Search

Objective: The purpose of this study was to determine the efficacy of a 3D-printed aneurysm simulation model (3DPM) in educating patients and improving physicians’ comprehension and performance.Methods: This prospective study involved 40 patients who were diagnosed with unruptured intracranial aneurysms (UIAs) and scheduled for surgical clipping or endovascular coiling and randomly divided into two groups (the 3DPM group and the non-3DPM group). The 3DPM was used in preoperative consultation with patients and intraoperatively referenced by surgeons. The patients, 7 neurosurgical residents, and 10 surgeons completed questionnaires (5-point Likert scale) to determine the usefulness of the 3DPM.Results: Patients in the 3DPM group had significantly higher scores in terms of their understanding of the disease (mean 4.85 vs. 3.95, p

The coronavirus disease 2019 (COVID-19) pandemic resulted from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Variants of SARSCoV-2 have caused distinct COVID-19 surges worldwide. The Omicron variant has replaced other variants as a cause of COVID-19 in the Republic of Korea. Fortunately, COVID-19 patients infected with Omicron have a decreased disease severity. Tuberculosis (TB) remains a major public health threat worldwide, and the incidence of TB is still high in the Republic of Korea. We report the case of a deceased illegal migrant who died at home. An autopsy revealed fatal pneumonia with pulmonary TB caused by the Omicron subvariant BA.2 of SARS-CoV-2. We assumed that a superimposed SARS-CoV-2 infection caused this fatal pneumonia with a previous TB infection. After a comprehensive postmortem (PM) examination, including gross dissection, microscopic studies, PM computed tomography, and PM laboratory tests, the cause of death was determined to be pneumonia, and the death manner was natural. We present this case with a comprehensive PM examination from the perspective of forensic pathology and the public healthcare system.

Forensic autopsy is performed to investigate a death. However, this is difficult in some cases, particularly in putrefied bodies. Pulmonary ossification is a rare pathological process, characterized by progressive and metaplastic ossification, which leads to the formation of small bony fragments in the pulmonary tissue. This condition can develop within the pulmonary tissues that are injured due to various causes. Metastatic and dystrophic calcification occur in normal tissues in conditions of deranged calcium metabolism and dead or degenerative tissue, respectively. Here, we describe the case of a 54-year-old man who lived alone and whose putrefied body was discovered by his landlord. A forensic pathologist identified needle-like sharp materials in both the lower lobes of the lungs during autopsy. Microscopic examination revealed dendriform pulmonary ossification with calcification. After autopsy, his medical history, including chronic kidney disease, was recorded by forensic pathologist. A review of his past medical history and comprehensive postmortem examination findings of the gross dissection, microscopic examination, and postmortem laboratory tests led to the determination of the cause of death as renal problems.

STUDY DESIGN Retrospective cohort study. OBJECTIVE The aim of this study was to analyze postoperative complications and recovery patterns in different modified 11-item frailty index (mFI-11) groups after lateral lumbar interbody fusion (LLIF) surgery. SUMMARY OF BACKGROUND DATA The relationship between the mFI-11 score and LLIF surgery has not been previously reported. METHODS A single-center, consecutive series of patients who underwent LLIF with at least two years of follow-up were retrospectively reviewed. Complications after LLIF surgery were recorded. Clinical outcomes, including the visual analog scale (VAS) for back/leg pain and the Oswestry Disability Index (ODI), were evaluated preoperatively and at 1 and 2 years postoperatively. The proportions of patients who achieved substantial clinical benefit (SCB) for the VAS-B, VAS-L, and ODI were also analyzed. RESULTS One hundred fifty-two patients included in the present study were grouped according to their mFI-11 score: 0 (n = 39), 0.09 (n = 69), 0.18 (n = 31), and ≥0.27 (n = 13). An mFI-11 score ≥0.27 was a significant predictor of urinary complications (adjusted odds ratio: 3.829, P = 0.013). At 2 years postoperatively, patients in all frailty categories experienced improvements in the VAS for back pain, VAS for leg pain, and ODI, without significant differences between the four groups (p = 0.182, 0.121, and 0.804, respectively). There were also no significant differences in the proportions of patients achieving SCB for back/leg pain and the ODI between the four groups (P = 0.843, 0.957, and 0.915, respectively). CONCLUSION An mFI-11 score was found to be independently associated with urologic complications in patients who underwent LLIF. Patients in all frailty categories experienced significant improvements in back pain, leg pain, and the ODI at 1 year and 2 years postoperatively. LLIF surgery may be useful for patients with high frailty index.Level of Evidence: 4.

OBJECTIVE Combined anterior-posterior (AP) surgery is considered the gold standard for surgical treatment of Scheuermann kyphosis. There are trends toward posterior-only (PO) surgery for correcting this deformity because of the availability of multisegmental compression instruments and posterior shortening osteotomy. To date, surgical strategies for Scheuermann kyphosis remain controversial. The purpose of this study was to compare various surgical approaches for the treatment of Scheuermann kyphosis, including radiological correction and intraoperative outcomes, using a systematic review and meta-analysis. METHODS A comprehensive database search of PubMed, EMBASE, Web of Science, and Cochrane Library was performed to identify studies concerning Scheuermann kyphosis. The inclusion criteria were direct comparisons between AP and PO surgeries for Scheuermann kyphosis and assessment of the angle of thoracic kyphosis preoperatively and postoperatively. The authors used the principles of a cumulative meta-analysis by updating the pooled estimate of the treatment effect. RESULTS Data from 13 studies involving 1147 participants (542 patients in the AP group and 605 patients in the PO group) were included. The average age was 18.2 years for the AP and 17.9 years for the PO group. The overall mean difference of changes in thoracic kyphosis angles between the AP and PO surgeries was 0.23° (95% CI −2.24° to 2.71°). In studies in which posterior shortening osteotomies were not performed, PO surgery resulted in a significantly low degree of correction of thoracic kyphosis, with a mean difference of 5.59° (95% CI 0.34°–10.83°). Studies in which osteotomies were performed revealed that the angle of correction for PO surgery was comparable to that of AP surgery. Regardless of fixation methods, PO surgical approaches achieved comparable angles. CONCLUSIONS PO surgery using posterior osteotomies can achieve correction of Scheuermann kyphosis as successfully as AP surgery does. Reflecting the advancement of surgical technology, large prospective studies are necessary to identify the proper treatments for Scheuermann kyphosis.

