Associations between quantitative measures of mammographic density and terminal ductal lobular unit involution in Chinese breast cancer patients.

BACKGROUND: Higher mammographic density (MD), a radiological measure of the proportion of fibroglandular tissue in the breast, and lower terminal duct lobular unit (TDLU) involution, a histological measure of the amount of epithelial tissue in the breast, are independent breast cancer risk factors. Previous studies among predominantly white women have associated reduced TDLU involution with higher MD. METHODS: In this cohort of 611 invasive breast cancer patients (ages 23-91 years [58.4% ≥ 50 years]) from China, where breast cancer incidence rates are lower and the prevalence of dense breasts is higher compared with Western countries, we examined the associations between TDLU involution assessed in tumor-adjacent normal breast tissue and quantitative MD assessed in the contralateral breast obtained from the VolparaDensity software. Associations were estimated using generalized linear models with MD measures as the outcome variables (log-transformed), TDLU measures as explanatory variables (categorized into quartiles or tertiles), and adjusted for age, body mass index, parity, age at menarche and breast cancer subtype. RESULTS: We found that, among all women, percent dense volume (PDV) was positively associated with TDLU count (highest tertile vs. zero: Expbeta = 1.28, 95% confidence interval [CI] 1.08-1.51, ptrend = < .0001), TDLU span (highest vs. lowest tertile: Expbeta = 1.23, 95% CI 1.11-1.37, ptrend = < .0001) and acini count/TDLU (highest vs. lowest tertile: Expbeta = 1.22, 95% CI 1.09-1.37, ptrend = 0.0005), while non-dense volume (NDV) was inversely associated with these measures. Similar trend was observed for absolute dense volume (ADV) after the adjustment of total breast volume, although the associations for ADV were in general weaker than those for PDV. The MD-TDLU associations were generally more pronounced among breast cancer patients ≥ 50 years and those with luminal A tumors compared with patients < 50 years and with luminal B tumors. CONCLUSIONS: Our findings based on quantitative MD and TDLU involution measures among Chinese breast cancer patients are largely consistent with those reported in Western populations and may provide additional insights into the complexity of the relationship, which varies by age, and possibly breast cancer subtype.

Proficiency testing of diagnosis in histopathology and immunohistochemistry of breast pathology in China: results from a pilot work of National Single Disease Quality Control Program for breast cancer.

AIM: Pathologists are currently supposed to be aware of both domestic and international guidelines for breast cancer diagnosis, but it is unclear how successfully these guidelines have been integrated into routine clinical practice in China. Thus, this national proficiency testing (PT) scheme for breast pathology was set up to conduct a baseline assessment of the diagnostic capability of pathologists in China. METHODS: This national PT plan is designed and implemented according to the "Conformity assessment-General requirements for proficiency testing" (GB/T27043-2012/ISO/IEC 17043:2010). Five cases of breast cancer with six key items, including histologic type, grade, ER, PR, HER2, and Ki67, were selected for testing among 96 participants. The final PT results were published on the website of the National Quality Control Center for Cancer ( http://117.133.40.88:3927/cn/col22/362 ). RESULTS: Our study demonstrated that the median PT score was 89.5 (54-100). Two institutions with scores < 67 were deemed unacceptable. The accuracy of histologic type, ER, PR, HER2, and Ki67 was satisfactory (all > 86%). However, the histologic grade showed low accuracy (74.0%). The unacceptable results mainly included incorrect evaluation of histologic grade (36.7%), inaccurate evaluation of ER/PR/HER2/Ki67 (28.2%), incorrect identification of C-AD as IBC-NST (15.7%), inappropriate use of 1+/2+/3+ rather than staining percentage for ER/PR (6.1%), misclassification of ER/PR < 1% weak expression as positive staining (1.4%), and no evaluation of histologic grade in ILC, MC, and IMC (5.8%). CONCLUSIONS: our nationwide PT program exhibited a satisfactory baseline assessment of the diagnostic capability of pathologists in China. More importantly, we identify some areas for further improvement.

Integrated molecular characterization of esophageal basaloid squamous cell carcinoma: a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations.

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with a different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using whole exome sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and tumor mutational burden (TMB) was lower in bSCC. bSCC with an RNA expression pattern resembling cSCC had a better survival than other bSCCs. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, and epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p < 0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had a worse pathological response than bSCC receiving neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with a distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. After outcome analysis for six bSCCs with neoadjuvant immunotherapy treatment and four late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCCs. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explain the conflicting results of bSCC outcomes in existing studies. © 2022 The Pathological Society of Great Britain and Ireland.

