Cytokeratin 15 is a novel and independent predictor of poor outcome in luminal B HER2-negative breast carcinomas.

Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas.

TRPS1 is a promising marker for all subtypes of breast cancer.

AIMS: Trichorhinophalangeal syndrome-1 (TRPS1) has been proposed as a novel breast marker with equally high expression in breast cancer (BC) subtypes, making it a useful diagnostic tool. Here, its expression was evaluated alongside other commonly used markers [GATA3, GCDFP15, mammaglobin (MGB) and SOX10] in a large cohort of BCs (n = 1852) and their corresponding nodal metastases. Its usefulness as a diagnostic tool and its correlation with clinicopathological features were assessed. METHODS AND RESULTS: TRPS1 was expressed at 75.8% overall in the BC cohort, with at least 58% expression among BC subtypes. It was less sensitive than GATA3 for luminal and HER2-overexpressing (HER2-OE) cancers (luminal A: 82 versus 97%; luminal B: 80 versus 95%; HER2-OE: 62 versus 76%), but it was the most sensitive for TNBC (60 versus ≤ 41%). It showed a stable expression in nodal metastases (primary tumour 76 versus nodal metastasis 78%), unlike a reduced nodal expression for GATA3 (86 versus 77%). TRPS1 outperformed GATA3 in detecting non-luminal cancers when paired with other breast markers. TRPS1 and GCDFP15 was the most sensitive combination in TNBC detection, with a 76% detection rate. For TRPS1-negative and GCDFP15-negative TNBCs, SOX10 was more sensitive than GATA3 (29 versus 24%). CONCLUSIONS: TRPS1 is a highly sensitive marker for all breast cancer subtypes, outperforming GATA3 in non-luminal cancers and displaying the highest sensitivity for TNBC detection when combined with GCDFP15. It is a valuable addition to the breast marker panel for accurate identification of BC.

Comprehensive characterization of HER2-low breast cancers: implications in prognosis and treatment.

BACKGROUND: HER2-low cancers are heterogeneous with different degrees of HER2 expression and hormone receptor (HR) status. Currently, its analysis is mostly focused on the standard clinic-pathologic features or common biomarkers expression, without considering the heterogeneity within the category. A further characterization and understanding of this cancer subgroup will facilitate its management. METHODS: A large cohort of HER2-negative cancers (N = 1464) was included. The HER2-low (N = 412) and HER2-zero cancers (N = 1052) were compared and correlated with a comprehensive panel of clinico-pathologic features and biomarker expression according to different HER2 expressions and HR statuses. The prognostic values of these features in HER2-low cancers were also evaluated. FINDINGS: The characteristics of HER2-low breast cancers, as compared to HER2-zero, varied with the HR status. HER2-low luminal cancers were associated with younger age, larger tumor, high pAKT and high HLA expression. Among TNBCs, opposite trends in age and tumor size were found. Additionally, HER2-low TNBC showed less necrosis, higher pN, lower c-kit and CK14 than HER2-zero cancers. Nonetheless, regardless of HR status, HER2-low status was associated with increased COX2 and AR expression, implicated in the biology of HER2-low cancers. HER2-low cancers showed high expression of HLAs in tumors and PD-L1 in immune cells. In particular, the co-expression of HLAs was found to be associated with better survival in HER2-low cancers. INTERPRETATION: This study revealed further characteristic of HER2-low breast cancers as compared to HER2-zero cancers, provided further insights into its prognostication and therapeutic strategies. FUNDING: Health and Medical Research Fund (08190586), Cheng Yue Pui Charity Foundation and CUHK direct grant.

Combining Analysis of Tumor-infiltrating Lymphocytes (TIL) and PD-L1 Refined the Prognostication of Breast Cancer Subtypes.

BACKGROUND: PD-L1 has been used as a biomarker to select patients for treatment of PD-1/PD-L1 inhibitors. MATERIALS AND METHODS: In this study, we assessed the clinicopathological features of breast cancers that are associated with PD-L1 expression, as well as its relationship with other immune components and its prognostic significance. RESULTS: Totally 1752 cases were included in this cohort. PD-L1 expression in tumor-infiltrating immune cells (PD-L1-IC) expression and in tumor cells (PD-L1-TC) expression were identified in 34.2% and 10.1% of cases, respectively, and they showed a positive correlation with higher tumor grade, morphological apocrine features, presence of necrosis, and higher stromal tumor-infiltrating lymphocytes (sTIL). PD-L1-IC and PD-L1-TC expression correlated positively with each other, and both of them were negatively associated with estrogen receptor and progesterone receptor and positively associated with Ki67, HER2, EGFR, p63, and p-cadherin. In survival analysis, PD-L1-IC expression was associated with better disease-free survival (DFS) and breast cancer-specific survival (BCSS) in HER2-overexpressed (HER2-OE) cancers and high-grade luminal B cancers. In triple-negative breast cancers (TNBC) and HER2-OE cancers, compared with sTIL low PD-L1-IC negative cases, sTIL high cases showed significantly better DFS independent of PD-L1-IC status. sTIL low PD-L1-IC positive cases also demonstrated a better DFS in HER2-OE cancers. In high-grade luminal B cancers, sTIL high PD-L1-IC positive cases showed the best BCSS. CONCLUSION: The data suggested that the combining analysis of sTIL and PD-L1-IC expression refined the prognostication of breast cancer subtypes. Cases with high TIL and PD-LI-IC expression appear to be more immune active.

