Tracheal repair with sternocleidomastoid flap in mediastinoscopic surgery for esophageal cancer.

Tracheal injury during mediastinoscopic esophagectomy is a life-threatening complication that is challenging to manage. However, no precise treatment has been defined. An 80-year-old male patient with upper esophageal cancer underwent a mediastinoscopic esophagectomy and gastric tube reconstruction through the posterior mediastinal route. When the esophagus was separated from the trachea using a bipolar vessel sealing system, the left side of the membranous trachea incurred a 3-cm defect 7 cm below the sternal notch. We successfully repaired the tracheal injury not by directly suturing the defect but by reinforcing it with a pedicle sternocleidomastoid flap. The gastric tube was placed over the tracheal repair for esophageal reconstruction via a posterior mediastinal route. As a result, the patient recovered well and was discharged. A sternocleidomastoid flap might be another surgical option for reinforcement flaps in tracheal injuries.

Recurrence-free survival curve for pulmonary metastasectomy in colorectal cancer plateaus at 3 years.

Pulmonary metastasectomy in colorectal cancer (CRC) has encouraging results; however, specific criteria for lung resection and the timing of resection remain undetermined. Therefore, in this study, we aimed to examine the long-term prognosis and 10-year survival rates and analyze poor prognostic factors in patients who underwent resection of pulmonary metastases from CRC. This retrospective, single-institution study included 156 patients with controlled primary CRC and metastases confined to the lungs or liver who underwent pulmonary metastasectomy between 2005 and 2022. Statistical analyses were conducted using the X2 and two-tailed Student's t test to compare variables. The receiver operating characteristic (ROC) curve was used to determine the appropriate cut-off point for tumor size as a predictive factor of survival. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and non-parametric group comparisons were performed using log-rank tests. The 5- and 10-year OS rates were 67% and 59%, respectively. Further, there was no recurrence 38 months post-surgery, and the RFS curve plateaued. Moreover, by 88 months post-surgery, no deaths occurred, and the OS curve plateaued. Multivariate analysis revealed that a pulmonary metastatic tumor >14 mm and disease-free interval <2 years indicated poor prognosis. The RFS curve for pulmonary metastasectomy may plateau approximately 3 years after surgery. Pulmonary metastasectomy can achieve long-term survival in selected patients with CRC. Furthermore, surgical resection of recurrence after pulmonary metastasectomy may lead to better results. Thus, tumor size and disease-free interval may be independent prognostic factors.

Siglec10 Expression on Tumor-associated Macrophages Is an Independent Prognostic Factor in Stage I Lung Adenocarcinoma.

BACKGROUND/AIM: Prognostic indicators for postoperative lung adenocarcinoma are elusive. The interaction between CD24 on tumor cells and sialic-acid-binding Ig-like lectin 10 (Siglec10) on tumor-associated macrophages (TAMs) is implicated in immune evasion in distinct tumors. However, the therapeutic significance of phagocytic checkpoints in lung adenocarcinoma remains unknown. We aimed to investigate the clinical relevance and prognostic significance of phagocytosis checkpoints mediated by Siglec10 in TAMs of patients with lung adenocarcinoma who underwent curative resection. PATIENTS AND METHODS: In this single-center retrospective study, we analyzed the data of 423 patients with stage I lung adenocarcinoma resected between 1999 and 2016. Tissue microarrays were constructed, and CD24, CD68, and Siglec10 immunohistochemistry was performed. Additionally, we assessed the clinical significance and prognostic associations of these markers. RESULTS: CD24 expression was higher in the Siglec10-high expression group than that in the -low expression group. Multivariate analysis showed that combined high Siglec10 and CD24 expression was an independent predictor of recurrence-free probability. The combined high Siglec10 and CD68 expression was a significant independent predictor of overall survival. Univariate analysis demonstrated that the 5-year probability of post-recurrence survival of patients with combined high Siglec10 and CD68 expression was lower than that of the other patients. CONCLUSION: High TAM Siglec10 expression and tumor CD24 expression are correlated, and the high Siglec10+CD24 combination is a major risk factor for recurrence. CD68+Siglec10 TAMs are important prognostic factors. Siglec10 expression on TAMs is essential for tumor microenvironment immunoregulation and offers a promising new immunotherapeutic approach for lung adenocarcinoma.