STUDY DESIGN Retrospective cohort study. OBJECTIVE The aim of this study was to investigate the prognosis of symptomatic pseudarthrosis observed at 1 year after lateral lumbar interbody fusion (LLIF) surgery and to analyze the risk factors for persistent pseudarthrosis for 2 years postoperatively. SUMMARY OF BACKGROUND DATA Few articles have evaluated the prognosis of symptomatic pseudarthrosis following LLIF surgery. METHODS One hundred fifty-two patients with a minimum follow-up of 2 years were screened. Fusion status was assessed at 1 year postoperatively, and unfused segments were reevaluated at 2 years postoperatively. Dynamic x-rays and computed tomography images were acquired to evaluate the fusion status. Demographic data were evaluated to identify the risk factors associated with persistent pseudarthrosis. Clinical outcomes, including the visual analog scale (VAS) for back/leg pain and the Oswestry disability index (ODI), were evaluated preoperatively and at 1 and 2 years postoperatively. RESULTS Symptomatic pseudarthrosis was detected in 42 patients at 1 year postoperatively. Among them, 23 patients (54.8%) exhibited solid bony fusion 2 years postoperatively without further intervention. Fourteen patients (33.3%) showed asymptomatic pseudarthrosis, and the remaining five patients (11.9%) showed symptomatic pseudarthrosis. Multivariable analysis showed that diabetes (adjusted odds ratio [OR]: 2.817, P = 0.007), smoking (adjusted OR: 6.497, P = 0.008), and fusion at more than three levels (adjusted OR: 2.525, P = 0.031) were risk factors for persistent pseudarthrosis. Improvements in the VAS scores for back pain and ODI scores were significantly lower in the persistent pseudarthrosis group than in the final solid fusion group at 2 years postoperatively. CONCLUSION It is not necessary to intervene for all patients in whom symptomatic pseudarthrosis is detected at 1 year postoperatively because only 11.9% of them will show persistent symptomatic pseudarthrosis. However, early revision surgery should be considered when severe symptomatic pseudarthrosis associated with diabetes, smoking, and fusion at more than three levels is present.Level of Evidence: 4.

Some of the improvements in DH, FH, and SLL achieved intraoperatively during lateral lumbar interbody fusion surgery were lost by the postoperative 1-week follow-up. An intraoperative radiograph can predict radiographic and clinical outcomes of the 2-year follow-up. The difference between preoperative DH and intraoperative DH should be4.18 mm.Retrospective cohort study The aim of this study was to evaluate whether the intraoperatively estimated parameters, as calculated on a cross-table lateral radiograph, are maintained in an upright position at discharge and at 2 years postoperatively and to identify the appropriate disc height (DH) to achieve substantial clinical benefit. The amount of correction retained following lateral lumbar interbody fusion (LLIF) surgery had not been reported. A single-center, consecutive series of patients who underwent single-level LLIF with at least 2 years of follow-up were retrospectively reviewed. Upright standardized preoperative, 1-week, and 2-year postoperative radiographs, as well as intraoperative lateral radiographs, were analyzed for DH, foraminal height (FH), and segmental lumbar lordosis (SLL) at the index level. Clinical outcomes were compared between preoperatively and 1 week and 2 years postoperatively. In total, 89 patients were evaluated (mean follow-up, 42.8 months [range, 24–83 months]). DH decreased from 12.5 ± 2.7 mm intraoperatively to 11.7 ± 3.1 mm at 1 week postoperatively, FH decreased from 15.9 ± 3.6 mm to 15.1 ± 3.6 mm, and SLL decreased from 13.6° ± 1.7° to 12.4° ± 1.7°. A linear correlation between intraoperative and 2-year postoperative parameters was found (R2 = 0.552, 0.518, and 0.616, respectively). Clinical outcomes, including back pain, leg pain, and Oswestry Disability Index (ODI), significantly improved 2 years postoperatively. The optimal cutoff point for substantial clinical benefit thresholds for the ODI was a 4.18 mm increase in DH (sensitivity, 64.3%; specificity, 80.3%; area under the curve, 0.793; 95% confidence interval, 0.642–0.855). Some of the improvements in DH, FH, and SLL achieved intraoperatively during LLIF surgery were lost by the postoperative 1-week follow-up. An intraoperative radiograph can predict radiographic and clinical outcomes of the 2-year follow-up. The difference between preoperative DH and intraoperative DH should be4.18 mm. Level of Evidence: 4.

The aim of this study was to elucidate the role of NF-κB activation in benign prostatic hyperplasia (BPH) using immunohistochemistry.Immunohistochemical staining for NF-κB was performed and evaluated, dividing into glands and stroma in 101 human BPH tissues. To evaluate the impacts of NF-κB activation on BPH progression, correlations between NF-κB expression and clinical findings, hormone receptors, and HIF-1α were evaluated.NF-κB expression was found in 37.6% and 30.7% in glands and stroma of BPH, respectively. Total and T-zone volumes in transrectal ultrasonography were significantly higher in patients with NF-κB activation than those without NF-κB activation in the stroma. However, NF-κB activation of stroma was not correlated with HIF-1α expression and microvessel density. In subgroup analysis based on NF-κB activation, androgen and progesterone receptors of stroma were highly expressed in HIF-1α negative cases than in HIF-1α positive cases. In cases without NF-κB activation, patients with HIF-1α positivity showed a high frequency of diffuse fibrosis than those with HIF-1α negativity (P = 0.001).Taken together, our result showed that NF-κB activation of stroma was significantly correlated with low total and T-zone volumes in transrectal ultrasonography. Diffuse fibrosis was frequently found in patients with NF-κB inactivation and HIF-1α positivity.

