Tmem119 expression is downregulated in a subset of brain metastasis-associated microglia.

Under pathological conditions, the immune-specialized brain microenvironment contains both resident microglia and bone marrow-derived myeloid cells recruited from peripheral circulation. Due to largely overlapping phenotypic similarities between these ontogenically distinct myeloid populations, studying their individual functions in central nervous system diseases has been challenging. Recently, transmembrane protein 119 (Tmem119) has been reported as a marker for resident microglia which is not expressed by bone marrow-derived myeloid cells. However, several studies have reported the loss or reduction of Tmem119 expression in pathologically activated microglia. Here, we examined whether Tmem119 could be used as a robust marker to identify brain metastasis-associated microglia. In addition, we also compared Tmem119 expression of primary microglia to the immortalized microglia-like BV2 cell line and characterized expression changes after LPS treatment. Lastly, we used a commercially available transgenic mouse line (Tmem119-eGFP) to compare Tmem119 expression patterns to the traditional antibody-based detection methods. Our results indicate that brain metastasis-associated microglia have reduced Tmem119 gene and protein expression.

The classification of benign and malignant lung nodules based on CT radiomics: a systematic review, quality score assessment, and meta-analysis.

Radiomics methods are increasingly used to identify benign and malignant lung nodules, and early monitoring is essential in prognosis and treatment strategy formulation. To evaluate the diagnostic performance of computed tomography (CT)-based radiomics for distinguishing between benign and malignant lung nodules by performing a meta-analysis. Between January 2000 and December 2021, we searched the PubMed and Embase electronic databases for studies in English. Studies were included if they demonstrated the sensitivity and specificity of CT-based radiomics for diagnosing benign and malignant lung nodules. The studies were evaluated using the QUADAS-2 and radiomics quality scores (RQS). The inhomogeneity of the data and publishing bias were also evaluated. Some subgroup analyses were performed to investigate the impact of diagnostic efficiency. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Guidelines were followed for this meta-analysis. A total of 20 studies involving 3793 patients were included. The combined sensitivity, specificity, diagnostic odds ratio, and area under the summary receiver operating characteristic curve based on CT radiomics diagnosis of benign and malignant lung nodules were 0.81, 0.86, 27.00, and 0.91, respectively. Deek's funnel plot asymmetry test confirmed no significant publication bias in all studies. Fagan nomograms showed a 40% increase in post-test probability among pretest-positive patients. Current evidence shows that CT-based radiomics has high accuracy in the diagnosis of benign and malignant lung nodules.

Clinical Outcomes of Metastatic Breast Cancer in Patients Having Imaging Liver Pseudocirrhosis with or without Evident Varices.

BACKGROUND: Pseudocirrhosis is an imaging finding of malignancies with liver metastasis with or without clinical liver cirrhosis-related portal hypertension (pHTN). This study defined evident pHTN by the presence of esophageal or gastric varices and compared patients' outcomes of metastatic breast cancer with imaging-diagnosed pseudocirrhosis with or without varices. METHODS: The medical records from patients with metastatic breast cancer and pseudocirrhosis between 2005 and 2017 were retrospectively analyzed. Survival outcomes were compared based on endoscopic evidence of esophageal or gastric varices. RESULTS: Among 106 patients with pseudocirrhosis, 33 (31%) had de novo stage IV disease, and 66 (62%) had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eighty-one (76%) had initial metastases in both hepatic lobes, and 32 (30%) had esophageal or gastric varices. The median overall survival (OS) was 5 and 13 months in patients with and without varices (P = .002). The median OS in patients with HER2-positive, HR-positive/HER2-negative, and triple-negative subtype was 16, 9, and 2 months, respectively (P = .001). Patients with varices usually had cirrhotic complications, including gastrointestinal bleeding, hyperbilirubinemia, hyperammonemia, and coagulopathy. Despite their challenging clinical conditions, 7 patients with varices had OS exceeding 1 year. In multivariate analysis, evident varices (P = .007) and triple-negative subtype (P = .013) were associated with poor OS. CONCLUSIONS: Patients with pseudocirrhosis and evident varices had a significantly shorter median OS, and were usually associated with clinical cirrhosis-related complications. To maximize OS, early identification and meticulous supportive care are warranted.

