Cytomorphological disparities in invasive breast cancer cells following neoadjuvant endocrine therapy and chemotherapy.

INTRODUCTION: Neoadjuvant endocrine therapy (NAE) offers a breast-conserving surgery rate and clinical response rate similar to those of neoadjuvant chemotherapy (NAC), while presenting fewer adverse events and lower pathological complete response rates. The assessment of pathological response determines degenerative changes and predicts the prognosis of breast cancer treated with NAC. This study clarified the degenerative changes occurring in breast cancer following NAE. METHODS: Our study encompassed two groups: NAE, consisting of 15 patients, and NAC, comprising 18 patients. Tissue samples were obtained from core needle biopsies and surgeries. Nuclear and cell areas were calculated using Autocell analysis. Furthermore, we assessed markers associated with microtubule depolymerization (KIF2A) and initiators of apoptosis (caspase-9). RESULTS: In the NAC group, we observed significant increases in both cytoplasmic and cell areas. These changes in cytoplasm and cells were notably more pronounced in the NAC group compared to the NAE group. Post-treatment, KIF2A exhibited a decrease, with the magnitude of change being greater in the NAE group than in the NAC group. However, no discernible differences were found in caspase-9 expression between the two groups. CONCLUSION: Our findings indicate that NAE induces condensation in cancer cells via cell cycle arrest or apoptosis. Conversely, NAC leads to cell enlargement due to the absence of microtubule depolymerization. These discrepancies underscore the importance of accounting for these distinctions when establishing criteria for evaluating pathological responses.

Autopsy case with concurrent transthyretin and immunoglobulin amyloidosis.

An 85-year-old man with a history of aortic dissection suddenly fainted, underwent cardiac heart arrest, and died. An autopsy was performed, but the cause of death was not grossly identified. Congo red staining detected amyloid deposits in systemic organs, including the heart, lungs, liver, and kidneys. Immunohistochemical (IHC) analysis revealed immunoglobulin (Ig) λ light chain (-λ) in systemic blood vessels and transthyretin (TTR) in the heart and lungs. Ig-λ was predominantly positive in the blood vessels of the lungs, while TTR was detected in the alveolar septum. In the heart, Ig-λ was positive in the endocardium and blood vessels, and TTR was positive in nodular deposits between cardiomyocytes. The concurrent deposition of Ig-λ and TTR in the heart was further substantiated by laser microdissection (LMD)-liquid chromatography-tandem mass spectrometry (LC-MS/MS) at each deposition site. Despite systemic deposition of Ig-λ, bone marrow biopsy findings were not diagnostic for multiple myeloma. In summary, we present an autopsy case of concurrent Ig-λ and TTR deposition as revealed by IHC and LC-MS/MS. When Congo red staining and IHC results are indeterminate due to the deposition of multiple amyloid proteins, LMD-LC-MS/MS is useful for determining the precursor protein.

Nuclear grade and comedo necrosis of ductal carcinoma in situ as histopathological eligible criteria for the Japan Clinical Oncology Group 1505 trial: an interobserver agreement study.

OBJECTIVE: The Japan Clinical Oncology Group 1505 trial is a single-arm multicentre prospective study that examined the possibility of non-surgical follow-up with endocrine therapy for patients with low-grade ductal carcinoma in situ. In that study, the eligible criteria included histopathological findings comprising low to intermediate nuclear grade and absence of comedo necrosis, and cases were entered according to the local histopathological diagnosis. Nuclear grade is largely based on the Consensus Conference criteria (1997), whereas comedo necrosis is judged according to the Rosen's criteria (2017). The purpose of this study was to standardize and examine the interobserver agreement levels of these histopathological criteria amongst the participating pathologists. METHODS: We held slide conferences, where photomicrographs of haematoxylin-eosin-stained slides from 68 patients with ductal carcinoma in situ were presented using PowerPoint. The nuclear grade and comedo necrosis statuses individually judged by the pathologists were analysed using κ statistics. RESULTS: In the first and second sessions, where 22 cases each were presented, the interobserver agreement levels of nuclear grade whether low/intermediate grade or high grade were moderate amongst 29 and 24 participating pathologists, respectively (κ = 0.595 and 0.519, respectively). In the third session where 24 cases were presented, interobserver agreement levels of comedo necrosis or non-comedo necrosis were substantial amongst 25 participating pathologists (κ = 0.753). CONCLUSION: Although the concordance rates in nuclear grade or comedo necrosis were not high in a few of the cases, we believe that these results could provide a rationale for employing the present criteria of nuclear grade and comedo necrosis in the clinical study of ductal carcinoma in situ.

