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.

Invasive and non-invasive assessment of portal hypertension.

Portal hypertension is the central driver of complications in patients with chronic liver diseases and cirrhosis. The diagnosis of portal hypertension has important prognostic and clinical implications. In particular, screening for varices in patients with portal hypertension can effectively reduce the morbidity and mortality of variceal bleeding. In this article, we review the invasive and non-invasive methods to assess portal hypertension. Hepatic venous pressure gradient remains the gold standard to measure portal pressure but is invasive and seldom performed outside expert centers and research settings. In recent years, a number of non-invasive tests of fibrosis have shown good correlation with liver histology. They also show promise in identifying patients with portal hypertension and large varices. As a result, the latest Baveno VI consensus guidelines endorse the use of liver stiffness measurement by transient elastography and platelet count as initial assessment to select patients for varices screening. On the other hand, the performance of non-invasive tests in assessing the response to non-selective beta-blockers or transjugular intrahepatic portosystemic shunting is either suboptimal or unclear.

Application of the combined FibroMeter vibration-controlled transient elastography algorithm in Chinese patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIM: The FibroMeter vibration-controlled transient elastography (FM VCTE) is a new formula combining the serum test FM and liver stiffness measurement (LSM) by VCTE. We tested the accuracy and utility of FM VCTE for fibrosis staging in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Two hundred fifteen NAFLD patients with LSM, FM NAFLD, FM VCTE, and other serum tests (aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, BARD score, NAFLD fibrosis score, and aspartate aminotransferase-to-alanine aminotransferase ratio) performed 1 day before liver biopsy were evaluated. RESULTS: Sixty-nine (32.1%) and 43 (20.0%) patients had F2-4 and F3-4, respectively. LSM had higher diagnostic accuracy (area under receiver-operating characteristics curves [AUROC] 0.851 for F2-4, 0.940 for F3-4; Obuchowski index 0.937 ± 0.007) than all evaluated serum tests, while FM NAFLD was the most accurate serum test (AUROC 0.775 and 0.774; Obuchowski index 0.891 ± 0.013). FM VCTE had similar accuracy to LSM (AUROC 0.855 and 0.901; Obuchowski index 0.927 ± 0.009). LSM had excellent negative predictive values of 92.4% and 99.2% to exclude F2-4 and F3-4, but the positive predictive values (PPV) were only 71.4% and 61.0%, respectively. In patients with high LSM, the use of FM VCTE improved the PPV from 71.4% to 84.4% for F2-4 and from 61.0% to 88.9% for F3-4. Liver biopsy could be spared in around 50-65% of patients. CONCLUSIONS: Liver stiffness measurement alone can confidently exclude significant and advanced fibrosis in NAFLD patients. Using FM VCTE in patients with high liver stiffness can increase the positive predictive value to rule in F2-4 and F3-4.

Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients.

Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%-20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 ± 1.3 vs. 3.8 ± 1.2; P = 0.019), mainly contributed by steatosis (1.7 ± 0.8 vs. 2.0 ± 0.8; P = 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P = 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 ± 1.5 vs. 1.7 ± 1.4; P = 0.004), serum cytokeratin-18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio [OR], 1.644; P = 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P = 0.025). After a median follow-up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. CONCLUSION: Nonobese NAFLD patients tend to have less-severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54-64).

Prevalence and Severity of Nonalcoholic Fatty Liver Disease in Non-Obese Patients: A Population Study Using Proton-Magnetic Resonance Spectroscopy.

OBJECTIVES: Some studies suggest that non-obese patients with nonalcoholic fatty liver disease (NAFLD) may have more severe disease. We aim to study the epidemiology and severity of non-obese NAFLD. METHODS: A total of 911 community subjects were randomly recruited from the census database of the Hong Kong Government. Intrahepatic triglycerides (IHTG) and liver fibrosis were assessed by proton-magnetic resonance spectroscopy and transient elastography, respectively. The Asian body mass index cutoff of 25 kg/m(2) was used to define non-obese NAFLD. RESULTS: The prevalence of NAFLD was 19.3% in non-obese subjects and 60.5% in obese subjects (P<0.001). Compared with obese NAFLD patients, non-obese NAFLD patients had similar IHTG content (median 9.8% vs. 9.9%; P=0.100) but lower cytokeratin-18 fragments (149 vs. 182 IU/l; P=0.019) and liver stiffness (4.6 vs. 5.6 kPa; P<0.001). The G allele at the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3 rs738409) was more common in non-obese than obese NAFLD patients (78.4% vs. 59.8%; P=0.001). Obesity, high hemoglobin A1c, insulin resistance, hyperferritinemia, and the PNPLA3 G allele were independent factors associated with NAFLD in non-obese subjects. Even among non-obese subjects with normoglycemia, those with NAFLD were more insulin resistant (mean homeostasis model assessment of insulin resistance: 2.0±1.0 vs. 1.1±1.1; P<0.001). CONCLUSIONS: One-fifth of the general non-obese Chinese population has NAFLD. Non-obese patients with NAFLD do not have a higher risk of steatohepatitis or advanced fibrosis. Patients with risk factors of advanced fibrosis such as metabolic syndrome and PNPLA3 G allele carriage should be assessed for severe NAFLD.