Comparing the diagnostic performance of radiotracers in prostate cancer biochemical recurrence: a systematic review and meta-analysis.

OBJECTIVES: To systematically assess the early detection rate of biochemical prostate cancer recurrence using choline, fluciclovine, and PSMA. METHODS: Under the guidance of the Preferred Reporting Items for Systematic reviews and Meta-Analysis Diagnostic Test Accuracy guidelines, literature that assessed the detection rates (DRs) of choline, fluciclovine, and PSMA in prostate cancer biochemical recurrence was searched in PubMed and EMBASE databases for our systematic review from 2012 to July 15, 2021. In addition, the PSA-stratified performance of detection positivity was obtained to assess the DRs for various methods, including fluciclovine, PSMA, or choline PET/CT, with respect to biochemical recurrence based on different PSA levels. RESULTS: In total, 64 studies involving 11,173 patients met the inclusion criteria. Of the studies, 12, 7, and 48 focused on choline, fluciclovine, and PSMA, respectively. The pooled DRs were 24%, 37%, and 44%, respectively, for a PSA level less than 0.5 ng/mL (p < 0.001); 36%, 44%, and 60% for a PSA level of 0.5-0.99 ng/mL (p < 0.001); and 50%, 61%, and 80% for a PSA level of 1.0-1.99 ng/mL (p < 0.001). The DR with 18F-labeled PSMA was higher than that with 68Ga-labeled PSMA, and the DR was 58%, 72%, and 88% for PSA levels < 0.5 ng/mL, 0.5-0.9 ng/mL, and 1.0-1.99 ng/mL, respectively. CONCLUSION: The DRs of PSMA-radiotracers were greater than those of choline-radiotracers and fluciclovine-radiotracers at the patient level. 18F-labeled PSMA achieved a higher DR than 68Ga-labeled PSMA. KEY POINTS: • The DRs of PSMA-radiotracers were greater than those of choline-radiotracers and fluciclovine-radiotracers at the patient level. • 18F-labeled PSMA achieved a higher DR than 68Ga-labeled PSMA.

Occurrence of ventricular septal perforation in patients with permanent left bundle branch pacing followed up using echocardiographic and computed tomography images.

OBJECTIVE: To explore short-term changes after left bundle branch pacing (LBBP) using echocardiography and computed tomography (CT), especially for postoperative ventricular septal perforation. METHODS: Between January and September 2019, 33 patients with atrioventricular block underwent LBBP at Beijing Anzhen Hospital. All the patients were evaluated using electrocardiography, pacing, parameters and echocardiographic measurements, including for major complications, during the 1, 3, 6, 12 and 24-month follow-up. Interval perforations were examined during a 1-month follow-up echocardiogram and CT. RESULTS: Left bundle branch pacing was successfully performed in 100% (33/33) of patients. The mean seizure threshold was stable and unchanged postoperatively at the 1, 3, 6, 12 and 24-month follow-up. The paced QRS duration of the LBBP was 119.72 ± 2.53 ms and <130 ms in all patients. Unipolar impedance during the procedure was higher than 500 Ω (662.00 ± 181.50 Ω). No ventricular septal perforation occurred at the end of the procedure. At the 1-month follow-up, two patients reported transthoracic echocardiography, with CT revealing septal lead perforation. Through CT, two other patients were found to have septal lead perforation, and echocardiography indicated that the pacing lead had penetrated the interventricular septum and entered the left subendocardium. At the 1, 3, 6, 12 and 24-month follow-up, these four patients exhibited no significant increase in pacing threshold or impedance (p > .05). No ventricular thrombus or stroke was detected. CONCLUSION: Permanent LBBP is safe and feasible in patients with bradycardia. Echocardiography and/or CT can more accurately evaluate changes in cardiac structure and function after LBBP.

Comparison of clinicopathological features and treatment outcomes in aggressive primary intestinal B- and T/NK-cell lymphomas.