Objective : To evaluate the stent apposition of a low-profile visualized intraluminal support (LVIS) device in distal internal carotid artery (ICA) aneurysms, examine its correlation with clinical and angiographic outcomes, and determine the predictive factors of ischemic adverse events (IAEs) related to stent-assisted coiling.Methods : We retrospectively analyzed a prospectively maintained database of 183 patients between January 2017 and February 2020. The carotid siphon from the cavernous ICA to the ICA terminus was divided into posterior, anterior, and superior bends. The anterior bends were categorized into angled (V) and non-angled (C, U, and S) types depending on the morphology and measured angles. Complete stent apposition (CSA) and incomplete stent apposition (ISA) were evaluated using unsubtracted angiography and flat-panel detector computed tomography. Dual antiplatelet therapy with aspirin 200 mg and clopidogrel 75 mg was administered. Clopidogrel resistance was defined as fewer responders (≥10%, 0.05). The %INH of 27 IAEs (13.78%±14.78%) was significantly lower than that of 156 non-IAEs (26.82%±20.23%) (p

Objective Theoretically, the optimal approach is determined by the status of ossification of the posterior longitudinal ligament (OPLL) and sagittal alignment. However, there have long been disputes about the optimum surgical approach of OPLL. This study is to compare risk-effectiveness between anterior decompression and fusion (ADF) and laminoplasty and laminectomy with fusion (LP/LF) for the patient with cervical myelopathy due to multilevel cervical OPLL. Methods We searched core databases, and compared complication and outcomes between ADF and LP/LF for patients with multiple OPLL for the cervical spine. The incidence of complications such as neurologic deterioration, C5 palsy, and dura tear was assessed. Changes in JOA score between baseline and final evaluations were assessed for 2 groups. The minimal clinically important difference (MCID) was utilized for evaluating clinical significance. We calculated Peto odds ratio (POR) and mean difference for the incidence and continuous variables, respectively. Results We included data from 21 articles involving 3,872 patients with cervical myelopathy with OPLL. Major neurologic deficits such as paraplegia, quadriplegia developed 2.17% in the ADF group and 1.11% in the LP/LF group, and POR was 2.16. Mean difference of JOA score improvement of 2 groups was 1.30, and the mean difference showed a statistical significance. However, 1.3 points of JOA improvement cannot reach 2.5 points of the MCID. Conclusion Anterior surgery often led to rare but critical complications, and the difference of neurological improvement between 2 groups was below a clinically meaningful level. Posterior surgeries may be appropriate in the treatment of multilevel cervical myelopathy with OPLL.

Magnetic resonance imagining (MRI) is helpful for diagnosis of leptomeningeal carcinomatosis (LMC) and localizing LMC symptoms. Goal of this study is how MRI findings of LMC are associated with clinical characteristics or prognosis in patients with non-small cell lung cancer (NSCLC). We retrospectively collected data on 283 patients with LMC from NSCLC, adenocarcinoma based on cerebrospinal fluid cytology. All patients had brain MRI with gadolinium enhancement at LMC diagnosis, and spinal MRI was performed at the physician’s discretion. We evaluated the prognostic factors for overall survival (OS) of all patients and subgroup of patients with central nervous system cause of death. Two-hundred sixteen patients (76%) had definite or suggestive LMC findings and 67 had negative findings on brain MRI. Of the 37 patients who presented with cauda equina syndrome, 35 (95%) exhibited typical spinal MRI findings. Median OS of all patients was 3.65 months (95% confidence interval, 3.06–4.18). There was no significant difference in median OS between MRI-negative and MRI-positive groups (4.31 vs. 3.48 months, p = 0.711), whereas negative MRI finding showed longer median OS significantly in a subgroup of 77 patients with a central nervous system cause of death (p = 0.035). Considering clinical characteristics, progressive systemic disease, and altered mentality were significant prognostic factors associated with poor OS, whereas presenting symptom of headache with nausea/vomiting, intra-CSF chemotherapy, WBRT after LMC diagnosis, and concurrent RTKi treatment were significant for favorable OS in multivariable analysis. Positive MRI findings suggests heavier disease burden than negative MRI findings in patients with LMC who died of a central nervous system cause. Spinal MRI findings in patients with LMC correlate with cauda equina symptoms.

Objective Cervical expansive laminoplasty is an effective surgical method to address multilevel cervical spinal stenosis. During surgery, the spinous processes of C2 and C7 are usually preserved to keep the insertion points of the cervical musculature and nuchal ligament intact. In this regard, dome-like laminectomy (undercutting of C7 lamina) instead of laminoplasty is performed on C7 in selected cases. However, resection of the lamina can weaken the C7 lamina, and stress fractures may occur, but this complication has not been characterized in the literature. The objective of the present study was to investigate the incidence and risk factors for C7 laminar fracture after C7 dome-like laminectomy and its impact on clinical and radiological outcomes. Methods Patients who underwent cervical open-door laminoplasty combined with C7 dome-like laminectomy (n=123) were classified according to the presence of C7 laminar fracture. Clinical parameters (neck/arm pain score and neck disability index) and radiologic parameters (C2-7 angle, C2-7 sagittal vertical axis, and C7-T1 angle) were compared between the groups preoperatively and at postoperatively at 3, 6, 12, and 24 months. Risk factors for complications were evaluated, and a formula estimating C7 fracture risk was suggested. Results C7 lamina fracture occurred in 32/123 (26%) patients and occurred at the bilateral isthmus in 29 patients and at the spinolaminar junction in three patients. All fractures appeared on X-ray within 3 months postoperatively, but patients did not present any neurological deterioration. The fracture spontaneously healed in 27/32 (84%) patients at 1 year and in 29/32 (91%) at 2 years. During follow-up, clinical outcomes were not significantly different between the groups. However, patients with C7 fractures showed a more lordotic C2-7 angle and kyphotic C7-T1 angle than patients without C7 fractures. C7 fracture was significantly associated with the extent of bone removal. By incorporating significant factors, the probability of C7 laminar fracture could be assessed with the formula 'Risk score = 1.08 × depth (%) + 1.03 × length (%, of the posterior height of C7 vertebral body)', and a cut-off value of 167.9% demonstrated a sensitivity of 90.3% and a specificity of 65.1% (area under the curve, 0.81). Conclusion C7 laminar fracture can occur after C7 dome-like laminectomy when a substantial amount of lamina is resected. Although C7 fractures may not cause deleterious clinical outcomes, they can lead to an unharmonized cervical curvature. The chance of C7 fracture should be discussed in the shared decision-making process.

Until now, we have introduced classic example of tumors and elucidated operative strategy depending on each anatomical compartments. As mentioned at the beginning, the best benefit using the concept of anatomical compartments in surgery is that if we can confine our work in one compartment, other compartments will be beyond of our concern. In this chapter, we are going to solely focus on operative strategy for securing specific anatomical space depending on anatomical compartment of each tumor.