Investigating the association of maternal heart rate variability with fetal birth weight.

Maternal heart rate (HR) was reported to affect birth weight and birth outcomes. Low birth weight constitutes a major health problem, and it is estimated that around 15% to 20% of births worldwide are low weight. In our previous study, we discussed the presence of similarities between maternal and fetal HRs, therefore, here, we propose to develop a parameter based on maternal and fetal HR variability (HRV) to divide data into two patterns to investigate the association of fetal birth weight with maternal HR and HRV. The parameter was derived from non-invasive records of maternal and fetal electrocardiograms (ECGs) that were collected from 78 subjects (age: 22 - 44 years old, gestational age (GA): 19 - 40 weeks). The HRV parameter was calculated by first evaluating the standard deviation (SD) of the number of R peaks occurring per 2 seconds (snRpp2s). Then, the difference between maternal and fetal snRpp2s (dmf) was calculated. The correlation between our derived parameter [dmf] with GA revealed a significant correlation that suggested the dmf's association with fetal development. The association analysis results between birthweight with maternal HR and HRV per pattern showed that significant negative correlations exist between them in one pattern. Still, the same correlations were not observed in the other pattern. This study's findings emphasise maternal health's role in fetal development assessment. In addition, this study highlights the importance of developing novel factors for properly assessing fetal development and birth outcomes.

(Pro)renin Receptor Down-regulation Is Associated With a Higher Risk of Recurrence in Lung Adenocarcinoma.

BACKGROUND/AIM: The (pro)renin receptor [(P)RR] plays a role not only in cardiovascular and renal diseases, but also in tumorigenesis. (P)RR contributes to the activation of the Wnt/ß-catenin signaling pathway, independent of the renin-angiotensin system. Accumulating evidence has shown that (P)RR is expressed in various human cancers. However, its clinical impact in lung carcinomas remains unclear. This study aimed to clarify the associations between (P)RR expression and clinical outcomes in patients with non-small cell lung carcinoma (NSCLC). PATIENTS AND METHODS: We analyzed the data of 913 patients with NSCLC who underwent resection between 1999 and 2016. Tissue microarrays were constructed and the expression of (P)RR and ß-catenin was investigated using immunohistochemistry. Recurrence-free probability and overall survival were analyzed using a log-rank test and Cox proportional hazards model. RESULTS: In adenocarcinomas, (P)RR down-regulation correlated significantly with high-grade tumors (p=0.026) and a higher risk of recurrence in all patients (p=0.001). Among patients with (P)RR-positive tumors, the nuclear expression of ß-catenin was associated with a higher risk of recurrence (p=0.001). Multivariate analysis revealed that (P)RR down-regulation was an independent predictor of disease recurrence (p=0.031). Conversely, in squamous cell carcinoma, (P)RR was not associated with patient outcomes. CONCLUSION: (P)RR down-regulation is associated with a higher risk of recurrence in lung adenocarcinomas, thereby characterizing a prognostic subset within high-grade tumors.

Prediction of fetal RR intervals from maternal factors using machine learning models.

