CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling.

Cyclin-dependent kinase 12 (CDK12) has emerged as an effective therapeutic target due to its ability to regulate DNA damage repair in human cancers, but little is known about the role of CDK12 in driving tumorigenesis. Here, we demonstrate that CDK12 promotes tumor initiation as a novel regulator of cancer stem cells (CSCs) and induces anti-HER2 therapy resistance in human breast cancer. High CDK12 expression caused by concurrent amplification of CDK12 and HER2 in breast cancer patients is associated with disease recurrence and poor survival. CDK12 induces self-renewal of breast CSCs and in vivo tumor-initiating ability, and also reduces susceptibility to trastuzumab. Furthermore, CDK12 kinase activity inhibition facilitates anticancer efficacy of trastuzumab in HER2+ tumors, and mice bearing trastuzumab-resistant HER2+ tumor show sensitivity to an inhibitor of CDK12. Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. These results suggest that CDK12 is a major oncogenic driver and an actionable target for HER2+ breast cancer to replace or augment current anti-HER2 therapies.

Multicenter retrospective analysis of the clinicopathologic features of monomorphic epitheliotropic intestinal T-cell lymphoma.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a provisional entity in the 2017 World Health Organization classifications. To further elucidate the clinicopathologic features of this new disease, we carried out a retrospective, multicenter analysis of 42 patients with MEITL. The median age of the patients was 59 years (range, 20-84 years), and 27 patients (64 %) were male. Thirty-two patients (76 %) were Ann-Arbor stages I-II and 28 (67 %) were Lugano stages I-II1&2. The most frequent site of involvement was the jejunum (N = 21). Most cases expressed CD8 (79 %) and CD56 (95 %) and did not express CD30 (5 %) or EBER (0 %). The median progression-free survival was 6.9 months (95 % CI 4.3-9.6); the median OS was 14.8 months (2.4-27.2). Thirty-two patients (76 %) underwent surgery and 37 (88 %) received chemotherapy. A complete response (CR) rate was 38 %. Sixteen patients had undergone autologous stem cell transplantation (ASCT). Relapse or progression was documented in 24 cases, most frequently in the primary site (N = 23). Four cases showed central nervous system relapse. Age over 55 years, poor performance scale, advanced Lugano stage (IIE-IV), not achieving CR, and not receiving ASCT were associated with inferior OS. While the optimal management of MEITL remains undetermined, achieving CR and consolidative ASCT seem essential. As CHOP might be insufficient for achieving CR, more efficient combinations should be investigated. Additionally, considering the frequent local failure and CNS relapse, novel therapeutic approaches are required to improve survival.

Measurement invariance of the patient health questionnaire-9 (PHQ-9) depression screener in U.S. adults across sex, race/ethnicity, and education level: NHANES 2005-2016.

BACKGROUND: Despite its popularity, little is known about the measurement invariance of the Patient Health Questionnaire-9 (PHQ-9) across U.S. sociodemographic groups. Use of a screener shown not to possess measurement invariance could result in under/over-detection of depression, potentially exacerbating sociodemographic disparities in depression. Therefore, we assessed the factor structure and measurement invariance of the PHQ-9 across major U.S. sociodemographic groups. METHODS: U.S. population representative data came from the 2005-2016 National Health and Nutrition Examination Survey (NHANES) cohorts. We conducted a measurement invariance analysis of 31,366 respondents across sociodemographic factors of sex, race/ethnicity, and education level. RESULTS: Considering results of single-group confirmatory factor analyses (CFAs), depression theory, and research utility, we justify a two-factor structure for the PHQ-9 consisting of a cognitive/affective factor and a somatic factor (RMSEA = 0.034, TLI = 0.985, CFI = 0.989). On the basis of multiple-group CFAs testing configural, scalar, and strict factorial invariance, we determined that invariance held for sex, race/ethnicity, and education level groups, as all models demonstrated close model fit (RMSEA = 0.025-0.025, TLI = 0.985-0.992, CFI = 0.986-0.991). Finally, for all steps ΔCFI was <-0.004, and ΔRMSEA was <0.01. CONCLUSIONS: We demonstrate that the PHQ-9 is acceptable to use in major U.S. sociodemographic groups and allows for meaningful comparisons in total, cognitive/affective, and somatic depressive symptoms across these groups, extending its use to the community. This knowledge is timely as medicine moves towards alternative payment models emphasizing high-quality and cost-efficient care, which will likely incentivize behavioral and population health efforts. We also provide a consistent, evidence-based approach for calculating PHQ-9 subscale scores.

