The SCRUM-MONSTAR Cancer-Omics Ecosystem: Striving for a Quantum Leap in Precision Medicine.

The SCRUM-Japan MONSTAR-SCREEN consortium is a nationwide molecular profiling project employing artificial intelligence-driven multi-omics analyses for patients with advanced malignancies, aiming to develop novel therapeutics and diagnostics and deliver effective drugs to patients. Concurrently, studies assessing molecular residual disease-based precision medicine for resectable solid tumors, including CIRCULATE-Japan, are ongoing. The substantial data generated by these platforms are stored within a state-of-the-art supercomputing infrastructure, VAPOR CONE. Since 2015, our project has registered over 24,000 patients as of December 2023. Among 16,144 patients with advanced solid tumors enrolled in MONSTAR-SCREEN projects, 5.0% participated in matched clinical trials, demonstrating a 29.2% objective response rate and 14.8-month median survival (95% confidence interval, 13.4-16.3), for patients treated in the matched clinical trials. Notably, patients who received matched therapy demonstrated significantly prolonged overall survival compared with those who did not (hazard ratio 0.77; 95% confidence interval, 0.71-0.83).

Efficacy of anti-PD-1 monotherapy for recurrent or metastatic olfactory neuroblastoma.

Background: Olfactory neuroblastoma (ONB) is a rare malignant tumor of the head and neck. Due to its rarity, standard systemic therapy for this condition has yet to be established. In particular, the use of immune checkpoint inhibitors (ICIs) for the recurrent or metastatic (R/M) ONB population remains unclear. Methods: We retrospectively evaluated 11 patients with R/M ONB who received any systemic chemotherapy at two Japanese institutions (National Cancer Center Hospital East and Kyushu Medical Center) between January 2002 and March 2022 and analyzed outcomes by use of anti-PD-1 antibody (nivolumab or pembrolizumab) monotherapy. Results: Of the 11 patients, 6 received ICI (ICI-containing treatment group) and the remaining 5 were treated with systemic therapy but not including ICI (ICI-non-containing treatment group). Overall survival (OS) was significantly longer in the ICI-containing group (median OS: not reached vs. 6.4 months, log-rank p-value: 0.035). The fraction of ICI systemic therapy in the entire treatment period of this group reached 85.9%. Four patients (66.7%) in the ICI-containing treatment group experienced immune-related adverse events (irAE), with grades of 1/2. No irAE of grade 3 or more was seen, and no patient required interruption or discontinuation of treatment due to toxicity. Conclusion: ICI monotherapy appears to be effective and to contribute to prolonged survival in R/M ONB.

Prognostic significance of micronest in cancer stroma in resected lung squamous cell carcinoma.

Tumor budding in the cancer stroma has been reported to be a prognostic factor in non-small cell lung cancer. Micronest in cancer stroma (MICS) is often observed as a formation that is larger and more conspicuous than budding, but its clinicopathologic significance is unclear. In this study, we aimed to examine the clinicopathological significance of MICS in lung squamous cell carcinoma (LSqCC). A total of 198 consecutive patients with pathologically diagnosed LSqCC (anyT N0-1M0) were enrolled in this study. MICS were defined as those that met the following criteria: (1) consisting of 5-200 tumor cells or less than 200 µm in diameter and (2) more than 200 µm away from the adjacent main lesion. The prognostic impact of the presence or absence of MICS and the characteristics of MICS-forming cancer cells were evaluated by immunohistochemistry (IHC). MICS was observed in 57 patients (28.8%), and overall survival (OS) and recurrence-free survival (RFS) were significantly shorter in the MICS-positive group (OS: 44.4% vs. 84.4%, p < 0.001; RFS: 30.0% vs. 82.6%, p < 0.001). Univariate and multivariate analyses revealed that the presence of MICS was an independent poor prognostic factor for OS (hazard ratio [HR] 3.54, p < 0.001) and RFS (HR 4.99, p < 0.001). Immunohistochemistry showed that the expression levels of the cell-cell adhesion molecule E-cadherin and hypoxia-induced protein GLUT-1 were significantly decreased in cancer cells forming MICS lesions compared to the tumor component excluding MICS within the same tumor (non-MICS lesions). Our data show that MICS is a distinct morphological feature with important biological and prognostic significance.