Combined SOX10 GATA3 is most sensitive in detecting primary and metastatic breast cancers: a comparative study of breast markers in multiple tumors.

PURPOSE: For invasive breast cancer (IBC), high SOX10 expression was reported particularly in TNBC. This raised the possibility that SOX10 may complement other breast markers for determining cancers of breast origin. METHODS: Here, we compared the expression of SOX10 with other breast markers (GATA3, mammaglobin and GCDFP15) and their combined expression in a large cohort of IBC together with nodal metastases. We have also evaluated the expression of GATA3 and SOX10 in a wide spectrum of non-breast carcinomas to assess their value as breast specific markers. RESULTS: Compared with other markers, SOX10 showed lower overall sensitivity (6.5%), but higher sensitivity in TNBC (31.4%) than other breast markers including GATA3 (29.7% for TNBC). Its expression demonstrated the highest concordance between the paired IBC and nodal metastases (96.4%, κ = 0.663) among all the breast markers. More importantly, SOX10 identified many GATA3-negative TNBC, thus the SOX10/GATA3 combination was the most sensitive marker combination for IBC (86.6%). For non-breast carcinoma, a high SOX10/GATA3 expression rate was found in melanoma (77.9%, predominately expressed SOX10), urothelial carcinoma (82.0%, predominately expressed GATA3) and salivary gland tumors (69.4%). Other carcinomas, including cancers from lungs, showed very low expression for the marker combination. CONCLUSIONS: The data suggested that SOX10/GATA3 combination can be used for differentiating metastases of breast and multiple non-breast origins. However, the differentiation with melanoma and urothelial tumors required more careful histologic examination, thorough clinical information and additional site-specific IHC markers. For salivary gland tumors, the overlapping tumor types with IBC renders the differentiation difficult.

The Clinical Significance of Neuroendocrine Features in Invasive Breast Carcinomas.

The latest World Health Organization (WHO) classification categorized invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiations into neuroendocrine neoplasms (including well-differentiated neuroendocrine tumor [NET] and poorly differentiated neuroendocrine carcinoma [NEC]) and IBC no special type with NE features (IBC-NST-NE). However, little is documented of the clinical significance of this classification; also the precise thresholds and choices of NE markers were variable. In the current study, a large cohort of patients with IBC with NE differentiation were morphologically classified based on the WHO criteria and the clinical relevance of expression of different NE markers (synaptophysin [SYN], chromogranin [CG], and CD56) was evaluated. Among 1,372 IBCs, 52 NET (3.8%) and 172 IBC-NST-NE (12.5%) were identified. Compared with the IBC-no NE cases, NET and IBC-NST-NE were similarly associated with positive estrogen receptor (ER) expression and lower grade (p < .001). For patient outcome, IBC-NST-NE, but not NET, demonstrated significantly worse survival than the IBC-no NE cases. Based on high (≥50%) and low (<50%) expression for each NE marker, independent poor disease-free survival for SYNlo CGlo and SYNhi CGlo cancers (IBC-no NE cases as references, hazard ratio [HR], ≤1.429; p ≤ .026) was found. Interestingly, SYN and CG expression correlated with each other and they shared similar clinicopathologic characteristics; but not with with CD56. In addition, CD56-only positive cases were associated with hormone receptors negativity and basal markers positivity (p ≤ .019), and patients' outcome was similar to IBC-no NE cancers. Our findings suggested that NE markers expression may provide information to fine tune treatment strategy. The relevance of CD56 as NE marker requires further studies. IMPLICATIONS FOR PRACTICE: Invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiation are heterogeneous in clinicopathologic parameters, biomarker expression, and prognosis. However, there are no specific therapies targeting NE differentiation, and all carcinomas with any NE differentiation are treated similarly as other IBCs. The results of this study suggest that stratification based on NE marker expression levels may provide added prognostically pertinent information, aiding better treatment strategy. In addition, CD56-only positive carcinomas showed a different clinicopathologic and biomarker expression profile compared with those with chromogranin and synaptophysin expression. Relevance of CD56 as an NE marker requires further studies.

Predictors of functioning in people suffering from first-episode psychosis 1 year into entering early intervention service in Hong Kong.