Previous literature has highlighted the importance of maternal behavior during the prenatal period for the upbringing of healthy adults. During pregnancy, fetal health assessments are mainly carried out non-invasively by monitoring fetal growth and heart rate (HR) or RR interval (RRI). Despite this, research entailing prediction of fHRs from mHRs is scarce mainly due to the difficulty in non-invasive measurements of fetal electrocardiogram (fECG). Also, so far, it is unknown how mHRs are associated with fHR over the short term. In this study, we used two machine learning models, support vector regression (SVR) and random forest (RF), for predicting average fetal RRI (fRRI). The predicted fRRI values were compared with actual fRRI values calculated from non-invasive fECG. fRRI was predicted from 13 maternal features that consisted of age, weight, and non-invasive ECG-derived parameters that included HR variability (HRV) and R wave amplitude variability. 156 records were used for training the models and the results showed that the SVR model outperformed the RF model with a root mean square error (RMSE) of 29 ms and an average error percentage (< 5%). Correlation analysis between predicted and actual fRRI values showed that the Spearman coefficient for the SVR and RF models were 0.31 (P < 0.001) and 0.19 (P < 0.05), respectively. The SVR model was further used to predict fRRI of 14 subjects who were not included in the training. The latter prediction results showed that individual error percentages were (≤ 5%) except in 3 subjects. The results of this study show that maternal factors can be potentially used for the assessment of fetal well-being based on fetal HR or RRI.

Synthesis and anti-tumor activities in human leukemia-derived cells of polyenylpyrroles with a methyl group at the conjugated polyene terminus.

To develop novel drugs for treating T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) which are highly malignant hematological tumors, a series of analogs having a polyenylpyrrole structure of natural compounds (rumbrin and auxarconjugatin B) were synthesized and investigated their structure-activity relationships (SAR) of in vitro anti-T-ALL and anti-AML activities. We obtained three findings: (1) introduction of a methyl group at the conjugated polyene terminus enhanced anti-T-ALL activity, (2) analogs with a 3-chloropyrrole moiety had even higher selectivity for T-ALL cells, and (3) some analogs were effective against AML-derived cells. Among the studied compounds, 3-chloro-2-(8-ethoxycarbonylnona-1,3,5,7-tetraenyl) pyrrole 4e was the most promising candidate of T-ALL- and AML-treating drug. This study provides useful structural information for designing novel drugs treating T-ALL and AML.

Potentialities of CdZnTe Quasi-Hemispherical Detectors for Hard X-ray Spectroscopy of Kaonic Atoms at the DAΦNE Collider.

Kaonic atom X-ray spectroscopy is a consolidated technique for investigations on the physics of strong kaon-nucleus/nucleon interaction. Several experiments have been conducted regarding the measurement of soft X-ray emission (<20 keV) from light kaonic atoms (hydrogen, deuterium, and helium). Currently, there have been new research activities within the framework of the SIDDHARTA-2 experiment and EXCALIBUR proposal focusing on performing precise and accurate measurements of hard X-rays (>20 keV) from intermediate kaonic atoms (carbon, aluminum, and sulfur). In this context, we investigated cadmium-zinc-telluride (CdZnTe or CZT) detectors, which have recently demonstrated high-resolution capabilities for hard X-ray and gamma-ray detection. A demonstrator prototype based on a new cadmium-zinc-telluride quasi-hemispherical detector and custom digital pulse processing electronics was developed. The detector covered a detection area of 1 cm2 with a single readout channel and interesting room-temperature performance with energy resolution of 4.4% (2.6 keV), 3% (3.7 keV), and 1.4% (9.3 keV) FWHM at 59.5, 122.1, and 662 keV, respectively. The results from X-ray measurements at the DAΦNE collider at the INFN National Laboratories of Frascati (Italy) are also presented with particular attention to the effects and rejection of electromagnetic and hadronic background.

CD44v6 downregulation as a prognostic factor for distant recurrence in resected stage I lung adenocarcinomas.

