innovative statistical techniques unveiled non-linear influences of predictive biomarkers on treatment benefit, highlighting also the importance of early breast cancer diagnosis.

Development and validation of a nomogram based on CT texture analysis for discriminating minimally invasive adenocarcinoma from glandular precursor lesions in sub‑centimeter pulmonary ground glass nodules

Development and validation of a nomogram based on CT texture analysis for discriminating minimally invasive adenocarcinoma from glandular precursor lesions in sub‑centimeter pulmonary ground glass nodules

Differential spatial distribution of HNF4α isoforms during dysplastic progression of intraductal papillary mucinous neoplasms of the pancreas

Hepatocyte Nuclear Factor 4-alpha (HNF4α) comprises a nuclear receptor superfamily of ligand-dependent transcription factors that yields twelve isoforms in humans, classified into promoters P1 or P2-associated groups with specific functions. Alterations in HNF4α isoforms have been associated with tumorigenesis. However, the distribution of its isoforms during progression from dysplasia to malignancy has not been studied, nor has it yet been studied in intraductal papillary mucinous neoplasms, where both malignant and pre-malignant forms are routinely clinically identified. We examined the expression patterns of pan-promoter, P1-specific, and P2-specific isoform groups in normal pancreatic components and IPMNs. Pan-promoter, P1 and P2 nuclear expression were weakly positive in normal pancreatic components. Nuclear expression for all isoform groups was increased in low-grade IPMN, high-grade IPMN, and well-differentiated invasive adenocarcinoma. Poorly differentiated invasive components in IPMNs showed loss of all forms of HNF4α. Pan-promoter, and P1-specific HNF4α expression showed shifts in subnuclear and sub-anatomical distribution in IPMN, whereas P2 expression was consistently nuclear. Tumor cells with high-grade dysplasia at the basal interface with the stroma showed reduced expression of P1, while P2 was equally expressed in both components. Additional functional studies are warranted to further explore the mechanisms underlying the spatial and differential distribution of HNF4α isoforms in IPMNs.

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.

Vascular invasion predicts the subgroup of lung adenocarcinomas ≤2.0 cm at risk of poor outcome treated by wedge resection compared to lobectomy

BackgroundRecent randomized control trials (JCOG0802 and CALGB140503) have shown sublobar resection to be noninferior to lobectomy for non–small cell lung cancer (NSCLC) ≤2.0 cm. We have previously proposed histologic criteria stratifying lung adenocarcinoma into indolent low malignant potential (LMP) and aggressive angioinvasive adenocarcinomas, resulting in better prognostication than provided by World Health Organization grade. Here we determine whether pathologic classification is reproducible and whether subsets of adenocarcinomas predict worse outcomes when treated by wedge resection compared to lobectomy. MethodsA retrospective cohort of 108 recipients of wedge resection and 187 recipients of lobectomy for stage I/0 lung adenocarcinomas ≤2.0 cm was assembled from 2 institutions. All tumors were classified by a single pathologist, and interobserver reproducibility was assessed in a subset (n = 92) by 5 pathologists. ResultsAngioinvasive adenocarcinoma (21%-27% of cases) was associated with worse outcomes when treated with wedge resection compared to lobectomy (5-year recurrence-free survival, 57% vs 85% [P = .007]; 5-year disease-free survival [DSS], 70% vs 90% [P = .043]; 7-year overall survival, 37% vs 58% [P = .143]). Adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and LMP exhibited 100% 5-year DSS regardless of the surgical approach. Multivariable analysis showed that angioinvasion, tumor size, margin status, and extent of nodal sampling were significantly associated with recurrence but not with surgical procedure. There was substantial interobserver reproducibility among the pathologists for the diagnosis of angioinvasive adenocarcinoma (κ = 0.71) and the combined indolent AIS/MIA/LMP group (κ = 0.74). ConclusionsThe majority (∼75%) of lung adenocarcinomas ≤2 cm are adequately managed with wedge resection; however, angioinvasive adenocarcinomas (∼25%) treated by wedge resection with suboptimal nodal sampling exhibit poor outcomes, with a 40% to 45% rate of recurrence within 5 years and 60% to 65% overall mortality at 7 years.

Prognostic implications of CT-defined ground glass opacity in clinical stage I–IIA grade 3 invasive non-mucinous pulmonary adenocarcinoma

To investigate the prognostic impact of computed tomography (CT)-defined ground glass opacity (GGO) in patients with clinical stage I-IIA grade 3 invasive non-mucinous pulmonary adenocarcinoma (INPA). The present study retrospectively enrolled 187 patients diagnosed with stage I-IIA grade 3 INPA. Their clinicopathological, radiological, and genetic information was evaluated systematically, and a 5-year follow-up was conducted to monitor disease recurrence and mortality. Patients were stratified based on the presence of a GGO component, and the Cox proportional hazard model was employed to assess the influence of clinicopathological factors and genetic variables on tumour outcomes. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Significant differences were observed in both OS and RFS based on the presence of a GGO component. The group with GGO exhibited superior OS (p=0.002) and RFS (p=0.029). Multivariate analysis revealed that the presence of a GGO component (hazard ratio [HR]=0.412, 95% confidence interval [CI]: 0.177-0.959, p=0.040), clinical T2 stage (HR=2.473, 95% CI: 1.498-4.083, p<0.001), pathological N2 stage (HR=3.049, 95% CI: 1.800-5.167, p<0.001), and mixed high-grade patterns (HR=2.392, 95% CI: 1.418-4.036, p=0.001) were predictors of RFS. The presence of a GGO component is strongly associated with a favourable prognosis in grade 3 INPA.