Long-Term Outcomes After Metal-on-Metal Total Hip Arthroplasty With a 28-mm Head: A 17- to 23-Year Follow-Up Study of a Previous Report.

BACKGROUND: Second-generation, metal-on-metal total hip arthroplasty (MoM THA) using a 28-mm head has shown favorable results compared with large head MoM THA. The purpose of this study is to evaluate the long-term outcomes of cementless primary MoM THA with a 28-mm head and the incidence of osteolysis using computed tomography. METHODS: A total of 92 patients (53 men and 39 women) who underwent primary cementless MoM THA (114 hips) with a 28-mm head were enrolled in this study. Their mean age was 46.2 years at the time of surgery. The mean follow-up duration was 20 years. The Harris hip score, presence of thigh or groin pain, radiographic results, presence of peri-implant osteolysis, histologic analysis, and Kaplan-Meier survival curves were evaluated. RESULTS: The mean preoperative Harris hip score of 50.5 improved to 85.1 at the final follow-up. Eight patients (8 hips) experienced groin pain, but none had thigh pain. Twelve revisions (6.2%) were performed including 10 hips for aseptic loosening with osteolysis and 2 hips for periprosthetic fracture around the stem. At 23 years, 91% of patients were free from revision of the acetabular component due to aseptic loosening and 90.1% were free from revision of both femoral and acetabular components due to any reason. Osteolysis was identified around the cup in 12 cases (10.5%) and around the stem in 7 cases (6.1%). CONCLUSION: MoM THA with a 28-mm head showed a relatively low rate of aseptic implant loosening at a mean follow-up of 20 years.

Increased expression of forkhead box M1 is associated with aggressive phenotype and poor prognosis in estrogen receptor-positive breast cancer.

Fox transcription factors play a critical role in the regulation of a variety of biological processes. While FoxM1 behaves like the oncogenic transcription factor, FoxO3a is known as a tumor suppressor by inhibiting FoxM1. This study aimed to investigate the clinicopathological significance of FoxM1 and FoxO3a expression in breast cancer. Expression of FoxM1 and FoxO3a were analyzed by immunohistochemical staining on tissue microarray sections from 236 breast cancer patients, and correlated with various clinicopathological characteristics. Overexpression of FoxM1 correlated with adverse clinicopathological features, such as larger tumor size, lymph node metastasis, advanced tumor stage, and lymphovascular invasion. The Kaplan-Meier survival curves revealed no prognostic significance of FoxM1 expression. However, in subgroup analyses with patients of estrogen receptor (ER) positive breast cancers, FoxM1 overexpression associated with poor disease free and overall survival. No association was found between FoxO3a and FoxM1 expression. Regarding clinicopathological variables, the only association between histologic grade and FoxO3a was observed. In conclusion, FoxM1 overexpression was significantly associated with aggressive phenotypes and poor prognosis of ER-positive breast cancer. These findings suggest the possible role of FoxM1 as a prognostic biomarker and putative target of anti-cancer therapy.

Diagnostic and prognostic relevance of MMP-11 expression in the stromal fibroblast-like cells adjacent to invasive ductal carcinoma of the breast.

BACKGROUND: Matrix metalloproteinase 11 (MMP-11) is a matrix degrading enzyme known to be involved in the remodeling of extracellular matrix proteins. This enzyme recently has been reported to play a key role in tumor progression and results in poor clinical outcomes for several different types of tumors. METHODS: A total of 192 patients diagnosed with invasive ductal carcinoma between 2000 and 2005 were included in this study. MMP-11 expression in tumors and stromal fibroblast-like cells was analyzed by immunohistochemical staining on a tissue microarray. Subsequently, evaluation of the associations between MMP-11 expression and clinicopathological characteristics was performed. RESULTS: MMP-11 expression of stromal fibroblast-like cells was correlated with prognostic factors, including tumor size, metastasis, histological grade, central tumor fibrosis, p53 expression, and luminal A subtype and was linked to therapeutic markers, such as ER and HER2 (all p < 0.05). There was a significant relationship between worse overall survival and MMP-11 expression in both tumors and stromal fibroblast-like cells (all p < 0.05). In multivariate analysis, MMP-11 expression of stromal fibroblast-like cells was still significantly associated with poor prognosis (p = 0.043). CONCLUSIONS: MMP-11 expression was significantly related to clinicopathological parameters, which may be essential to the prediction of disease outcome in patients with invasive ductal carcinoma of the breast.

Expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor is associated with the favorable clinicopathologic parameters in small intestinal carcinomas.

OBJECTIVE: The insulin-like growth factor (IGF) system has been known to play a critical role in tumor development and progression in many human cancers. However, the role of the IGF system in small intestinal carcinoma (SIC) has not been studied yet. METHODS: We evaluated the expression of IGF1 and IGF1 receptor (IFG1R) in a total of 194 cases of SIC. RESULTS: IGF1 expression was associated with well/moderate differentiation, better survival, lower pT, lower stage and no lymph node metastasis. IGF1R was more diffusely and strongly expressed in tumors with lower pT and lower stage. CONCLUSIONS: IGF1 and IGF1R expression is associated with favorable clinicopathologic parameters and may involve early carcinogenesis of SICs. Target therapy for the IGF1R signaling pathway may not have a major therapeutic role in treating SIC.

Does submucosal fibrosis affect the results of endoscopic submucosal dissection of early gastric tumors?

BACKGROUND: Endoscopic submucosal dissection (ESD) is an effective treatment of early gastric tumors, but submucosal fibrosis can be an obstacle to successful ESD. OBJECTIVE: To examine the association between endoscopic and pathologic factors and submucosal fibrosis in early gastric tumors, and to measure the association between degree of submucosal fibrosis and outcomes of ESD. DESIGN: A retrospective study. SETTING: An academic medical center. PATIENTS: From November 2006 to April 2011, 161 patients with 167 early gastric tumors treated by ESD. INTERVENTION: ESD. MAIN OUTCOME MEASUREMENTS: Endoscopic and pathologic factors related to submucosal fibrosis. Procedure time, en bloc resection rate, and complications according to degree of submucosal fibrosis. RESULTS: In univariate analysis, the presence of endoscopic submucosal fibrosis was significantly related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Multivariate analysis for these factors showed that endoscopic submucosal fibrosis was independently associated with lesions in tumor size greater than 30 mm, in the proximal portion of the stomach, and more common in adenocarcinomas than in adenomas. After correction for multiple testing, only the middle of the stomach as a locational risk factor retains statistical significance. Also, the more advanced the endoscopic submucosal fibrosis, the longer the time required for ESD (P < .0001). The severity of endoscopic submucosal fibrosis was associated with a lower en bloc resection rate and with abundant immediate bleeding. LIMITATIONS: Retrospective, single-center study. CONCLUSION: Submucosal fibrosis of early gastric tumors is closely related to tumor size, location, ulceration, histologic findings, and submucosal invasion. Moreover, the greater the degree of submucosal fibrosis the longer the time taken for the ESD procedure and the higher the frequency of complications such as perforation and immediate bleeding.

Expression of hMLH1, hMSH2 and hMSH6 in small intestinal carcinomas.

BACKGROUND/AIMS: Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to investigate the role of defective MMR genes and correlation between clinicopathological factors and loss of MMR protein in SIC. METHODOLOGY: A total of 195 SIC cases were collected from 20 institutions in Korea and tissue microarrays (TMA) were made. The loss of expression of hMLH1, hMSH2 and hMSH6 was examined by immunohistochemistry (IHC). RESULTS: The loss of expression of hMLH1, hMSH2 and hMSH6 was identified in 25/193 (13.0%), 25/193 (13%) and 29/195 (15%), respectively. The loss of hMSH2 expression was associated with retroperitoneal seeding. Patients with loss of hMSH6 expression had a tendency to invade deeply and a higher frequency of pancreas invasion. The loss of hMSH6 expression was associated less frequently with peritumoral adenoma. There was no survival difference by MMR protein expression status. CONCLUSIONS: The loss of MMR protein was associated with some distinct clinicopathological features. MMR pathway seems to be major pathway in carcinogenesis of SICs. MMR defect seems to be related with sporadic-microsatellite instability (MSI).

