Clinicopathological and prognostic features of HER2-null and HER2-low advanced breast cancer treated with eribulin or capecitabine.

BACKGROUND: HER2-low populations constitute a heterogeneous group, and the cytotoxic anticancer agent efficacy based on HER2 status remains unclear. This study evaluated the clinicopathological features and outcomes of patients with advanced breast cancer showing HER2-low expression treated with eribulin or capecitabine, two treatment options after anthracycline and taxane treatment. METHODS: We retrospectively evaluated patients who were treated with eribulin or capecitabine between 2011 and 2015. HER2 status was evaluated according to the ASCO/CAP guidelines. RESULTS: No significant difference was observed in overall survival (OS; eribulin: hazard ratio [HR], 0.66; 95% CI 0.40-1.10; capecitabine: HR, 0.76; 95% CI 0.45-1.30) or progression-free survival (PFS; eribulin: HR, 1.13; 95% CI 0.72-1.78; capecitabine: HR, 0.90; 95% CI 0.56-1.44) between patients receiving eribulin (HER2-null: 35, HER2-low: 44) and those receiving capecitabine (HER2-null: 41, HER2-low: 33). Subgroup analysis revealed no significant differences in OS between the two groups in the hormone-positive and -negative populations for eribulin and capecitabine. HER2-null and HER2-low patients showed objective response rates (ORRs) of 22.5% and 9.1% (p = 0.09) overall, and 32.0% and 10.5% (p = 0.03), respectively, in hormone-positive cases among eribulin-treated patients. No response was observed in hormone-negative patients. Capecitabine treatment in HER2-null and HER2-low patients had overall ORRs of 26.8% and 15.2% (p = 0.23), respectively, with 27.3% and 16.1% (p = 0.28) for hormone-positive cases; and 25.0% and 0% (p = 1.0), respectively, for hormone-negative cases. CONCLUSIONS: Eribulin and capecitabine sensitivity may vary based on HER2 expression in patients with HER2-low and HER2-null breast cancer. Prognosis was similar between the HER2-low and the HER2-null groups.

[Antibody-Drug Conjugates in Breast Cancer and Gynecologic Cancer].

Antibody-drug conjugates(ADCs)have become widely used in the treatment of various malignancies over the past 15 years. In breast cancer, T-DM1 and T-DXd which is HER2-targeted ADC have been approved and are broadly used in Japan. Sacituzumab govitecan, TROP2-ADC has been approved in US. Hence, multiple ADCs could be used for breast cancer treatment. In gynecological cancers, tisotumab vedotin for cervical cancer and mirvetuximab soravtansine for ovarian cancer have been approved in the US. Optimizing treatment sequences and overcoming resistance mechanisms for ADC are important challenges in the situations where multiple ADCs are available. The current development landscape suggests further enhancement of ADC treatment efficacy through new targets, novel payloads, bispecific ADCs, and combination therapies with immunotherapy. This article outlines the current status of ADCs in breast and gynecological cancers, highlighting ongoing development and challenges emerging in the field.

Folate Receptor Alpha Expression and the Tumor Immune Microenvironment in Patients with Cervical Cancer.

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.

Trop-2 expression and the tumor immune microenvironment in cervical cancer.

OBJECTIVE: Trophoblast Cell Surface Antigen 2 (Trop-2) is a transmembrane glycoprotein that is overexpressed in various cancers, with immunological significance as a target for tumor-reactive T-cells. We aimed to investigate the association between the expression of Trop-2 and the tumor immune microenvironment in cervical cancer. METHODS: The study included 123 patients with cervical cancer who underwent primary surgery between 2000 and 2020 in our hospital. Trop-2 expression was evaluated using anti-Trop-2 monoclonal antibody clone MAB650. Immune biomarkers, including PD-L1 (22C3), CD3 (PS1), and CD8 (4B11), were also evaluated. Trop-2 and PD-L1 positivity were defined by an H-score ≥ 10 and a combined positive score (CPS) ≥1, respectively. Tumor-infiltrating lymphocytes (TILs) were assessed in the five selected independent areas. The correlation between Trop-2 expression and immune biomarkers was analyzed. RESULTS: The cohort comprised patients with squamous cell carcinoma (SCC) (54.5%) and non-SCC (45.5%). Trop-2 was positive in 84.6% of samples and more commonly expressed in SCC (SCC vs. non-SCC; 97.0% vs. 69.6%, p < 0.001). Intratumoral CD3+ and CD8 + TILs were significantly more common in Trop-2-positive cases (CD3, Mann-Whitney U = 383, p < 0.0001; CD8, U = 442, p < 0.0001). Additionally, significant positive correlations were found between the Trop-2 H-score and immune markers (CD3 + TILs, r = 0.295, p < 0.001; CD8 + TILs, r = 0.267, p = 0.001; PD-L1 CPS, r = 0.178, p = 0.025). No significant associations were detected between TILs and other clinicopathological features, including prognosis. CONCLUSION: Expression of Trop-2 in cervical cancer is associated with increased levels of intratumoral TILs, indicating the potential of Trop-2 targeted therapy alone or in combination with immune checkpoint inhibitors.

