Identification of CD5/SOX11 double-negative pleomorphic mantle cell lymphoma.

Cyclin D1 protein-positive diffuse large B cell lymphoma (DLBCL) has an immunophenotype of CD5(-) cyclin D1(+) SOX11(-), and most cases lack a CCND1 rearrangement and have a gene expression profile of DLBCL. Rarely, cyclin D1 protein-positive DLBCL harbors a CCND1 rearrangement, and some genetic copy number features typical of mantle cell lymphoma (MCL) have been detected. Since gene expression studies have not been performed, whether such CCND1-rearranged cases represent cyclin D1 protein-positive DLBCL or CD5/SOX11 double-negative pleomorphic MCL remains unclear. To date, no cases of CD5/SOX11 double-negative MCL have been reported. In this study, we collected eight cases initially diagnosed as cyclin D1 protein-positive DLBCL, including four with a CCND1 rearrangement and four without. Immunohistochemically, all four CCND1-rearranged cases had >50% of tumor cells positive for cyclin D1 protein, whereas only one (25%) non-rearranged case had >50% positive tumor cells. Analysis of genome-wide copy number, mutational, and gene expression profiles revealed that CCND1-rearranged cases were similar to MCL, whereas CCND1-non-rearranged cases resembled DLBCL. Despite the SOX11 negativity by immunohistochemistry, CCND1-rearranged cases had a notable trend (P = 0.064) of higher SOX11 mRNA levels compared to non-rearranged cases. Here, we show for the first time that CCND1 rearrangement could be useful for identifying CD5/SOX11 double-negative pleomorphic MCL in cases diagnosed as cyclin D1 protein-positive DLBCL. Cases with >50% cyclin D1 protein-positive tumor cells immunohistochemically and higher SOX11 mRNA levels are more likely to have a CCND1 rearrangement, and fluorescence in situ hybridization can be used to detect the rearrangement.

The application of electrical impedance tomography and surgical outcomes of thoracoscope-assisted surgical stabilization of rib fractures in severe chest trauma.

Serious blunt chest trauma usually induces hemothorax, pneumothorax, and rib fractures. More studies have claimed that early video-assisted thoracoscopic surgery with surgical stabilization of rib fractures (SSRF) results in a good prognosis in patients with major trauma. This study aimed to verify the outcomes in patients with chest trauma whether SSRF was performed. Consecutive patients who were treated in a medical center in Taiwan, for traumatic events between January 2015 and June 2020, were retrospectively reviewed. This study focused on patients with major trauma and thoracic injuries, and they were divided into groups based on whether they received SSRF. We used electrical impedance tomography (EIT) to evaluate the change of ventilation conditions. Different scores used for the evaluation of trauma severity were also compared in this study. Among the 8396 patients who were included, 1529 (18.21%) had major trauma with injury severity score > 16 and were admitted to the intensive care unit initially. A total of 596 patients with chest trauma were admitted, of whom 519 (87%) survived. Younger age and a lower trauma score (including injury severity scale, new injury severity score, trauma and injury severity score, and revised trauma score) account for better survival rates. Moreover, 74 patients received SSRF. They had a shorter intensive care unit (ICU) stay (5.24, p = 0.045) and better performance in electrical impedance tomography (23.46, p < 0.001). In patients with major thoracic injury, older age and higher injury survival scale account for higher mortality rate. Effective surgical stabilization of rib fractures shortened the ICU stay and helped achieve better performance in EIT. Thoracoscope-assisted rib fixation is suggested in severe trauma cases.

Renal lipid accumulation and aging linked to tubular cells injury via ANGPTL4.