Breast cancer survival among Japanese individuals and US residents of Japanese and other origins: a comparative registry-based study.

BACKGROUND: Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO). METHOD: Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status. RESULTS: We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45-0.47 for Japanese and 0.66 [95% CI 0.59-0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51-0.55] for Japanese and 0.53 [95% CI 0.52-0.74] for USJ). CONCLUSIONS: In stage I-III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.

Expression level of long noncoding RNA H19 of normotensive placentas in late pregnancy relates to the fetal growth restriction.

AIM: Infants with fetal growth restriction (FGR) are at an increased risk of perinatal morbidity and mortality. The long noncoding RNA H19 gene is expressed abundantly in placental villi and recent studies suggest that it regulates FGR. However, the role of H19 in the FGR placenta remains unclear. This study aimed to clarify the relationship between H19 expression and FGR using normotensive placentas after 34 weeks of gestation. METHODS: Formalin-fixed paraffin-embedded tissues from human placentas collected from pregnancies resulting in small for gestational age (SGA) and appropriate for gestational age (AGA) newborns were used. The histopathological features of placenta tissues, such as villous stromal fibrosis, the numbers of terminal villi, villous vessels and cytotrophoblasts were analyzed using hematoxylin and eosin, Masson's trichrome staining and immunostaining. The localization and expression of H19 in the placentas were demonstrated by in situ hybridization and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. Moreover, the expression levels of H19-regulated molecules such as IGF2 and decorin (DCN) were measured by RT-qPCR. RESULTS: Histopathological features of the placental villous were not different between placentas associated with SGA and AGA. H19 localized to the villous stroma, endothelial cells and cytotrophoblasts. Moreover, the expression level of H19 in SGA placentas was significantly lower than that in AGA placentas. The expression levels of IGF2 and DCN in SGA placentas tended to be lower than those in AGA placentas similarly to H19. CONCLUSION: This study highlights the potential importance of regulatory events mediated by H19 in SGA placentas without histopathological abnormalities in late pregnancy.

Mucin 21 is a key molecule involved in the incohesive growth pattern in lung adenocarcinoma.

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness.

Farnesoid X receptor induces cell death and sensitizes to TRAIL-induced inhibition of growth in colorectal cancer cells through the up-regulation of death receptor 5.

Farnesoid X receptor (FXR) exhibits critical anti-cancer functions in several types of cancer, including colorectal cancer, in vitro and in vivo. However, the underlying mechanism remains unclear. We evaluated pharmacological activation of FXR with the synthetic agonist GW4064 using comprehensive proteomic analysis in colorectal cancer cell lines (HCT116, SW480, and DLD1). Among the commonly detected proteins in all three cell lines, death receptor 5 (DR5) was the most up-regulated protein, and key autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 alpha/beta (MLP3A/3B) and p62 sequestosome-1 (SQSTM), were also differentially expressed. Western blot analysis showed that GW4064 stimulation induced activation of the extrinsic death signaling pathway in all cell lines and induced activation of the intrinsic death signaling pathway in DLD1 cells. Western blotting showed that DR5 up-regulation was associated with inhibition of autophagic activity. These results suggest that FXR activation induced DR5 up-regulation through inhibition of autophagic activity and the DR5-related death signaling pathway. In addition, DR5 selective ligand, also known as TRAIL, has been widely used for anti-cancer treatment in several clinical trials. Co-treatment of TRAIL with GW4064 synergistically inhibited colorectal cancer cell proliferation as compared with single treatments. To the best of our knowledge, our results provide novel insights into FXR function in cancer cell lines. These findings may contribute to a new therapeutic strategy for colorectal cancer.