Predicting Trabectedin Efficacy in Soft Tissue Sarcoma: Inflammatory Biomarker Analysis.

BACKGROUND/AIM: Trabectedin is used as a treatment for advanced-stage soft tissue sarcomas (STSs), particularly liposarcoma and leiomyosarcoma. Aside from its direct effect on tumor cells, trabectedin can affect the immune system in the tumor microenvironment. This study aimed to evaluate whether inflammatory biomarkers predict trabectedin efficacy in STSs. PATIENTS AND METHODS: We retrospectively reviewed the clinical features and outcomes of patients with STS treated with trabectedin at our institution between 2016 and 2020. The neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI=neutrophil × monocyte/lymphocyte) were calculated based on the blood samples obtained prior to trabectedin treatment initiation. Analyses of overall survival (OS) and progression-free survival (PFS) were performed according to various factors. RESULTS: Of the 101 patients identified, 54 had L-sarcoma (leiomyosarcoma: 30; liposarcoma: 24), and 47 had other types of STSs. Elevated SIRI, NLR, PLR, LMR, and C-reactive protein (CRP) were associated with worse PFS (p<0.001, p=0.008, p=0.027, p=0.013, and p<0.001, respectively) according to the results of the univariate analysis. Multivariate analysis showed that elevated SIRI, other histology, and CRP were associated with poor PFS (p=0.007, p=0.008, and p=0.029, respectively). In addition, the multivariate analysis of OS showed that SIRI was an independent prognostic factor (hazard ratio=2.16, p=0.006). CONCLUSION: Pretreatment SIRI can be considered a biomarker for the prognostic prediction of patients with STS treated with trabectedin.

Discordance in PD-L1 expression using 22C3 and SP142 assays between primary and metastatic triple-negative breast cancer.

AIMS: SP142 and 22C3 assays are approved companion diagnostic assays for anti-PD-1/PD-L1 therapy selection in metastatic triple-negative breast cancer (TNBC). The discordance in PD-L1 status between primary and metastatic tumors in the same patient has been poorly characterized. Here, we examined the concordance of PD-L1 status between the two assays and between primary tumors and metastases for each assay. METHODS: We retrospectively evaluated tumor samples from 160 patients with TNBC, including 45 patients with paired primary and metastatic tumors. PD-L1 status was assessed using SP142 and 22C3 assays, to determine the immune cell (IC) score, tumor cell (TC) score (SP142 and 22C3), and combined proportion score (CPS: 22C3). RESULTS: The concordance of PD-L1 positivity at diagnostic cutoffs for SP142 (IC ≥ 1) and 22C3 (CPS ≥ 10) was substantial (κ = 0.80) in primary tumors and moderate (κ = 0.60) in metastatic tumors. In comparison, between primary and metastatic tumors, the concordance with 22C3 was moderate (κ = 0.50), whereas that with SP142 was poor (κ = -0.03). Among patients who were PD-L1 negative for both assays in primary tumors, 7/30 (23.3%) were PD-L1 positive for both or either 22C3 or SP142 in the metastatic tumors. CONCLUSIONS: The inter-assay concordance of PD-L1 positivity at diagnostic cutoffs was substantial in primary tumors and moderate in metastatic tumors. Discordance between PD-L1 status in primary and metastatic tumors was frequently observed, especially with SP142. Some patients with a PD-L1-negative status in primary tumors may still be candidates for immunotherapy, depending on the PD-L1 status in their metastatic tumors.

Lymphocyte-to-monocyte ratio as a prognostic and potential tumor microenvironment indicator in advanced soft tissue sarcoma treated with first-line doxorubicin therapy.

