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.

Comparing the Long-Term Cardiovascular Outcomes of Lumbo-Peritoneal, Ventriculo-Peritoneal, or Non-Shunting Treatment after Idiopathic Normal Pressure Hydrocephalus: A Nationwide Retrospective Cohort Study.

Purpose: With advances in medical technology, the average lifespan has increased, leading to a growing significance of idiopathic normal pressure hydrocephalus (iNPH), particularly in the elderly population. Most patients with iNPH have been treated either with ventriculo-peritoneal shunts (VPS) or conservative measures. However, lumbo-peritoneal shunts (LPS) have emerged as an alternative treatment option for iNPH in recent decades, extensive research still lacks comparing outcomes with LPS to those with VPS or non-surgical treatment. The aim of the resent study is to disclose the long-term therapeutic outcomes of LPS, VPS, and non-shunting in patients with iNPH. Methods: We used the National Health Insurance Research Database in Taiwan to assess the long-term outcomes of these treatment options. We enrolled 5,537 iNPH patients who received shunting surgery, of which 5,254 were VPS and 283 were LPS. To compare the difference between each group, matching was conducted by propensity score matching using a 1:1 ratio based on LPS patients. Primary outcomes included death and major adverse cardiovascular events (MACEs) Results: Our findings show that VPS resulted in significantly more MACEs than non-surgical treatment (Odds ratio: 1.83, 95% confidence interval: 1.16-2.90). In addition, both VPS and LPS groups had significantly lower overall mortality rates than non-shunting group. Moreover, LPS had lower overall mortality but similar MACEs rates to VPS. Conclusions: Based on these findings, we propose that the LPS is preferable to the VPS, and surgical treatment should be considered the primary choice over conservative treatment unless contraindications are present.

The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Extracellular vesicles called exosomes are primarily used as mediators of intercellular signal transmission to control tumor metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with exosome generation in chondrosarcoma motility remains undetermined. Our results found that overexpressing visfatin augments the production of exosomes from chondrosarcoma cells. Visfatin-treated chondrosarcoma exosomes educate macrophage polarization towards the M2 but not M1 phenotype. Interestingly, M2 macrophages polarized by exosomes return to chondrosarcoma cells to facilitate cell motility. According to these findings, chondrosarcoma cells emit more exosomes when treated with visfatin. The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Clinicopathological and molecular characterisation of papillary renal neoplasm with reverse polarity and its renal papillary adenoma analogue.

AIMS: Papillary renal neoplasm with reverse polarity (PRNRP) is a newly defined entity with distinct histomorphology and recurrent KRAS mutation. It has been estimated to constitute 4% of previously diagnosed papillary renal cell carcinoma (PRCC). Renal papillary adenoma (PA) is suggested to be the precursor of PRCC. This study aimed to investigate the association between PRNRP and PA, particularly the morphologically similar type D PA. METHODS AND RESULTS: Nephrectomy specimens of PRCC and PA from our 10-year pathology archives were retrieved and reviewed. GATA3 immunohistochemistry and RAS/BRAF testing were performed in all cases reclassified as PRNRP and all PAs with sufficient materials. Overall, PRNRP accounted for 9.1% (10 of 110) of PRCC and there was no recurrence/metastasis with a mean follow-up period of 39 months. Three novel morphological features were described, including clear cell change, mast cell infiltration and metaplastic ossification. Nine of the 10 PRNRPs showed diffuse and strong GATA3 expression and KRAS missense mutations at codon 12. One case exhibited moderate GATA3 staining on 80% of the tumour cells and RAS/BRAF wild-type. In a total of 73 PAs, 11 were classified as type D. GATA3 expression was significantly more frequent in type D versus non-type D PAs (100 versus 35%, P < 0.01). KRAS missense mutations were identified in six of eight (75%) of the type D PAs but none of the 18 non-type D PAs. CONCLUSIONS: Type D PA was different from other types of PA and represented an analogue or a small-sized PRNRP for their identical morphology, immunophenotype and molecular signature.

Impact of tumor disappearance ratio on the prognosis of lung adenocarcinoma ≤2 cm in size: A retrospective cohort study.