CD44 and CD44 variant isoforms have been reported as contributing factors to cancer progression. In this study, we aimed to assess whether CD44 and its variant isoforms were correlated with the prognostic factors for distant metastasis in stage I lung adenocarcinomas using tissue microarray and immunohistochemistry. In this single-center retrospective study, we analyzed the data of 490 patients with stage I lung adenocarcinoma resected between 1999 and 2016. We constructed tissue microarrays and performed immunohistochemistry for CD44s, CD44v6, and CD44v9. The risk of disease recurrence and its associations with clinicopathological risk factors were assessed. CD44v6 expression was significantly associated with recurrence. Patients with CD44v6-negative tumors had a significantly increased risk of developing distant recurrence than patients with CD44v6-positive tumors (5-year cumulative incidence of recurrence (CIR), 10.7% vs. 4.6%; P = 0.009). However, CD44v6-negative tumors were not associated with an increased risk of locoregional recurrence compared to CD44v6-positive tumors (5-year CIR, 6.0% vs. 4.0%; P = 0.39). The overall survival (OS) of patients with CD44v6-negative tumors was significantly lower than that of patients with CD44v6-positive tumors (5-year OS: 87% vs. 94%, P = 0.016). CD44v6-negative tumors were also associated with invasive tumor size and lymphovascular invasion. Even in stage I disease, tumors with negative-CD44v6 expression had more distant recurrences than those with positive-CD44v6 expression and were associated with poor prognosis in resected stage I lung adenocarcinomas. Thus, CD44v6 downregulation may be a prognostic factor for distant metastasis in stage I lung adenocarcinomas.

Identification of compounds that preferentially suppress the growth of T-cell acute lymphoblastic leukemia-derived cells.

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most frequently occurring cancers in children and is associated with a poor prognosis. Here, we performed large-scale screening of natural compound libraries to identify potential drugs against T-ALL. We identified three low-molecular-weight compounds (auxarconjugatin-B, rumbrin, and lavendamycin) that inhibited the proliferation of the T-ALL cell line CCRF-CEM, but not that of the B lymphoma cell line Raji in a low concentration range. Among them, auxarconjugatin-B and rumbrin commonly contained a polyenyl 3-chloropyrrol in their chemical structure, therefore we chose auxarconjugatin-B for further analyses. Auxarconjugatin-B suppressed the in vitro growth of five human T-ALL cell lines and two T-ALL patient-derived cells, but not that of adult T-cell leukemia patient-derived cells. Cultured normal T cells were several-fold resistant to auxarconjugatin-B. Auxarconjugatin-B and its synthetic analogue Ra#37 depolarized the mitochondrial membrane potential of CCRF-CEM cells within 3 h of treatment. These compounds are promising seeds for developing novel anti-T-ALL drugs.

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder.

Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. The kynurenine pathway (KP) is a major route of the essential amino acid L-tryptophan (Trp) catabolism in mammalian cells. Activation of the KP following neuro-inflammation can generate various endogenous neuroactive metabolites that may impact brain functions and behaviors. Additionally, neurotoxic metabolites and excitotoxicity cause long-term changes in the trophic support, glutamatergic system, and synaptic function following KP activation. Therefore, investigating the role of KP metabolites during neurodevelopment will likely promote further understanding of additional pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). In this review, we describe the changes in KP metabolism in the brain during pregnancy and represent how maternal inflammation and genetic factors influence the KP during development. We overview the patients with ASD clinical data and animal models designed to verify the role of perinatal KP elevation in long-lasting biochemical, neuropathological, and behavioral deficits later in life. Our review will help shed light on new therapeutic strategies and interventions targeting the KP for neurodevelopmental disorders.

MMP-7 expression is associated with a higher rate of tumor spread through air spaces in resected lung adenocarcinomas.

OBJECTIVES: The spread through air spaces (STAS) of adenocarcinoma (ADC) is a unique pattern for local invasion, which comprises the spread of tumor cells within air spaces beyond the tumor edge without a direct connection with the primary tumor. Matrix metalloproteinase-7 (MMP-7), a secreted proteolytic enzyme that degrades various extracellular matrix components and other substrates, regulates several pathophysiological processes as well as the occurrence and development of cancers in humans. Here, we retrospectively analyzed a cohort of Japanese patients with treatment-naive, surgically-resected lung ADC to assess whether MMP-7 is associated with STAS development and if it could be used as a predictor of STAS. MATERIALS AND METHODS: We performed histological evaluation using hematoxylin and eosin staining and immunohistochemical analysis using microarrays. Thereafter, we scored the examined tissues for immune markers to identify significant tumor STAS predictors. RESULTS: We identified that high MMP-7 expression is an independent predictor of a high STAS incidence. Multivariate analysis revealed that MMP-7 expression was correlated with tumor behavior and poor prognosis. Furthermore, STAS remained significantly associated with a higher risk of ADC recurrence. CONCLUSION: The development of tumor STAS could be promoted by the functioning of MMP-7. This study could be a crucial basis for future investigations on the detection of tumor STAS.