Predicting pathological complete response of neoadjuvant radiotherapy and targeted therapy for soft tissue sarcoma by whole-tumor texture analysis of multisequence MRI imaging.

OBJECTIVES: To construct effective prediction models for neoadjuvant radiotherapy (RT) and targeted therapy based on whole-tumor texture analysis of multisequence MRI for soft tissue sarcoma (STS) patients. METHODS: Thirty patients with STS of the extremities or trunk from a prospective phase II trial were enrolled for this analysis. All patients underwent pre- and post-neoadjuvant RT MRI examinations from which whole-tumor texture features were extracted, including T1-weighted with fat saturation and contrast enhancement (T1FSGd), T2-weighted with fat saturation (T2FS), and diffusion-weighted imaging (DWI) sequences and their corresponding apparent diffusion coefficient (ADC) maps. According to the postoperative pathological results, the patients were divided into pathological complete response (pCR) and non-pCR (N-pCR) groups. pCR was defined as less than 5% of residual tumor cells by postoperative pathology. Delta features were defined as the percentage change in a texture feature from pre- to post-neoadjuvant RT MRI. After data reduction and feature selection, logistic regression was used to build prediction models. ROC analysis was performed to assess the diagnostic performance. RESULTS: Five of 30 patients (16.7%) achieved pCR. The Delta_Model (AUC 0.92) had a better predictive ability than the Pre_Model (AUC 0.78) and Post_Model (AUC 0.76) and was better than AJCC staging (AUC 0.52) and RECIST 1.1 criteria (AUC 0.52). The Combined_Model (pre, post, and delta features) had the best predictive performance (AUC 0.95). CONCLUSION: Whole-tumor texture analysis of multisequence MRI can well predict pCR status after neoadjuvant RT and targeted therapy in STS patients, with better performance than RECIST 1.1 and AJCC staging. KEY POINTS: • MRI multisequence texture analysis could predict the efficacy of neoadjuvant RT and targeted therapy for STS patients. • Texture features showed incremental value beyond routine clinical factors. • The Combined_Model with features at multiple time points showed the best performance.

The efficacy of additional surgical resection after endoscopic resection in pT1b esophageal squamous cell carcinoma: A multi-institutional retrospective study in China.

BACKGROUND: pT1b esophageal squamous cell carcinoma (ESCC) patients treated by endoscopic resection (ER) required additional treatment with surgical resection (SR) or chemoradiotherapy (CRT) according to 2020 Japan Gastroenterological Endoscopy Society (JGES) guideline. Given the evidences for this recommendation were largely based on small-size studies, our study collected 166 cases of ER-treated pT1b patients in order to investigate the efficacy of additional SR as compared to ER-alone treatment. METHODS: A multi-institutional retrospective study in China was conducted. The pT1b ESCC treated by ER + SR (n = 42) and ER-alone (n = 124) from 2007 to 2018 were recruited. Meanwhile, patients with positive lymphovascular invasion (LVI(+)) and/or with positive vertical margin (VM(+)) were put into high-risk group, and those with both VM(-) and LVI(-) were selected into low-risk group. The clinicopathological parameters, lymph node metastasis (LNM), and survival between ER + SR and ER-alone groups were analyzed. RESULTS: In high-risk group, concurrent LNM revealed in surgically resected specimens accounted for 52.6% cases in ER + SR group. After surgical removal, the incidence of post-resection LNM dropped down to 5.6%. However, in low-risk group, patients with ER + SR treatment did not exhibit any concurrent LNM in surgically resected specimens, and the incidence of their overall LNM was similar to that in ER-alone group (0% vs. 2.8%, p = 1.000). More importantly, these cases demonstrated significantly shorter overall survival (OS) than that in ER-alone group (81.8% and 100.0%, respectively, at 3 years; log-Rank: P = 0.010). CONCLUSIONS: For ER-treated pT1b patients in high-risk group, additional SR is strongly recommended. However, for those in low-risk group, additional SR does not generate much benefit for clearance of LNM, but brings harm to shorten their OS. Therefore, additional SR is not recommended for ER-treated pT1b patient in low-risk group.

Investigation of the Vibrational Characteristics of 6-Isocyano-1-Methyl-1H-Indole: Utilizing the Isonitrile Group as an Infrared Probe.