Prognostic value of the international association for the study of lung cancer grading system and its association with the tumor microenvironment in stage I EGFR-muted lung adenocarcinoma.

INTRODUCTION: The International Association for the Study of Lung Cancer (IASLC) grading system predicts early lung adenocarcinoma outcomes. METHODS: The purpose of this study is to examine prognostic value of the IASLC grading system and its association with the tumor microenvironment (TME) in Stage I EGFR-muted lung adenocarcinoma. Based on the IASLC grading system, we compared the clinicopathological characteristics of EGFR-mutated lung adenocarcinoma (n = 296). In addition, we examined the expression level of E-cadherin in tumor cells and counted the number of tumor-infiltrating lymphocytes (TILs; CD8, CD20, CD138, and Foxp3), tumor-associated macrophages (TAMs; CD204), and cancer-associated fibroblasts (CAFs; podoplanin) using semi-automatic digital pathology image analysis. RESULTS: Recurrence-free survival (RFS) curve showed that survival of grade 3 was significantly shorter than that of grade 1 (P < 0.01) and grade 2 (P = 0.03). Multivariate analysis of RFS revealed the invasive size, lymphatic permeation, and grade 3 (P < 0.01) as independent poor prognostic factors. The number of CD204 +TAMs and PDPN+CAFs was significantly higher in grade 3 than in grade 1 or 2 (all P < 0.01). Among the intermediate grade by the predominant subtype based classification, cases classified as grade 3 by the new classification had higher number of CD204 +TAMs (P < 0.01) and PDPN+CAFs (P = 0.02) than those classified as grade 2. CONCLUSION: The IASLC grading system correlated with the outcomes of EGFR-mutated lung adenocarcinoma. Grade 3 was found to have the TME that most contributes to tumor progression, which probably explained their poor prognosis.

The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma.

Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with NL tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics through interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo.

Clinicopathological differences between EGFR mutated and EGFR wild-type lung adenocarcinoma with papillary predominant pattern.

OBJECTIVES: We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype. METHODS: This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA). RESULTS: Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01). CONCLUSIONS: The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA.

Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma.

BACKGROUND: Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment. METHODS: In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC. RESULTS: CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival. CONCLUSIONS: This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

Imaging of salivary gland cancers derived from a sublingual gland herniated into the submandibular space: a report of three cases.

Sublingual gland herniation into the submandibular space through a mylohyoid muscle defect is a common anatomical variation; however, salivary gland cancers that arise from a herniated sublingual gland have not been described yet. Here, we report three patients with salivary gland cancers originating from a herniated sublingual gland. All tumors were detected as palpable submandibular masses, located anterior to the submandibular gland, medial to the mandible, and lateral to the mylohyoid muscle, with contact with the sublingual gland through a mylohyoid muscle defect. Intraoperative findings confirmed that the masses were derived from herniated sublingual glands. Pathological examination showed one case of mucoepidermoid carcinoma and two cases of adenoid cystic carcinoma. Imaging findings of the tumor location, in addition to the continuity with the sublingual gland through the mylohyoid muscle defect, are crucial for accurately diagnosing the tumor origin, which is essential for determining the appropriate clinical management.

An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections.

PURPOSE: Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces. METHODS: The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases). RESULTS: The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R2 = 0.68) and with the number of mitochondria counted using electron microscopy (R2 = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002). CONCLUSION: The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.

Spatial intratumor heterogeneity of programmed death-ligand 1 expression predicts poor prognosis in resected non-small cell lung cancer.