Prognostic value of hematologic indices and their association with the tumor microenvironment (TME) remain unclear in advanced soft tissue sarcoma (STS). We aimed to evaluate their prognostic value and correlation with the TME status in advanced STS treated with first-line doxorubicin (DXR) therapy. Clinical data and three hematological indices, including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio, were collected from 149 patients with advanced STS. The TME status was pathologically examined by CD3, CD68, and CD20 staining of resected tumor slides. In a multivariate Cox analysis, low LMR and absence of primary tumor resection were independently associated with worse overall survival (OS) (HR 3.93, p = 0.001; HR 1.71, p = 0.03). A prognostic model using these variables predicted OS with greater area under curves than those obtained using Systemic Inflammatory Score and Glasgow Prognostic Score. The LMR significantly correlated with the tumoral CD3/CD68-positive cell ratio in surgical specimens (R = 0.959, p = 0.04). In conclusion, LMR was a prognostic factor in advanced STS treated with first-line DXR therapy. LMR could partially reflect anti-tumor immunity in the TME and have the prognostic value. The potential role of LMR as an indicator of TME status warrants further investigation.

Folate receptor alpha is widely expressed and a potential therapeutic target in uterine and ovarian carcinosarcoma.

OBJECTIVE: Folate receptor alpha (FRα), which is expressed in various cancers, is a potential therapeutic target. However, its expression and clinical significance in uterine (UCS) and ovarian carcinosarcoma (OCS) remain to be elucidated. METHODS: This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery between 1997 and 2019 at our institution. Immunohistochemical staining of surgical FFPE specimens was performed for FRα and HER2. FRα was evaluated using the H-score and the 4-tired scoring system (0 to 3+). Subsequently, FRα expression (≥5% of tumor cells with ≥1+ intensity) and FRα-high (score 2+ and 3+) were evaluated. HER2 was scored according to the modified ASCO/CAP criteria. The association between FRα-high and clinicopathological features, HER2 expression, and survival was assessed in UCS. RESULTS: A total of 120 patients with UCS and nine patients with OCS were included. In UCS, FRα expression was observed in all patients, whereas FRα-high status was present in 20% of patients. Among HER2-negative UCS, 34% exhibited FRα-high. No significant association was observed between clinicopathological characteristics and FRα status. During the follow-up period (median 34.5 mo), FRα-high was not strongly associated with progression, free survival, and overall survival. All the OCS tumor specimens showed FRα-high expression. CONCLUSIONS: FRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis.

Discordances in expression of human epidermal growth factor receptor 2 between primary and metastatic uterine carcinosarcoma: A proposal for HER2-targeted therapy specimen selection.

Uterine carcinosarcoma (UCS) frequently expresses human epidermal growth factor receptor 2 (HER2) and metastasizes. However, little is known about changes in the HER2 expression status in metastatic lesions and its impact on clinical outcomes. In 41 patients with synchronous or metachronous metastases and matched primary UCSs, we assessed the HER-2 expression using immunohistochemistry and scored it per the 2016 American Society of Clinical Oncology/College of American Pathologists guidelines, modified for UCS. We compared HER2 scores between paired primary and metastatic lesions and reviewed the association between clinicopathological characteristics and impact on overall survival. HER2 scores of 3+, 2+, 1+, and 0 were observed in 12.2 %, 34.2 %, 26.8 %, and 26.8 % of primary tumors, respectively, and 9.8 %, 19.5 %, 43.9 %, and 26.8 % of metastatic tumors, respectively. HER2 intratumoral heterogeneity occurred in 46.3 % and 19.5 % of the primary and metastatic lesions, respectively. The agreement rate of the HER2 score was 34.2 % in the four-tiered scale, while it was 70.7 % in the two-tiered scale (score 0 vs. score ≥ 1+) with fair agreement (к = 0.26). Patients with HER2 discordance showed significantly shorter overall survival (hazard ratios = 2.38, 95 % confidence interval 1.01-5.5, p = 0.049). HER2 discordance was not associated with specific clinicopathological characteristics. Discordance in HER2 status between primary and metastatic tumors in UCS was frequently observed regardless of clinicopathological characteristics and was a poor prognostic factor. Even if one tumor (primary or metastatic) is HER2 negative, HER2 testing of other tumors may be beneficial in terms of patient treatment options.

Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer.

Introduction: Triple-negative breast cancer (TNBC) is negative for hormone receptors and human epidermal growth factor receptor 2 (HER2). In stage I TNBC, adjuvant therapy or follow-up are performed according to risk factors, but clinical trial data is scarce. In recent years, it has been reported that HER2-low cases (1+/2+ and in situ hybridization negative) have different prognoses than HER2-0 cases. However, the risk of recurrence and risk factors in this HER2-low population for stage I TNBC have not yet been investigated. Methods: Herein, out of 174 patients with TNBC who underwent surgery from June 2004 to December 2009 at the National Cancer Center Hospital (Tokyo), we retrospectively examined 42 cases diagnosed as T1N0M0 TNBC after excluding those treated with preoperative chemotherapy. Results: All patients were female, the median age was 60.5 years, and 11 cases were HER2-low and 31 cases were HER2-0. The median follow-up period was 121 months. Postoperative adjuvant therapy was administered in 30 patients and recurrence occurred in 8 patients. HER2-low cases showed a significantly shorter disease-free survival (HR: 7.0; 95% CI: 1.2- 40.2; P=0.0016) and a trend towards shorter overall survival (hazard ratio [HR]: 4.2, 95% confidence interval [CI]: 0.58-31.4) compared with that of HER2-0 cases. HER2 was also identified as a factor for poor prognosis from the point- estimated values in univariate and multivariate analyses after confirming that there was no correlation between the other factors. Conclusion: For patients with stage I TNBC, the HER2-low population had a significantly worse prognosis than the HER2-0 population.

Integrative prognostic analysis of tumor-infiltrating lymphocytes, CD8, CD20, programmed cell death-ligand 1, and tertiary lymphoid structures in patients with early-stage triple-negative breast cancer who did not receive adjuvant chemotherapy.

PURPOSE: Stromal tumor-infiltrating lymphocytes (TILs) are independent prognostic factors in systemically untreated early-stage triple-negative breast cancer (TNBC). Other immune biomarkers including CD8, CD20, programmed cell death-ligand 1 (PD-L1), and tertiary lymphoid structures (TLS) are also reported to be associated with prognosis. However, whether combining other immune biomarkers with TILs would allow for further prognostic stratification is unknown. METHODS: We retrospectively analyzed 125 patients with early-stage TNBC not receiving perioperative chemotherapy. Stromal TILs and TLS were evaluated on hematoxylin-eosin slides. PD-L1 expression was evaluated using the SP142 assay. CD8 and CD20 were assessed by immunohistochemistry and counted by digital pathology. RESULTS: Immune biomarker levels were positively correlated (p < 0.001). Adding CD8 and PD-L1 to multivariable analysis including clinicopathological factors (stage and histological grade) and TILs significantly improved the prognostic model (likelihood ratio χ2 = 9.24, p = 0.01). In Cox regression analysis, high CD8 was significantly associated with better prognosis [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.48-0.98, p = 0.04], and PD-L1 positivity was significantly associated with worse prognosis (HR 4.33, 95%CI 1.57-11.99, p = 0.005). Patients with high CD8/PD-L1 (-) tumors had the most favorable prognosis [5 year invasive disease-free survival (iDFS), 100%], while patients with low CD8/PD-L1( +) tumors had the worst prognosis (5 year iDFS, 33.3%). CONCLUSION: CD8 and PD-L1 levels add prognostic information beyond TILs for early-stage TNBC not receiving perioperative chemotherapy. CD8-positive T cells and PD-L1 may be useful for prognostic stratification and in designing future clinical trials of TNBC.

High expression of folate receptor alpha is associated with poor prognosis in patients with cervical cancer.