AIM: To explore the changes of functioning in people suffering from first-episode psychosis throughout their first year into an early intervention service, and the baseline predictors of their functioning levels at baseline, 6 and 12 months METHOD: Consecutive subjects presenting to an early intervention service were recruited from 1 February 2013 to 31 May 2015. Information on their socio-demographic status was collected. Structured instruments were used to assess their premorbid functioning, duration of untreated psychosis, psychopathology and insight at baseline. Psychosocial functioning was assessed by Social Occupational Functioning Assessment Scale (SOFAS) and Role Functioning Scale at baseline, 6 and 12 months. RESULTS: A total of 269 subjects were recruited. The mean baseline scores for SOFAS were 53.1 (standard deviation = 13.6) and 21.5 (standard deviation = 4.0), respectively. Positive and negative psychopathology, insight and mode of onset were significant factors associated with baseline functioning. Functioning by both instruments showed significant improvement after 6 months, and the gains were maintained at 12 months. For SOFAS, baseline insight (P = 0.008), education attainment (P = 0.016) and its own baseline score (P = 0.024) were predictive at 6 months, while for 12 months, only education attainment was predictive (P = 0.008). For Role Functioning Scale, its baseline score (P = 0.034) was predictive at 6 months, while at 12 months, only female gender predicted better role functioning. CONCLUSION: Factors predictive of functioning levels at the three time points were different. Phase-specific intervention should be offered to enhance functional recovery of people with first-episode psychosis.

Safety and palatability of polyethylene glycol 3350 as an oral laxative in cats.

Recurrent constipation is a common problem in cats. Laxatives often are the cornerstone for management of recurrent constipation; however, there is a paucity of published research on laxative use in cats. This study investigated the safety and palatability of polyethylene glycol (PEG3350) in normal cats. All cats consumed the PEG3350 laxative for 4 weeks without changes in weight or food intake. In all cats soft stools were achieved. Effective doses varied widely in experimental cats, so individualized dosing is important. Mild, non-clinical hyperkalemia was noted although the cause is unknown.

Idiopathic cervical fibrosis--a new member of IgG4-related sclerosing diseases: report of 4 cases, 1 complicated by composite lymphoma.

Idiopathic cervical fibrosis is a rare tumefactive inflammatory-sclerosing lesion involving the soft tissues of the head and neck, and a proportion of patients also have synchronous or metachronous inflammatory fibrosclerosing lesions in other anatomic sites. The latter finding suggests that this entity may represent a member of IgG4-related sclerosing diseases. We report 4 cases to support this postulation. The patients were male adults aged 42 to 89 years, who presented with an infiltrative, firm cervical mass. Two patients also had IgG4-related chronic sclerosing sialadenitis of submandibular gland and lymphadenopathy. Histologically, the cervical soft tissue lesions had ill-defined borders, consisting of coalescent nodular lymphoid aggregates accompanied by a sclerotic stroma. Nerve infiltration, skeletal muscle invasion, and phlebitis were present. There was a significant increase in IgG4 plasma cells (87 to 327 per high-power field, with IgG4/IgG ratio of 63% to 98%). In the soft tissue lesion of 1 patient, there were expansile foci comprising dense sheets of plasma cells and small lymphoid cells that exhibited κ light chain restriction and clonal immunoglobulin gene rearrangement, consistent with supervening extranodal marginal zone lymphoma. The adjacent lymph node from the same patient showed Epstein-Barr virus (EBV)-positive classical Hodgkin lymphoma with typical morphology and immunophenotype (CD30, CD15, PAX5). Thus lymphoma can supervene in the chronic inflammatory background similar to that recently documented for IgG4-related sclerosing disease of the ocular adnexa.

A 33-year-old Chinese woman with a left frontal tumor.

Rhabdoid tumor cells are typically observed in atypical teratoid/rhabdoid tumor (AT/RT) but may also be seen in meningioma,glioma, melanoma, rhabdomyosarcoma and metastatic carcinoma.We present an astroblastoma with unusual rhabdoid features which is rarely described in the English literature. Apart from the rhabdoid tumor cells, all the histopathological features typical for astroblastoma are present in this case. These features include pseudopapillary arrangement, astroblastic pseudorosettes, perivascular hyalinization and calcifications, absence of fibrillary background and a pushing tumor border. The tumor cells display a multilineage immunohistochemical profile. In addition, diffuse and strong membranous and cytoplasmic dot-like pattern is appreciated with epithelial membrane antigen (EMA). The diagnosis of astroblastoma is also well supported by the age of presentation, anatomical location and radiological features of the tumor.We believe that on top of the above-mentioned unusual tumors with rhabdoid cells, astroblastoma should also be considered in the list of differential diagnosis.

Coexistence of struma ovarii with marked ascites and elevated CA-125 levels: case report and literature review.

INTRODUCTION: Struma ovarii is a rare form of ovarian neoplasm and consists mainly of thyroid tissue. Ascites has been reported in approximately one-third of all the cases. However, the combination of struma ovarii and elevated CA-125 has rarely been reported. MATERIALS AND METHODS: We described a case of benign struma ovarii, presenting with the clinical features of ovarian cancer: large complex pelvic mass, gross ascites and markedly elevated serum CA-125 levels. Surgical excision of the ovarian mass was followed by rapid resolution of the ascites and reduction of the serum CA-125 level. CONCLUSION: Struma ovarii can mimic ovarian malignancy clinically, when presented with ascites and an elevated CA-125 level.