Renal tubular epithelial cells are vulnerable to stress-induced damage, including excessive lipid accumulation and aging, with ANGPTL4 potentially playing a crucial bridging role between these factors. In this study, RNA-sequencing was used to identify a marked increase in ANGPTL4 expression in kidneys of diet-induced obese and aging mice. Overexpression and knockout of ANGPTL4 in renal tubular epithelial cells (HK-2) was used to investigate the underlying mechanism. Subsequently, ANGPTL4 expression in plasma and kidney tissues of normal young controls and elderly individuals was analyzed using ELISA and immunohistochemical techniques. RNA sequencing results showed that ANGPTL4 expression was significantly upregulated in the kidney tissue of diet-induced obesity and aging mice. In vitro experiments demonstrated that overexpression of ANGPTL4 in HK-2 cells led to increased lipid deposition and senescence. Conversely, the absence of ANGPTL4 appears to alleviate the impact of free fatty acids (FFA) on aging in HK-2 cells. Additionally, aging HK-2 cells exhibited elevated ANGPTL4 expression, and stress response markers associated with cell cycle arrest. Furthermore, our clinical evidence revealed dysregulation of ANGPTL4 expression in serum and kidney tissue samples obtained from elderly individuals compared to young subjects. Our study findings indicate a potential association between ANGPTL4 and age-related metabolic disorders, as well as injury to renal tubular epithelial cells. This suggests that targeting ANGPTL4 could be a viable strategy for the clinical treatment of renal aging.

Efficacy of Sacubitril-Valsartan on Survival and Cardiac Remodeling in Hypotensive Heart Failure With Reduced Ejection Fraction: A Multicenter Study.

OBJECTIVE: To investigate whether hypotensive patients diagnosed with heart failure and reduced ejection fraction (HFrEF) might benefit from angiotensin receptor-neprilysin inhibitors (ARNis) in real-world practice because patients with baseline systolic blood pressure (SBP) of less than 100 mm Hg have been excluded from landmark trials. PATIENTS AND METHODS: In this multicenter study conducted between January 1, 2013, and December 31, 2021, a total of 7562 symptomatic patients with HFrEF were enrolled and grouped by SBP (hypotension was defined as an SBP of less than 100 mm Hg) and ARNi use as follows: group 1, hypotensive/non-ARNi users (n=484); group 2, hypotensive/ARNi users (n=308); group 3, nonhypotensive/non-ARNi users (n=4560); and group 4, nonhypotensive/ARNi users (n=2210). Inverse probability of treatment weighting was used to balance baseline characteristics for survival analysis. RESULTS: Diverse baseline characteristics and lower rates of medication use were found among non-ARNi users compared with ARNi users. Hypotensive/ARNi users had lower ARNi initiation doses than nonhypotensive/ARNi users. We observed significantly lower mortality, composite heart failure hospitalization, and CV death for hypotensive/ARNi and the other 2 nonhypotensive groups (groups 3 and 4) during a median follow-up of 3.43 years (all P<.05), with a similar effect on reverse remodeling for the hypotensive/ARNi group compared with the hypotensive/non-ARNi group. The event-free survival benefits of ARNi vs renin-angiotensin system inhibitors were consistent with the lower boundary of SBP for clinical benefits found until 88 mm Hg (spline curves) after inverse probability of treatment weighting. CONCLUSION: Patients with HFrEF and hypotension may still benefit from ARNi treatment. Patients with hypotensive HFrEF should not be routinely excluded from ARNi use in a real-world setting.

Major impact of prognosis by age and sex in patients with primary mediastinal large B­cell lymphoma.

The effective prognostic factors for primary mediastinal large B-cell lymphoma (PMLBCL) vary among published studies. The aim of the present study was to explore the factors influencing the overall survival (OS) and progression-free survival (PFS) of patients with PMLBCL at a single institute in Taiwan. This retrospective study was conducted to analyze the prognostic impact of age, sex, disease stage, International Prognostic Index (IPI) score, treatment modality and initial response. A total of 72 patients with a median age of 28 years were included in the study. The mean OS and PFS were 171.40 and 159.77 months, respectively. Female sex, age ≤60 years, receiving radiotherapy (RT) and achieving a complete response were found to be associated with a significantly improved OS and PFS. In addition, high-intensity chemotherapy and an IPI score ≤1 were associated with longer OS, and early-stage disease was associated with a PFS superior to that of advanced-stage disease. The predictive value of IPI is limited in PMLBCL. Therefore, it is necessary to develop a novel prognostic system. The present study revealed the impact of sex on prognosis and, therefore, this factor should be considered in future prognostic evaluations. Since a complete post-treatment response was found to be important, high-intensity chemotherapy is recommended. However, low-intensity treatment followed by RT consolidation appears to be a feasible approach in elderly patients.