BACKGROUND/PURPOSE: Lung cancer patients can have advanced-stages at diagnosis, even the tumor size is ≤2 cm. We aimed to study the relationship between image characteristics, clinical, and patholoigcal results. METHODS: We retrospectively enrolled patients with lung adenocarcinoma at Taichung Veterans General Hospital and Chang Gung Memorial Hospital from 2007 to 2015, who were diagnosed with treatment naïve primary tumor lesions at sizes less than 2 cm, as measured by computed tomography (CT) scans. The patient was analyzed for lymph node (LN) and distant metastasis evaluation, with clinicopathological characteristics, including tumor-disappearance ratio (TDR) (tumor diameter at the mediastinal/lung window) over chest CT scans, pathological diagnosis, disease-free survival (DFS), and overall survival (OS). RESULTS: Totally 280 patients were surveyed initially and showed significantly increase of clinical LN involvement and distant metastasis when TDR ≤75% compared with >75% (21.6% vs 0% for LN involvement; 27.1% vs 0% for distant metastasis; both p < 0.001). We included 199 patients having surgical treatment and follow-up for the survival analysis. With a TDR ≤75%, significantly worse DFS (HR, 19.23; 95% CI, 2.60-142.01; p = 0.004) and a trend of worse OS (HR, 4.97; 95% CI, 0.61-40.61; p = 0.134) were noted by Kaplan-Meier method. TDR ≤75% revealed more advanced pathological stage, and more tumors containing micropapillary or solid subtypes when diagnosed adenocarcinoma. CONCLUSION: For lung cancer patients with primary tumor ≤2 cm, TDR ≤75% was related to more advanced stages, the presence of micropapillary or solid components of adenocarcinoma subtypes, worse DFS, and a trend of worse OS.

A common polymorphism decreases LRP1 mRNA stability and is associated with increased plasma factor VIII levels.

The low-density lipoprotein receptor-related protein 1 (LRP1) gene is associated with increased levels of plasma factor VIII (FVIII). We aimed to explore eight functional genetic LRP1 variants for their potential roles in regulating FVIII levels and acute ischemic stroke (AIS). This genetic association study enrolled 192 patients with AIS and 134 controls. There were no significant differences in the genetic frequency of the eight functional single-nucleotide polymorphisms (SNPs) between the control and AIS groups. However, while analyzing the association between the eight SNPs and plasma FVIII levels, subjects with T/T genotype of rs1800137 (vs. CC+CT) were found to be associated with higher FVIII levels (23.5IU/dL; 95% confidence interval, 7.4-39.5IU/dL; P=0.0044) after adjusting for age, gender, estimated glomerular filtration rate, O blood type, inflammatory state, and body mass index. An analysis of the mRNA stability and abundance was designed and performed using minigene system transfected into HepG2 cells to assess the possible differences in mRNA stabilities between rs1800137 CC (rs1800137C) and TT (rs1800137T) genotypes. Site-directed mutagenesis revealed that rs1800137T accounts for the observed decrease in mRNA stability. The SNP rs1800137, located in exon 8, has been identified as an exon-splicing enhancer in silico. However, alternative splicing of LRP1 without inclusion of exon 8 was not identified. In transfected HepG2 cells, cycloheximide slowed down the degradation of the rs1800137T-containing minigene. These results demonstrate that synonymous SNP rs1800137 can lead to increased plasma FVIII levels due to decreased mRNA stability via translation-dependent mRNA degradation associated with codon optimality.

Primary Intraosseous Hemangioma of the Orbital Roof: A Pitfall of Surgery.

A primary intraosseous hemangioma (IOH) of the orbital bone is extremely rare. The preferred method of treatment for IOH is total surgical excision with reconstruction. Herein, the authors describe a patient with an orbital roof IOH and the unexpected complications of ptosis and deteriorated exophthalmos. These findings showed that the total surgical excision and subsequent reconstruction provided adequate decompression and prevented further ocular complications from the orbital wall defect.

Shortened Activated Partial Thromboplastin Time Is Associated With Acute Ischemic Stroke, Stroke Severity, and Neurological Worsening.