BACKGROUND: We quantified the pathological spatial intratumor heterogeneity of programmed death-ligand 1 (PD-L1) expression and investigated its relevance to patient outcomes in surgically resected non-small cell lung carcinoma (NSCLC). METHODS: This study enrolled 239 consecutive surgically resected NSCLC specimens of pathological stage IIA-IIIB. To characterize the spatial intratumor heterogeneity of PD-L1 expression in NSCLC tissues, we developed a mathematical model based on texture image analysis and determined the spatial heterogeneity index of PD-L1 for each tumor. The correlation between the spatial heterogeneity index of PD-L1 values and clinicopathological characteristics, including prognosis, was analyzed. Furthermore, an independent cohort of 70 cases was analyzed for model validation. RESULTS: Clinicopathological analysis showed correlations between high spatial heterogeneity index of PD-L1 values and histological subtype (squamous cell carcinoma; P < .001) and vascular invasion (P = .004). Survival analysis revealed that patients with high spatial heterogeneity index of PD-L1 values presented a significantly worse recurrence-free rate than those with low spatial heterogeneity index of PD-L1 values (5-year recurrence-free survival [RFS] = 26.3% vs 47.1%, P < .005). The impact of spatial heterogeneity index of PD-L1 on cancer survival rates was verified through validation in an independent cohort. Additionally, high spatial heterogeneity index of PD-L1 values were associated with tumor recurrence in squamous cell carcinoma (5-year RFS = 29.2% vs 52.8%, P < .05) and adenocarcinoma (5-year RFS = 19.6% vs 43.0%, P < .01). Moreover, we demonstrated that a high spatial heterogeneity index of PD-L1 value was an independent risk factor for tumor recurrence. CONCLUSIONS: We presented an image analysis model to quantify the spatial intratumor heterogeneity of protein expression in tumor tissues. This model demonstrated that the spatial intratumor heterogeneity of PD-L1 expression in surgically resected NSCLC predicts poor patient outcomes.

Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer.

One drawback of existing artificial intelligence (AI)-based histopathological prediction models is the lack of interpretability. The objective of this study is to extract p16-positive oropharyngeal squamous cell carcinoma (OPSCC) features in a form that can be interpreted by pathologists using AI model. We constructed a model for predicting p16 expression using a dataset of whole-slide images from 114 OPSCC biopsy cases. We used the clustering-constrained attention-based multiple-instance learning (CLAM) model, a weakly supervised learning approach. To improve performance, we incorporated tumor annotation into the model (Annot-CLAM) and achieved the mean area under the receiver operating characteristic curve of 0.905. Utilizing the image patches on which the model focused, we examined the features of model interest via histopathologic morphological analysis and cycle-consistent adversarial network (CycleGAN) image translation. The histopathologic morphological analysis evaluated the histopathological characteristics of image patches, revealing significant differences in the numbers of nuclei, the perimeters of the nuclei, and the intercellular bridges between p16-negative and p16-positive image patches. By using the CycleGAN-converted images, we confirmed that the sizes and densities of nuclei are significantly converted. This novel approach improves interpretability in histopathological morphology-based AI models and contributes to the advancement of clinically valuable histopathological morphological features.

Posttreatment Head and Neck Cancer Imaging: Anatomic Considerations Based on Cancer Subsites.

Posttreatment imaging surveillance of head and neck cancer is challenging owing to complex anatomic subsites and diverse treatment modalities. Early detection of residual disease or recurrence through surveillance imaging is crucial for devising optimal treatment strategies. Posttreatment imaging surveillance is performed using CT, fluorine 18-fluorodeoxyglucose PET/CT, and MRI. Radiologists should be familiar with postoperative imaging findings that can vary depending on surgical procedures and reconstruction methods that are used, which is dictated by the primary subsite and extent of the tumor. Morphologic changes in normal structures or denervation of muscles within the musculocutaneous flap may mimic recurrent tumors. Recurrence is more likely to occur at the resection margin, margin of the reconstructed flap, and deep sites that are difficult to access surgically. Radiation therapy also has a varying dose distribution depending on the primary site, resulting in various posttreatment changes. Normal tissues are affected by radiation, with edema and inflammation occurring in the early stages and fibrosis in the late stages. Distinguishing scar tissue from residual tumor becomes necessary, as radiation therapy may leave behind residual scar tissue. Local recurrence should be carefully evaluated within areas where these postradiation changes occur. Head and Neck Imaging Reporting and Data System (NI-RADS) is a standardized reporting and risk classification system with guidance for subsequent management. Familiarity with NI-RADS has implications for establishing surveillance protocols, interpreting posttreatment images, and management decisions. Knowledge of posttreatment imaging characteristics of each subsite of head and neck cancers and the areas prone to recurrence empowers radiologists to detect recurrences at early stages. ©RSNA, 2024 Test Your Knowledge questions in the supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Prognosis of patients with residual pathological disease after neoadjuvant docetaxel, cisplatin, and 5-fluorouracil therapy and surgery for esophageal squamous cell carcinoma: a retrospective cohort study.