BACKGROUND: Primary intestinal lymphomas (PILs) are rare, and this study compared the clinical outcomes of aggressive primary intestinal B-cell lymphomas (aB-PILs) and T/natural killer-cell lymphomas (T/NK-PILs). METHODS: The clinical information of patients diagnosed with aggressive PILs at our institution between 1995 and 2015 were retrospectively investigated. Pathological subtypes were confirmed according to the 2016 revision of the World Health Organization classification. The correlation between clinicopathological features and overall survival (OS) was determined using univariate and multivariate analyses. RESULTS: Cases of T/NK-PILs had higher initial bowel perforation incidence (67% vs. 7%, P < 0.001) and lower complete response rate to first-line chemotherapy regimens (22% vs. 69%, P = 0.009) than aB-PILs. Patients with aB-PILs had a better 5-year event-free survival rate (55.8% vs. 13.9%, P = 0.026) and a 5-year OS rate (74.3% vs. 29.6%, P = 0.036) than those with T/NK-cell lymphomas. Multivariate analysis identified that female gender and stage III/IV were unfavorable prognostic factors. Among the 54 patients with diffuse large B-cell lymphoma (DLBCL), those with International Prognostic Index (IPI) scores of 0-2 had a better 5-year OS rate than those with scores of 3-5 (84.2% vs. 46.8%, P = 0.002). IPI scores of 3-5 (P = 0.026) and tumors located in the large intestine (P = 0.015) were poor prognostic factors based on the multivariate analysis. CONCLUSION: The prognosis of T/NK-PILs was less favorable than that of aB-PILs. Female gender, stage III/IV disease, DLBCL with IPI scores of 3-5, or tumors in the large intestine were poor prognostic factors.

Efficacy of a programmed death-1 checkpoint inhibitor in a case of cutaneous squamous cell carcinoma harboring mutations of TP53 and BRCA2.

Immune checkpoint blockades were reported to result in clinical responses in inoperable and metastatic cutaneous squamous cell carcinoma (cSCC). This report describes an 87-year-old woman with recurrent cSCC that was initially responsive to cetuximab (the monoclonal antibody against epithelial growth factor receptor) but eventually became refractory to cetuximab and multiple subsequent salvage chemotherapy regimens. Next-generation sequencing of the tumor discovered three single-nucleotide mutations in TP53, copy number amplification in Src, and a heterozygous deletion in BRCA2. Because of the high mutation burden of her neoplasm (35.2 mutations per megabase), we treated her with a programmed death-1 (PD-1) checkpoint inhibitor, pembrolizumab, for 10 months. The tumor regressed 3 months later and complete pathological remission was achieved 10 months after starting treatment. As of writing, the patient has been disease free for 17 months after discontinuing treatment. This is the first reported case of heterozygous deletion of BRCA2 in cSCC. The high mutation burden and BRCA2 mutation might explain why this tumor was highly sensitive to anti-PD-1 treatment.

Third-order shear deformation beam model for flexural waves and free vibration of pipes.

A third-order shear deformation beam model is proposed to analyze dynamic behavior of straight hollow cylinders of annular cross-section, in which shear stress vanishes on the inner and outer surfaces of the pipe. Shear deformation, warping, and rotational inertia of cross-section are all considered, and the shear correction factor is not needed. A single governing differential equation is derived for analyzing flexural wave propagation and free vibration of straight pipe-beams. The phase and group speeds of flexural waves propagating in pipes are determined for acoustic and optical modes. The dispersion of flexural waves is analyzed. The frequency equations are obtained explicitly for pipe-beams with ten typical boundary conditions including clamped, pinned, guided, and free ends. The natural frequencies of clamped-free, clamped-clamped, and pinned-pinned pipe-beams are evaluated for the first four vibration modes. A comparison of this paper's numerical results of the natural frequencies with the previous ones is made and turns out the effectiveness of the suggested method. The influences of the pipe's thickness and length on the natural frequencies and mode shapes for a cantilever pipe are presented.

ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress.