BACKGROUND: The role played by hemostasis in the pathogenesis of ischemic strokes is still controversial. The activated partial thromboplastin time (APTT) measures the time necessary to generate fibrin from initiation of the intrinsic pathway. In the present study, we looked for a possible association of ischemic strokes with the shortened APTT. METHODS: The study population consisted of 154 patients with acute ischemic strokes who had been admitted from December 2013 to December 2014 to the Department of Neurology, Chiayi Chang Gung Memorial Hospital, and 71 control subjects with no history of stroke. RESULTS: In a univariate risk analysis, shortened APTT was associated with an odds ratio (OR) for acute ischemic strokes of up to 1.86 (95% confidence interval [CI], 1.06-3.29, P = .031). In a multivariate analysis using a logistic regression model including age, sex, hypertension, diabetes mellitus, and shortened APTT, shortened APTT was still found to significantly add to the risk of ischemic stroke (OR = 2.12 with 95% CI, 1.13-3.98, P = .020). Shortened APTT was also associated significantly with neurological worsening (OR = 3.72 with 95% CI 1.03-13.5, P = .046). As for stroke severity, shortened APTT was associated with an OR for moderate/severe stroke of up to 3.42 (95% CI, 1.53-7.61, P = .003). CONCLUSION: Shortened APTT is a prevalent and independent risk factor for ischemic stroke, stroke severity, and neurological worsening after acute stroke.

Transforaminal Unilateral Biportal Endoscopic Spinal Surgery for Extraforaminal Lumbar Disc Herniation: A Retrospective Observational Study.

OBJECTIVE: Biportal endoscopic spinal surgery (BESS) is recommended as a safer and less destructive option for lumbar disc herniations. However, limited data exist on clinical outcomes for extraforaminal lumbar disc herniation (ELDH) surgery. This retrospective study presents our preliminary experience with transforaminal unilateral BESS for ELDH. METHODS: Patients with lumbar radiculopathy refractory to conservative treatment, diagnosed with ELDH by magnetic resonance imaging, and treated with transforaminal unilateral BESS in 2021-2023 in 2 institutions in Taiwan were eligible for inclusion. Those with lumbar spondylolisthesis grade 2 or more with segmental instability, history of drug abuse or psychiatric diseases, or with a follow-up duration <1 year were excluded. Primary outcomes included visual analog scale for pain, assessed at 1 week, 1 month, 6 months, and 1 year using generalized estimating equations analysis; success and satisfaction of BESS graded by the Macnab criteria; and perioperative complications. Secondary outcomes were operative time and hospital length of stay. RESULTS: Seventeen patients were included in the analysis, with a mean age of 65.8 years; 11 (64.7%) were males and 15 (88.2%) had no prior lumbar spine surgery. mean operative time was 107.9 minutes, and length of stay was 3.5 days. Graded by Macnab criteria, 16 (94.1%) of patients had good to excellent outcomes. Only 1 patient experienced complications. No recurrence/reoperation was observed. Generalized estimating equations analysis showed that postoperative visual analog scale scores decreased significantly at 1 week (adjusted Beta [aBeta] = -5.47, standard error: 0.29, P < 0.001), 1 month (aBeta = -5.82), 6 months (aBeta = -5.88), and 1 year (aBeta = -6.29). CONCLUSIONS: Transforaminal unilateral BESS is an alternative and feasible method for treating ELDH, producing good surgical outcomes with few complications and sustaining pain improvement. Future studies with larger patient numbers and comparisons between BESS and other minimally invasive techniques for ELDH are warranted.

Effects of Fu's Subcutaneous Needling on Postoperative Pain in Patients Receiving Surgery for Degenerative Lumbar Spinal Disorders: A Single-Blind, Randomized Controlled Trial.

Background: Fu's subcutaneous needling (FSN) is a novel acupuncture technique for pain treatment. This study investigated the effects of postsurgical FSN on postoperative pain in patients receiving surgery for degenerative spinal disorders. Methods: This single-center, single-blind, randomized-controlled study involved patients undergoing surgery for degenerative spinal disorders. Participants were randomized into either an FSN group or a control group that received sham FSN. The primary outcomes were scores on the Brief Pain Inventory Taiwan version (BPI-T) and Oswestry Disability Index before and at 1, 24, and 48 hours after surgery. Secondary outcomes were muscle hardness, pethidine use, and inflammatory biomarker presence. Results: Initially, 51 patients met the inclusion criteria and were allocated (26 in the FSN group and 25 in the control group). Two patients were lost to follow-up, and finally, 49 patients (25 in the FSN group and 24 in the control group) who completed the study were analyzed. The FSN group had significantly lower pain intensity measured on the BPI-T compared with the control group at 1, 24, 48, and 72 hours after surgical treatment (all p < 0.001). Additionally, pain interference as measured on the BPI-T was lower in the FSN group than in the control group 1 hour (p = 0.001), 24 hours (p = 0.018), 48 hours (p = 0.001), and 72 hours (p = 0.017) after surgical treatment. Finally, the FSN group exhibited less muscle hardness in the latissimus dorsi and gluteus maximus 24, 48, and 72 hours (all p < 0.05) after surgery compared with the control group; patients in the FSN group also exhibited less muscle hardness in the L3 paraspinal muscle 48 hours (p = 0.001) and 72 hours (p < 0.001) after surgery compared with the control group. There were no significant differences in serum CRP, IL-1ß, IL-2, IL-6, and TNF-α levels between the FSN and control groups at 24 hours, 72 hours, and 1-month post-surgery (all p > 0.05). Conclusion: FSN treatment can reduce postoperative pain in patients receiving surgery for degenerative spinal disorders. However, larger sample sizes and multicenter clinical trials are required to verify these findings.

The joint protective function of live- and dead-Lactobacillus plantarum GKD7 on anterior cruciate ligament transection induces osteoarthritis.

Osteoarthritis (OA) is a chronic inflammatory disease accompanied by joint pain, bone degradation, and synovial inflammation. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß play key roles in chronic inflammation, and matrix metalloproteinase (MMP)3 is the first enzyme released by chondrocytes and synovial cells that promotes MMPs' degrading cartilage matrix (including collage II and aggrecan) function. Using an anterior cruciate ligament transection (ACLT) rat model, Lactobacillus plantarum GKD7 has shown anti-inflammatory and analgesic properties. The present investigation examined the chondroprotective effects of several dosages and formulas of GKD7 on rats in an ACLT-induced OA model. The findings indicate that oral treatment with both live-GKD7 (GKD7-L) and dead-GKD7 (GKD7-D), along with celecoxib (positive control), all reduce post-ACLT pain and inflammation in OA joints. Subsequently, the immunohistochemical staining results demonstrate that following GKD7-L and GKD7-D treatment, there was a reversal of the degradation of collagen II and aggrecan, as well as a decrease in the expression of IL-1ß and TNF-α on the synovial tissue and MMP3 on the cartilage. Accordingly, our findings imply that the treatment of both GKD7-L and GKD7-D has chondroprotective and analgesic effects on the OA rat model, and that celecoxib and GKD7-L at dosages (100 mg/kg) have comparable therapeutic benefits. As a result, we propose that both GKD7-L and GKD7-D are helpful supplements for OA management.

Ugonin L inhibits osteoclast formation and promotes osteoclast apoptosis by inhibiting the MAPK and NF-κB pathways.

Bone loss is a major issue for patients with osteoporosis, arthritis, periodontitis, and bone metastasis; however, anti-resorption drugs used to treat bone loss have been linked to a variety of adverse effects. Helminthostachys zeylanica (L.) Hook, belonging to the family Ophioglossaceae, is commonly used in traditional Chinese medicine to treat inflammation and liver problems. In the current study, ugonin L extracted from H. zeylanica was shown to reduce the receptor activator of nuclear factor kappa beta ligand (RANKL)-induced osteoclastogenesis in RAW264.7 cells in a concentration-dependent manner. Ugonin L treatment also inhibited the mRNA expression of osteoclast markers. Ugonin L was also shown to promote cell apoptosis in mature osteoclasts and suppress RANKL-induced ERK, p38, JNK, and NF-κB activation. Taken together, ugonin L appears to be a promising candidate for the development of novel anti-resorption therapies.

Visfatin upregulates VEGF-C expression and lymphangiogenesis in esophageal cancer by activating MEK1/2-ERK and NF-κB signaling.