Prognostic Value of LC3B and p62 Expression in Small Intestinal Adenocarcinoma.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p < 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p < 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

NSD3-Induced Methylation of H3K36 Activates NOTCH Signaling to Drive Breast Tumor Initiation and Metastatic Progression.

Histone methyltransferase NSD3 is frequently dysregulated in human cancers, yet the epigenetic role of NSD3 during cancer development remains elusive. Here we report that NSD3-induced methylation of H3K36 is crucial for breast tumor initiation and metastasis. In patients with breast cancer, elevated expression of NSD3 was associated with recurrence, distant metastasis, and poor survival. In vivo, NSD3 promoted malignant transformation of mammary epithelial cells, a function comparable to that of HRAS. Furthermore, NSD3 expanded breast cancer-initiating cells and promoted epithelial-mesenchymal transition to trigger tumor invasion and metastasis. Mechanistically, the long isoform (full-length transcript) of NSD3, but not its shorter isoform lacking a catalytic domain, cooperated with EZH2 and RNA polymerase II to stimulate H3K36me2/3-dependent transactivation of genes associated with NOTCH receptor cleavage, leading to nuclear accumulation of NICD and NICD-mediated transcriptional repression of E-cadherin. Furthermore, mice harboring primary and metastatic breast tumors with overexpressed NSD3 showed sensitivity to NOTCH inhibition. Together, our findings uncover the critical epigenetic role of NSD3 in the modulation of NOTCH-dependent breast tumor progression, providing a rationale for targeting the NSD3-NOTCH signaling regulatory axis in aggressive breast cancer. SIGNIFICANCE: This study demonstrates the functional significance of histone methyltransferase NSD3 in epigenetic regulation of breast cancer stemness, EMT, and metastasis, suggesting NSD3 as an actionable therapeutic target in metastatic breast cancer.

Prognostic Significance of Stromal and Intraepithelial Tumor-Infiltrating Lymphocytes in Small Intestinal Adenocarcinoma.

OBJECTIVES: Assessment of tumor-infiltrating lymphocytes (TILs) may predict the prognosis and therapeutic benefit of immunotherapy in small intestinal adenocarcinoma (SIAC) patients. METHODS: TILs were evaluated in 231 surgically resected SIACs and compared with microsatellite instability (MSI) and clinicopathologic variables. The average number of intraepithelial TILs (iTILs) and the average density of stromal TILs (sTILs) were calculated separately. RESULTS: High iTIL count (≥2 per high-power field) was associated with MSI-high, whereas high sTIL density (≥20% on ×200 magnification) was not. High iTIL count and high sTIL density were related to distal tumor location, medullary carcinoma, high Crohn-like lymphoid reaction counts, and fewer pancreatic invasions. SIAC patients with high iTIL count or high sTIL density had better survival than those with low values. On multivariate analysis, MSI, high sTIL density, proximal locations, lower N category, and absence of lymphovascular invasions and retroperitoneal seeding were the best independent prognostic predictors. CONCLUSIONS: High sTIL density can be used as a prognostic indicator and high iTIL count may provide a basis for the clinical use of targeted immunotherapy in SIAC patients.

Tumor Budding and Poorly Differentiated Clusters in Small Intestinal Adenocarcinoma.

The clinicopathologic and prognostic significances of tumor budding (TB) and poorly-differentiated clusters (PDC) have not been investigated in small intestinal adenocarcinomas (SIACs). In 236 surgically-resected SIACs, we counted TB (single cells or clusters ≤4 tumor cells) and PDC (clusters ≥5 tumor cells) at the peritumoral-invasive front (p) and in the intratumoral area (i) independently to classify as grade-1 (≤4), grade-2 (5-9), or grade-3 (≥10). Consequently, grades-2 and -3 were considered high-grade. High-pTB, -iTB, -pPDC, and -iPDC were observed in 174 (73.7%), 129 (54.7%), 118 (50.0%), and 85 (36.0%) cases, respectively. High-TB/PDCs were more frequently observed in tumors with high-grade, higher T- and N-categories and stage grouping, and perineural or lymphovascular invasion. Patients with high-TB/PDC had a shorter survival than those with low-TB/PDC. In a multivariate analysis, high-pTB, nonintestinal type, high N-category, retroperitoneal seeding, and microsatellite-stable were worse independent-prognostic predictors. Subgroup analysis demonstrated that patients with high-pTB showed worse survival (median: 42.5 months) than those with low-pTB (133.7 months; p = 0.007) in the lower stage (stages I-II) group. High-TB/PDC, both in peritumoral and intratumoral localizations, were associated with aggressive behaviors in SIACs. High-pTB can be used as an adverse prognostic indicator in SIAC patients, especially when patients are in early disease stages.