Primary breast diffuse large B-cell lymphoma characterized by CNS relapse and successful hematopoietic stem cell transplantation salvage therapy.

BACKGROUND: Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is rare, with a high incidence of central nervous system (CNS) relapse. This study aims to investigate clinical characteristics, prognostic factors, and outcomes in Taiwanese PB-DLBCL patients and review the literature on PB-DLBCL. METHODS: Thirty-one PB-DLBCL patients diagnosed between 2000 and 2021 were retrospectively enrolled for analysis. RESULTS: The median age was 49 (range 26-79) years. The complete remission (CR) rate was 90.3%. Nine (90%) of the ten patients who experienced relapse had CNS involvement at the time of relapse. The one-year, two-year, and five-year progression-free survival (PFS) rates were 86.6% (95% confidence interval [CI] 75.2-99.8), 75.8% (95% CI 61.6-93.2), and 45.1% (95% CI 29.5-68.9), respectively. The five-year overall survival (OS) rate was 64.1% (95 % CI 48.4-85.0). A stage-modified International Prognostic Index (mIPI) less than two (five-year PFS rate 52.5% vs. 17.1%, P = 0.02) and the achievement of CR after first-line treatment (two-year PFS rate 80.3% vs. 33.3%, P < 0.001) were significant favorable prognostic factors for PFS. Hematopoietic stem cell transplantation (HSCT) after the first relapse was associated with significantly improved post-relapse OS (five-year OS rate 85.7% vs. 20.0%, P = 0.02) and PFS (five-year PFS rate 85.7% vs. 20.0%, P = 0.02). CONCLUSION: Patients with low-risk mIPI scores, CR after first-line treatment, and those who underwent HSCT after the first relapse had significantly better survival. Intrathecal chemotherapy conferred no benefit in preventing CNS relapse. Further research is needed to assess frontline HSCT's effectiveness in improving outcomes and preventing CNS relapses in PB-DLBCL patients.

Attenuative effects of collagen peptide from milkfish (Chanos chanos) scales on ovariectomy-induced osteoporosis.

Osteoporosis is characterized by low bone mass, bone microarchitecture disruption, and collagen loss, leading to increased fracture risk. In the current study, collagen peptides were extracted from milkfish scales (MS) to develop potential therapeutic candidates for osteoporosis. MS was used to synthesize a crude extract of fish scales (FS), collagen liquid (COL), and hydroxyapatite powder (HA). COL samples were further categorized according to the peptide size of total COL (0.1 mg/mL), COL < 1 kDa (0.1 mg/mL), COL: 1-10 kDa (0.1 mg/mL), and COL > 10 kDa (0.1 mg/mL) to determine it. Semi-quantitative reverse transcription polymerase chain reaction (sqRT-PCR) and immunofluorescence labeling were used to assess the expression levels of specific mRNA and proteins in vitro. For in vivo studies, mice ovariectomy (OVX)-induced postmenopausal osteoporosis were developed, while the sham surgery (Sham) group was treated as a control. Collagen peptides (CP) from MS inhibited osteoclast differentiation in RAW264.7 cells following an insult with nuclear factor kappa-B ligand (RANKL). CP also enhanced osteoblast proliferation in MG-63 cells, possibly through downregulating NFATc1 and TRAP mRNA expression and upregulating ALP and OPG mRNA levels. Furthermore, COL1 kDa also inhibited bone density loss in osteoporotic mice. Taken together, CP may reduce RANKL-induced osteoclast activity while promoting osteoblast synthesis, and therefore may act as a potential therapeutic agent for the prevention and control of osteoporosis.