Purpose: This study aimed to elucidate the clinicopathological significance and prognostic role of tumor-infiltrating lymphocytes in colorectal cancer. Methods: The immunohistochemistry of CD3 and CD8 was performed on 265 human colorectal cancer tissues to investigate the tumor-infiltrating lymphocytes using Immunoscore. The correlation between Immunoscore and clinicopathological characteristics, including survival rates, was elucidated. In addition, the impact of tumor-infiltrating lymphocytes on programmed death-ligand 1 (PD-L1) protein expression was evaluated through immunohistochemistry. Results: Of the 265 colorectal cancer tissues, 40.8% had high Immunoscore, while 59.2% had low Immunoscore. A high Immunoscore was significantly correlated with favorable tumor behaviors, including lower rates of vascular, lymphatic, and perineural invasion; lymph node metastasis; and distant metastasis. PD-L1 expressions of tumor and immune cells were significantly higher in patients with high Immunoscore than in those with low Immunoscore. In addition, colorectal cancer tissues with high CD8-positive lymphocytes showed higher PD-L1 expressions of tumor and immune cells than colorectal cancer tissues with low CD8-positive lymphocytes. There was a significant correlation between high Immunoscore and better overall survival. However, there was no significant difference in survival rate according to PD-L1 expressions of tumor and immune cells in high and low Immunoscore subgroups. Conclusions: Taken together, our results showed that high tumor-infiltrating lymphocytes were significantly correlated with favorable tumor behaviors and better survival. In addition, there was a significant correlation between PD-L1 expression and tumor-infiltrating lymphocytes.

This study aimed to evaluate the clinicopathological significance of phospho-forkhead box O1 (pFOXO1) expression and its impact on the angiogenesis of colorectal cancer (CRC).We performed immunohistochemistry in 266 human CRC tissues for pFOXO1, and evaluated its cytoplasmic expression, regardless of its nuclear expression. We also investigated the correlation between pFOXO1 expression and clinicopathological characteristics, survival, microvessel density (MVD), and angiogenesis-related molecules in CRC.pFOXO1 was expressed in the cytoplasm of 100 (37.6 %) of the 266 CRC tissues. Furthermore, pFOXO1 expression was significantly correlated with the left colon and rectum, and with vascular invasion, lymph node metastasis, distant metastasis, and higher pTNM stage. However, there was no significant correlation between pFOXO1 expression and other clinicopathological parameters. MVD was significantly higher in pFOXO1-positive tumors than in pFOXO1-negative tumors (P = 0.025). Among the angiogenesis-related molecules examined, pFOXO1 expression was significantly correlated with SIRT1 (P = 0.002) and VEGF expression (P0.001), but not with HIF-1α expression. pFOXO1 expression was significantly correlated with poor overall and recurrence-free survival rates (P = 0.001 and P0.001, respectively).Taken together, our results showed that the pFOXO1 expression was significantly correlated with aggressive tumor behavior and poor survival rates. Moreover, pFOXO1 expression may affect tumor progression through SIRT1- and VEGF-induced angiogenesis.

Study Design: A systematic literature review and meta-analysis Objective: The aim of this study is to compare hybrid constructs with traditional fusion-only constructs for the incidence of adjacent segment degeneration (ASDeg) and clinical outcomes in patients with degenerative lumbar diseases. Summary of Background Data: Spinal fusion is a standard surgery for various pathologies of the lumbar spine, which results in changes to the biomechanics of the spine, potentially leading to ASDeg. Although ASDeg can occur slowly as a natural course, early-onset ASDeg is regarded to be related to fusion surgery. Materials and Methods: A systematic search was conducted to identify studies that match the purpose. Included studies were compared using the incidence of ASDeg, Oswestry Disability Index, Visual Analog Score, and perioperative outcomes. We calculated the Peto odds ratio and mean difference (MD) for the continuous variables, respectively. In the hybrid group, subgroup analysis was also performed among devices. Results: Among 10 papers involving 767 patients, 372 patients underwent hybrid fusion and 395 patients underwent fusion-only. ASDeg occurred in 10.2% in the hybrid and 21.5% in the fusion-only group [Peto odds ratio, 0.39; 95% confidence interval (CI), 0.23-0.64]. The MD for Visual Analog Score were 0.45 (95% CI, 0.05-0.85) between 2 groups, which was statistically significant but was too small to have clinical significance. The MD for Oswestry Disability Index was 0.93 (95% CI, -1.016 to 2.872), which was not statistically different between 2 groups. The hybrid is superior for 18 minutes (95% CI, 5.78-30.72) shorter than typical surgery. Conclusions: Hybrid lumbar surgery decreased the incidence of early-onset ASDeg for about 2 years of follow-up. Among the hybrid constructs, the interspinous devices group accomplished favorable results with a lower risk. Adjacent segment disease was not as statistically significant as ASDeg, but adjacent segment disease may show a substantial difference for >2-year follow-up.

Cranial nerve palsies are relatively common after trauma, but trochlear nerve palsy is relatively uncommon. Although traumatic trochlear nerve palsy is easy to diagnose clinically because of extraocular movement disturbances, radiologic evaluations of this condition are difficult to perform because of the nerve's small size. Here, we report the case of a patient with delayed traumatic trochlear nerve palsy associated with a traumatic subarachnoid hemorrhage (SAH) and the related radiological findings, as obtained with high-resolution three-dimensional (3D) magnetic resonance imaging (MRI). A 63-year-old woman was brought to the emergency room after a minor head trauma. Neurologic examinations did not reveal any focal neurologic deficits. Brain computed tomography showed a traumatic SAH at the left ambient cistern. The patient complained of vertical diplopia at 3 days post-trauma. Ophthalmologic evaluations revealed trochlear nerve palsy on the left side. High-resolution 3D MRI, performed 20 days post-trauma, revealed continuity of the trochlear nerve and its abutted course by the posterior cerebral artery branch at the brain stem. Chemical irritation due to the SAH and the abutting nerve course were considered causative factors. The trochlear nerve palsy completely resolved during follow-up. This case shows the usefulness of high-resolution 3D MRI for evaluating trochlear nerve palsy.