Dual Image Navigation to Secure Surgical Margins in Thoracoscopic Segmentectomy.

PURPOSE: Video-assisted thoracoscopic surgery (VATS) segmentectomy is being increasingly used for the management of non-small cell lung cancer. For non-palpable lesions, surgeons frequently find difficulty in ensuring a sufficient surgical resection margin. OBJECTIVE: The purpose of this study was to evaluate the role of intraoperative dual image navigation in combination with the infrared thoracoscopy with intravenous injection of indocyanine green (IRT-ICG) method and intraoperative computed tomography (CT) in detecting oncological margins. METHODS: This study involved 34 consecutive patients who underwent both IRT-ICG and intraoperative CT-assisted thoracoscopic segmentectomy between October 2017 and July 2021. The intersegmental line on the visceral pleura was visualized using the IRT-ICG method. The intersegmental line was marked by clipping, and an intraoperative CT scan was performed under bilateral lung ventilation. Intraoperative CT or three-dimensional CT reconstruction images were used by surgeons to confirm the correct anatomic segmental border and to secure a sufficient resection margin. RESULTS: A well-defined intersegmental line was observed in 91.2% of patients. In eight cases, the surgeon needed to make some modifications to the resection line to secure a sufficient surgical margin. The mean surgical margin assessed on gross examination by the pathologist was 23.4 ± 9.0 mm. Complete resection was achieved in all patients using this approach. CONCLUSIONS: Intraoperative dual image navigation combined with the IRT-ICG method and intraoperative CT scan enables surgeons to perform definitive VATS segmentectomy for non-palpable lesions.

Similarities between maternal and fetal RR interval tachograms and their association with fetal development.

An association between maternal and fetal heart rate (HR) has been reported but, so far, little is known about its physiological implication and importance relative to fetal development. Associations between both HRs were investigated previously by performing beat-by-beat coupling analysis and correlation analysis between average maternal and fetal HRs. However, studies reporting on the presence of similarities between maternal and fetal HRs or RR intervals (RRIs) over the short term (e.g., 5-min) at different gestational ages (GAs) are scarce. Here, we demonstrate the presence of similarities in the variations exhibited by maternal and fetal RRl tachograms (RRITs). To quantify the same similarities, a cross-correlation (CC) analysis between resampled maternal and fetal RRITs was conducted; RRITs were obtained from non-invasive electrocardiogram (ECG). The degree of similarity between maternal and fetal RRITs (bmfRRITs) was quantified by calculating four CC coefficients. CC analysis was performed for a total of 330 segments (two 5-min segments from 158 subjects and one 5-min from 14 subjects). To investigate the association of the similarity bmfRRITs with fetal development, the linear correlation between the calculated CC coefficients and GA was calculated. The results from the latter analysis showed that similarities bmfRRITs are common occurrences, they can be negative or positive, and they increase with GA suggesting the presence of a regulation that is associated with proper fetal development. To get an insight into the physiological mechanisms involved in the similarity bmfRRITs, the association of the same similarity with maternal and fetal HR variability (HRV) was investigated by comparing the means of two groups in which one of them had higher CC values compared to the other. The two groups were created by using the data from the 158 subjects where fetal RRI (fRRI) calculation from two 5-min ECG segments was feasible. The results of the comparison showed that the maternal very low frequency (VLF) HRV parameter is potentially associated with the similarity bmfRRITs implying that maternal hormones could be linked to the regulations involved in the similarity bmfRRITs. Our findings in this study reinforce the role of the maternal intrauterine environment on fetal development.