Predictive model for treatment outcomes of peripheral T-cell lymphoma, not otherwise specified, in Taiwanese patients.

PURPOSE: We aimed to explore the clinical outcomes and prognostic factors for PTCL-NOS patients in the real world. METHODS: Clinical data were retrospectively collected from adult patients with PTCL-NOS treated at a single center in Taiwan. RESULTS: 104 PTCL-NOS patients with a median age of 53.0 years were enrolled. Patients with the International Prognostic Index (IPI) or prognostic index for peripheral T-cell lymphoma (PIT) scores of zero had a longer overall survival (OS) and progression free survival (PFS), while patients with IPI or PIT scores ≥1 did poorly. For patients who are eligible for transplantation, the use of pralatrexate as salvage chemotherapy has shown better OS (2-year OS 83.3% vs. 24.4%, P = 0.011) compared to patients who did not. By multivariate analysis, age >60 years, male, B symptoms, ECOG >1, lung involvement, and thrombocytopenia were independent adverse factors for OS. Incorporating factors in multivariate analysis, we established a novel predictive index for PTCL-NOS which efficiently stratifies patients into low (0-1 factor), intermediate-1 (2 factors), intermediate-2 (3 factors), and high risk (4-6 factors) groups with 2-year OS rates of 81.5%, 32.9%, 8.8%, and 0%, respectively (P < 0.001). CONCLUSION: PTCL-NOS patients have a dismal prognosis in Taiwan. Novel agents may improve the outcomes of PTCL-NOS patients. The usefulness of the novel prognostic index for PTCL-NOS needs further validation.

Clinical effects of dupilumab: A novel treatment for Kimura disease.

BACKGROUND: Kimura disease (KD) is a rare chronic inflammatory disorder involving the Th2 pathway. Although medical treatment with steroids or other immunosuppressants is available, they may cause developmental issues in the pediatric population. Surgical intervention has also been suggested; however, it is associated with high recurrence rates. CASE PRESENTATION: A 14-year-old boy presented with left retroauricular lymph node enlargement at the age of 5 years. At the age of 7 years, he was diagnosed with nephrotic syndrome which subsided after steroid treatment for approximately 6 years. The retroauricular lymph node was surgically excised, and KD was confirmed. However, recurrent enlargement of the left retroauricular and neck lymph nodes occurred after 2 years. Persistently high IgE levels and fluctuating eosinophil counts were observed following steroid treatment. Dupilumab was prescribed because of the difficulty in tapering the steroid dosage. A loading dose of 600 mg was administered, followed by a maintenance dose of 300 mg every 2 weeks. The IgE level decreased after 3 months, and a low eosinophil count was maintained after steroid discontinuation. Follow-up computed tomography revealed a decrease in the size of the lymph nodes with no side effects such as conjunctivitis. CONCLUSION: Traditional treatments have raised developmental concerns in the pediatric population and are associated with high recurrence rates. Dupilumab targets the Th2 pathway and provides effective results, with few adverse effects. Dupilumab may be a therapeutic option for KD and other diseases involving the Th2 pathway.

Understanding the need for digital twins' data in patient advocacy and forecasting oncology.

Digital twins are made of a real-world component where data is measured and a virtual component where those measurements are used to parameterize computational models. There is growing interest in applying digital twins-based approaches to optimize personalized treatment plans and improve health outcomes. The integration of artificial intelligence is critical in this process, as it enables the development of sophisticated disease models that can accurately predict patient response to therapeutic interventions. There is a unique and equally important application of AI to the real-world component of a digital twin when it is applied to medical interventions. The patient can only be treated once, and therefore, we must turn to the experience and outcomes of previously treated patients for validation and optimization of the computational predictions. The physical component of a digital twins instead must utilize a compilation of available data from previously treated cancer patients whose characteristics (genetics, tumor type, lifestyle, etc.) closely parallel those of a newly diagnosed cancer patient for the purpose of predicting outcomes, stratifying treatment options, predicting responses to treatment and/or adverse events. These tasks include the development of robust data collection methods, ensuring data availability, creating precise and dependable models, and establishing ethical guidelines for the use and sharing of data. To successfully implement digital twin technology in clinical care, it is crucial to gather data that accurately reflects the variety of diseases and the diversity of the population.