Purpose Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. Materials and methods Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription-polymerase chain reaction were performed. Results SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. Conclusion FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

Objective The aim of this study was to elucidate the clinicopathological significance and prognostic role of microvessel density (MVD) in gastric cancer (GC) through a meta-analysis. Methods This meta-analysis included 4094 patients from 26 eligible studies. We investigated the correlation between MVD and clinicopathological characteristics, including survival rate. In addition, subgroup analysis based on microscopic magnification among evaluation criteria of MVD was performed. Results High MVD was significantly correlated with worse overall and disease-free survival rates [hazard ratio (HR), 3.028, 95% confidence interval (CI) 2.105–4.357 and HR 2.045, 95% CI 1.530–2.732, respectively]. MVD was significantly increased in GC with diffuse type of Lauren’s classification [mean difference (MD) 3.091, 95% CI 0.615–5.567], lymphatic invasion (MD 8.262, 95% CI 3.310–13.214), lymph node metastasis (MD 5.730, 95% CI 2.444–9.016), higher pT stage (pT3-4) (MD 7.093, 95% CI 0.060–14.126) and higher pTNM stage (III–IV) (MD 3.023, 95% CI 0.181–5.865). However, MD of MVD was not significantly different in regard to vascular invasion (MD 7.430, 95% CI 1.015–15.875), tumor differentiation (MD 5.501, 95% CI 1.353–12.355) and tumor size (MD 4.731, 95% CI 2.003–11.465). Conclusion Taken together, higher MVD was significantly correlated with worse prognosis. In addition, MVD was significantly higher in GC with aggressive tumor behavior than in GC without aggressive features.

Gastric cancer (GC) is a major of cause of cancer-related death and is characterized by its heterogeneity and molecular complexity. FOXO1 is a transcription factor that plays a key role in GC growth and metastasis. However, the implication of FOXO1 in GC cell stemness has been elusive. This study, for the first time, demonstrates that FOXO1 regulates GC cell stemness in association with LGR5. FOXO1 expression was significantly lower in GC tumorsphere cells than in adherent GC cells. FOXO1 silencing and overexpression promoted and inhibited the tumorsphere formation capacity of GC cells, respectively. Additionally, there was an inverse correlation between FOXO1 and GC stem cell marker LGR5 in human GC specimens. Further in vitro and in vivo experiments showed that negative crosstalk between these two molecules exists and that LGR5 silencing reversed the FOXO1 shRNA-induced tumorsphere formation even without FOXO1 restoration. Taken together, our results suggest that FOXO1 inhibits the self-renewal capacity of GC cells through interaction with LGR5. Thus, FOXO1/LGR5 signaling pathway may provide a novel targeted therapy for GC.

Background Diabetes mellitus (DM) is associated with poor postoperative outcomes and increased morbidity after surgeries. Some previous studies have addressed the close association between DM and those leading to reoperations, whereas others have rejected this theory. This study aimed to evaluate the long-term effect of DM on lumbar spinal surgery using data from a nationwide sample cohort. Methods A population-based cohort comprised one million people, which is a 2.1% representative sample of the Korean population. The present study included adult patients with lumbar degenerative diseases (e.g., lumbar spinal stenosis and spondylolisthesis), who underwent their first lumbar surgery in 2006. The cumulative incidence function for reoperation was calculated and multivariate analysis was performed to define correlation between reoperation and independent factors. Results A total of 2020 patients were enrolled and followed up for 10 years. Nondiabetic patients, patients with DM without complication (DwoC), and patients with DM with complication (DwC) accounted for 79.5%, 9.36%, and 11.14% of all patients, respectively. Reoperation incidence stratified by DM was 12.7% for nondiabetic patients, 22.2% for patients with DwoC, and 20.0% for patients with DwC in 10 years of follow-up. During the same period, death, a competing event of reoperation, occurred in 7.8% of nondiabetic patients, in 13.2% of patients with DwoC, and in 20.9% of patients with DwC. Conclusions DM increased 1.65 times the overall cumulative incidences of reoperation after lumbar spinal surgeries for 10 years of follow-up. The reoperation incidence for DwC may be lower than that for DwoC because of a high incidence of death as a competing event of reoperation.

Since the molecular mechanism of hypoxic adaptation in cancer cells is cell-type specific, we investigated whether glycogen synthase kinase-3β (GSK-3β) activation is involved in hypoxia-induced gastric tumor promotion. Stable gastric cancer cell lines (SNU-638, SNU-484, MKN1, and MKN45) were cultured under hypoxic conditions. Cells overexpressing wild-type GSK-3β (WT-GSK-3β) or kinase-dead mutant of GSK-3β (KD-GSK-3β) were generated and used for cell culture and animal studies. In cell culture experiments, hypoxia decreased GSK-3β activation in gastric cancer cells. Cell viability and the expressions of HIF-1α protein and VEGF mRNA in gastric cancer cells were higher in KD-GSK-3β transfectants than in WT-GSK-3β transfectants under hypoxic conditions, but not under normoxic conditions. Gastric cancer xenografts showed that tumor growth, microvessel area, HIF-1α activation, and VEGF expression were higher in KD-GSK-3β tumors than in WT-GSK-3β tumors in vivo. In addition, the expression of hypoxia-induced HIF-1α protein was regulated by GSK-3β at the translational level. Our data suggest that GSK-3β is involved in hypoxic adaptation of gastric cancer cells as an inhibitory upstream regulator of the HIF-1α/VEGF signaling pathway.

Purpose We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. Materials and methods Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. Results In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. Conclusion Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.

Background: The biological significance of FOXO1, a member of the forkhead box O transcription factor family, in gastric cancer (GC) remains unclear. The present study provides direct evidence of the role of FOXO1 in tumour growth and metastasis of GC in relation to human epidermal growth factor receptor 2 (HER2). Methods: The expressions of FOXO1 and HER2 were modulated in GC cell lines (SNU-638, MKN45, SNU-216 and NCI-N87) by stable transfections. The effects of transfection on GC phenotypes were evaluated in vitro and in animal models. In addition, the relationship between FOXO1 and HER2 was analysed using GC clinical specimens, cell lines and xenografts. Results: FOXO1 silencing in GC cells increased colony formation and mesenchymal transition in vitro, as well as tumour growth and metastasis in nude mice, whereas HER2 silencing induced the opposite results.. Furthermore, an inverse relationship between FOXO1 and HER2 was found in clinical specimens of GC, GC cells and GC xenograft tumours. Although a negative crosstalk between these two molecules was shown, double knockdown of both FOXO1 and HER2 in GC cells revealed that HER2 silencing reversed the FOXO1 shRNA-induced migration and invasion even without the FOXO1 restoration. Conclusions: Our results indicate that loss of FOXO1 promotes GC growth and metastasis by upregulating HER2 expression and that the HER2 expression is more critical to the induction of GC cell metastasis. The present study provides evidence that the FOXO1/HER2 pathway may regulate GC progression in a subgroup of GC patients.