Correlation between maternal and fetal heart rate increases with fetal mouse age in typical development and is disturbed in autism mouse model treated with valproic acid.

Introduction: Autism spectrum disorder (ASD) is considered a significant behavioral problem that is characterized by impairment in social interaction and communication. It is believed that some cases of ASD originate in the intrauterine maternal environment. Therefore, we hypothesized that there might be qualitative changes in the interaction between the mother and fetus in ASD during the prenatal period, hence, we investigated the similarity patterns between maternal and fetal heart rate (HR). Methods: In this study, we first demonstrate the presence and formation of similarities between maternal and fetal RR interval (RRI) collected from typical developmental mice at different embryonic days (EDs), ED13.5, ED15.5, ED17.5, and ED18.5. The similarities were quantified by means of cross-correlation (CC) and magnitude-squared coherence (MSC) analyses. Correlation analysis between the CC coefficients and EDs and between MSC coefficients and EDs showed that the same coefficients increase with EDs, suggesting that similarities between maternal and fetal RRI are associated with typical fetal development. Next, because maternal and fetal similarities were indicative of development, a comparison analysis between the autism mouse model (injected with valproic acid (VPA)), and the control group (injected with saline) was performed for ED15.5 and ED18.5. Results: The results of the comparison showed that the CC and MSC coefficients of VPA fetuses were significantly lower than that of the control group. The lower coefficients in VPA-treated mice suggest that they could be one of the features of ASD symptoms. The findings of this study can assist in identifying potential ASD causes during the prenatal period.

Immunogenicity and safety of COVID-19 vaccine in lung cancer patients receiving anticancer treatment: A prospective multicenter cohort study.

This study assessed the immunogenicity and safety of the BNT162b2 mRNA vaccine in lung cancer patients receiving anticancer treatment. We enrolled lung cancer patients receiving anticancer treatment and non-cancer patients; all participants were fully vaccinated with the BNT162b2 vaccine. Blood samples were collected before the first and second vaccinations and 4 ± 1 weeks after the second vaccination. Anti-severe respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein S1 subunit receptor-binding domain antibody titers were measured using the Architect SARS-CoV-2 IgG II Quant and Elecsys Anti-SARS-CoV-2 S assays. Fifty-five lung cancer patients and 38 non-cancer patients were included in the immunogenicity analysis. Lung cancer patients showed significant increase in the geometric mean antibody concentration, which was significantly lower than that in the non-cancer patients after the first (30 vs. 121 AU/mL, p < .001 on Architect; 4.0 vs 1.2 U/mL, p < .001 on Elecsys) and second vaccinations (1632 vs. 3472 AU/mL, p = .005 on Architect; 213 vs 573 A/mL, p = .002 on Elecsys). The adjusted odds ratio (aOR) for seroprotection was significantly lower (p < .05) in lung cancer patients than that in non-cancer patients. Analysis of the anticancer treatment types showed that the aOR for seroprotection was significantly lower (p < .05) in lung cancer patients receiving cytotoxic agents. They showed no increase in adverse reactions. BNT162b2 vaccination in lung cancer patients undergoing anticancer treatment significantly increased (p < .05) antibody titers and showed acceptable safety. Immunogenicity in these patients could be inadequate compared with that in non-cancer patients.

Model-based estimation of QT intervals of mouse fetal electrocardiogram.

BACKGROUND: Abnormal prolongation in the QT interval or long QT syndrome (LQTS) is associated with several cardiac complications such as sudden infant death syndrome (SIDS). LQTS is believed to be linked to genetic mutations which can be understood by using animal models, such as mice models. Nevertheless, the research related to fetal QT interval in mice is still limited because of challenges associated with T wave measurements in fetal electrocardiogram (fECG). Reliable measurement of T waves is essential for estimating their end timings for QT interval assessment. RESULTS: A mathematical model was used to estimate QT intervals. Estimated QT intervals were validated with Q-aortic closure (Q-Ac) intervals of Doppler ultrasound (DUS) and comparison between both showed good agreement with a correlation coefficient higher than 0.88 (r > 0.88, P < 0.05). CONCLUSION: Model-based estimation of QT intervals can help in better understanding of QT intervals in fetal mice.