Background: Docetaxel, cisplatin, and 5-fluorouracil (DCF) combination chemotherapy has been established as one of the standard neoadjuvant therapies for locally advanced esophageal squamous cell carcinoma (ESCC). However, little is known about prognostic factors in patients with residual pathological disease after neoadjuvant DCF followed by surgery for locally advanced ESCC who are candidates for adjuvant nivolumab. Objectives: This study aimed to investigate prognostic factors in patients with residual pathological disease after neoadjuvant DCF chemotherapy followed by surgery for locally advanced ESCC. Design: This was a retrospective cohort study. Methods: This retrospective cohort study included patients who received neoadjuvant DCF followed by surgery for locally advanced ESCC between June 2014 and January 2020 at the National Cancer Center Hospital East. Results: Among a total of 210 patients, 45 patients (21.4%) achieved a pathological complete response. The 3-year disease-free survival (DFS) rate was significantly lower in patients with residual pathological disease than in those with a pathological complete response [53.5% versus 74.5%; hazard ratio (HR): 2.09, 95% confidence interval (CI): 1.16-3.77, p = 0.01]. In patients with residual pathological disease (n = 165), multivariate analysis revealed that pathological node positivity (HR: 3.59, 95% CI: 1.92-6.71, p < 0.01), supraclavicular lymph node metastasis (HR: 2.15, 95% CI: 1.19-3.90, p = 0.01), and lymphovascular invasion (HR: 1.90, 95% CI: 1.14-3.17, p = 0.02) were significantly associated with poor DFS. Conclusion: In this largest-to-date cohort study, patients with residual pathological disease after neoadjuvant DCF followed by surgery for locally advanced ESCC had a poor prognosis. In these patients, pathological node positivity, including supraclavicular lymph node metastasis, and lymphovascular invasion were considered significant prognostic factors.

Prognostic value of predominant subtype in pathological stage II-III lung adenocarcinoma with epidermal growth factor receptor mutation.

OBJECTIVES: This study extracted clinicopathological features associated with recurrence and evaluated the tumor microenvironment in consecutive cases with resected pathological stage II-III epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (EGFR-mt). METHODS: Between January 2008 and November 2018, we retrospectively reviewed 387 consecutive patients with pathological stage II-III lung adenocarcinoma who underwent surgical resection. We examined the EGFR mutation status (wild-type or mutant) and the evaluated clinicopathological features of all patients. In addition, tumor-promoting cancer-associated fibroblasts (CAFs), tumor-associated M2 macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment of EGFR-mt cells were evaluated by immunohistochemical analysis. RESULTS: EGFR-mt (n = 124, 32 %) had more lymph node and pulmonary metastases than EGFR-wild-type lung adenocarcinoma (EGFR-wt) despite the smaller invasive component size. The disease-free survival (DFS) of patients with EGFR-mt tended to be shorter than that of patients with EGFR-wt. In the analysis according to the predominant subtype, EGFR-mt with papillary-predominant subtype had a significantly shorter 5-year DFS than that of EGFR-wt with papillary-predominant subtype (15.3 % vs. 44.1 %, p < 0.01). We observed no significant differences among the other subtypes. Multivariate analysis of DFS in patients with EGFR-mt revealed that male sex, pathological stage III, lymph node metastasis, pulmonary metastasis in the same lobe and non-acinar and non-lepidic predominant subtypes (papillary, solid, or micropapillary) were independent poor prognostic factors. Immunohistochemical analysis of EGFR-mt revealed that non-acinar- and non-lepidic-predominant subtypes were associated with a higher frequency of podoplanin-positive CAFs (36 % vs. 13 %, p = 0.01) and a higher median number of CD204-positive TAMs (61 vs. 49, p = 0.07) compared to the acinar- or lepidic-predominant subtypes. CONCLUSIONS: Non-acinar and non-lepidic predominant subtypes were predictors of recurrence and had an aggressive tumor microenvironment in pathological stage II-III EGFR-mt.