Degenerative and Regenerative Actin Cytoskeleton Rearrangements, Cell Death, and Paradoxical Proliferation in the Gills of Pearl Gourami (Trichogaster leerii) Exposed to Suspended Soot Microparticles.

The effect is studied of water-suspended soot microparticles on the actin cytoskeleton, apoptosis, and proliferation in the gill epithelium of pearl gourami. To this end, the fish are kept in aquariums with 0.005 g/L of soot for 5 and 14 days. Laser confocal microscopy is used to find that at the analyzed times of exposure to the pollutant zones appear in the gill epithelium, where the actin framework of adhesion belts dissociates and F-actin either forms clumps or concentrates perinuclearly. It is shown that the exposure to soot microparticles enhances apoptosis. On day 5, suppression of the proliferation of cells occurs, but the proliferation increases to the control values on day 14. Such a paradoxical increase in proliferation may be a compensatory process, maintaining the necessary level of gill function under the exposure to toxic soot. This process may occur until the gills' recovery reserve is exhausted. In general, soot microparticles cause profound changes in the actin cytoskeleton in gill cells, greatly enhance cell death, and influence cell proliferation as described. Together, these processes may cause gill dysfunction and affect the viability of fish.

Different patterns of failure in two treatment regimens for primary central nervous system lymphoma, a retrospective analysis of 124 cases in Taiwan.

To explore prognostic factors and outcomes of primary central nervous system lymphoma (PCNSL) of diffuse large B-cell lymphoma (DLBCL) in Taiwan, 124 PCNSL-DLBCL patients (from 1995 to 2021) were retrospectively analyzed. Mainly, two treatment modalities including sandwich chemoradiotherapy and modified MATRix regimen were employed in these patients. Overall survival (OS) was determined by log-rank test and time-dependent Cox analysis. Median OS of all patients was 27.1 months. 47 (37.9%) patients who underwent sandwich chemoradiotherapy had a complete remission (CR) rate of 87.2%, median OS of 53.9 months, and progression free survival (PFS) of 42.9 months. 11 (8.9%) patients who underwent modified MATRix regimen had CR rate of 72.7%, median OS of 18.9, and PFS of 11.2 months. There are no significant OS differences between treatment groups or addition of Rituximab. Patients treated with the modified MATRix regimen experienced a higher early mortality rate followed by a survival plateau. IELSG low-risk group had significantly improved OS and PFS than IELSG intermediate- or high-risk group. In multivariant analysis, age > 60 years old and bilateral cerebral lesions are associated with significantly inferior OS. Sandwich chemoradiotherapy demonstrated better early survival and reduced treatment-related toxicity for PCNSL patients compared to the modified MATRix regimen. However, the long-term follow-up revealed a higher rate of treatment failure events in the sandwich chemoradiotherapy group. IELSG and MSKCC scores served as reliable risk assessment models. Incorporating bilateral cerebral lesions as a risk factor further improved risk evaluation.

Goldilocks principle of minimally invasive surgery for gastric subepithelial tumors.