Prognostic impact of tumor-infiltrating lymphocytes and neutrophils in resected non-small cell lung carcinoma.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) has been determined in non-small cell lung carcinoma; however, there is no standardized method for counting TILs. In this report, we applied the method proposed by the International Immuno-Oncology Biomarkers Working Group for the assessment of TILs to count the number of tumor-infiltrating neutrophils (TINs). We then analyzed the association between TIL counts, TIN counts, and clinicopathological factors in lung cancer. We retrospectively analyzed a series of 1191 Japanese patients with resected lung adenocarcinoma and squamous cell carcinoma, which were restaged according to the eighth edition of the TNM staging system. Tumors were classified according to the 2015 WHO classification of lung carcinoma. Recurrence-free probability (RFP) and overall survival (OS) were analyzed using the log-rank test and Cox proportional hazard model. Using multivariate analysis for patient outcome in patients with adenocarcinoma, high TIN counts were an independent prognostic factor for worse RFP (hazard ratio [HR]: 1.94, p < 0.001) and worse OS (hazard ratio [HR]: 1.75, p = 0.006). On the other hand, TIL counts were not related to patient outcome. We have demonstrated that high TINs are unfavorable prognostic markers for resected lung adenocarcinoma. In resected lung squamous cell carcinoma, TIL and TIN counts were not related to patient prognosis. It has been suggested that the immune response to cancer cells may differ depending on the histological type. An understanding of how neutrophils are programmed to perform protumor activities is necessary for the future design of targeted immunotherapies.

Tumor-associated CD163+ macrophage as a predictor of tumor spread through air spaces and with CD25+ lymphocyte as a prognostic factor in resected stage I lung adenocarcinoma.

OBJECTIVE: Lung cancer can spread in numerous ways, including spread through air spaces (STAS). A high number of CD68+ tumor-associated macrophages (TAMs), which creates a favorable microenvironment for tumor progression, is an independent predictor of increased STAS rate and is used as a pan-macrophage marker, whereas CD163 is used as an M2 macrophage marker. A high number of CD25+ tumor-infiltrating lymphocytes (TILs) is associated with the frequency of STAS. This study investigated the influence of M2 macrophages and CD25+ TILs on STAS and postoperative recurrence in patients with stage I lung adenocarcinoma who underwent curative resection. METHODS: We analyzed data from 485 patients with stage 0-I lung adenocarcinoma who underwent resection between 1999 and 2016. Tissue microarrays were constructed, and immunohistochemical analysis was performed for CD3, CD4, CD8, CD45RO, CD25, CD20, CD68, and CD163. Three tumor areas with the highest density of immune cells were photographed, and the immune cells were quantified. Associations between variables were analyzed using chi-square tests and Mann-Whitney U tests. Recurrence-free probability (RFP) was analyzed using log-rank tests and Cox proportional hazards models. RESULTS: CD163+ TAMs were identified as an independent predictor of a higher rate of STAS (P < 0.001). Analysis of biologically relevant immune cell combinations revealed that patients with high CD25+ TILs and high CD163+ TAMs had a significantly lower RFP (5-year RFP, 74%) than those with other combinations of CD25 and CD163 (5-year RFP, 90%; P < 0.001). Multivariate analysis showed that high CD25+/high CD163+ immune cell infiltration was an independent predictor of RFP. CONCLUSION: We demonstrated that a higher density of M2 macrophages is an independent predictor of a higher STAS incidence. A high CD25+/high CD163+ immune cell infiltration ratio is a significant prognostic factor for stage 0-I lung adenocarcinoma.