Loss of HES-1 Expression Predicts a Poor Prognosis for Small Intestinal Adenocarcinoma Patients.

Objective: Hairy and enhancer of split-1 (HES-1), which is a downstream target of the Notch signaling pathway, has been linked to KRAS mutations. HES-1 has been proposed as harboring oncogenic activity in colorectal cancer but has not been investigated in adenocarcinoma of the small intestine, where the drivers of oncogenesis are not as well-understood. Materials and Methods: To investigate the clinicopathologic and prognostic implications of HES-1, HES-1 immunohistochemical expression was analyzed in digital images along with clinicopathological variables, including survival and KRAS genotype, in 185 small intestinal adenocarcinomas. Results: The loss of HES-1 expression (HES-1Loss) was observed in 38.4% (71/185) of the patients, and was associated with higher pT category (P = 0.018), pancreatic invasion (P = 0.005), high grade (P = 0.043), and non-tubular histology (P = 0.004). Specifically, in tumors with mutant KRAS (KRAS MT), HES-1Loss was related to proximal location (P = 0.024), high T and N categories (P = 0.005 and 0.047, respectively), and pancreatic invasion (P = 0.004). Patients with HES-1Loss showed worse overall survival compared to those with intact HES-1 (HES-1Intact) (P = 0.013). Patients with HES-1Loss/KRAS MT (median, 17.3 months) had significantly worse outcomes than those with HES-1Intact/KRAS WT (39.9 months), HES-1Intact/KRAS MT (47.6 month), and HES-1Loss/KRAS WT (36.2 months; P = 0.010). By multivariate analysis, HES-1Loss (hazard ratio = 1.55, 95% confidence interval (CI), 1.07-2.26; P = 0.022) remained an independent prognostic factor. Conclusion: HES-1expression can be used as a potential prognostic marker and may aid in the management of patients with small intestinal adenocarcinomas.

Pancreatic acinar cell carcinomas and mixed acinar-neuroendocrine carcinomas are more clinically aggressive than grade 1 pancreatic neuroendocrine tumours.

Acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MAcNECs) of the pancreas are extremely rare carcinomas with a significant component with acinar differentiation. To date, the clinicopathological behaviours of these neoplasms remain unclear. In this study, we evaluated the histopathological and molecular characteristics of 20 ACCs and 13 MAcNECs and compared them to a cohort of 269 well-differentiated pancreatic neuroendocrine tumours (PanNETs). Compared to PanNETs, both ACCs and MAcNECs had an advanced pT classification (p<0.001), as well as more prevalent lymphovascular and perineural invasion (p=0.002) and lymph node and distant metastases (p<0.001). Patients with MAcNECs had worse overall (p<0.001) and recurrence-free survival (p<0.001) than those with PanNETs, but no significant difference with those with ACCs. Subgroup analyses revealed that patients with ACCs and MAcNECs had significantly worse recurrence-free survival than those with grade 1 PanNET (p<0.001), and patients with MAcNECs also had worse overall survival than those with grade 1 and 2 PanNETs (p<0.001, and p=0.001). ACCs presented more commonly with intraductal growth (p=0.014) than MAcNECs, while MAcNECs more often had lymph node metastasis (p=0.012) than ACCs. The telomere maintenance mechanism Alternative Lengthening of Telomeres (ALT) was assessed by telomere-specific FISH, and ALT was detected in 1 of 20 ACCs and in three of the 13 MAcNECs. Patients with MAcNECs and ACCs had worse survival and more aggressive behaviour than those with grade 1 PanNETs; thus, the clinicopathological behaviour of MAcNECs resembles ACCs rather than PanNETs. Combined neuroendocrine and acinar cell immunohistochemical markers are helpful for differentiating these different tumour types.