BACKGROUND: Minimally invasive surgery had been tailored to individual cases of gastric subepithelial tumors (SETs) after comparing the clinical outcomes of endoscopic resection (ER), laparoscopic resection (LR), and hybrid methods. AIM: To study the use of Goldilocks principle to determine the best form of minimally invasive surgery for gastric SETs. METHODS: In this retrospective study, 194 patients of gastric SETs with high probability of surgical intervention were included. All patients underwent tumor resection in the operating theater between January 2013 and December 2021. The patients were divided into two groups, ER or LR, according to the tumor characteristics and the initial intent of intervention. Few patients in the ER group required further backup laparoscopic surgery after an incomplete ER. The patients who had converted open surgery were excluded. A logistic regression model was used to assess the associations between patient characteristics and the likelihood of a treatment strategy. The area under the curve was used to assess the discriminative ability of tumor size and Youden's index to determine the optimal cut-off tumor size. RESULTS: One-hundred ninety-four patients (100 in the ER group and 94 in the LR group) underwent tumor resection in the operating theater. In the ER group, 27 patients required backup laparoscopic surgery after an incomplete ER. The patients in the ER group had small tumor sizes and shorter procedure durations while the patients in the LR group had large tumor sizes, exophytic growth, malignancy, and tumors that were more often located in the middle or lower third of the stomach. Both groups had similar durations of hospital stays and a similar rate of major postoperative complications. The patients in the ER group who underwent backup surgery required longer procedures (56.4 min) and prolonged stays (2 d) compared to the patients in the LR group without the increased rate of major postoperative complications. The optimal cut-off point for the tumor size for laparoscopic surgery was 2.15 cm. CONCLUSION: Multidisciplinary teamwork leads to the adoption of different strategies to yield efficient clinical outcomes according to the tumor characteristics.

Mouse maternal odontogenic infection with Porphyromonas gingivalis induces cognitive decline in offspring.

Introduction: Porphyromonas gingivalis (P. gingivalis), a major periodontal pathogen, causes intrauterine infection/inflammation. Offspring exposed to intrauterine infection/inflammation have an increased risk of neurological disorders, regardless of gestational age. However, the relationship between maternal periodontitis and offspring functional/histological changes in the brain has not yet been elucidated. Methods: In this study, we used a gestational mouse model to investigate the effects of maternal odontogenic infection of P. gingivalis on offspring behavior and brain tissue. Results: The step-through passive avoidance test showed that the latency of the acquisition trial was significantly shorter in the P. gingivalis group (p < 0.05), but no difference in spontaneous motor/exploratory parameters by open-field test. P. gingivalis was diffusely distributed throughout the brain, especially in the hippocampus. In the hippocampus and amygdala, the numbers of neuron cells and cyclic adenosine monophosphate response element binding protein-positive cells were significantly reduced (p < 0.05), whereas the number of ionized calcium binding adapter protein 1-positive microglia was significantly increased (p < 0.05). In the hippocampus, the number of glial fibrillary acidic protein-positive astrocytes was also significantly increased (p < 0.05). Discussion: The offspring of P. gingivalis-infected mothers have reduced cognitive function. Neurodegeneration/neuroinflammation in the hippocampus and amygdala may be caused by P. gingivalis infection, which is maternally transmitted. The importance of eliminating maternal P. gingivalis-odontogenic infection before or during gestation in maintenance healthy brain function in offspring should be addressed in near future.

2023 Expert Consensus of the Taiwan Society of Cardiology on the Diagnosis and Treatment of Cardiac Amyloidosis.

Cardiac amyloidosis is one form of systemic amyloidosis caused by abnormal amyloid fibrils deposited in the extracellular space of the myocardium causing heart failure because of restrictive cardiomyopathy and conduction disturbances. The incidence and prevalence of cardiac amyloidosis are higher than previously noted, particularly among special populations. The most common forms of cardiac amyloidosis are light chain and transthyretin amyloid cardiomyopathy. Even though more than 70% of patients with systemic amyloidosis have cardiac amyloidosis, the diagnosis is often delayed, suggesting significant gaps in the knowledge of cardiac amyloidosis and a lack of multidisciplinary teamwork in our daily practice. The Taiwan Society of Cardiology Heart Failure Committee organized experts to draft the "Expert Consensus on the diagnosis and treatment of cardiac amyloidosis." This statement aims to help clinicians and healthcare professionals improve early diagnosis and management of cardiac amyloidosis in Taiwan. The expert panel met virtually to review the data and discuss the consensus statements. Our review provided practical information about diagnostic methods and algorithms, clinical clues and red-flag signs, cardiac amyloidosis per se and its comorbidities treatment modalities, and follow-up plans for asymptomatic transthyretin gene carriers. We especially innovate two acronyms, "HFpEF MUTED CALL" and "HFmrEF MUST COUNT", to help in the early diagnosis and screening of transthyretin amyloid cardiomyopathy as shown in the Central Illustration.