The transcription factor signal transducers and activators of transcription 3 (STAT3) can promote cancer metastasis, but its underlying regulatory mechanisms in gastric cancer cell invasiveness still remain obscure. We investigated the relationship between STAT3 and glycogen synthase kinase-3β (GSK-3β) and its significance in metastatic potential in gastric cancer cells. Immunohistochemical tissue array analysis of 267 human gastric carcinoma specimens showed that the expressions of active forms of STAT3 (pSTAT3) and GSK-3β (pGSK-3β) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p

Fascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4); however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including PD0332991 and LY2835219, on lung cancer cells that are wild-type or null for retinoblastoma (RB), indicating that unknown target molecules might be involved in the inhibition of tumor growth by fascaplysin. Fascaplysin treatment significantly decreased tumor angiogenesis and increased cleaved-caspase-3 in xenografted tumor tissues. In addition, survivin and HIF-1α were downregulated in vitro and in vivo by suppressing 4EBP1-p70S6K1 axis-mediated de novo protein synthesis. Kinase screening assays and drug-protein docking simulation studies demonstrated that fascaplysin strongly inhibited vascular endothelial growth factor receptor 2 (VEGFR2) and tropomyosin-related kinase A (TRKA) via DFG-out non-competitive inhibition. Overall, these results suggest that fascaplysin inhibits TRKA and VEGFR2 and downregulates survivin and HIF-1α, resulting in suppression of tumor growth. Fascaplysin, therefore, represents a potential therapeutic approach for the treatment of multiple types of solid cancer.

Purpose: This study aimed to elucidate the concordance between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and in situ hybridization (ISH) and the diagnostic accuracy of HER2 IHC in non-small cell lung cancer (NSCLC) through a meta-analysis and diagnostic test accuracy review. Methods: Seven eligible studies and 1,217 patients with NSCLC were included in the review. The concordance between HER2 IHC and ISH was analyzed. To confirm the diagnostic accuracy of HER2 IHC, the sensitivity and specificity were analyzed and the area under the curve (AUC) in the summary receiver operating characteristic (SROC) curve was calculated. Results: The concordance rate between HER2 IHC and ISH was 0.795 (95% confidence interval [CI] 0.534-0.929). In the HER2 IHC-negative (score 0/1+) subgroup, the concordance rate was 0.975 (95% CI 0.854-0.996). The concordance rates of the HER2 IHC score 2+ and 3+ subgroups were 0.091 (95% CI 0.039-0.197) and 0.665 (95% CI 0.446-0.830), respectively. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.67 (95% CI 0.54-0.78) and 0.89 (95% CI 0.87-0.91), respectively. The AUC in the SROC curve was 0.891 and the diagnostic odds ratio was 16.99 (95% CI 5.08-56.76). Conclusions: HER2 IHC was largely in agreement with ISH in cases of HER2 IHC score 0/1+. Because the concordance rates of HER2 IHC score 2/3+ cases were lower than that of HER2 IHC score 0/1+ cases, further studies for detailed analysis criteria for HER2 IHC score 2+ or 3+ are required.

Bile acids might induce mucin expression and regulate tumor behavior in esophageal and colon cancers. However, little is known about the effect of bile acids on tumor invasiveness of gastric carcinoma (GC). The aim of the current study was to elucidate the mechanisms by which bile acids regulate tumor invasion in GC. We investigated bile acid-induced MUC2 expression and cell invasion and migration in the cultured GC cell lines, SNU-216, and MKN45. In addition, immunohistochemical analysis of MUC2 and Snail was performed on 389 archival paraffin-embedded tissues of GC to evaluate the correlation of their expression with prognosis. Deoxycholic acid (DCA), a secondary bile acid, had no effect on the viability of SNU-216 and MKN45 GC cells at low concentrations (0–100 μM), but decreased viability at a higher concentration (200 μM). MKN45 cells showed higher MUC2 expression than SNU-216 cells under basal conditions. DCA treatment upregulated MUC2 mRNA expression in both SNU-216 and MKN45 cells. Expression of Snail and MMP9 was markedly decreased by DCA treatment, and E-cadherin expression was subsequently increased. DCA significantly inhibited invasion and migration of SNU-216 and MKN45 cells. In human GC, MUC2 expression showed a negative correlation with Snail expression (P = 0.021) and a significantly positive correlation with better prognosis (P = 0.023). Taken together, our data suggest that DCA induced MUC2 expression in GC cells and inhibited tumor invasion and migration. Additionally, MUC2-expressing GCs showed low rates of Snail expression and were associated with a favorable prognosis.

Cisplatin (CDDP) is one of the most important chemotherapeutic agents in the treatment of advanced gastric cancer, but its efficacy is limited by CDDP resistance. Because the transcription factor FOXO1 is related to chemoresistance in various cancer cells, we investigated the function of FOXO1 in CDDP resistance in human gastric cancer cells.Human gastric cancer cell lines MKN45 and SNU-601 were used. FOXO1 activation was modulated by transfection of FOXO1 AAA mutant gene or FOXO1 shRNA. The effects of FOXO1 on cell growth and CDDP cytotoxicity were assessed by crystal violet assay. Protein expressions of FOXO1, p110α, pAkt, and Akt were analyzed by Western blotting, and FOXO1 mRNA expression was evaluated by semiquantitative reverse transcription-polymerase chain reaction. FOXO1 activity was determined by luciferase reporter assay, and cell apoptosis was assessed by DAPI staining and Western blotting for PARP cleavage.Cisplatin treatment induced FOXO1 expression and activation in both gastric cancer cell lines. FOXO1 overexpression increased the CDDP resistance without changes in cell growth, whereas FOXO1 silencing enhanced CDDP cytotoxicity along with apoptotic characteristics. Both constitutive and CDDP-induced FOXO1 activations were accompanied by an increase in p110α and pAkt expression. Furthermore, Akt inhibition by LY294002 treatment restored the CDDP cytotoxicity that was suppressed by FOXO1 overexpression.FOXO1 inhibits CDDP-induced apoptosis in gastric cancer cells via activating PI3K/Akt pathway. Thus, FOXO1 may be an useful pharmacological indicator to predict CDDP efficacy in gastric cancer treatment.