Oncocytic carcinoma arising in the submandibular gland with disseminated bone metastases.

Oncocytic carcinoma of the head and neck is a very rare neoplasm. It usually occurs in the parotid glands. Only 11 cases of oncocytic carcinoma of the submandibular gland have been reported, and no cases have shown distant bone metastasis. A 67-year-old man presented with a tingling sensation in both hands due to a herniated cervical disc. A whole body bone scan and PET-CT showed disseminated bone metastases. Neck CT revealed a 1.7 cm calcified left submandibular mass. The submandibular gland and bone marrow biopsies were consistent with oncocytic carcinoma. Our case is the first report of oncocytic carcinoma of the submandibular gland with disseminated bone metastases.

Effect of Brief Admission to Hospital by Self-referral for Individuals Who Self-harm and Are at Risk of Suicide: A Randomized Clinical Trial.

Importance: To our knowledge, there is no consensus regarding when individuals who repeatedly self-harm and are at risk of suicide should be hospitalized. To evaluate a new alternative, we examined the effects of brief admission (BA) to hospital by self-referral. Objectives: To determine the effects of BA on inpatient service use and on secondary outcomes of daily life functioning, nonsuicidal self-injuries, and attempted suicide among individuals who self-harm and are at risk of suicide. Design, Setting, and Participants: The single-masked Brief Admission Skåne Randomized Clinical Trial was conducted from September 2015 to June 2018 at 4 psychiatric health care facilities in southern Sweden. Data were collected 6 months retrospectively at baseline and at 6-month and 12-month follow-ups. Participants were randomized to either BA and treatment as usual (BA group) or treatment as usual (control group). The sample was a referral population, with the most important inclusion criteria being current episodes of self-harm and/or recurrent suicidality, at least 3 diagnostic criteria for borderline personality disorder, and hospitalization in the last 6 months. Interventions: Self-referred BA was offered for 12 months, with standard limits for duration and frequency, after the negotiation of a contract outlining the intervention. Main Outcomes and Measures: Prespecified main outcome measures were days admitted to the hospital, including voluntary admission, BA, and compulsory admission. Results: The 125 participants had a mean (SD) age of 32.0 (9.4) years, 106 (84.8%) were women, and 63 were randomized to the BA group and 62 to the control group. No significant advantage was observed in the number of days in the hospital for the BA group compared with the control group. Within-group analyses demonstrated significant decreases in both groups regarding days admitted to the hospital (BA group: χ2 = 22.71; P < .001; control group: χ2 = 23.01; P < .001) and visits to the emergency department (BA group: χ2 = 13.95; P < .001; control group: χ2 = 21.61; P < .001), but only the BA group showed a reduction in days with compulsory admission (χ2 = 7.67; P = .02) and nonsuicidal self-injuries (χ2 = 6.13; P = .047). The BA group showed significantly greater improvements in the mobility domain of daily life functioning (z = -2.39; P = .02) and significant within-group improvements in 3 other domains (cognition: F = 9.02; P < .001; domestic responsibilities: F = 3.23; P = .049; and participation: F = 3.79; P = .03). Conclusions and Relevance: Brief admission appears no more efficacious in reducing use of inpatient services than usual care for individuals who self-harm and are at risk of suicide. Future studies should explore other possible beneficial effects. Trial Registration: ClinicalTrials.gov identifier: NCT02985047.

Higher Acid-Base Imbalance Associated with Respiratory Failure Could Decrease the Survival of Patients with Scrub Typhus during Intensive Care Unit Stay: A Gene Set Enrichment Analysis.

Ninety percent of patients with scrub typhus (SC) with vasculitis-like syndrome recover after mild symptoms; however, 10% can suffer serious complications, such as acute respiratory failure (ARF) and admission to the intensive care unit (ICU). Predictors for the progression of SC have not yet been established, and conventional scoring systems for ICU patients are insufficient to predict severity. We aimed to identify simple and robust indicators to predict aggressive behaviors of SC. We evaluated 91 patients with SC and 81 non-SC patients who were admitted to the ICU, and 32 cases from the public functional genomics data repository for gene expression analysis. We analyzed the relationships between several predictors and clinicopathological characteristics in patients with SC. We performed gene set enrichment analysis (GSEA) to identify SC-specific gene sets. The acid-base imbalance (ABI), measured 24 h before serious complications, was higher in patients with SC than in non-SC patients. A high ABI was associated with an increased incidence of ARF, leading to mechanical ventilation and worse survival. GSEA revealed that SC correlated to gene sets reflecting inflammation/apoptotic response and airway inflammation. ABI can be used to indicate ARF in patients with SC and assist with early detection.

Role of MEL-18 Amplification in Anti-HER2 Therapy of Breast Cancer.

BACKGROUND: Resistance to HER2-targeted therapy with trastuzumab still remains a major challenge in HER2-amplified tumors. Here we investigated the potential role of MEL-18, a polycomb group gene, as a novel prognostic marker for trastuzumab resistance in HER2-positive (HER2+) breast cancer. METHODS: The genetic alteration of MEL-18 and its clinical relevance were examined in multiple breast cancer cohorts including METABRIC (n = 1,980), TCGA (n = 825), and our clinical specimens (n = 213, trastuzumab-treated HER2+ cases). MEL-18 amplification was validated by fluorescence in situ hybridization (FISH) analysis. The MEL-18 effect on trastuzumab response was confirmed by in vitro cell viability assays and an in vivo xenograft experiment (n = 7 per group). Gene expression microarray and receptor tyrosine kinase array were performed to identify the trastuzumab resistance mechanism by MEL-18 loss. All statistical tests were two-sided. RESULTS: MEL-18 was exclusively amplified in approximately 30-50% of HER2+ breast tumors and was associated with a favorable clinical outcome (disease-free survival: P = .02 in HER2+ cases, METABRIC; P = .04 in patients receiving trastuzumab). In MEL-18-amplified HER2+ breast cancer, MEL-18 depletion induced trastuzumab resistance by increasing ADAM sheddase-mediated ErbB ligand production and receptor heterodimerization. MEL-18 epigenetically silenced ADAM10/17 expression in cooperation with polycomb-repressive complex (PRC) 1 and PRC2. Combination treatment with an ADAM10/17 inhibitor and trastuzumab could overcome MEL-18 loss-mediated trastuzumab resistance in vivo (BT474/shMEL-18 xenograft: trastuzumab, mean [SD] tumor volume = 406.1 [50.1] mm3, vs trastuzumab + GW280264 30 mg/kg, mean [SD] tumor volume = 68.4 [15.6] mm3, P < .001). Consistently, trastuzumab-treated patients harboring concomitant MEL-18 amplification and low ADAM17 expression showed prolonged relapse-free survival (P = .02 in our cohort, n = 213). CONCLUSION: MEL-18 serves to prevent ligand-dependent ErbB heterodimerization and trastuzumab resistance, suggesting MEL-18 amplification as a novel biomarker for HER2+ breast cancer.

LGR5 and Downstream Intracellular Signaling Proteins Play Critical Roles in the Cell Proliferation of Neuroblastoma, Meningioma and Pituitary Adenoma.

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been reported to play critical roles in the proliferation of various cancer cells. However, the roles of LGR5 in brain tumors and the specific intracellular signaling proteins directly associated with it remain unknown. Expression of LGR5 was first measured in normal brain tissue, meningioma, and pituitary adenoma of humans. To identify the downstream signaling pathways of LGR5, siRNA-mediated knockdown of LGR5 was performed in SH-SY5Y neuroblastoma cells followed by proteomics analysis with 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). In addition, the expression of LGR5-associated proteins was evaluated in LGR5-inhibited neuroblastoma cells and in human normal brain, meningioma, and pituitary adenoma tissue. Proteomics analysis showed 12 protein spots were significantly different in expression level (more than two-fold change) and subsequently identified by peptide mass fingerprinting. A protein association network was constructed from the 12 identified proteins altered by LGR5 knockdown. Direct and indirect interactions were identified among the 12 proteins. HSP 90-beta was one of the proteins whose expression was altered by LGR5 knockdown. Likewise, we observed decreased expression of proteins in the hnRNP subfamily following LGR5 knockdown. In addition, we have for the first time identified significantly higher hnRNP family expression in meningioma and pituitary adenoma compared to normal brain tissue. Taken together, LGR5 and its downstream signaling play critical roles in neuroblastoma and brain tumors such as meningioma and pituitary adenoma.