Lymph node metastasis is a recognized prognostic factor in esophageal cancer. Adipokines, including visfatin, and the molecule vascular endothelial growth factor (VEGF)-C, are implicated in lymphangiogenesis, but whether any association exists between esophageal cancer, adipokines and VEGF-C is unknown. We examined the relevance of adipokines and VEGF-C in esophageal squamous cell carcinoma (ESCC) in the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. We found significantly higher levels of visfatin and VEGF-C expression in esophageal cancer tissue than in normal tissue. Immunohistochemistry (IHC) staining identified that higher levels of visfatin and VEGF-C expression were correlated with advanced stage ESCC. Visfatin treatment of ESCC cell lines upregulated VEGF-C expression and VEGF-C-dependent lymphangiogenesis in lymphatic endothelial cells. Visfatin induced increases in VEGF-C expression by activating the mitogen-activated protein kinase kinases1/2-extracellular signal-regulated kinase (MEK1/2-ERK) and Nuclear Factor Kappa B (NF-κB) signaling cascades. Transfecting ESCC cells with MEK1/2-ERK and NF-κB inhibitors (PD98059, FR180204, PDTC, and TPCK) and siRNAs inhibited visfatin-induced increases in VEGF-C expression. It appears that visfatin and VEGF-C are promising therapeutic targets in the inhibition of lymphangiogenesis in esophageal cancer.

Ugonin P inhibits lung cancer motility by suppressing DPP-4 expression via promoting the synthesis of miR-130b-5p.

Lung cancer is the leading cause of cancer-related death worldwide, and the survival rate of metastatic lung cancer is exceedingly low. Helminthostatchys Zeylanica (H. Zeylanica) is a Chinese herbal medicine renowned for its anti-inflammatory, immunomodulatory, and anti-cancer activities in various cellular and animal studies. The current study evaluated the effects of H. Zeylanica derivatives on lung cancer cells. We determined that dipeptidyl peptidase-4 (DPP-4) expression levels were higher in lung cancer tissues than in normal tissues. We also determined that DPP-4 expression levels were higher in the metastatic stage and strongly correlated with lung cancer survival rates. An H. Zeylanica derivative (ugonin P) was shown to inhibit DPP-4 mRNA and protein expression in two lung cancer cell lines in a dose-dependent manner. Ugonin P was shown to decrease migration and invasion activities in lung cancer cells while promoting the synthesis of miR-130b-5p, which was found to negatively regulate DPP-4 protein expression and cell motility in lung cancer. We determined that ugonin P suppresses the DPP-4-dependent migration and invasion of lung cancer cells by downregulating the RAF/MEK/ERK signalling pathway and enhancing the expression of miR-130b-5p. This study provides compelling evidence that ugonin P could be used to develop novel therapeutic agents for the treatment of lung cancer.

Diffuse symptomatic pneumocephalus after biportal endoscopic spinal surgery: illustrative case.

BACKGROUND: Percutaneous endoscopic lumbar decompression is gaining attention as a minimally invasive surgery. Here, the authors report a rare complication of pneumocephalus caused by vacuum drain after biportal endoscopic spinal surgery (BESS) for lumbar stenosis. OBSERVATIONS: A 79-year-old woman with spinal stenosis over the L4-5 level received BESS. No visible dural tear was encountered during surgery, and a vacuum drain was placed after surgery. Approximately 150 mL of cerebrospinal fluid was drained on postoperative day 1. Simultaneously, symptoms of intracranial hypotension were noted. Brain computed tomography (CT) revealed pneumocephalus. The patient was advised to have bed rest and hydration, and her symptoms improved subsequently. Follow-up brain CT indicated the resolution of pneumocephalus. LESSONS: Pneumocephalus after endoscopic lumbar surgery is rare. Dural tear, high rate of normal saline irrigation, and vacuum drain placement are the associated risk factors.

Erythromycin reduces nasal inflammation by inhibiting immunoglobulin production, attenuating mucus secretion, and modulating cytokine expression.

Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) share some similar pathological mechanisms. In current study, we intend to investigate the impact of AR on CRS. In addition, we explored the efficacy of erythromycin (EM) treatment on CRS mice with or without AR (CRSwoAR, CRSwAR). Study subjects were divided into control, CRSwoAR, and CRSwAR groups. Experimental mice were divided similarly into control, CRSwoAR, and CRSwAR groups. In addition, CRS mice were treated with EM at 0.75, 7.5, or 75 mg/kg or with dexamethasone (Dex) at 1 mg/kg. In our results, allergy exacerbates inflammation that was evident in nasal histology and cytokine expression both in patients and in mice with CRS. Dex 1 mg/kg, EM 7.5 or 75 mg/kg treatments significantly inhibited serum IgE and IgG2a in CRS mice. EM-treated CRS mice had significantly elevated IL-10 levels and had a reversal of Th-1/Th-2 cytokine expression in nasal-associated lymphoid tissue. MUC5AC expressions were significantly reduced in the 7.5 or 75 mg/kg EM-treated mice compared with untreated mice. EM showed inhibitions on immunoglobulin production and mucus secretion stronger than Dex. We concluded that comorbid AR enhanced inflammation of CRS. EM and Dex treatments showed similar anti-inflammatory effects on CRS but through partly different mechanisms.

Stroke risk factors and subtypes in different age groups: a hospital-based study.

BACKGROUND/AIMS: To compare the influence of stroke risk factors between different stroke types and age groups in Taiwan. MATERIALS AND METHODS: During the study period, March 2007 to August 2008, 1,161 patients with acute ischemic stroke were admitted to the neurological ward. All the patients had risk factors work up and stroke subtype categorization. RESULTS: The study cohort included 736 men and 425 women. Patients were grouped into three age groups: below 50 years (153, 13.2%); 50-75 years, (702, 60.5%) and above 75 years (306, 26.4%). Stroke subtypes included: (1) large-artery atherosclerosis (14.6%), cardioembolism (12%), small-artery occlusion (39.4%), stroke of other determined etiology (1.5%) and stroke of undetermined etiology (32.6%). Older patient group had higher frequency of hypertension and diabetes mellitus. Younger age group of patients had high frequency of obesity and elevated serum triglyceride levels. Smoking and alcohol consumption were strongly related to men, and heart disease and obesity were related to women. CONCLUSIONS: The influence of risk factors at different ages is different. Awareness of the stroke risk factors before stroke and treatment with appropriate therapies or life modifications may have a bearing on the outcomes.

How does benevolent leadership lead to work-family enrichment? The mediating role of positive group affective tone.

Although researchers have confirmed the relationship between positive leadership styles and work-family enrichment, benevolent leadership has received little attention. Drawing from the concept of mood contagion, this study explores the underlying mechanism between benevolent leadership and work-family enrichment. Using a survey of 459 employees, across 36 supervisors and their work groups, and multilevel structural equation modelling, this study revealed that benevolent leadership is positively associated with work-family enrichment via cross-level paths. The results indicated that benevolent leadership is associated with positive group affective tone, which further predicts subordinates' work-family enrichment. Moreover, work engagement mediates the relationship between positive group affective tone and work-family enrichment. Theoretical and practical implications are discussed.

Granuloma With an Underlying Lymphoma: A Diagnostic Challenge and a Wider Histologic Spectrum Including Adult T-Cell Leukemia/Lymphoma.

Granulomatous reaction is not uncommon in histopathology, with various etiologies in different organs and geographic regions. Lymphoma is one of the underlying causes of granuloma; and sometimes the neoplastic cells may be masked by the granulomatous reaction. In this report, we present our experience with 7 lymphoma cases of various histologic types with coexisting granuloma to show the diagnostic challenges. In all cases, a granulomatous reaction was simultaneously present with the neoplastic cells. The 7 cases included 3 cases of adult T-cell leukemia/lymphoma in the lymph node or skin including one coexisting with mycobacterial infection, 2 cases of classical Hodgkin lymphoma involving the liver, and 1 case each of systemic Epstein-Barr virus-positive peripheral T-cell lymphoma and a hepatic inflammatory pseudotumor-like follicular dendritic cell sarcoma. Three cases were initially misdiagnosed as reactive change or mycobacterial infection instead of lymphoma, and a wrong histologic lymphoma type was diagnosed in 1 case. In this report, we showed that granulomatous reaction might mask lymphomas of various histologic types; and a diagnosis of mycobacterial infection or sarcoidosis could not exclude the possibility of an underlying lymphoma. We emphasized the importance of detailed histologic examination with the aid of ancillary studies to reach a correct diagnosis and to avoid inappropriate management of the patients. Our study also broadened the spectrum of lymphoma types coexisting with granuloma.