Background Since the biological function of c-Jun N-terminal kinase (JNK) in gastric cancer remains unclear, we investigated the clinical significance of JNK activation and its association with FOXO1 activation. Methods Immunohistochemical tissue array analysis of 483 human gastric cancer specimens was performed, and the results of the immunostaining were quantified. The correlation between JNK activation (nuclear staining for pJNK) and clinicopathological features, the proliferation index, prognosis or FOXO1 inactivation (cytoplasmic staining for pFOXO1) was analyzed. The SNU-638 gastric cancer cell line was used for in vitro analysis. Results Nuclear staining of pJNK was found in 38 % of the gastric carcinomas and was higher in the early stages of pTNM (P

Background: The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-κB (NF-κB) as well as HIF-1 have been implicated in angiogenesis of various cancers, we investigated their relationship in gastric cancer. Methods: Nuclear expressions of HIF-1α and NF-κB/RelA were assessed in 251 human gastric carcinoma specimens by immunohistochemical tissue array analysis. Stable human gastric cancer cells, infected with a retroviral vector containing super-suppressive mutant form of IκBα (IκBαM), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and IκBαM effects on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription–polymerase chain reaction. In addition, NF-κB effects on the HIF-1α degradation and synthesis were examined. Results: Hypoxia-inducible factor-1α activation positively correlated with RelA activation in clinical gastric cancer samples (P

The regulation of β-catenin activation by glycogen synthase kinase-3β (GSK-3β) in cancer has been shown to be cell type-specific. This study was performed to investigate the relationship between activated GSK-3β (phosphorylated at Tyr216) and β-catenin in gastric cancer. Immunohistochemical tissue array analysis of 278 human gastric carcinoma specimens showed positive immunoreactivity for activated GSK-3β in 44% of the samples, whereas membranous β-catenin and nuclear β-catenin were observed in 19% and 20% of the samples, respectively. However, GSK-3β activation was not correlated with the expression of either membranous β-catenin or nuclear β-catenin. Moreover, SNU gastric cancer cell lines over-expressing kinase dead GSK-3β and the same cells treated with a GSK-3β inhibitor showed that GSK-3β inhibition did not alter either the protein expression or transcriptional activity of β-catenin. In addition, GSK-3β activation was positively correlated with the expressions of anti-adenomatous polyposis coli (p = 0.002), p16 (p < 0.001), p21 (p < 0.001), p27 (p = 0.001), and p53 (p = 0.013). On the other hand, the nuclear expression of β-catenin was positively correlated with those of Bcl-2 (p = 0.025) and cyclin D1 (p = 0.043), but these expressions were not correlated with GSK-3β activation. Thus, the GSK-3β pathway seems to function in gastric cancer cells without involving the β-catenin pathway.

The role of nuclear factor-kappaB (NF-kappaB) activation in cancer cell apoptosis appears to be tailored specifically for each cell type and the type of NF-kappaB inducer. The present study aimed to determine whether or not NF-kappaB activation is associated with chemosensitivity to doxorubicin (DOX) using the DOX-sensitive SNU-601 and DOX-resistant SNU-216 gastric cancer cell lines. The effect of NF-kappaB activation on DOX (1 microg/mL) sensitivity was analyzed after the suppression of NF-kappaB activation using transfection of the super-suppressive mutant form of IkappaBalpha (mIkappaBalpha) or pretreatment with pyrrolidine dithiocarbamate. In addition, the association between NF-kappaB and manganese superoxide dismutase (MnSOD) in relation to DOX sensitivity was analyzed after the modulation of MnSOD expression. The NF-kappaB activity was much higher in DOX-resistant SNU-216 cells than in DOX-sensitive SNU-601 cells before and after DOX treatment. Overexpression of mIkappaBalpha or pyrrolidine dithiocarbamate pretreatment decreased the DOX resistance in SNU-601 cells with low MnSOD expression, but not in SNU-216 cells with high MnSOD expression. In comparison, the overexpression of MnSOD, which also suppressed NF-kappaB activation in both cell lines, increased DOX resistance in SNU-601 cells. Blocking of MnSOD expression using RNA interference techniques increased DOX sensitivity in SNU-216 cells, which was further augmented by the additional inhibition of NF-kappaB activity. Our results showed that whether NF-kappaB contributes to DOX sensitivity in gastric cancer cells is determined by the level of MnSOD expression. Thus, targeting both MnSOD and NF-kappaB may be helpful for increasing the efficacy of DOX treatment of DOX-resistant SNU gastric cancer cells.

Surgery, anticoagulation therapy, pregnancy, and hormone treatments, such as bromocriptine, are well-characterized precipitating factors for pituitary apoplexy. However, whether cytotoxic chemotherapy for systemic cancer could cause pituitary apoplexy has not been investigated. Here, we present a case of a 41-year-old woman who developed a severe headache with decreased visual acuity after intravenous cytotoxic chemotherapy to treat metastatic breast cancer. Preoperative neuroimaging revealed pituitary adenoma with necrosis. Operative findings and pathologic examination concluded extensive necrosis with a small intratumoral hemorrhage in a pre-existing pituitary adenoma. We reviewed two additional previously published cases of pituitary apoplexy after systemic chemotherapy and suggest that cytotoxic chemotherapy may induce pituitary apoplexy.

FOXO1, a forkhead box O (FOXO) transcription factor, and nuclear factor-κB (NF-κB) are prognostically significant transcription factors in gastric cancer. As their relationship has been inconsistent depending on the cell type, we aimed to investigate whether FOXO1 is associated with NF-κB p65 (RelA) in gastric cancer. Immunohistochemistry was performed on tissue array slides containing 298 gastric carcinoma specimens. We found that the cytoplasmic expression of pFOXO1, the inactive form of FOXO1, was positively correlated with nuclear RelA expression (p = 0.024). In addition, the expressions of pFOXO1 and RelA were positively related with cyclin D1 expression (p = 0.014 and p = 0.001, respectively) and Ki-67 labeling index (p = 0.025 and p = 0.017, respectively). However, they did not show association with the expressions of cyclin E, p53 and pRb. Cell culture experiments showed that FOXO1 overexpression by transfection of FOXO1 AAA mutant gene suppressed NF-κB activation in SNU-484 gastric cancer cells. These results suggest that FOXO1 and NF-κB are negatively associated and that FOXO1 is a negative upstream regulator of NF-κB in gastric cancer.