The p53 protein is activated by stress signals and exhibits both protective and death-promoting functions that are considered important for its tumor suppressor function. Emerging evidence points toward an additional role for p53 in metabolism. Here, we identify Lpin1 as a p53-responsive gene that is induced in response to DNA damage and glucose deprivation. Lpin1 is essential for adipocyte development and fat metabolism, and mutation in this gene is responsible for the lypodystrophy phenotype in fld mice. We show that p53 and Lpin1 regulate fatty acid oxidation in mouse C2C12 myoblasts. p53 phosphorylation on Ser18 in response to low glucose is ROS and ATM dependent. Lpin1 expression in response to nutritional stress is controlled through the ROS-ATM-p53 pathway and is conserved in human cells. Lpin1 provides a critical link between p53 and metabolism that may be an important component in mediating the tumor suppressor function of p53.

Clinical outcomes of primary intraocular lymphoma patients treated with front-line systemic high-dose methotrexate and intravitreal methotrexate injection.

A standard treatment for patients with primary intraocular lymphoma (PIOL) remains unclear. This study retrospectively analyzed the clinical features and outcomes of 19 patients with PIOL who were treated with a first-line therapy comprising combined intravenous high-dose methotrexate and intravitreal methotrexate between January 2003 and December 2013. Thirteen (68.4 %) patients were female, and the median age at diagnosis was 57 (39-77 years). Diagnoses were based on the identification of abnormal lymphoid cells in vitreous fluid. Ten (52.6 %) patients had bilateral eye involvement, and six had concurrent central nervous system (CNS) involvement. All 19 patients achieved complete remission (CR) as confirmed by cytological examination of vitreous and cerebrospinal fluid and brain imaging if CNS was involved. Patients with concurrent brain involvement required a longer time to achieve CR. However, the duration of complete remission did not differ between patients with and without CNS involvement. The 5-year overall survival rate was 55.8 % for the total cohort and was higher (68.8 %) in patients with isolated PIOL than in those with concurrent CNS involvement. In all patients, methotrexate treatment was well tolerated, with manageable side effects. We conclude that combined intravitreal methotrexate and systemic high-dose methotrexate treatment is effective in patients with PIOL.

Diagnostic role of F-18 FDG PET/CT in determining preoperative Lymph node status of patients with rectal cancer: a meta-analysis.

PURPOSE: To obtain performance values of PET/CT for determining the nodal status of rectal cancer. MATERIALS: A comprehensive literature search was performed on PubMed and Embase for original diagnostic accuracy studies on the diagnostic performance of PET-CT for detection of LN metastasis in rectal cancer. The QUADAS-2 was used to evaluate the methodological quality of each study. Pooled sensitivity, specificity, and AUC were calculated to estimate the diagnostic role of PET/CT using a random-effects model. A subgroup analysis was performed to investigate the influence of different parameters on diagnostic performance. RESULTS: A total of 15 studies and 1209 patients were included. A publication bias was observed. The pooled sensitivity, specificity, and AUC for PET/CT was 0.62 (95% CI 0.49, 0.74), 0.94 (95% CI 0.87, 0.97), and 0.87 (95% CI 0.83-0.89), respectively. Per-node basis yields higher accuracy than per-patient basis, with pooled sensitivities of 0.65 (95% CI 0.50-0.79) vs. 0.56 (95% CI 0.36-0.77) and specificities of 0.96 (95% CI 0.92-1.00) vs. 0.88 (95% CI 0.76-1.00), but there were no significant differences in diagnostic accuracy. CONCLUSION: PET/CT has high specificity but moderate sensitivity for the detection of LN metastasis in rectal cancer. The current data suggests that the diagnostic capabilities of this method is limited due to its moderate sensitivity.

Complete response to front-line therapies is associated with long-term survival in HIV-related lymphomas in Taiwan.