The impact of small-for-gestational-age Status on the outcomes in very-Low-birth-weight (VLBW) premature infants: a prospective cohort study in Taiwan.

Background: The impact of small-for-gestational-age (SGA) on very-low-birth-weight (VLBW) premature infants remains inconclusive. This study aimed to assess the effects of being born SGA status on the short-term and long-term outcomes in VLBW preterm infants. Methods: We conducted a population-based, prospective cohort study on VLBW preterm infants born in Taiwan between 2012 and 2017. Sociodemographic, neonatal, growth and neurological data at 2 years of corrected age were collected. A total of 4243 VLBW infants born at 24 through 32 completed weeks' gestation participated in this study, of whom 1,005 had SGA status defined as a birth weight <10th percentile of gestation, and 3,238 did not (the non-SGA group).We compared the risks of short-term outcomes (neonatal mortality and morbidities), long-term outcomes (growth status, including weight, height, and head circumference <10th percentile, and neurodevelopmental impairments at 2 years of age). Subgroup analysis was performed by stratification of gestation age (GA): GA 24-26, 27-29 and 30-32 weeks. Results: In the analysis of short-term outcomes, the SGA group had an increased risk of neonatal mortality [adjusted odds ratio (OR) = 2.66, 2.99, and 2.19, respectively] in all GA subgroups in comparison with the non-SGA group (p < 0.05). The SGA group had a significantly increased risk of bronchopulmonary dysplasia in GA 27-29 and 30-32 weeks (adjusted OR = 2.11 and 1.86, respectively). We also found that there was an increased risk of severe retinopathy of prematurity in GA 24-26 and 27-29 weeks in the SGA group compared with the non-SGA group (adjusted OR = 1.68 and 1.59, respectively).In the analysis of long-term outcomes, the SGA group had a significantly increased risk of NDI throughout all GA subgroups (adjusted = 1.94, 1.33, and 1.35, respectively) in comparison with the non-SGA group. The SGA groups also had an increased risk of growth status <10th percentile at 2 years of age (p < 0.05). Conclusions: SGA VLBW premature infants had higher risks of neonatal death, growth status <10th percentile, and NDI at 2 years of corrected age compared with the non- SGA premature infants. Prenatal surveillance, postnatal attention, and long- term follow-up are warranted to improve the outcomes of VLBW SGA premature infants.

The impact of preoperative waiting time in Stage II-III gastric or gastroesophageal junction cancer: A population-based cohort study.

BACKGROUND: Gastrectomy remains the curative option in gastric cancer. However, the growing concern that preoperative waiting jeopardizes survival has not been fully addressed. The present population-based cohort study aimed to clarify the impact of preoperative waiting time (PreWT). METHODS: We included patients with clinical Stage II-III gastric cancer who received curative surgery from 2008 to 2017 of Taiwan Cancer Registry. PreWT was defined as the time from endoscopic diagnosis to surgery. The prognostic impact on overall survival (OS) was evaluated with Cox and restricted cubic spline regressions. RESULTS: A total of 3059 patients with a median age of 68 years were evaluated. The median PreWT was 16 days (interquartile range, 11-24 days), and patients with a shorter PreWT were younger, had a more advanced disease and received adjuvant therapies. Despite a shorter OS occurring with prolonged PreWT (median OS by PreWT [days]: 7-13, 2.7 years; 14-20, 3.1 years; 21-27, 3.0 years; 28-34, 4.7 years; 35-31, 3.7 years; 42-48, 3.4 years; 49-118, 2.8 years; p = 0.029), the differences were not significant after adjustment. The Cox and restricted cubic spline regressions showed that prolonged PreWT was not a significant prognostic factor for OS (p = 0.719). CONCLUSIONS: The population-based study suggests that a PreWT of 49-118 days does not independently correlate with a poor prognosis in Stage II-III gastric cancer. The study provides rationale for a window period for preoperative therapies and patient optimization.