Background The transcription factor nuclear factor-κB (NF-κB) has been implicated in gastric cancer metastasis, but the underlying molecular mechanisms remain unclear. We investigated the role of the interaction between NF-κB and signal transducers and activators of transcription 3 (STAT3) in controlling metastatic potential of gastric cancer cells. Methods Immunohistochemistry for NF-κB p65 (RelA), phospho-Tyr705-STAT3 (pSTAT3), or matrix metalloproteinase 9 (MMP9) was performed on tissue array slides containing 255 gastric carcinoma specimens. NF-κB inhibition in SNU-638 and MKN1 gastric cancer cell lines were performed by transduction with a retroviral vector containing NF-κB repressor mutant of IκBα, and STAT3 was silenced by RNA interference. We also did luciferase reporter assay, double immunofluorescence staining and immunoblotting. Cell migration and invasion were determined by wound-healing assay and invasion assay, respectively. Results NF-κB and STAT3 were constitutively activated and were positively correlated (P = 0.038) in gastric cancer tissue specimens. In cell culture experiments, NF-κB inhibition reduced STAT3 expression and activation, whereas STAT3 silencing did not affect NF-κB activation. Moreover, both NF-κB inhibition and STAT3 silencing decreased gastric cancer cell migration and invasion in a synergistic manner. In addition, both NF-κB activation and STAT3 activation were positively correlated with MMP9 in gastric cancer tissues (P = 0.001 and P = 0.022, respectively), decreased E-cadherin expression and increased Snail and MMP9 expressions in cultured cells. Conclusion NF-κB and STAT3 are positively associated and synergistically contribute to the metastatic potential of gastric cancer cells. Thus, dual use of NF-κB and STAT3 inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.

The regulation of β-catenin activation by glycogen synthase kinase-3β (GSK-3β) in cancer has been shown to be cell type-specific. This study was performed to investigate the relationship between activated GSK-3β (phosphorylated at Tyr216) and β-catenin in gastric cancer. Immunohistochemical tissue array analysis of 278 human gastric carcinoma specimens showed positive immunoreactivity for activated GSK-3β in 44% of the samples, whereas membranous β-catenin and nuclear β-catenin were observed in 19% and 20% of the samples, respectively. However, GSK-3β activation was not correlated with the expression of either membranous β-catenin or nuclear β-catenin. Moreover, SNU gastric cancer cell lines over-expressing kinase dead GSK-3β and the same cells treated with a GSK-3β inhibitor showed that GSK-3β inhibition did not alter either the protein expression or transcriptional activity of β-catenin. In addition, GSK-3β activation was positively correlated with the expressions of anti-adenomatous polyposis coli (p = 0.002), p16 (p0.001), p21 (p0.001), p27 (p = 0.001), and p53 (p = 0.013). On the other hand, the nuclear expression of β-catenin was positively correlated with those of Bcl-2 (p = 0.025) and cyclin D1 (p = 0.043), but these expressions were not correlated with GSK-3β activation. Thus, the GSK-3β pathway seems to function in gastric cancer cells without involving the β-catenin pathway.

Background Aberrant regulation of glycogen synthase kinase-3β (GSK-3β) has been implicated in several human cancers; however, it has not been reported in the gastric cancer tissues to date. The present study was performed to determine the expression status of active form of GSK-3β phosphorylated at Tyr216 (pGSK-3β) and its relationship with other tumor-associated proteins in human gastric cancers. Methods Immunohistochemistry was performed on tissue array slides containing 281 human gastric carcinoma specimens. In addition, gastric cancer cells were cultured and treated with a GSK-3β inhibitor lithium chloride (LiCl) for immunoblot analysis. Results We found that pGSK-3β was expressed in 129 (46%) of 281 cases examined, and was higher in the early-stages of pathologic tumor-node-metastasis (P < 0.001). The expression of pGSK-3β inversely correlated with lymphatic invasion (P < 0.001) and lymph node metastasis (P < 0.001) and correlated with a longer patient survival (P < 0.001). In addition, pGSK-3β expression positively correlated with that of p16, p21, p27, p53, APC, PTEN, MGMT, SMAD4, or KAI1 (P < 0.05), but not with that of cyclin D1. This was confirmed by immunoblot analysis using SNU-668 gastric cancer cells treated with LiCl. Conclusions GSK-3β activation was frequently observed in early-stage gastric carcinoma and was significantly correlated with better prognosis. Thus, these findings suggest that GSK-3β activation is a useful prognostic marker for the early-stage gastric cancer.

Mutations in the superoxide dismutase 1 (SOD1) gene are linked to glutamate excitotoxicity in familial amyotrophic lateral sclerosis (fALS), but the underlying mechanism remains unclear. We investigated whether nuclear factor-kappaB (NF-kappaB) activation is involved in glutamate excitotoxicity by using motor neuron-neuroblastoma hybrid cells that expressed a mutant (G93A) SOD1 (mtSOD1) or wild-type SOD1 (wtSOD1). MtSOD1 cells were more vulnerable to glutamate excitotoxicity than wtSOD1 cells and showed higher NF-kappaB activity, higher nuclear cRel expression, and lower nuclear RelA expression under basal conditions. Glutamate treatment increased NF-kappaB activation along with nuclear expressions of RelA and cRel in wtSOD1 cells but induced only weak nuclear RelA expression in mtSOD1 cells. Suppression of NF-kappaB activation using transfection of the superrepressive mutant form of IkappaBalpha (mIkappaBalpha) inhibited nuclear RelA expression in both types of SOD1 cells, which increased glutamate excitotoxicity in wtSOD1 cells but not in mtSOD1 cells. Furthermore, immunohistochemistry confirmed stronger RelA immunoreactivity in the nuclei of motor neurons of spinal cord in wild-type SOD1 transgenic mice than in those in SOD1 G93A transgenic mice. In addition, we found that glutamate treatment decreased XIAP expression and increased caspase-3 activity in mtSOD1 cells and mIkappaBalpha-overexpressing wtSOD1 cells. Our results suggest that glutamate excitotoxicity in motor neurons of SOD1-linked fALS is attributable, at least in part, to the impairment of IkappaBalpha-dependent RelA activation and subsequent apoptosis mediated by XIAP inhibition and caspase-3 activation.