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

AIMS: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. METHODS AND RESULTS: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. CONCLUSIONS: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Dysregulation of Epstein-Barr Virus Infection in Hypomorphic ZAP70 Mutation.

Background: Some patients with genetic defects develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD)/lymphoma as the main feature. Hypomophic mutations can cause different clinical and laboratory manifestations from null mutations in the same genes. Methods: We sought to describe the clinical and immunologic phenotype of a 21-month-old boy with EBV-associated LPD who was in good health until then. A genetic and immunologic analysis was performed. Results: Whole-exome sequencing identified a novel compound heterozygous mutation of ZAP70 c.703-1G>A and c.1674G>A. A small amount of the normal transcript was observed. Unlike ZAP70 deficiency, which has been previously described as severe combined immunodeficiency with nonfunctional CD4+ T cells and absent CD8+ T cells, the patient had slightly low numbers of CD8+ T cells and a small amount of functional T cells. EBV-specific CD8+ T cells and invariant natural killer T (iNKT) cells were absent. The T-cell receptor repertoire, determined using next generation sequencing, was significantly restricted. Conclusions: Our patient showed that a hypomorphic mutation of ZAP70 can lead to EBV-associated LPD and that EBV-specific CD8+ T cells and iNKT cells are critically involved in immune response against EBV infection.

Prognostic utility of atypical mitoses in patients with breast cancer: A comparative study with Ki67 and phosphohistone H3.

BACKGROUND AND OBJECTIVES: Emerging evidence suggests that the presence of atypical mitoses is associated with poor prognosis in some types of cancer, but its clinical significance remains uncertain. Here, we investigated the occurrence of atypical mitoses in breast cancers. METHODS: Mitotic figures, including normal and atypical mitoses, were assessed in resected histological sections from 109 patients with invasive carcinoma of no special type (ICNST). Comparisons with clinicopathological features and biomarkers such as Ki67 and phosphohistone H3 (PHH3) were performed. RESULTS: The total number of mitotic figures, including atypical mitoses, was higher in situ and invasive ductal carcinoma components than in normal ducts. Morphological characteristics of atypical mitoses included multipolar, lagged, ring, asymmetrical mitoses, and anaphase bridge. Patients with higher total mitoses and PHH3, and the presence of atypical mitoses showed reduced overall survival (OS), compared to those with lower total mitoses and PHH3, and without atypical mitoses (P = 0.03, 0.02, and <0.001, respectively). In multivariate analysis, the presence of atypical mitoses alone attained significant correlation with shorter OS (P < 0.001). CONCLUSIONS: Atypical mitoses in routinely resected specimens have a robust prognostic value for ICNST of the breast, but its clinical utility remains to be validated in a multicenter large material.

Breast carcinoma with osteoclast-like giant cells: A cytological-pathological correlation with a literature review.

Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare disease characterized by the infiltration of OGCs in the tumor; however, cytological aspects of this tumor type remain elusive. We examined the cytological features in fine needle aspiration (FNA) biopsy smears obtained from 5 patients who were histologically diagnosed with breast carcinoma with OGCs. We compared FNA and clinicopathological findings with results from the published literature. Histological assessment of the resected samples showed that all tumors exhibited a histological grade 1 phenotype with a predominant cribriform architecture. Four patients were estrogen receptor positive, and 1 patient showed a triple negative phenotype. All patients survived without tumor recurrence. In the FNA smears, tumor cells were arranged in loosely cohesive clusters, characterized by varying degrees of OGCs infiltration and rare formation of solid tumor nests. Occasionally, 2- or 3-dimensional clusters of tumor cells were found, accompanied by OGCs at the peripheral regions. In all patients, tumor cells were small without severe nuclear atypia. None of the patients showed significant background necrosis. In summary, cytological features of breast carcinoma with OGCs are characterized by loose aggregates of low grade tumor cells, the presence of OGCs, and the absence of necrosis, all of which were consistent with features reported previously. This peculiar form of breast tumors should be included in the differential diagnosis, when physicians encounter FNA findings including low grade ductal carcinoma with the admixture of multinucleated giant cells or OGCs.

Clinicopathological significance of a solid component in papillary thyroid carcinoma.

AIMS: Solid variant of papillary thyroid carcinoma (SVPTC) is characterized by a solid component (SC) involving more than 50% of the tumour with the preservation of the classical cytological features of papillary thyroid carcinoma (PTC). However, the clinical significance of SC in PTC has been rarely examined. Herein, we investigated retrospectively the clinicopathological features of PTC with various degrees (10-85%) of SC (PTCSC). METHODS AND RESULTS: Patients with PTCSC (n = 27) were stratified into SC-major (SC > 50% of the tumour) and SC-minor (SC < 49%) groups. The clinicopathological parameters were compared to the well-differentiated PTC (WPTC) group (n = 47). Both SC-minor (n = 18) and SC-major (n = 9) groups had increased incidence of a large-sized tumour, extracapsular extension and a high recurrence rate, compared to WPTC. Disease-free survival (DFS) of both SC-minor and SC-major was shorter than that of WPTC (P = 0.035 and P = 0.016, respectively). Overall survival was similar among all the groups. Univariate analysis revealed that SC was associated significantly with a recurrence rate (P = 0.018). Using multivariate analysis, SC appeared to be associated with a recurrence rate with borderline significance (P = 0.055). CONCLUSIONS: Our findings indicate that the presence of SC in PTC, regardless of the proportion, is associated with adverse clinical parameters and a shorter DFS.

An international study to increase concordance in Ki67 scoring.

Although an important biomarker in breast cancer, Ki67 lacks scoring standardization, which has limited its clinical use. Our previous study found variability when laboratories used their own scoring methods on centrally stained tissue microarray slides. In this current study, 16 laboratories from eight countries calibrated to a specific Ki67 scoring method and then scored 50 centrally MIB-1 stained tissue microarray cases. Simple instructions prescribed scoring pattern and staining thresholds for determination of the percentage of stained tumor cells. To calibrate, laboratories scored 18 'training' and 'test' web-based images. Software tracked object selection and scoring. Success for the calibration was prespecified as Root Mean Square Error of scores compared with reference <0.6 and Maximum Absolute Deviation from reference <1.0 (log2-transformed data). Prespecified success criteria for tissue microarray scoring required intraclass correlation significantly >0.70 but aiming for observed intraclass correlation ≥0.90. Laboratory performance showed non-significant but promising trends of improvement through the calibration exercise (mean Root Mean Square Error decreased from 0.6 to 0.4, Maximum Absolute Deviation from 1.6 to 0.9; paired t-test: P=0.07 for Root Mean Square Error, 0.06 for Maximum Absolute Deviation). For tissue microarray scoring, the intraclass correlation estimate was 0.94 (95% credible interval: 0.90-0.97), markedly and significantly >0.70, the prespecified minimum target for success. Some discrepancies persisted, including around clinically relevant cutoffs. After calibrating to a common scoring method via a web-based tool, laboratories can achieve high inter-laboratory reproducibility in Ki67 scoring on centrally stained tissue microarray slides. Although these data are potentially encouraging, suggesting that it may be possible to standardize scoring of Ki67 among pathology laboratories, clinically important discrepancies persist. Before this biomarker could be recommended for clinical use, future research will need to extend this approach to biopsies and whole sections, account for staining variability, and link to outcomes.

A lethal intracranial Rosai-Dorfman disease of the brainstem diagnosed at autopsy.

Rosai-Dorfman disease (RDD) is a benign histiocytic proliferative disorder characterized by the accumulation of histiocytes in lymph nodes and various other organs. RDD seldom involves the central nervous system, and cases of purely intracranial RDD are particularly rare. We report a case of purely intracranial RDD involving the brainstem that was diagnosed at autopsy. A 68-year-old woman visited our hospital because of visual disturbances and loss of energy. Magnetic resonance imaging revealed an obscure mass in the brainstem. Despite exhaustive work-ups, the etiology of the intracranial mass remained unclear. The patient died of respiratory depression, and an autopsy was performed for pathological investigation. Macroscopically, a pink pale mass 2.5 cm in diameter was found in the brainstem, with no attachment to the dura. Histologically, it was composed of histiocytic cells with incorporation of small lymphocytes (emperipolesis). Immunohistochemical staining revealed that the cells were positive for CD68 and S100 and negative for CD1a, consistent with a diagnosis of RDD. Purely intracranial RDD is extremely rare and considered benign. To date, nine cases (including ours) have been reported. To our knowledge, this is the first case of intracranial RDD with autopsy. Although generally considered benign, RDD involving the brainstem might be lethal.

Reduction in the size of enlarged pelvic lymph nodes after chemoradiation therapy is associated with fewer lymph node metastases in locally advanced rectal carcinoma.

PURPOSE: We hypothesized that a reduction in the size of the lymph nodes after neoadjuvant therapy for locally advanced rectal carcinoma would be associated with decreased lymph node metastases and/or a better prognosis. METHODS: Between March 2006 and April 2012, 71 patients with primary rectal cancer received neoadjuvant chemoradiation therapy (CRT). For all lymph nodes 5 mm or larger in size, the major and minor axes were measured on CT scan images, and the product was calculated. The lymph node size was determined before and after CRT. The patients were divided into three groups based on the lymph node size before and after treatment. Group A exhibited a reduction in size of 60% or more, Group B a reduction of less than 60% and Group C had no lymph node enlargement before treatment. RESULTS: The incidence of lymph node metastases on pathological examination was 15% in Group A and 50% in Group B (p = 0.006). The five-year disease-free survival in Group A was 84% compared with 78% in Group B (log rank p = 0.34). The five-year overall survival in Group A was 92% compared with 74% in Group B (log rank p = 0.088). CONCLUSIONS: A reduction in the size of enlarged lymph nodes after neoadjuvant therapy may be a useful prognostic factor for recurrence and survival.

Immunohistochemical analysis of the expression of E-cadherin and ZEB1 in non-small cell lung cancer.

We performed an immunohistochemical analysis of the expression of zinc-finger E-box binding homeobox 1 (ZEB1), a master regulator of epithelial-mesenchymal transition (EMT), and determined its relationship with E-cadherin in 157 non-small cell lung carcinomas (93 adenocarcinomas, 36 squamous cell carcinomas, 18 large cell carcinomas, and 10 pleomorphic carcinomas). Although the expression of E-cadherin was low in the subset of adenocarcinomas (10%) and squamous cell carcinomas (11%), ZEB1 expression was only observed in one case of squamous cell carcinoma and none of the adenocarcinomas. In contrast, the low expression of E-cadherin (50% and 90%, respectively) and the positive expression of ZEB1 (11% and 50%, respectively) were more frequently observed in poorly differentiated carcinomas (large cell carcinomas and pleomorphic carcinomas). Overall, the expression of ZEB1 was inversely correlated with that of E-cadherin. Furthermore, the distribution of ZEB1-positive cancer cells was more restricted than in the area in which the expression of E-cadherin was lost, and the former was detected within the latter. We concluded that the expression of ZEB1 was not necessarily associated with the low expression of E-cadherin in lung adenocarcinomas and squamous cell carcinomas. The expression of ZEB1 correlated with an undifferentiated and/or sarcomatoid morphology that may occur in the late stage of EMT.