Indole derivatives have garnered considerable attention in the realm of biochemistry due to their multifaceted properties. In this study, we undertake a systematic investigation of the vibrational characteristics of a model indole derivative, 6-isocyano-1-methyl-1H-indole (6ICMI), by employing a combination of FTIR, IR pump-probe spectroscopy, and theoretical calculations. Our findings demonstrate a strong dependence of the isonitrile stretching frequency of 6ICMI on the polarizability of protic solvents and the density of hydrogen-bond donor groups in the solvent when the isonitrile group is bonded to aromatic groups. Both experimental and theoretical analyses unveil a significant correlation between the isonitrile stretch vibration of 6ICMI and the solvent acceptor number of alcohols. Furthermore, the polarization-controlled infrared pump-probe conducted on 6ICMI in dimethyl sulfoxide provides additional support for the potential use of the isonitrile stretching mode of 6ICMI as an effective infrared probe for local environments.

Immune-related histologic phenotype in pretreatment tumour biopsy predicts the efficacy of neoadjuvant anti-PD-1 treatment in squamous lung cancer.

BACKGROUND: Although neoadjuvant anti-PD-1 immunotherapies have shown good efficacy in non-small cell lung cancer (NSCLC) patients, there is still a lack of effective predictive markers. We aimed to develop a pretreatment histologic scoring system to predict the efficacy of neoadjuvant immunotherapy. METHODS: One hundred forty NSCLC cases were evaluated in this study. Initially, surgical specimens from 31 squamous cell lung cancer patients treated with neoadjuvant anti-PD-1 therapy and their eligible paired pretreatment biopsies were used for pathologic evaluation and developing the pretreatment scoring system, immune-related histologic phenotype assessment criteria (irHPC). Three trained pathologists independently scored the haematoxylin-eosin (HE) slides of the pretreatment tumour biopsies according to irHPC. The follow-up was from 07 March 2018 to 31 December 2021, mainly focusing on disease-free survival (DFS) and overall survival (OS). Second, 109 biopsies of lung squamous cell carcinoma were evaluated to explore the relationship between eosinophils and PD-L1 expression. RESULTS: Superior 2-year DFS rates and 2-year OS rates were observed in patients who achieved major pathologic response (MPR) (MPR vs. non-MPR: 92.9% vs. 78.6%; 100.0% vs. 93.3%). Whether necrosis was included in the calculation of the per cent of residual viable tumour (%RVT) or not had almost no effect on the consistency of pathologic assessment and the histological response grouping. The interpathologist variability in assessing %RVT with immune-activated phenotype was not statistically significant (P = 0.480). Four immune-related features of pretreatment biopsies were included for calculating the predictive score. The trained pathologist accurately predicted most cases according to irHPC. For interobserver reproducibility using "2 points" as the cutoff, the overall per cent agreement was 77.8%. The reliability between pathologists for a binary tumour evaluation showed "moderate" agreement (κ = 0.54). Patients with scores ≥ 2 points tended to have better 2-year DFS rates and 2-year OS rates than those with scores < 2 points (85.7% vs. 71.4%; 100.0% vs. 87.5%). CONCLUSIONS: The irHPC scoring system reflecting the preexisting immune response could be used to predict pathologic response to neoadjuvant immunotherapy, possibly further predicting the long-term prognosis, but larger trials are needed for verification.

Nano-Sized Niobium Tungsten Oxide Anode for Advanced Fast-Charge Lithium-Ion Batteries.

The further demand for electric vehicles and smart grids prompts that the comprehensive function of lithium-ion batteries (LIBs) has been improved greatly. However, due to sluggish Li+ diffusion rate, thermal runway and volume expansion, the commercial graphite as an important part of LIBs is not suitable for fast-charging. Herein, nano-sized Nb14 W3 O44 blocks are effectively synthesized as a fast-charge anode material. The nano-sized structure provides shorter Li+ diffusion pathway in the solid phase than micro-sized materials by several orders of magnitude, corresponding to accelerating the Li+ diffusion rate, which is beneficial for fast-charge characteristics. Consequently, Nb14 W3 O44 displays excellent long-term cycling life (135 mAh g-1 over 1000 cycles at 10 C) and rate capability at ultra-high current density (≈103.9 mAh g-1 , 100 C) in half-cells. In situ X-ray diffraction and Raman combined with scanning electron microscopy clearly confirms the stability of crystal and microstructure. Furthermore, the fabricated Nb14 W3 O44 ||LiFePO4 full cells exhibit a remarkable power density and demonstrate a reversible specific capacity. The pouch cell delivers long cycling life (the capacity retention is as high as 96.6% at 10 C after 5000 cycles) and high-safety performance. Therefore, nano-sized Nb14 W3 O44 could be recognized as a promising fast-charge anode toward next-generation practical LIBs.

Impact of breast cancer risk factors on clinically relevant prognostic biomarkers for primary breast cancer.

PURPOSE: In addition to impacting incidence, risk factors for breast cancer may also influence recurrence and survival from the disease. However, it is unclear how these factors affect combinatorial biomarkers for aiding treatment decision-making in breast cancer. METHODS: Patients were 8179 women with histologically confirmed invasive breast cancer, diagnosed and treated in a large cancer hospital in Beijing, China. Individual clinicopathological (tumor size, grade, lymph nodes) and immunohistochemical (IHC: ER, PR, HER2, KI67) markers were used to define clinically relevant combinatorial prognostic biomarkers, including the Nottingham Prognostic Index (NPI: combining size, grade, nodes) and IHC4 score (combining ER, PR, HER2, KI67). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between breast cancer risk factors and quartiles (Q1-Q4) of NPI and IHC4 were assessed in multivariable polytomous logistic regression models. RESULTS: Overall, increasing parity (ORtrend(95% CI) = 1.20(1.05-1.37);Ptrend = 0.007), overweight (OR(95% CI)vs normal = 1.60(1.29-1.98)), and obesity (OR(95% CI) vs normal = 2.12(1.43-3.14)) were associated with higher likelihood of developing tumors with high (Q4) versus low (Q1) NPI score. Conversely, increasing age (ORtrend(95% CI) = 0.75(0.66-0.84);Ptrend < 0.001) and positive family history of breast cancer (FHBC) (OR(95% CI) = 0.66(0.45-0.95)) were inversely associated with NPI. Only body mass index (BMI) was associated with IHC4, with overweight (OR(95% CI) vs normal = 0.82(0.66-1.02)) and obese (OR(95% CI) vs normal = 0.52(0.36-0.76)) women less likely to develop high IHC4 tumors. Notably, elevated BMI was associated with higher NPI irrespective of hormone receptor-expression status. CONCLUSIONS: Our findings indicate that factors affecting breast cancer incidence, particularly age, parity, FHBC, and BMI, may impact clinically relevant prognostic biomarkers with implications for surveillance, prognostication, and counseling.

Esophageal squamous cell carcinoma or high-grade dysplasia overlying leiomyoma, rare but not to be neglected.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) and leiomyoma are common tumors. The coexistence of these two tumors can be classified into two types: the overlying type and the separate type. The overlying type is rare. METHODS: We report 12 cases of the overlying type treated by endoscopic submucosal dissection (ESD). They underwent pre-ESD endoscopic examination with white-light imaging, iodine staining, narrow-band imaging, endoscopic ultrasound, and biopsy. The clinical, endoscopic and pathologic characteristics were reviewed. RESULTS: Among the 12 patients, 3 were female and 9 were male. The age range was 49-76 years. They accounted for 4.0% of 300 cases of esophageal leiomyoma and 1.3% of 955 cases of superficial ESCC or high-grade dysplasia treated by endoscopic resection. After endoscopic examination and biopsy, ESCC or high-grade dysplasia, combined with leiomyoma was considered in four cases; leiomyoma was considered but without the squamous lesion (underdiagnosis) in another case; and leiomyoma was mistaken for submucosal ESCC (overdiagnosis) in the other seven cases. ESD specimens showed that nine cases were intramucosal or submucosal ESCC, and three cases were high-grade dysplasia, overlying leiomyoma originating from the muscularis mucosae or muscularis propria. The 12 cases were successfully treated by ESD, with no recurrence during follow-up. CONCLUSIONS: We must keep in mind that ESCC or high-grade dysplasia can occur overlying leiomyoma. These cases are rare but should not be neglected, especially in high-risk areas for ESCC. These patients can receive appropriate treatment if overdiagnosis or underdiagnosis can be avoided.

PSMP/MSMP promotes hepatic fibrosis through CCR2 and represents a novel therapeutic target.

BACKGROUND & AIMS: C-C motif chemokine receptor 2 (CCR2) has been recognized as a promising target for the treatment of liver fibrosis. PC3-secreted microprotein (PSMP)/microseminoprotein (MSMP) is a novel chemotactic cytokine and its receptor is CCR2. In the present study we investigated the expression and role of PSMP in liver fibrosis/cirrhosis. METHODS: PSMP expression was studied in patients with fibrosis/cirrhosis and in 3 murine models of liver fibrosis, including mice treated with carbon tetrachloride (CCl4), bile-duct ligation, or a 5-diethoxycarbonyl-1,4-dihydrocollidine diet. The role of PSMP was evaluated in Psmp-/- mice and after treatment with a PSMP antibody in wild-type mice. The direct effects of PSMP on macrophages and hepatic stellate cells were studied in vitro. RESULTS: In this study, we found that PSMP was highly expressed in fibrotic/cirrhotic tissues from patients with different etiologies of liver disease and in the 3 experimental mouse models of fibrosis. Damage-associated molecular pattern molecules HMGB-1 and IL-33 induced hepatocytes to produce PSMP. PSMP deficiency resulted in a marked amelioration of hepatic injury and fibrosis. In CCl4-induced hepatic injury, the infiltration of macrophages and CCR2+ monocytes into the liver was significantly decreased in Psmp-/- mice. Consistent with the decreased levels of intrahepatic macrophages, proinflammatory cytokines were significantly reduced. Moreover, adeno-associated virus-8 vectors successfully overexpressing human PSMP in Psmp-/- mouse livers could reverse the attenuation of liver injury and fibrosis induced by CCl4 in a CCR2-dependent manner. Treatment with a specific PSMP-neutralizing antibody, 3D5, prevented liver injury and fibrosis induced by CCl4 in mice. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of LX-2 cells. CONCLUSION: PSMP enhances liver fibrosis through its receptor, CCR2. PSMP is a potentially attractive therapeutic target for the treatment of patients with liver fibrosis. LAY SUMMARY: Our present study identifies the essential role of the protein PSMP for the development and progression of liver fibrosis in humans and mice. PSMP promotes liver fibrosis through inflammatory macrophage infiltration, polarization and production of proinflammatory cytokines, as well as direct activation of hepatic stellate cells via its receptor CCR2. A PSMP antibody can significantly reduce liver fibrosis development in vivo. These findings indicate that PSMP is a potential therapeutic target and its antibody is a potential therapeutic agent for the treatment of liver fibrosis.

The relationship between terminal duct lobular unit features and mammographic density among Chinese breast cancer patients.

Extensive mammographic density (MD), a well-established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low-risk population but with high prevalence of dense breasts. Diagnostic pre-treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI-RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2 , span [µm], and acini count/TDLU) in benign tissues. Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI-RADS, c-d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 µm [SE = 24.6] vs. 393.8 µm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08-63.1; ptrend < 0.0001) compared to those with non-dense breasts (BI-RADS, a-b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of "at-risk" epithelium.

Associations between mammographic density and tumor characteristics in Chinese women with breast cancer.

PURPOSE: Mammographic density (MD) is a strong risk factor for breast cancer, yet its relationship with tumor characteristics is not well established, particularly in Asian populations. METHODS: MD was assessed from a total of 2001 Chinese breast cancer patients using Breast Imaging Reporting and Data System (BI-RADS) categories. Molecular subtypes were defined using immunohistochemical status on ER, PR, HER2, and Ki-67, as well as tumor grade. Multinomial logistic regression was used to test associations between MD and molecular subtype (luminal A = reference) adjusting for age, body mass index (BMI), menopausal status, parity, and nodal status. RESULTS: The mean age at diagnosis was 51.7 years (SD = 10.7) and the average BMI was 24.7 kg/m2 (SD = 3.8). The distribution of BI-RADS categories was 7.4% A = almost entirely fat, 24.2% B = scattered fibroglandular dense, 49.4% C = heterogeneously dense, and 19.0% D = extremely dense. Compared to women with BI-RADS = A/B, women with BI-RADS = D were more likely to have HER2-enriched tumors (OR = 1.81, 95% CI 1.08-3.06, p = 0.03), regardless of menopausal status. The association was only observed in women with normal (< 25 kg/m2) BMI (OR = 2.43, 95% CI 1.24-4.76, p < 0.01), but not among overweight/obese women (OR: 0.98, 95% CI 0.38-2.52, p = 0.96). CONCLUSIONS: Among Chinese women with normal BMI, higher breast density was associated with HER2-enriched tumors. The results may partially explain the higher proportion of HER2+ tumors previously reported in Asian women.

Age-related terminal duct lobular unit involution in benign tissues from Chinese breast cancer patients with luminal and triple-negative tumors.

BACKGROUND: Terminal duct lobular unit (TDLU) involution is a physiological process of breast tissue aging characterized by a reduction in the epithelial component. In studies of women with benign breast disease, researchers have found that age-matched women with lower levels of TDLU involution are at increased risk of developing breast cancer. We previously showed that breast cancer cases with core basal phenotype (CBP; estrogen receptor negative [ER-], progesterone receptor-negative [PR-], human epidermal growth factor receptor 2-negative [HER2-], cytokeratins (CK 5 or CK5/6)-positive [CK5/6+] and/or epidermal growth factor receptor-positive [EGFR+]) tumors had significantly reduced TDLU involution compared with cases with luminal A (ER+ and/or PR+, HER2-, CK5/6-, EGFR-) tumors from a population-based case-control study in Poland. We evaluated the association of TDLU involution with tumor subtypes in an independent population of women in China, where the breast cancer incidence rate, prevalence of known risk factors, and mammographic breast density are thought to be markedly different from those of Polish women. METHODS: We performed morphometric assessment of TDLUs by using three reproducible semiquantitative measures that inversely correlate with TDLU involution (TDLU count/100 mm2, TDLU span in micrometer, and acini count/TDLU) by examining benign tissue blocks from 254 age-matched luminal A and 250 triple-negative (TN; ER-, PR-, HER2-, including 125 CBP) breast cancer cases treated in a tertiary hospital in Beijing, China. RESULTS: Overall, we found that TN and particularly CBP cases tended to have greater TDLU measures (less involution) than luminal A cases in logistic regression models accounting for age, body mass index, parity, and tumor grade. The strongest association was observed for tertiles of acini count among younger women (aged <50 years) (CBP vs. luminal A; ORtrend 2.11, 95% CI 1.22-3.67, P = 0.008). CONCLUSIONS: These data extend previous findings that TN/CBP breast cancers are associated with reduced TDLU involution in surrounding breast parenchyma compared with luminal A cases among Chinese women, providing further support for differences in the pathogenesis of these tumor subtypes.

PC3-secreted microprotein is a novel chemoattractant protein and functions as a high-affinity ligand for CC chemokine receptor 2.

PC3-secreted microprotein (PSMP) or microseminoprotein is a newly discovered secreted protein whose function is currently unknown. In this study, PSMP was found to possess chemotactic ability toward monocytes and lymphocytes, and its functional receptor was identified as CCR2B. PSMP was identified as a chemoattractant protein from a PBMC chemoattractant platform screen that we established. The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, PBLs, and CCR2B-expressing THP-1 cells, but not peripheral blood neutrophils, even though it does not contain the classical structure of chemokines. CCR2B was identified as one receptor for PSMP-mediated chemotaxis by screening HEK293 cells that transiently expressed classical chemokine receptors; results obtained from the chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays all confirmed this finding. To further identify the major function of PSMP, we analyzed its expression profile in tissues. PSMP is highly expressed in benign prostatic hyperplasia and in some prostate cancers, and can also be detected in breast tumor tissue. In response to PSMP stimulation, phosphorylated ERK levels downstream of CCR2B signaling were upregulated in the PC3 cell line. Taken together, our data collectively suggest that PSMP is a chemoattractant protein acting as a novel CCR2 ligand that may influence inflammation and cancer development.

[Correlation between BRAF V600E mutation and clinicopathologic features of papillary thyroid carcinoma].

OBJECTIVE: To study the prevalence of the BRAF V600E mutation in papillary thyroid carcinoma (PTC) and its association with clinicopathologic features. METHODS: Two hundred and ninety-two patients with primary PTC encountered during the period from December 2010 to December 2012 and underwent surgery in Cancer Hospital, Chinese Academy of Medical Science were enrolled into the study. Polymerase chain reaction was used to amplify exon 15 of the BRAF gene from paraffin-embedded thyroid tumor specimens, followed by direct sequencing to detect the BRAF V600E mutation. Statistical analysis was performed with SPSS 16.0 for Windows. Association between BRAF mutation and clinicopathologic parameters was tested with the χ(2) test or Fisher exact test as appropriate. RESULTS: There were 87 males and 205 females in the cohort. The age of patients ranged from 13 to 84 years (mean = 43.1 years). BRAF V600E mutation was found in 190 cases (65.1%). The presence of BRAF V600E mutation correlated with age at diagnosis (older than 45 years), tumor volume (larger than 1 cm), extrathyroidal extension, classic type/tall-cell variant and advanced disease stage (P < 0.05). BRAF V600E mutation did not correlate significantly with gender, multicentricity, lymph node metastasis or anatomic location (P > 0.05). CONCLUSION: BRAF V600E mutation is associated with high-risk clinicopathologic characteristics in patients with PTC. The BRAF V600E mutation may be a potential prognostic factor in PTC patients.

Exosomal secreted SCIMP regulates communication between macrophages and neutrophils in pneumonia.

In pneumonia, the deficient or delayed pathogen clearance can lead to pathogen proliferation and subsequent overactive immune responses, inducing acute lung injury (ALI). While screening human genome coding genes using our peripheral blood cell chemotactic platform, we unexpectedly find SLP adaptor and CSK interacting membrane protein (SCIMP), a protein with neutrophil chemotactic activity secreted during ALI. However, the specific role of SCIMP in ALI remains unclear. In this study, we investigate the secretion of SCIMP in exosomes (SCIMPexo) by macrophages after bacterial stimulation, both in vitro and in vivo. We observe a significant increase in the levels of SCIMPexo in bronchoalveolar lavage fluid and serum of pneumonia patients. We also find that bronchial perfusion with SCIMPexo or SCIMP N-terminal peptides increases the survival rate of the ALI model. This occurs due to the chemoattraction and activation of peripheral neutrophils dependent on formyl peptide receptor 1/2 (FPR1/2). Conversely, exosome suppressors and FPR1/2 antagonists decrease the survival rate in the lethal ALI model. Scimp-deficient and Fpr1/2-deficient mice also have lower survival rates and shorter survival times than wild-type mice. However, bronchial perfusion of SCIMP rescues Scimp-deficient mice but not Fpr1/2-deficient mice. Collectively, our findings suggest that the macrophage-SCIMP-FPRs-neutrophil axis plays a vital role in the innate immune process underlying ALI.

Development and validation of nomograms for predicting axillary non-SLN metastases in breast cancer patients: A retrospective analysis.

Purpose: The aim of this study was to develop a nomogram for predicting positive non-sentinel lymph nodes (non-SLNs) in positive SLN breast cancer patients and validate the Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram for non-SLN metastasis in Chinese patients. Methods: The pathological features of 2,561 breast cancer patients were retrospectively reviewed, and the patients were divided into training and validation cohorts. Positive non-SLN predictors were identified using univariate and multivariate analyses and used to construct the nomogram. In patients with positive SLNs, the MSKCC nomogram was used to calculate the probability of non-SLN metastasis. The area under the receiver operating characteristic curve (AUC) was calculated to assess the accuracy of this model and the MSKCC nomogram. Results: According to multivariate logistic regression analysis, the number of positive and negative SLNs, tumor stage, lymphovascular invasion, perineural invasion, and extracapsular extension were independent predictive factors for non-SLN metastasis and were selected to establish the nomogram for predicting positive non-SLNs. This nomogram performed favorably in predicting positive non-SLNs, with AUCs of 0.765 and 0.741 for the training and validation cohorts, respectively. The MSKCC nomogram predicted non-SLN metastasis with an AUC of 0.755. Conclusion: A nomogram was developed and validated to assist clinicians in evaluating the likelihood of positive non-SLN. For Chinese patients with a known ER status before surgery, the MSKCC nomogram can be used to predict non-SLN metastases.

Case report: A rare case of tumor-to-tumor metastasis: metastatic lobular breast carcinoma to clear cell renal cell carcinoma.

Tumor-to-tumor metastasis is a rare phenomenon. Although renal cell carcinoma is the most common recipient tumor, metastatic lobular breast carcinoma to clear cell renal cell carcinoma is even rarer, with only one case reported to date. We present a 66-year-old female patient with an invasive lobular carcinoma history who was admitted to the hospital with a right renal mass. The patient received partial nephrectomy. The final established diagnosis is lobular breast carcinoma metastasizing to clear cell renal cell carcinoma (ccRCC). Thus, although rare, the simultaneous or consecutive find of a renal mass in follow-up should be carefully evaluated, especially in high-risk patients, including women with an advanced breast cancer history, as in this scenario.