OBJECTIVE: Folate receptor α (FRα) is a membrane protein expressed in various solid tumors but has limited expression in normal cells. Therefore, FRα is an attractive target for cancer treatment. This study aimed to investigate the relationship between FRα expression and the clinicopathological characteristics and survivals of cervical cancer. METHODS: This retrospective study included patients with cervical cancer who underwent primary surgery between 2000 and 2020 at our institution. Immunohistochemical staining of FRα was performed using an anti-folate-binding protein/FBP antibody. FRα-positive staining was defined as ≥5% of tumor staining and FRα-high as ≥50% tumor staining with ≥2+ intensity. The association between FRα expression and survival was assessed using multivariate Cox regression analysis, adjusting for established prognostic factors. RESULTS: Overall, 123 patients were identified, and 140 tumor samples, including 17 paired primary and metastatic samples, were evaluated. As histological types, 67 patients had squamous cell carcinoma (SCC), and 56 patients had non-SCC. All primary tumors were FRα-positive. High FRα expression was observed in 25% of the cases and differed according to histology (SCC vs. non-SCC, 14.9% vs. 37.5%, p=0.004). FRα expression was significantly higher in metastatic tumors than in primary (170 [IQR, 140-205] vs. 125 [IQR, 110-150], p=0.0006). High FRα expression was significantly associated with worse overall survival (hazard ratio, 6.73; 95% confidence interval, 2.21-20.53; p=0.001). CONCLUSION: In cervical cancer, FRα expression was elevated in metastatic tumors and high expression was associated with a worse prognosis. Our study supports the development of FRα-targeted therapy for advanced cervical cancer.

The Lumbar Stenosis Prognostic Subgroups for Personalizing Care and Treatment (PROSPECTS) study: protocol for an inception cohort study.

BACKGROUND: Lumbar spinal stenosis (LSS) is a common degenerative condition that contributes to back and back-related leg pain in older adults. Most patients with symptomatic LSS initially receive non-operative care before surgical consultation. However, there is a scarcity of data regarding prognosis for patients seeking non-surgical care. The overall goal of this project is to develop and evaluate a clinically useful model to predict long-term physical function of patients initiating non-surgical care for symptomatic LSS. METHODS: This is a protocol for an inception cohort study of adults 50 years and older who are initiating non-surgical care for symptomatic LSS in a secondary care setting. We plan to recruit up to 625 patients at two study sites. We exclude patients with prior lumbar spine surgeries or those who are planning on lumbar spine surgery. We also exclude patients with serious medical conditions that have back pain as a symptom or limit walking. We are using weekly, automated data pulls from the electronic health records to identify potential participants. We then contact patients by email and telephone within 21 days of a new visit to determine eligibility, obtain consent, and enroll participants. We collect data using telephone interviews, web-based surveys, and queries of electronic health records. Participants are followed for 12 months, with surveys completed at baseline, 3, 6, and 12 months. The primary outcome measure is the 8-item PROMIS Physical Function (PF) Short Form. We will identify distinct phenotypes using PROMIS PF scores at baseline and 3, 6, and 12 months using group-based trajectory modeling. We will develop and evaluate the performance of a multivariable prognostic model to predict 12-month physical function using the least absolute shrinkage and selection operator and will compare performance to other machine learning methods. Internal validation will be conducted using k-folds cross-validation. DISCUSSION: This study will be one of the largest cohorts of individuals with symptomatic LSS initiating new episodes of non-surgical care. The successful completion of this project will produce a cross-validated prognostic model for LSS that can be used to tailor treatment approaches for patient care and clinical trials.

Case report: Response to platinum agents and poly (adenosine diphosphate-ribose) polymerase inhibitor in a patient with BRCA1 c.5096G>A (R1699Q) intermediate-risk variant.

BACKGROUND: BRCA1 c.5096G>A (p. Arg1699Gln) (hereinafter BRCA1 R1699Q) is classified as a pathogenic genetic variant despite its lower penetrance of breast and ovarian cancers compared to other BRCA1 variants. However, this mutation is currently reported as a 'special interpretation' variant in the BRACAnalysis® because the response to platinum agents and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors remains unknown in patients with this mutation. CASE PRESENTATION: We present a case of stage IIIc high-grade primary peritoneal cancer in a 69-year-old woman with germline BRCA1 R1699Q variant. She received platinum-containing chemotherapy followed by surgery. Eight months later, the patient experienced recurrence and received six cycles of chemotherapy and olaparib maintenance therapy. However, the disease progressed after only 5 months, and she received another chemotherapy drug. This patient responded slightly to platinum agents and had shorter progression-free survival on olaparib compared with clinical trial data. myChoice® CDx also showed Genomic Instability Score (GIS) was 50. This patient had no other gene mutations which could cause homologous recombination deficiency. CONCLUSION: This is the first report of the clinical outcome of PARP inhibitor and platinum-containing chemotherapy in a patient with a BRCA1 R1699Q variant. Despite BRCA1 mutation and high GIS, used as indicators of drug sensitivity, the recurrent tumor did not respond well to platinum agents and olaparib. BRCA1 R1699Q variant could differ from others in cancer risk and in drug response. Further studies are needed to confirm these observations.

ANGPTL4 Expression Is Increased in Epicardial Adipose Tissue of Patients with Coronary Artery Disease.

Epicardial adipose tissue (EAT) is known to affect atherosclerosis and coronary artery disease (CAD) pathogenesis, persistently releasing pro-inflammatory adipokines that affect the myocardium and coronary arteries. Angiopoietin-like 4 (ANGPTL4) is a protein secreted from adipose tissue and plays a critical role in the progression of atherosclerosis. Here, the expression of ANGPTL4 in EAT was investigated in CAD subjects. Thirty-four consecutive patients (13 patients with significant CAD; 21 patients without CAD) undergoing elective open-heart surgery were recruited. EAT and pericardial fluid were obtained at the time of surgery. mRNA expression and ANGPTL4 and IL-1ß levels were evaluated by qRT-PCR and ELISA. The expression of ANGPTL4 (p = 0.0180) and IL-1ß (p < 0.0001) in EAT significantly increased in the CAD group compared to that in the non-CAD group and positively correlated (p = 0.004). Multiple regression analysis indicated that CAD is a contributing factor for ANGPTL4 expression in EAT. IL-1ß level in the pericardial fluid was significantly increased in patients with CAD (p = 0.020). Moreover, the expression of ANGPTL4 (p = 0.004) and IL-1ß (p < 0.001) in EAT was significantly increased in non-obese patients with CAD. In summary, ANGPTL4 expression in EAT was increased in CAD patients.

Diagnostic value of tumor markers in identifying favorable or unfavorable subsets in patients with cancer of unknown primary: a retrospective study.

BACKGROUND: Routine measurement of tumor markers is not recommended in daily clinical practice for patients with cancer of unknown primary (CUP). We evaluated the diagnostic value of tumor markers in identifying favorable or unfavorable subsets in patients with CUP. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with CUP between October 2010 and July 2015 at the National Cancer Center Hospital. The tumor markers of the patients were examined, including squamous cell carcinoma antigen, cytokeratin fraction, carcinoembryonic antigen, sialyl Lewis X, neuron-specific enolase, pro-gastrin-releasing peptide, α-fetoprotein, protein induced by vitamin K absence or antagonist II, prostate-specific antigen, soluble interleukin-2 receptor, carbohydrate antigen 19-9, cancer antigen 125, cancer antigen 15-3, NCC-ST-439 (ST439), elastase-1, human chorionic gonadotropin, and sialyl-Tn (STN). RESULTS: Among 199 patients with suspected CUP, 90 were diagnosed with confirmed CUP (12 in the favorable subset and 78 in the unfavorable subset). No tumor markers showed 100% sensitivity for unfavorable subsets. ST439 (p = 0.03) and STN (p = 0.049) showed 100% specificity for unfavorable subsets. CONCLUSIONS: For patients with suspected CUP who show elevated ST439 or STN levels, the treatment strategy should be based on the premise that the patient is likely to be placed in the unfavorable subset.

Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives.

Endometrial cancer is the most common gynecological cancer in developed countries, and its incidence has increased. The majority of patients with endometrial cancer have an early disease and favorable prognosis; however, a significant proportion of endometrial cancer, which mainly comprises high-grade or type II endometrial cancer such as serous, clear cell, and carcinosarcoma, shows advanced/recurrent disease and dismal prognosis. Novel therapeutic development is required for patients with aggressive endometrial cancers. Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2 (HER2) overexpression/gene amplification in 20%-40% of patients with type II endometrial cancer. Historically, HER2 targeted therapy has been developed for various major cancers, including breast and gastric cancer. Notably, recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change. Simultaneously, an optimized HER2 test for endometrial cancer as companion diagnostics should be established. In this review, we summarize the recent findings on endometrial cancer, current treatment, optimized HER2 testing, key clinical trials on HER2 targeted therapy, and future directions in aggressive endometrial cancer, including serous carcinoma and carcinosarcoma.

Association of oral HPV16 infection with periodontal inflammation and the oral microbiome in older women.

The present preliminary study aimed to investigate the association between oral human papillomavirus type 16 (HPV16) DNA prevalence and periodontal inflammation in older women. The association between oral HPV16 infection and oral health status has not been fully elucidated in older Japanese women. The present study investigated older women aged ≥60 years who visited Hiroshima University Hospital. The present study excluded subjects with clinical factors affecting HPV infection, such as current smoking, oral cancer and pre-malignant lesions, and immunodeficiency. Finally, 46 female patients (mean age, 74.6 years) were analyzed. Quantitative PCR analysis was performed to detect HPV16 DNA in oral rinse samples. A total of 4 participants (8.7%) were HPV16 DNA positive. There was a significant association between the HPV16 DNA positivity rate and bleeding on probing (P=0.03). Additionally, Prevotella intermedia positive cases exhibited a significantly higher HPV16 DNA positivity rate than negative cases (33.3 vs 3.8%). Furthermore, analysis of 16S ribosomal RNA in bacterial flora was performed to examine microbiome diversity in participants with ≥6 mm periodontal pockets and bleeding on probing. Importantly, the average percentage of Porphyromonas was significantly higher in HPV16 DNA positive cases compared with in HPV16 DNA negative cases (5.57 vs. 1.44%). By contrast, the average percentage of Veillonella was significantly lower in HPV16 DNA positive cases than in HPV16 DNA negative cases (2.43 vs. 8.51%). Prevotella was also lower in HPV16 DNA positive cases than in HPV16 DNA negative cases (4.0 vs. 8.23%). These results indicated that people with both deep periodontal pocket inflammation and oral HPV16 infection may not have Prevotella- or Veillonella-dominant oral microbiomes, and their microbiomes may exhibit their own distinctive characteristics. In conclusion, the results suggested that oral HPV16 infection may be associated with periodontal inflammation in older Japanese women. Further research is required to clarify the detailed association between oral HPV infection and the oral microbiome.

Betel Quid Health Risks of Insulin Resistance Diseases in Poor Young South Asian Native and Immigrant Populations.

Betel quid, traditionally prepared with areca nut, betel leaf, and slaked lime, has been consumed for thousands of years, mainly in the form of chewing. Originally used for cultural, medicinal, and ceremonial purposes mainly in South Asian countries, its use has recently spread across the globe due to its psychoactive, euphoric, and aphrodisiac properties. Now it is widely used as a social lubricant and source of financial profit. Unfortunately, the profit motive has led to high rates of habitual consumption with eventual conversion to addiction among young girls and boys. Moreover, the worrisome practice of including tobacco in quid preparations has grown, particularly among pregnant women. Major health concerns include increased rates of malignancy, oral pathology, and cardiovascular, hepatic, fertility, metabolic, and neuropsychiatric disorders. Metabolic disorders and insulin resistance disease states such as type 2 diabetes, obesity, and metabolic syndrome contribute to cognitive decline and neurodegeneration. Mechanistically, the constituents of areca nut/betel quid are metabolized to N-nitroso compounds, i.e., nitrosamines, which are carcinogenic at high doses and cause insulin resistance following chronic low-level exposures. From an epidemiological perspective, the rising tide of insulin resistance diseases including obesity, diabetes, and dementias that now disproportionately burden poor countries has been propagated by rapid commercialization and enhanced access to betel quid. Public health measures are needed to impose socially and ethically responsible barriers to yet another cause of global health disparity.

A case of protein-losing gastroenteropathy caused by systemic AA amyloidosis secondary to undifferentiated carcinoma of unknown primary origin.

We report the case of a 61-year-old woman with Kartagener syndrome who presented with a 3-month history of chronic watery diarrhoea and severe hypoalbuminaemia. Histopathological examination of duodenum and large intestine biopsies showed amyloid A (AA) amyloid deposition. Scintigraphy and alpha-1 anti-trypsin clearance evaluations revealed protein-losing gastroenteropathy. Computed tomography with contrast and positron emission tomography showed a pelvic mass with multiple para-aortic lymph node enlargement. We suspected protein-losing gastroenteropathy secondary to AA amyloid produced related to malignant tumours. Following tumour resection, histopathological examination of the lesion revealed undifferentiated carcinoma of unknown origin. Postoperatively, the patient's nutritional condition improved. There has been no recurrence of protein-losing gastroenteropathy 6 months postoperatively. This is the first report of protein-losing gastroenteropathy and AA amyloidosis secondary to undifferentiated carcinoma. Early recognition and intervention could increase the likelihood of amyloidosis remission.