Weekly paclitaxel, carboplatin and cetuximab (PCE) combination followed by nivolumab for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

OBJECTIVES: Cetuximab-based chemotherapy is a standard 1st-line treatment for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, few studies have reported survival data for a treatment sequence consisting of a PCE regimen (paclitaxel + carboplatin + cetuximab) followed by an immune checkpoint inhibitor. MATERIALS AND METHODS: We retrospectively assessed 37 patients with R/M SCCHN from the oral cavity, oropharynx, hypopharynx, and larynx who received PCE as 1st-line treatment followed by nivolumab as 2nd-line at the National Cancer Center Hospital East between December 2016 and July 2021. For comparison, we also analyzed 14 patients who did not receive nivolumab after PCE. RESULTS: Of the 37 patients who received nivolumab, overall response rate (ORR) by PCE was 48.6%, and median time to response and median progression-free survival (PFS) were 2.1 months (range: 0.8-4.8) and 4.4 months, respectively. In the nivolumab phase, ORR was 10.8%. 23 patients received 3rd-line therapy. Median PFS2, PFS3, and overall survival (OS) were 6.8, 11.6, and 19.5 months, respectively. Subgroup analysis by PD-L1 expression showed no significant difference in OS. Analysis of the comparison group revealed a trend toward improved OS in those who received nivolumab compared to those who did not (HR 0.47, 95%CI [0.19-1.13], p = 0.084). CONCLUSION: PCE followed by nivolumab shows a favorable survival outcome, representing the potential for rapid tumor response with PCE and extension of OS by the addition of nivolumab regardless of combined positive score.

Common clinicopathological and immunological features of sarcomatoid carcinoma across organs: A histomorphology-based cross-organ study.

Sarcomatoid carcinoma (SC), which can occur in any organ, is a rare disease. To elucidate common characteristics of SC beyond organs, we evaluated clinicopathological and immunological features of SC defined by the single histological criterion beyond organs compared to randomly matched conventional carcinoma (non-SC) adjusted for the disease stage. Immunological features were assessed by multiplex immunohistochemistry, comparing immune cell density in tumor tissues and tumor programmed death-ligand 1 (PD-L1) expression. A total of 101 patients with SC or non-SC (31 lung, 19 esophagus, 22 pancreas, 15 liver, 4 bile duct, 6 kidney, 2 uterus and 2 ovary) were identified among 7197 patients who underwent surgery at our institute (1997-2020). SC was significantly associated with worse survival (HR: 1.571; 95% CI: 1.084-2.277; P = .017). The frequency of postoperative progression within 6 months was significantly higher for SC patients (54% vs 28%; P = .002). The immune profiling revealed the densities of CD8+ T cells (130 vs 72 cells/mm2 ; P = .004) and tumor-associated macrophages (566 vs 413 cells/mm2 ; P < .0001) and the tumor PD-L1 expression score (40% vs 5%; P < .0001) were significantly higher in SCs than in non-SCs. Among 73 SC patients with postoperative progression, multivariate Cox regression analysis showed that immunotherapy tended to be associated with favorable survival (HR: 0.256; 95% CI: 0.062-1.057; P = .060). Collectively, SCs shared clinicopathological and immunological features across organs. Our study can initiate to standardize the pathological definition of SC and provide a rationale for the investigation and development for this rare disease in a cross-organ manner.

The prognostic impact of a high number of peritumoral alveolar macrophages in neuroendocrine carcinoma in the lung.

Alveolar macrophages (AMs) are resident macrophages in the lungs; however, whether the number of AMs plays a role in the lung neuroendocrine tumor (NET) prognosis remains unclear. We counted the number of AMs located around the tumor (peritumoral alveolar macrophages [pAMs]) and the number of AMs located apart from the tumor (distant macrophages; dAMs). In 73 cases of neuroendocrine carcinoma (NEC: small cell lung carcinoma and large cell neuroendocrine carcinoma), the group that contained higher pAMs (≥86/µm2 ) revealed shorter recurrent-free survival (RFS) than those with lower pAMs (<86/µm2 ) (p = 0.005). Bivariate analysis showed that the number of pAMs was an independent predictor of a poor RFS. In contrast, in the carcinoid tumor cohort (n = 29), there was no statistically significant correlation between the two groups with high and low numbers of pAMs in RFS (p = 0.113). Furthermore, we examined the correlation between genomic alterations and the number of pAMs in NEC, but no significant correlation was observed. In conclusion, the number of pAMs is a prognostic factor for NEC in the lung and pAMs may contribute to tumor progression within the peritumoral microenvironment.

Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer.

The extent of tumor spread influences on the clinical outcome, and which determine T stage of colorectal cancer. However, pathologic discrimination between pT3 and pT4a in the eighth edition of the American Joint Committee on Cancer (AJCC)-TNM stage is subjective, and more objective discrimination method for deeply invasive advanced colon cancer is mandatory for standardized patient management. Peritoneal elastic laminal invasion (ELI) detected using elastic staining may increase the objective discrimination of deeply invasive advanced colon cancer. In this study, we constructed ELI study group to investigate feasibility, objectivity, and prognostic utility of ELI. Furthermore, pT classification using ELI was investigated based on these data. At first, concordance study investigated objectivity using 60 pT3 and pT4a colon cancers. Simultaneously, a multi-institutional retrospective study was performed to assess ELI's prognostic utility in 1202 colon cancer cases from 6 institutions. In the concordance study, objectivity, represented by κ, was higher in the ELI assessment than in pT classification. In the multi-institutional retrospective study, elastic staining revealed that ELI was a strong prognostic factor. The clinical outcome of pT3 cases with ELI was significantly and consistently worse than that of those without ELI. pT classification into pT3 without ELI, pT3 with ELI, and pT4a was an independent prognostic factor. In this study, we revealed that ELI is an objective method for discriminating deeply invasive advanced colon cancer. Based on its feasibility, objectivity, and prognostic utility, ELI can subdivide pT3 lesions into pT3a (without ELI) and pT3b (with ELI).

Immunohistochemistry and oxygen saturation endoscopic imaging reveal hypoxia in submucosal invasive esophageal squamous cell carcinoma.

BACKGROUND: Hypoxic microenvironment is prominent in advanced esophageal squamous cell carcinoma (ESCC). However, it is unclear whether ESCC becomes hypoxic when it remains in the mucosal layer or as it invades the submucosal layer. We aimed to investigate whether intramucosal (Tis-T1a) or submucosal invasive (T1b) ESCC becomes hypoxic using endoscopic submucosal dissection samples. METHODS: We evaluated the expression of hypoxia markers including hypoxia inducible factor 1α (HIF-1α), carbonic anhydrase IX (CAIX), and glucose transporter 1 (GLUT1) by H-score and vessel density by microvessel count (MVC) and microvessel density (MVD) for CD31 and α-smooth muscle actin (α-SMA) with immunohistochemical staining (n = 109). Further, we quantified oxygen saturation (StO2 ) with oxygen saturation endoscopic imaging (OXEI) (n = 16) and compared them to non-neoplasia controls, Tis-T1a, and T1b. RESULTS: In Tis-T1a, cccIX (13.0 vs. 0.290, p < 0.001) and GLUT1 (199 vs. 37.6, p < 0.001) were significantly increased. Similarly, median MVC (22.7/mm2 vs. 14.2/mm2 , p < 0.001) and MVD (0.991% vs. 0.478%, p < 0.001) were markedly augmented. Additionally, in T1b, the mean expression of HIF-1α (16.0 vs. 4.95, p < 0.001), CAIX (15.7 vs. 0.290, p < 0.001), and GLUT1 (177 vs. 37.6, p < 0.001) were significantly heightened, and median MVC (24.8/mm2 vs. 14.2/mm2 , p < 0.001) and MVD (1.51% vs. 0.478%, p < 0.001) were markedly higher. Furthermore, OXEI revealed that median StO2 was significantly lower in T1b than in non-neoplasia (54% vs. 61.5%, p = 0.00131) and tended to be lower in T1b than in Tis-T1a (54% vs. 62%, p = 0.0606). CONCLUSION: These results suggest that ESCC becomes hypoxic even at an early stage, and is especially prominent in T1b.