Iron deficiency in Taiwanese patients with heart failure and reduced ejection fraction.

BACKGROUND: Iron deficiency (ID) is a common comorbidity among patients with heart failure and reduced ejection fraction (HFrEF), and is associated with poorer outcomes independent of anemia. This study aimed to evaluate the prevalence and prognostic significance of ID in Taiwanese patients with HFrEF. METHODS: We included HFrEF patients from two multicenter cohorts at different periods. The multivariate Cox regression analysis was applied to assess the risk of outcomes associated with ID, accounting for the varying risk of death. RESULTS: Of the 3612 patients with HFrEF registered from 2013 to 2018, 665 patients (18.4%) had available baseline iron profile measurements. Of these, 290 patients (43.6%) were iron deficient; 20.2% had ID+/anemia+, 23.4% ID+/anemia-, 21.5% ID-/anemia+, and 34.9% ID-/anemia-. Regardless of anemia status, patients with coexisting ID had a higher risk than those without ID (all-cause mortality: 14.3 vs 9.5 per 100 patient-years, adjusted hazard ratio [HR] 1.33; 95% confidence interval [CI], 0.96-1.85; p = 0.091; cardiovascular mortality: 10.5 per 100 patient-years vs 6.1, adjusted HR 1.54 [95% CI, 1.03-2.30; p = 0.037]; cardiovascular mortality or first unplanned hospitalization for HF: 36.7 vs 19.7 per 100 patient-years, adjusted HR 1.57 [95% CI, 1.22-2.01; p < 0.001]). Among patients eligible for treatment in the IRONMAN trial design (43.9%), parenteral iron therapy was estimated to reduce heart failure hospitalizations and cardiovascular deaths by 13.7 per 100 patient-years. CONCLUSION: Iron profiles were tested in less than one-fifth of the Taiwanese HFrEF cohort. ID was present in 43.6% of tested patients and was independently associated with poor prognosis in these patients.

The effect of patient volume on mortality and morbidity of extremely low birth weight infants in Taiwan.

BACKGROUND: To assess whether the number of extremely low birth weight (ELBW) infants treated annually in neonatal intensive care units (NICUs) in Taiwan affects the mortality and morbidity of this patient population. METHODS: This retrospective cohort study included preterm infants with ELBW (≤1000 g). NICUs were divided into three subgroups according to the annual admissions of ELBW infants (low, ≤10; medium, 11-25; and high, >25). Perinatal characteristics, mortality, and short-term morbidities were compared between groups. RESULTS: A total of 1945 ELBW infants from 17 NICUs were analyzed (low-volume, n = 263; medium-volume, n = 420; and high-volume, n = 1262). After risk adjustments, infants from NICUs with low patient volumes were at a higher risk of death. The risk-adjusted odds ratios (aOR) for mortality were 0.61 (95% CI, 0.43-0.86) in the high-volume NICUs and 0.65 (95% CI, 0.43-0.98) in medium-volume NICUs, compared with infants admitted to low-volume NICUs. Infants in medium-volume NICUs had the lowest incidence of prenatal steroid exposure (58.1%, P < 0.001) and were associated with the highest risk of necrotizing enterocolitis (aOR, 2.35 [95% CI, 1.48-3.72]), severe intraventricular hemorrhage (aOR, 1.55 [95% CI, 1.01-2.28]), and bronchopulmonary dysplasia (aOR, 1.61 [95% CI, 1.10-2.35]). However, survival without major morbidity did not differ between the groups. CONCLUSION: The mortality risk was higher among ELBW infants admitted to NICUs with a low annual patient volume. This may emphasize the importance of systematically referring patients from these vulnerable populations to appropriate care settings.

Diarylheptanoid 35d overcomes EGFR TKI resistance by inducing hsp70-mediated lysosomal degradation of EGFR in EGFR-mutant lung adenocarcinoma.

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70-mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease.