Unveiling the potential of breast MRI: a game changer for BI-RADS 4A microcalcifications.

PURPOSE: To assess the diagnostic performance of breast MRI for BI-RADS 4A microcalcifications on mammography and propose a potential clinical pathway to avoid unnecessary biopsies. METHODS: Bibliometrics analysis of breast MRI and BI-RADS 4 was provided. A retrospective analysis was conducted on 139 women and 142 cases of BI-RADS 4A microcalcifications on mammography from Fudan University Shanghai Cancer Center. The mammographic BI-RADS level and the MRI reports were compared with the final pathological diagnosis. RESULTS: Much attention has been given to breast MRI and BI-RADS 4 in the literature. However, studies on BI-RADS 4A are limited. Pathological results showed 117 cases (82.4%) were benign lesions, malignant cases of 25 (17.6%) in our study. The positive predictive values (PPV), specificity, sensitivity and negative predictive values (NPV) of MRI were 44.2% (23/52), 75.2% (88/117), 92.0% (23/25), and 97.8% (88/90), respectively. Therefore, 75.2% (88/117) of biopsies for benign lesions could potentially be avoided. There were 2.2% (2/90) malignant lesions missed. Logistic regression indicated that patients who are postmenopausal (HR = 2.655, p = 0.012), have a history of breast cancer (family history) (HR = 2.833, p = 0.029), and exhibit clustered microcalcifications (HR = 2.179, p = 0.046) are more likely to have a higher MRI BI-RADS level. CONCLUSIONS: Breast MRI has the potential to improve the diagnosis of BI-RADS 4A microcalcifications on mammography. We propose a potential clinical pathway that patients with BI-RADS 4A on mammography who are premenopausal, have no personal history of breast cancer (family history) or have non-clustered distribution of calcifications can undergo MRI to avoid unnecessary biopsies.

Histological diagnosis of unprocessed breast core-needle biopsy via stimulated Raman scattering microscopy and multi-instance learning.

Core-needle biopsy (CNB) plays a vital role in the initial diagnosis of breast cancer. However, the complex tissue processing and global shortage of pathologists have hindered traditional histopathology from timely diagnosis on fresh biopsies. In this work, we developed a full digital platform by integrating label-free stimulated Raman scattering (SRS) microscopy with weakly-supervised learning for rapid and automated cancer diagnosis on un-labelled breast CNB. Methods: We first compared the results of SRS imaging with standard hematoxylin and eosin (H&E) staining on adjacent frozen tissue sections. Then fresh unprocessed biopsy tissues were imaged by SRS to reveal diagnostic histoarchitectures. Next, weakly-supervised learning, i.e., the multi-instance learning (MIL) model was conducted to evaluate the ability to differentiate between benign and malignant cases, and compared with the performance of supervised learning model. Finally, gradient-weighted class activation mapping (Grad-CAM) and semantic segmentation were performed to spatially resolve benign/malignant areas with high efficiency. Results: We verified the ability of SRS in revealing essential histological hallmarks of breast cancer in both thin frozen sections and fresh unprocessed biopsy, generating histoarchitectures well correlated with H&E staining. Moreover, we demonstrated that weakly-supervised MIL model could achieve superior classification performance to supervised learnings, reaching diagnostic accuracy of 95% on 61 biopsy specimens. Furthermore, Grad-CAM allowed the trained MIL model to visualize the histological heterogeneity within the CNB. Conclusion: Our results indicate that MIL-assisted SRS microscopy provides rapid and accurate diagnosis on histologically heterogeneous breast CNB, and could potentially help the subsequent management of patients.

Discovery of Podofilox as a Potent cGAMP-STING Signaling Enhancer with Antitumor Activity.

Cyclic GMP-AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and other cytokines. Pharmacologic activation of STING is considered a potent therapeutic strategy in cancer. In this study, we used a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP-STING signaling pathway. We found that podofilox enhanced the cGAMP-mediated immune response by increasing STING-containing membrane puncta and the extent of STING oligomerization. Furthermore, podofilox changed the trafficking pattern of STING and delayed trafficking-mediated STING degradation. Importantly, the combination of cGAMP and podofilox had profound antitumor effects on mice by activating the immune response through host STING signaling. Together, these data provide insights into the regulation of cGAMP-STING pathway activation and demonstrate what we believe to be a novel approach for modulating this pathway and thereby promoting antitumor immunity.

LL-37 transports immunoreactive cGAMP to activate STING signaling and enhance interferon-mediated host antiviral immunity.

Cyclic 2',3'-GMP-AMP (cGAMP) binds to and activates stimulator of interferon genes (STING), which then induces interferons to drive immune responses against tumors and pathogens. Exogenous cGAMP produced by infected and malignant cells and synthetic cGAMP used in immunotherapy must traverse the cell membrane to activate STING in target cells. However, as an anionic hydrophilic molecule, cGAMP is not inherently membrane permeable. Here, we show that LL-37, a human host defense peptide, can function as a transporter of cGAMP. LL-37 specifically binds cGAMP and efficiently delivers cGAMP into target cells. cGAMP transferred by LL-37 activates robust interferon responses and host antiviral immunity in a STING-dependent manner. Furthermore, we report that LL-37 inducers vitamin D3 and sodium butyrate promote host immunity by enhancing endogenous LL-37 expression and its mediated cGAMP immune response. Collectively, our data uncover an essential role of LL-37 in innate immune activation and suggest new strategies for immunotherapy.

Trend and survival benefit of contralateral prophylactic mastectomy among men with stage I-III unilateral breast cancer in the USA, 1998-2016.

PURPOSE: Our study aimed to explore temporal trends and survival benefit of contralateral prophylactic mastectomy (CPM) in male breast cancer (MBC). METHODS: Men with stage I-III unilateral breast cancer between 1998 and 2016 were identified from the surveillance, epidemiology, and end results (SEER). We compared CPM rate over the study period using the Cochrane-Armitage test for trend. Logistic regression model was used to test for factors predicting CPM. Survival analysis was conducted in patients who underwent CPM or unilateral mastectomy (UM) with a first diagnosis of unilateral breast cancer. Kaplan-Meier curve and univariate and multivariable Cox proportional hazards regression analyses were performed to compare overall survival (OS) and breast cancer-specific survival (BCSS) between CPM and UM groups. Propensity score matching was adopted to balance baseline characteristics. RESULTS: 5118 MBC cases were included in the present study, with 4.1% (n = 209) patients underwent CPM. The proportion of men undergoing CPM increased from 1.7 in 1998 to 6.3% in 2016 (P < 0.0001). Young age, recent years of diagnosis, higher tumor grade and lower T stage were significantly associated with CPM. A cohort of 3566 patients were enrolled in survival analysis with a median follow-up of 65 months. CPM was associated with better OS (HR 0.58, 95% CI 0.37-0.89, P = 0.022) rather than BCSS (HR 0.57, 95% CI 0.29-1.11, P = 0.153) compared with UM. In propensity score-matched model, CPM was not an independent prognostic factor for OS (HR 0.83, 95% CI 0.46-1.52, P = 0.553) and BCSS (HR 0.98, 95% CI 0.39-2.47, P = 0.970). CONCLUSION: Our study revealed a dramatic increase in CPM utilization among MBC, especially in young patients. However, CPM provides no survival benefit for MBC compared with UM, indicating the decision of CPM should be fully discussed.

Microcalcification-Based Tumor Malignancy Evaluation in Fresh Breast Biopsies with Hyperspectral Stimulated Raman Scattering.

Precise evaluation of breast tumor malignancy based on tissue calcifications has important practical value in the disease diagnosis, as well as the understanding of tumor development. Traditional X-ray mammography provides the overall morphologies of the calcifications but lacks intrinsic chemical information. In contrast, spontaneous Raman spectroscopy offers detailed chemical analysis but lacks the spatial profiles. Here, we applied hyperspectral stimulated Raman scattering (SRS) microscopy to extract both the chemical and morphological features of the microcalcifications, based on the spectral and spatial domain analysis. A total of 211 calcification sites from 23 patients were imaged with SRS, and the results were analyzed with a support vector machine (SVM) based classification algorithm. With optimized combinations of chemical and geometrical features of microcalcifications, we were able to reach a precision of 98.21% and recall of 100.00% for classifying benign and malignant cases, significantly improved from the pure spectroscopy or imaging based methods. Our findings may provide a rapid means to accurately evaluate breast tumor malignancy based on fresh tissue biopsies.

Transcriptional and epigenetic regulation of PD-1 expression.

Programmed cell death-1 (PD-1) is a co-inhibitory receptor that plays important roles in regulating T cell immunity and peripheral tolerance. PD-1 signaling prevents T cells from overactivation during acute infections, but it maintains T cell exhaustion during chronic infections. Tumor cells can exploit the PD-1 signaling pathway to evade antitumor immune responses. The PD-1 signaling pathway is also essential for maintaining peripheral tolerance and prevention of autoimmunity. PD-1 expression is strictly and differentially regulated by diverse mechanisms in immune cells. It is activated and repressed by distinct transcription factors in different circumstances. Moreover, epigenetic mechanisms are also involved in regulating PD-1 expression. In this review, we summarize the knowledge of the transcriptional and epigenetic regulation of PD-1 expression during different immune responses.

Value of stereotactic 11-gauge vacuum-assisted breast biopsy in non-palpable suspicious calcifications: an eight-year single institution experience with 587 patients.

BACKGROUND: Vacuum-assisted breast biopsy (VABB) has been routinely recommended for stereotactic intervention in cases of isolate mammographically-detected calcifications. Herein we aimed to evaluate and compare the diagnostic consistency and accuracy of calcified and noncalcified specimens obtained from same sites of sampling on mammography-visible calcifications. In addition, we presented the biopsy procedure and retrospectively evaluated the usefulness of VABB as well as the complications of this technique over an eight-year experience in our centre. METHODS: This single-institution observational cohort study included 587 patients referred for stereotactic 11-gauge VABB of 594 mammographically-detected calcifications between January 2010 and December 2018. The rate of histopathological underestimation, the false negative, the diagnostic consistency and accuracy between calcified and noncalcified specimens of VABB were comprehensively evaluated based on the surveillance data and final histopathological result of the surgical specimens. RESULTS: In total, 594 biopsy procedures were performed in 587 patients (mean age 46 years, range, 21-80 years). The average number of biopsy specimens was 14.7 (range, 9-21) per lesion. VABB pathological results revealed 471 (79.3%) benign, 39 (6.6%) high-risk, and 84 (14.1%) malignant cases. The diagnostic inconsistency between calcified and noncalcified specimens was 14.6% (105/123) for high-risk and malignant lesions. Furthermore, calcified specimens exhibited higher diagnostic accuracy of malignant lesion as compared with the noncalcified specimens (97.7% versus 82.6%, respectively). Underestimation rate for high-risk lesions and in situ carcinoma was 5.1% and 54.1%, respectively, along with a false negative rate of 6.25%. In addition, mild complications were reported with high patient tolerance. CONCLUSIONS: Stereotactic 11G-VABB might be preferred for the investigation of non-palpable mammographically-detected calcifications in terms of accuracy and safety profile. The high prevalence of diagnostic discordance between the specimens with and without calcifications revealed a higher value of calcified specimens in diagnosing high-risk and malignant calcifications.

The YdiU Domain Modulates Bacterial Stress Signaling through Mn2+-Dependent UMPylation.

Sensing stressful conditions and adjusting the cellular metabolism to adapt to the environment are essential activities for bacteria to survive in variable situations. Here, we describe a stress-related protein, YdiU, and characterize YdiU as an enzyme that catalyzes the covalent attachment of uridine-5'-monophosphate to a protein tyrosine/histidine residue, an unusual modification defined as UMPylation. Mn2+ serves as an essential co-factor for YdiU-mediated UMPylation. UTP and Mn2+ binding converts YdiU to an aggregate-prone state facilitating the recruitment of chaperones. The UMPylation of chaperones prevents them from binding co-factors or clients, thereby impairing their function. Consistent with the recent finding that YdiU acts as an AMPylator, we further demonstrate that the self-AMPylation of YdiU padlocks its chaperone-UMPylation activity. A detailed mechanism is proposed based on the crystal structures of Apo-YdiU and YdiU-AMPNPP-Mn2+ and on molecular dynamics simulation models of YdiU-UTP-Mn2+ and YdiU-UTP-peptide. In vivo data demonstrate that YdiU effectively protects Salmonella from stress-induced ATP depletion through UMPylation.

RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2.

Deregulation of E3 ubiquitin ligases is intimately implicated in breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, functions as a tumor suppressor in breast cancer. RNF144A was  downregulated in a subset of primary breast tumors and restoration of RNF144A suppressed breast cancer cell proliferation, colony formation, migration, invasion in vitro, tumor growth, and lung metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted heat-shock protein family A member 2 (HSPA2), a putative oncoprotein that is frequently upregulated in human cancer and promotes tumor growth and progression, for ubiquitination and degradation. Notably, the ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of breast cancer growth and metastasis, and identify RNF144A as the first, to our knowledge, E3 ubiquitin ligase for HSPA2 in human cancer.

Phosphorylated Rasal2 facilitates breast cancer progression.

BACKGROUND: Rasal2 has diametric effects on progression of oestrogen receptor-positive (ER+) and -negative (ER-) breast cancers. The relevant causes are unknown. It is also unknown whether the effects of Rasal2 are mediated by an exosome-transport process. METHODS: Exosomes were purified from breast cancer cells and identified by transmission electron microscopy and flow cytometry analysis. In vivo and in vitro experiments were conducted to investigate the role of Rasal2 in exosome-mediated breast cancer progression. Western blot analysis was performed to detect Rasal2 and p-Rasal2 (phosphorylated Rasal2) expression in ER+/ER- breast cancer cells and in exosomes, cancer tissues and blood of patients with ER+ or ER- breast cancer. FINDINGS: Phosphorylation of Rasal2 at Serine 237 promoted tumour growth in both ER+ and ER- tumour cells and tissues. The functions of both p-Rasal2 and non-p-Rasal2 (non-phosphorylated-Rasal2) in the modulation of breast cancer progression are exosome-mediated. p-Rasal2 expression in ER+ breast cancer cells and exosomes, cancer tissues and blood was significantly lower than in ER- tumour cells and patients. INTERPRETATION: p-Rasal2 facilitates tumour progression in both ER+ and ER- breast cancers. The ratio of p-Rasal2/non-p-Rasal2 in ER+ and ER- breast cancers is one of the factors deciding the role of Rasal2 (or total Rasal2) as a suppressor in ER+ breast cancers or as a promoter in ER- breast cancers. Targeting the phosphorylation of Rasal2 machinery may therefore be useful as a therapy to restrain breast cancer progression by reducing p-Rasal2/non-p-Rasal2 ratio, especially in ER- breast cancers. FUND: NSFC and Hong Kong Research Grants Council.

Is core needle biopsy effective at diagnosing male breast lesions?

PURPOSE: The objective of this study was to examine the diagnostic accuracy of sonographically guided core needle biopsy (CNB) of breast lesions in men. METHODS: This was a retrospective study where we analyzed consecutive sonographically guided 14-gauge CNB results on 234 male breast lesions. The CNB accuracy is determined by the comparison between the CNB and its corresponding excisional biopsy or to long-term follow-up imaging. RESULTS: Sonographically guided CNB was effective to collect satisfactory samples from all 234 lesions. Out of those, 58.55% (137/234) were benign, 38.0% (89/234) were malignant, 1.71% (4/234) were papilloma with atypia and 1.71% (4/234) were atypical ductal hyperplasia lesions. Underestimation occurred in 3.4% (8/234) of the lesions. As for the detection of breast malignancy, the sensitivity of the CNB is 98.9%, specificity is 100%, negative predictive value is 99.3%, positive predictive value is 100%, false positive is 0% and false negative is 1.1%. The overall accuracy of sonographically guided CNB as a diagnostic tool is 99.6%. CONCLUSION: Sonographically guided 14-gauge CNB is an accurate, reliable and low invasive procedure for assessing breast lesions in men. Triple tests and follow-up checks of benign cases are essential for a successful breast biopsy program in men.

Rapid histology of laryngeal squamous cell carcinoma with deep-learning based stimulated Raman scattering microscopy.

Maximal resection of tumor while preserving the adjacent healthy tissue is particularly important for larynx surgery, hence precise and rapid intraoperative histology of laryngeal tissue is crucial for providing optimal surgical outcomes. We hypothesized that deep-learning based stimulated Raman scattering (SRS) microscopy could provide automated and accurate diagnosis of laryngeal squamous cell carcinoma on fresh, unprocessed surgical specimens without fixation, sectioning or staining. Methods: We first compared 80 pairs of adjacent frozen sections imaged with SRS and standard hematoxylin and eosin histology to evaluate their concordance. We then applied SRS imaging on fresh surgical tissues from 45 patients to reveal key diagnostic features, based on which we have constructed a deep learning based model to generate automated histologic results. 18,750 SRS fields of views were used to train and cross-validate our 34-layered residual convolutional neural network, which was used to classify 33 untrained fresh larynx surgical samples into normal and neoplasia. Furthermore, we simulated intraoperative evaluation of resection margins on totally removed larynxes. Results: We demonstrated near-perfect diagnostic concordance (Cohen's kappa, κ > 0.90) between SRS and standard histology as evaluated by three pathologists. And deep-learning based SRS correctly classified 33 independent surgical specimens with 100% accuracy. We also demonstrated that our method could identify tissue neoplasia at the simulated resection margins that appear grossly normal with naked eyes. Conclusion: Our results indicated that SRS histology integrated with deep learning algorithm provides potential for delivering rapid intraoperative diagnosis that could aid the surgical management of laryngeal cancer.

Spindle cell sarcoma: a SEER population-based analysis.

Due to the substantial limitation of study population, Spindle cell sarcoma (SCS) was unexplored comprehensively. In this study, we investigated the clinical characteristics and disease specific prognostic factors of SCS. 3299 SCS cases were identified and extracted from Surveillance, Epidemiology, and End Results (SEER) database (1973-2017). White people account for 79.1% with median age of 57 years without predominance in any gender. Significant disease specific survival (DSS) and overall survival (OS) were found differentiated in age, T stage, N stage, M stage, AJCC stage, SEER historic stage, tumor locations, surgery, and pathologic grade. In the multivariate Cox analysis, the age >64 years (for DSS, P < 0.001 and for OS, P < 0.001; Reference age ≤64 years), AJCC stage III (for DSS, P = 0.006 and for OS, P = 0.04; Reference: AJCC stage I), and non-surgical treatment (for DSS, P < 0.001 and for OS, P < 0.001; Reference: surgery) were independently associated with worse DSS and OS. In brief, our study demonstrated that SCS mostly found in white people at fifth to seventh decades of life without gender predilection. The patient's age, AJCC stage, tumor location and surgery were independent prognostic indicators for both DSS and OS of SCS.

Epigenetic silencing of RNF144A expression in breast cancer cells through promoter hypermethylation and MBD4.

Emerging evidence shows that ring finger protein 144A (RNF144A), a poorly characterized member of the Ring-between-Ring (RBR) family of E3 ubiquitin ligases, is a potential tumor suppressor gene. However, its regulatory mechanism in breast cancer remains undefined. Here, we report that RNF144A promoter contains a putative CpG island and the methylation levels of RNF144A promoter are higher in primary breast tumors than those in normal breast tissues. Consistently, RNF144A promoter methylation levels are associated with its transcriptional silencing in breast cancer cells, and treatment with DNA methylation inhibitor 5-Aza-2-deoxycytidine (AZA) reactivates RNF144A expression in cells with RNF144A promoter hypermethylation. Furthermore, genetic knockdown or pharmacological inhibition of endogenous methyl-CpG-binding domain 4 (MBD4) results in increased RNF144A expression. These findings suggest that RNF144A is epigenetically silenced in breast cancer cells by promoter hypermethylation and MBD4.

Salmonella STM1697 coordinates flagella biogenesis and virulence by restricting flagellar master protein FlhD4C2 from recruiting RNA polymerase.

Salmonella reduces flagella biogenesis to avoid detection within host cells by a largely unknown mechanism. We identified an EAL-like protein STM1697 as required and sufficient for this process. STM1697 surges to a high level after Salmonella enters host cells and restrains the expression of flagellar genes by regulating the function of flagellar switch protein FlhD4C2, the transcription activator of all other flagellar genes. Unlike other anti-FlhD4C2 factors, STM1697 does not prevent FlhD4C2 from binding to target DNA. A 2.0 Å resolution STM1697-FlhD structure reveals that STM1697 binds the same region of FlhD as STM1344, but with weaker affinity. Further experiments show that STM1697 regulates flagella biogenesis by restricting FlhD4C2 from recruiting RNA polymerase and the regulatory effect of STM1697 on flagellar biogenesis and virulence are all achieved by interaction with FlhD. Finally, we describe a novel mechanism mediated by STM1697 in which Salmonella can inhibit the production of flagella antigen and escape from the host immune system.

Predictive factors of pathologic complete response in HER2-positive and axillary lymph node positive breast cancer after neoadjuvant paclitaxel, carboplatin plus with trastuzumab.

OBJECTIVE: This study was performed to investigate the proportion as well as the predictive factors of pathologic complete response in HER2-positive and axillary lymph node positive breast cancer after neoadjuvant paclitaxel, carboplatin plus with trastuzumab (PCH). RESULTS: The pCR rate in the breast, axilla and both was 44.3% (39/88), 47.7% (42/88) and 34.1% (30/88), respectively. Patients with and without pCR were similar in term of age, BMI, menstrual status, family history, treatment cycles and tumor characteristics (laterality and size of tumor). Multivariate logistic regression demonstrated that pCR was significantly associated with HR negativity (HR = 5.587, 95% CI 2.25-3.889, p < 0.001), high Ki67 index (HR = 4.130, 95% CI 1.607-10.610, p = 0.003). Further investigation found that patients with HR-negative/high Ki67 index had higher pCR rate, compared to other patients (HR = 7.583, 95% CI 2.503-22.974, p < 0.001). MATERIALS AND METHODS: 88 consecutive Chinese HER2-positive/axillary lymph node-positive breast cancer patients with neodjuvant therapy regimen containing paclitaxel, carboplatin and trastuzumab were divided into two groups: pathological complete response (pCR) or non-pCR group. Clinico-pathological characteristics were compared and analyzed, and univariate and multivariate analyses were performed to detect the predictive factors of pCR. CONCLUSIONS: Preoperative PCH regimen was an effective neoadjuvant therapy in HER2 positive and axillary lymph node positive patients, and patients coexisting with HR-negative and high Ki67 index may benefit more from this regimen.

Spindle cell carcinoma: the general demographics, basic clinico-pathologic characteristics, treatment, outcome and prognostic factors.

BACKGROUND: Owing to the rarity, the general demographics, basic clinico-pathologic features, management, outcome and prognostic factors of spindle cell carcinoma (SpCC) were unexplored. METHODS: A SEER analysis was performed with 2336 cases (1973-2016). RESULTS: A peak incidence occurred at 70~80 years without any gender predominance and 83.13% occurred in white people. The respiratory system was mostly affected tumor site (35%). Significant overall survival (OS) and disease specific survival (DSS) were found differentiated in gender, age, marital status, primary tumor location, AJCC stage, T stage, N stage, M stage, pathologic grade and treatment modality. In the multivariate Cox model, the age > 69 years (Hazard ratio [HR] = 1.427 for OS, P = 0.01 and HR = 1.491 for DSS, P = 0.003; Reference [Ref] age ≤ 69 years), tumor location in respiratory system (HR = 1.550 for OS, P = 0.041 and HR = 1.561 for DSS, P = 0.04; Ref: digestive system), N2 stage (HR = 1.962 for OS, P = 0.006 and HR = 1.982 for DSS, P = 0.004; Ref: N0 stage) and AJCC stage IV (HR = 4.601 for OS, P = 0.000 and HR = 5.107 for DSS, P = 0.000; Ref: stage I) were independently associated with worse OS and DSS. CONCLUSIONS: SpCC mostly occurred in white people at 70~80 years old without predominance in any gender. The respiratory system was mostly affected site. The patient's age, primary tumor location, AJCC stage were independent prognostic indicators for both DSS and OS of SpCC.

The prognostic value of long noncoding RNA HOTTIP on clinical outcomes in breast cancer.

Although a few studies have assessed the prognostic value of long noncoding RNA HOTTIP in patients with malignant tumors, the relationship between HOTTIP and clinical outcome of breast cancer remains elusive. The aim of this study is to explore the prognostic significance of HOTTIP in breast cancer patients. A meta-analysis was performed to involve the eligible studies to investigate the association of HOTTIP expression level with outcome in cancer patients. Pooled hazard ratios (HRs) and 95% confidence interval (CI) of HOTTIP for cancer survival were calculated. Five relevant articles involving 460 patients with various solid carcinomas were included in this meta-analysis. For overall survival, high HOTTIP expression could significantly predict worse outcome with the pooled HR of 2.29 (95 % CI 1.72-3.03, P < 0.00001). Furthermore, Gene Expression Omnibus was performed to evaluate the association of HOTTIP expression with the prognosis in breast cancer patients. It was also found an indication that high HOTTIP expression was associated with worse survival in breast cancer patients by microarray analysis (GSE20711, GSE16446 and GSE9195). Finally, association between HOTTIP levels and clinicopathological factors and prognosis was also analyzed in an independent validation cohort including 100 breast cancer cases. HOTTIP expression was correlated with tumor size (P=0.025), lymph node status (P=0.009) and TNM stage (P=0.0001) in the breast cancer validation cohort. The Kaplan-Meier survival curves indicated that breast cancer patients with high HOTTIP expression had worse overall survival (P=0.0139) and disease-free survival (P=0.0003). Multivariate survival analysis based on the Cox proportional hazards model showed that HOTTP is considered as an independent prognostic factor in breast cancer patients. Together, our combined results suggest that high HOTTIP expression may be serving as an unfavorable prognosis predictor for breast cancer patients.