BACKGROUND: The prognosis for people living with HIV (PLWH) who develop lymphomas has been greatly improved by combination antiretroviral therapy (cART) and anti-CD20 monoclonal antibodies. However, real-world clinical data on this patient group in Asia are limited. METHODS: Treatment outcomes were retrospectively examined for 104 PLWH with lymphomas between 2000 and 2019. The cohort comprised five PLWH with Hodgkin lymphoma (HL) and 99 with non-Hodgkin lymphomas, including 61 with diffuse large B-cell lymphoma (DLBCL), 19 with Burkitt lymphoma (BL), nine with primary central nervous system lymphoma (PCNSL) and ten with other subtypes. RESULTS: The 5-year overall survival (OS) rates were as follows: HL (100%), PCNSL (76.2%), other subtypes (60.0%), BL (57.4%), and DLBCL (55.6%). Individuals who achieved complete response (CR) to front-line therapies had a significantly better 5-year OS rate than those without (96.2% vs. 17.8%, p < 0.001). PLWH who received cART for ≤6 months had significantly lower CD4+ T-cell counts at lymphoma diagnosis than those who received cART for longer periods (p = 0.048). Additionally, the 5-year OS rate was better for PLWH who received cART for ≤6 months before lymphomas diagnosis than those who received cART for longer periods (64.5% vs. 51.9%, p = 0.114). CONCLUSIONS: PLWH with DLBCL or BL had OS rates compatible to patients without HIV infection. Better outcomes for patients achieving CR to front-line therapy and those with shorter cART duration before lymphoma diagnosis suggest an underlying biological distinction in the lymphomas and the involvement of immunity, which warrants further studies.

Development and Validation of a Nomogram Based on DCE-MRI Radiomics for Predicting Hypoxia-Inducible Factor 1α Expression in Locally Advanced Rectal Cancer.

RATIONALE AND OBJECTIVES: The expression levels of hypoxia-inducible factor 1 alpha (HIF-1α) have been identified as a pivotal marker, correlating with treatment response in patients with locally advanced rectal cancer (LARC). This study aimed to develop and validate a nomogram based on dynamic contrast-enhanced MRI (DCE-MRI) radiomics and clinical features for predicting the expression of HIF-1α in patients with LARC. MATERIALS AND METHODS: A total of 102 patients diagnosed with locally advanced rectal cancer were divided into training (n = 71) and validation (n = 31) cohorts. The expression statuses of HIF-1α were histopathologically classified, categorizing patients into high and low expression groups. The intraclass correlation coefficient (ICC), minimum redundancy maximum relevance (mRMR), and the least absolute shrinkage and selection operator (LASSO) were employed for feature selection to construct a radiomics signature and calculate the radiomics score (Rad-score). Univariate and multivariate analyses of clinical features and Rad-score were applied, and the clinical model and the nomogram were constructed. The predictive performance of the nomogram incorporating clinical features and Rad-score was assessed using Receiver Operating Characteristics (ROC) curves, decision curve analysis (DCA), and calibration curves. RESULTS: Seven radiomics features from DCE-MRI were used to build the radiomics signature. The nomogram incorporating CEA, Ki-67 and Rad-score had the highest AUC values in the training cohort and in the validation cohort (AUC: 0.918 and 0.920). Decision curve analysis showed that the nomogram outperformed the clinical model and radiomics signature in terms of clinical utility. In addition, the calibration curve for the nomogram demonstrated good agreement between prediction and actual observation. CONCLUSION: The nomogram based on DCE-MRI radiomics and clinical features showed favorable predictive efficacy and might be useful for preoperatively discriminating the expression of HIF-1α.

Prediction by a multiparametric magnetic resonance imaging-based radiomics signature model of disease-free survival in patients with rectal cancer treated by surgery.

Objective: The aim of this study was to assess the ability of a multiparametric magnetic resonance imaging (MRI)-based radiomics signature model to predict disease-free survival (DFS) in patients with rectal cancer treated by surgery. Materials and methods: We evaluated data of 194 patients with rectal cancer who had undergone radical surgery between April 2016 and September 2021. The mean age of all patients was 62.6 ± 9.7 years (range: 37-86 years). The study endpoint was DFS and 1132 radiomic features were extracted from preoperative MRIs, including contrast-enhanced T1- and T2-weighted imaging and apparent diffusion coefficient values. The study patients were randomly allocated to training (n=97) and validation cohorts (n=97) in a ratio of 5:5. A multivariable Cox regression model was used to generate a radiomics signature (rad score). The associations of rad score with DFS were evaluated using Kaplan-Meier analysis. Three models, namely a radiomics nomogram, radiomics signature, and clinical model, were compared using the Akaike information criterion. Result: The rad score, which was composed of four MRI features, stratified rectal cancer patients into low- and high-risk groups and was associated with DFS in both the training (p = 0.0026) and validation sets (p = 0.036). Moreover, a radiomics nomogram model that combined rad score and independent clinical risk factors performed better (Harrell concordance index [C-index] =0.77) than a purely radiomics signature (C-index=0.73) or clinical model (C-index=0.70). Conclusion: An MRI radiomics model that incorporates a radiomics signature and clinicopathological factors more accurately predicts DFS than does a clinical model in patients with rectal cancer.