Immunohistochemical Diagnosis of Amyloid Typing: Utility and Limitations as Determined by Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Although immunohistochemical techniques and proteomic analysis are widely used for typing diagnosis of amyloidosis, the diagnostic utility of immunohistochemical evaluation is not well understood. METHODS: We used immunohistochemical techniques to characterize staining patterns of in-house rabbit polyclonal anti-κ, anti-λ, anti-transthyretin antibodies, and commercial anti-amyloid A and anti-ß2-microglobulin antibodies in 40 autopsy cases. RESULTS: In thirty cases (75%), the subtype was determined by using the criterion that amyloid is strongly and diffusely positive for one antibody while negative for other antibodies. We then performed proteomic analysis of all 40 cases. In 39 cases, we identified only one amyloid protein and confirmed the immunohistochemically determined subtypes of the abovementioned 30 cases. In seven other cases, we could retrospectively determine subtypes with immunohistochemistry by using information from proteomic analysis, which increased the immunohistochemistry diagnosis rate to 92.5% (37/40). In one case, we identified double subtypes, both immunohistochemically and with proteomic analysis. In the remaining three cases, proteomic analysis was essential for typing diagnosis. CONCLUSIONS: The present findings suggest that combined immunohistochemistry and proteomic analysis is more useful than immunohistochemistry alone. Our findings highlight the importance of carefully interpreting immunohistochemistry for anti-TTR and light chain and offer insights that can guide amyloid typing through immunohistochemistry.

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer.

Background: The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade. Methods: We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively. Results: bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis. Conclusion: Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

Trastuzumab deruxtecan for human epidermal growth factor receptor 2-low advanced or metastatic breast cancer: recommendations from the Japanese Breast Cancer Society Clinical Practice Guidelines.

The Japanese Breast Cancer Society Clinical Practice Guidelines are published as timely guidance on clinical issues in breast cancer treatment in Japan. In the recent edition of these guidelines, we addressed a new clinical question 34 (CQ 34, systemic treatment part) "Is trastuzumab deruxtecan recommended for patients with unresectable or metastatic HER2-low breast cancer?" and a new future research question 7 (FRQ 7, pathological diagnosis part) "How is HER2-low breast cancer diagnosed for the indication of trastuzumab deruxtecan?". These questions address use of trastuzumab deruxtecan in patients with unresectable or metastatic HER2-low breast cancer who have previously received chemotherapy for metastatic disease. The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7).

Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features.

BRG1 and BRM, two core catalytic subunits in SWI/SNF chromatin remodeling complexes, have been suggested as tumor suppressors, yet their roles in carcinogenesis are unclear. Here, we present evidence that loss of BRG1 and BRM is involved in the progression of lung adenocarcinomas. Analysis of 15 lung cancer cell lines indicated that BRG1 mutations correlated with loss of BRG1 expression and that loss of BRG1 and BRM expression was frequent in E-cadherin-low and vimentin-high cell lines. Immunohistochemical analysis of 93 primary lung adenocarcinomas showed loss of BRG1 and BRM in 11 (12%) and 16 (17%) cases, respectively. Loss of expression of BRG1 and BRM was frequent in solid predominant adenocarcinomas and tumors with low thyroid transcription factor-1 (TTF-1, master regulator of lung) and low cytokeratin7 and E-cadherin (two markers for bronchial epithelial differentiation). Loss of BRG1 was correlated with the absence of lepidic growth patterns and was mutually exclusive of epidermal growth factor receptor (EGFR) mutations. In contrast, loss of BRM was found concomitant with lepidic growth patterns and EGFR mutations. Finally, we analyzed the publicly available dataset of 442 cases and found that loss of BRG1 and BRM was frequent in E-cadherin-low, TTF-1-low, and vimentin-high cases and correlated with poor prognosis. We conclude that loss of either or both BRG1 and BRM is involved in the progression of lung adenocarcinoma into solid predominant tumors with features of epithelial mesenchymal transition and loss of the bronchial epithelial phenotype. BRG1 loss was specifically involved in the progression of EGFR wild-type, but not EGFR-mutant tumors.