A facile asymmetric synthesis of (s)-14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth.

An asymmetric synthesis of 14-methyl-1-octadecene, the sex pheromone of the peach leafminer moth has been achieved. The target molecule was synthesized in six linear steps and in 30.3% overall yield from commercially available hexanoyl chloride, (S)-4-benzyloxazolidin-2-one and 1,9-nonanediol. The hexanoyl chloride was connected with (S)-4-benzyloxazolidin-2-one, and with the induction of the chiral oxazolidinone auxiliary, after chiral methylation, LAH reduction and then tosylation gave the chiral key intermediate 5 in high stereoselectivity. 1,9-Nonanediol, was selectively brominated, THP protected and subjected to Li2CuCl4-mediated C-C coupling to afford a C12 intermediate. The target molecule, (S)-14-methyl-1-octadecene, was obtained after the two parts were subjected to a second Li2CuCl4-mediated C-C coupling. Our synthetic approach represents the first time a substrate-control asymmetric synthesis of (S)-14-methyl-1-octadecene has been reported.

Effect of anlotinib combined with ticeorgio for recurrent nasopharyngeal carcinoma: a case report.

For patients with locally unresectable recurrent nasopharyngeal carcinoma who relapsed after 2 years of radiotherapy, re-radiotherapy is also the preferred treatment. However, for patients relapsed within 2 years, the use of re-radiotherapy would be greatly limited by its adverse effects. Consequently, finding a new strategy to prolong the time of re-radiotherapy for locally recurrent nasopharyngeal carcinoma is very necessary to reduce the related side effects and improve the curative effect. Anlotinib is an orally available small molecule multi-target tyrosine kinase inhibitor that primarily inhibits VEGFR2/3, FGFR1-4, PDGFR α/ß, c-Kit, and Ret. However, whether recurrent nasopharyngeal carcinoma patients can be treated with anlotinib combined with ticeorgio (also called S-1) remains unknown. Herein, we report a nasopharyngeal carcinoma patient with local recurrence after radical radiotherapy who benefited from combination treatment of anlotinib with ticeorgio.

Long-term outcomes of combined intravitreal methotrexate and systemic high-dose methotrexate therapy in vitreoretinal lymphoma.

OBJECTIVE: The optimal treatment for vitreoretinal lymphoma (VRL) remains a challenge, as central nervous system (CNS) relapse occurs frequently, leading to the worst impact on survival. We previously proposed combined intravitreal methotrexate and systemic high-dose methotrexate therapy for this disease. This study aimed to report the long-term outcomes of patients with VRL using this combination treatment. METHODS: We conducted a retrospective cohort study on patients with VRL at a tertiary referral center between 2003 and 2018. RESULTS: Thirty-two patients were included, of whom 23 had primary VRL (PVRL) and nine had concurrent intraocular and CNS diseases. The treatment was well tolerated. Twenty-six (81.3%) patients achieved complete response (CR). After a median follow-up time of 103.5 months, the 5-year survival rate was 73.3%, whereas the 5-year progression-free survival (PFS) rate was 29.9%. Twenty-four (75%) patients relapsed, including 12 with isolated intraocular relapses at first relapse and a total of 17 with CNS/systemic relapses. The development of CNS/systemic relapse negatively affected survival, but intraocular relapse did not. The median CNS/systemic PFS was 69.5 months, but the risk of CNS/systemic relapse increased steadily with a cumulative incidence rate at 2, 5, and 10 years being 22.6%, 44.2%, and 65%, respectively. Multivariate analysis identified concurrent CNS disease at diagnosis as the only poor-risk factor for CNS/systemic relapse. CONCLUSIONS: This study confirms good efficacy and acceptable toxicities of the combination approach. However, incorporation of further intensive consolidation strategies into the treatment protocol to effectively prevent subsequent CNS/systemic relapse deserves to be considered.