LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIα and ERK.

BACKGROUND: LHPP was recently shown to be a risk gene for major depressive disorder. LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown about how LHPP contributes to depression. METHODS: In the current study, we addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing, and electrophysiology. RESULTS: We found that levels of LHPP were upregulated in glutamatergic neurons of the ventral hippocampus in mice that displayed stress-induced depression-like behaviors. Knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPPflox/flox·CaMKIIαCre+ (conditional knockout) mice. Adeno-associated virus-mediated LHPP knockdown in the ventral hippocampus enhanced resistance against chronic social defeat stress in mice. Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF (brain-derived neurotrophic factor) and PSD95 via the modulation of the dephosphorylation of CaMKIIα and ERK. Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIα/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP upregulation-induced depression-like behaviors. CONCLUSIONS: These findings provide evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, thereby identifying LHPP as a potential therapeutic target in treating patients with major depressive disorder.

Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer's disease.

Cognitive deterioration and memory decline associated with the progression of Alzheimer's disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.

HnRNPK is involved in stress-induced depression-like behavior via ERK-BDNF pathway in mice.

As a ubiquitous RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK) interacts with numerous nucleic acids and proteins and is involved in various cellular functions. Available literature indicates that it can regulate dendritic spine density through the extracellular signal-regulating kinase (ERK) - brain-derived neurotrophic factor (BDNF) pathway, which is crucial to retain the synaptic plasticity in patients with major depressive disorder (MDD) and mouse depression models. However, ERK upstream regulatory kinase has not been fully elucidated. Furthermore, it remains unexplored whether hnRNPK may impact the depressive condition via the ERK pathway. The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing. We found that hnRNPK in the brain was mainly distributed in the hippocampal neurons; that it was significantly downregulated in mice that displayed stress-induced depression-like behaviors; and that the level of hnRNPK markedly decreased in MDD patients from the GEO database. Further in vivo and in vitro analyses revealed that the changes in the expressions of BDNF and PSD95 and in the phosphorylation of ERK (Thr202/Tyr204) paralleled the variation of hnRNPK levels in the ventral hippocampal neurons in mice with depression-like behaviors. Finally, esketamine treatment significantly increased the level of hnRNPK in mice. These findings evidence that hnRNPK involved in the pathogenesis of depression via the ERK-BDNF pathway, pinpointing hnRNPK as a potential therapeutic target in treating MDD patients.

Effect of Dexmedetomidine on Postoperative Renal Function in Patients Undergoing Cardiac Valve Surgery Under Cardiopulmonary Bypass: A Randomized Clinical Trial.

OBJECTIVE: The effect of dexmedetomidine on postoperative renal function was investigated in patients undergoing cardiac valve surgery under cardiopulmonary bypass (CPB). DESIGN: A randomized controlled trial. SETTING: University teaching, grade A tertiary hospital. PARTICIPANTS: A total of 70 patients scheduled to undergo cardiac valve replacement or valvuloplasty under CPB were eligible and randomly divided into groups D (n = 35) and C (n = 35) between January 2020 and March 2021. INTERVENTIONS: Patients in group D were administered 0.6 µg/kg/h of dexmedetomidine intravenously from 10 minutes before anesthesia induction to 6 hours after surgery; normal saline was used instead of dexmedetomidine in group C. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of acute kidney injury (AKI). Acute kidney injury was defined according to the Kidney Disease Improving Global Outcomes (2012). It was 22.86% and 48.57% in groups D and C, respectively (p = 0.025). The secondary outcomes were intraoperative hemodynamics and various indices in serum. Ten minutes before CPB (T1), 10 minutes after CPB (T2), and 30 minutes after CPB (T3), mean arterial pressure in group D was lower than that in group C, with statistical significance (74.94 ± 8.52 v 81.89 ± 13.66 mmHg, p=0.013; 62.83 ± 11.27 v 71.86 ± 7.89 mmHg, p < 0.001; 72.26 ± 8.75 v 78.57 ± 8.83 mmHg, p = 0.004). At T1, the heart rate in group D was significantly lower than in group C (80.89 ± 14.04 v 95.54 ± 12.53 bpm, p=0.022). The tumor necrosis factor α, interleukin-6, C-reactive protein, and cystatin C levels in group D were lower than those in group C after the surgery (T4) and 24 hours after surgery (T5), with statistical significance. The duration of mechanical ventilation, intensive-care-unit stay time, and hospital stay time in group D were significantly shorter than in group C. The incidences of tachycardia, hypertension, nausea, and vomiting in group D were similar to those in group C. CONCLUSIONS: Dexmedetomidine may be considered as a way to reduce the incidence and severity of postoperative AKI in patients undergoing cardiac valve surgery under cardiopulmonary bypass.

Radiomics signature for prediction of long-term survival and recurrence patterns in patients with gastric cancer after radical gastrectomy: A multicenter study.

Background: This study aimed to develop and validate a radiomics score to predict the long-term survival and patterns of recurrence of gastric cancer (GC). Methods: A total of 513 patients who underwent radical gastrectomy for GC after curative resection between 2008 and 2016 at two institutions were analyzed. A radiomics score was generated using the least absolute shrinkage and selection operator Cox regression model on 327 patients and was validated in 186 patients. A nomogram consisting of the radiomics score and clinicopathological factors was created and compared with the tumor-lymph node-metastasis (TNM) staging system. Model performance was assessed using calibration, discrimination, and clinical usefulness. Results: The radiomics score was established based on five selected features. A higher score was significantly associated with poorer recurrence-free survival (RFS) and overall survival (OS) rates, both in the training and validation cohorts (P < 0.05). Multivariate analysis demonstrated that the radiomics score was an independent prognostic factor for both RFS and OS (P < 0.05). A nomogram incorporating the radiomics score had a significantly better prognostic value than the TNM system alone. Moreover, a high score was significantly associated with an increased risk of distant recurrence, a medium score was significantly associated with an increased risk of peritoneal recurrence, and a low score was significantly associated with an increased risk of locoregional recurrence, in the entire cohort (P < 0.05). Conclusions: The newly proposed radiomics score may be a powerful predictor of long-term outcomes and recurrence patterns of GC. Further studies are warranted to confirm these findings.

Hand-assisted laparoscopic resection versus total laparoscopic gastric surgery for primary gastric gastrointestinal stromal tumors (GISTs): an analysis from a high-volume institution.

BACKGROUND: Laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) is technically feasible and associated with favorable outcomes. We compared the clinical efficacy of hand-assisted laparoscopic surgery (HLS) and total laparoscopic surgery (TLS) for gastric GISTs. METHODS: We retrospectively analyzed the clinical data of 69 consecutive patients diagnosed with a gastric GIST in a tertiary referral teaching hospital from December 2016 to December 2020. Surgical outcomes were compared between two groups. RESULTS: Fifty-three patients (TLS group: n = 36; HLS group: n = 17) were included. The mean age was 56.9 and 58.1 years in the TLS and HLS groups, respectively. The maximum tumor margin was significantly shorter in the HLS group than in the TLS group (2.3 ± 0.9. vs. 3.0 ± 0.8 cm; P = 0.004). The operative time of the HLS group was significantly shorter than that of the TLS group (70.6 ± 19.1 min vs. 134.4 ± 53.7 min; P < 0.001). The HLS group had less intraoperative blood loss, a shorter time to first flatus, and a shorter time to fluid diet than the TLS group (P < 0.05). No significant difference was found between the groups in the incidence or severity of complications within 30 days after surgery. Recurrence or metastasis occurred in four cases (HLS group; n = 1; TLS group; n = 3). CONCLUSIONS: This study demonstrated that compared with TLS, HLS for gastric GISTs has the advantages of simpler operation, shorter operative time, and faster postoperative recovery.

Lymph node ratio-based the ypTNrM staging system for gastric cancer after neoadjuvant therapy: a large population-based study.

PURPOSES: The lymph node ratio (LNR) has been considered a better prognostic factor than traditional N staging in patients with gastric cancer (GC), but its accuracy is unclear for those who receive neoadjuvant therapy (NAT). We aimed to compare the node ratio (Nr) staging with the ypN staging and to thereby develop a modified staging system incorporating Nr staging. METHODS: A total of 1791 patients who underwent gastrectomy after NAT in the Surveillance, Epidemiology, and End Results database were retrospectively analyzed. ypTNrM staging was established based on the overall survival (OS). RESULTS: The Nr staging was generated using 0.2 and 0.5 as the cutoff values of LNR and represented patients with more homogeneous OS compared with ypN staging. The 5-year OS rates for ypTNrM stages IA, IB, II, IIIA, and IIIB were 70.2%, 54.2%, 36.0%, 21.2%, and 6.6%, respectively, compared with 58.8%, 39.1%, and 21.6% for ypTNM stages I, II, and III, respectively. Compared with the ypTNM staging system, the ypTNrM staging system had a lower misclassification rate (3.0% vs. 50.9%) and better prognostic predictive power (C-index: 0.645 vs. 0.589, P < 0.001). CONCLUSIONS: The ypTNrM staging system incorporating Nr staging may provide a more accurate assessment in the clinical decision-making process for GC after NAT.

Early and late recurrences in lymph node-negative gastric cancer: a retrospective cohort study.

BACKGROUND: Predictors of recurrence in patients with lymph node-negative gastric cancer (GC) who have undergone curative resection have been widely investigated, but not the effects of predictors on timing of recurrence. OBJECTIVE: Determine the factors associated with early and late recurrence in patients with node-negative GC. DESIGN: Retrospective cohort. SETTING: Academic tertiary care center. PATIENTS AND METHODS: The study included patients with node-negative GC after curative resection between 2008 and 2018 at two institutions. Early and late recurrences were determined using a minimum P value approach to evaluate the optimal cutoff for recurrence-free survival (RFS). A competing risk model and landmark analysis were used to analyze factors associated with early and late recurrences. MAIN OUTCOME MEASURES: Recurrence-free survival and factors associated with survival. SAMPLE SIZE: 606. RESULTS: After a median follow-up of 70 months, 50 (8.3%) patients experienced recurrent disease. The optimal length of RFS for distinguishing between early (n=26) and late recurrence (n=24) was 24 months (P=.0013). The median RFS in the early and late recurrence groups was 11 and 32 months, respectively. Diffuse tumors (hazard ratio 3.358, P=.014), advanced T stage (HR 8.804, P=.003), perineural invasion (HR 10.955, P<.001), and anemia (HR 2.351, P=.018) were independent predictors of early recurrence. Mixed tumor location (HR 5.586, P=.002), advanced T stage (HR 5.066, P<.001), lymphovascular invasion (HR 5.902, P<.001), and elevated CA19-9 levels (HR 5.227, P<.001) were independent predictors of late recurrence. Similar results were obtained in the landmark analysis. CONCLUSIONS: Individualized therapeutic and follow-up strategies should be considered in future studies because of distinct patterns in predictors of early and late recurrence. LIMITATIONS: Retrospective design, small sample size. CONFLICT OF INTEREST: None.

Prognostic models for 1-year survival of NPC after radiotherapy in different ages.

PURPOSE: Previous studies have shown that approximately 10% of nasopharyngeal cancer (NPC) patients die within a year of disease onset, and that age is an independent predictor. However, no predictive model has been developed. We aimed to establish novel prognostic models to predict the 1-year cancer-specific survival (CSS) of young, middle-aged, and older patients with NPC after radiotherapy. METHODS: The data of 2822 NPC patients who underwent radiotherapy between 2004 and 2015 were reviewed from the surveillance, epidemiology, and end results database. We divided them into young, middle-aged, and older people groups according to age (< 44 years, 45-59 years, and ≥ 60 years, respectively). Multivariate analyses were performed, and prognostic models were constructed. RESULTS: Multivariate analyses indicated that age, ethnicity, histological subtype, T, and M stage were independent predictors of 1-year CSS in the older people group. In contrast, ethnicity and age were not found to have predictive value in the young and middle-aged groups, respectively. Accordingly, three prognostic models with excellent predictive values were established for the three groups (C-indices: 0.791 [95% CI 0.722-0.859], 0.763 [95% CI 0.721-0.806] and 0.723 [95% CI 0.683-0.763], respectively). These predictive values are higher than those of the eighth edition American joint committee cancer tumor-node-metastasis (TNM) classification system. CONCLUSION: Three prognostic models for predicting the 1-year CSS of young, middle-aged, and older NPC patients after radiotherapy showed better predictive power than the TNM classification system. These models may guide treatment strategies and clinical decision-making in different cohorts.

Prognostic value of lymphocyte-to-C-reactive protein ratio in patients with gastric cancer after surgery: a multicentre study.

OBJECTIVE: The immune inflammation-based score is recognized as a prognostic marker for cancer. However, the most accurate prognostic marker for patients with gastric cancer remains undetermined. We aimed to evaluate the predictive value of the lymphocyte-to-C-reactive protein ratio for outcomes in gastric cancer patients after radical gastrectomy. METHODS: A total of 607 gastric cancer patients treated at three Chinese institutions were included. Receiver operating characteristic curves were generated, and the areas under the curve were calculated to compare the predictive value among the inflammation-based score, lymphocyte-to-C-reactive protein ratio, C-reactive protein/albumin and neutrophil-lymphocyte, platelet-lymphocyte and lymphocyte-monocyte ratios. Cox regression was performed to determine the prognostic factors for overall survival. RESULTS: The median follow-up time was 63 months (range: 1-84 months). The optimal cut-off value for lymphocyte-to-C-reactive protein ratio was 0.63. The patients were divided into the LCR <0.63 (LLCR, n = 294) group and the LCR ≥0.63 (HLCR, n = 313) group. LLCR was significantly correlated with poor clinical characteristics. Compared with inflammation-based score, lymphocyte-to-C-reactive protein ratio had the highest areas under the curve (0.695). Patients with LLCR experienced more post-operative complications than the HLCR group (20.4 vs. 12.1%, P = 0.006). Multivariate analysis showed that a higher lymphocyte-to-C-reactive protein ratio (HR: 0.545, 95%CI: 0.372-0.799, P = 0.002) was associated with better overall survival. The HLCR group had higher 5-year overall survival rate than the LLCR group (80.5 vs. 54.9%, P < 0.001). CONCLUSIONS: Preoperative lymphocyte-to-C-reactive protein ratio levels can effectively predict the short-term and oncological efficacy of gastric cancer patients after radical gastrectomy with a predictive value significantly better than other inflammation-based score.

Clinical features and genetic characteristics of hereditary diffuse leukoencephalopathy with spheroids due to CSF1R mutation: a case report and literature review.

BACKGROUND: Hereditary diffuse leukoencephalopathy with spheroid (HDLS) is an autosomal dominant white matter disease characterized by adult-onset cognitive impairment, behavioral or emotional changes, paresis, Parkinsonism, and seizures. Mutations in the gene encoding colony-stimulating factor 1 receptor (CSF1R) have been identified as the cause of HDLS. METHODS: Detail medical history, clinical features and brain imaging of a patient with adult-onset leukoencephalopathy, cognitive impairment and motor dysfunction was reviewed and next generation sequencing was performed. An extensive literature research was then performed to identify all patients with HDLS previously reported. The clinical characteristics, brain imaging and genetic features of patients with HDLS were reviewed. RESULTS: A novel CSF1R mutation, c.1952G>A p.G651E was identified in the patient. Extensive review showed that HDLS typically presents with broad phenotypic variability. The most common symptoms of HDLS were cognitive impairment, followed by psychiatric symptoms, Parkinsonism, gait disorder, and dysphagia. The most common brain imaging findings of HDLS were bilateral white matter lesion, mostly around the ventricles, frontal lobe, and parietal lobe. Calcifications in white matter on CT, cerebral atrophy and thinning of corpus callosum were also common features. Although HDLS demonstrates an autosomal dominant pattern, sporadic cases are not uncommon. CONCLUSIONS: Early recognition of clinical and neuroradiographical characteristics of HDLS is key for the correct diagnosis of the disease.

Comparative study of laparoscopic versus open radical gastrectomy in advanced gastric neuroendocrine carcinoma: Analysis from a high-volume institution.

BACKGROUND: Gastric neuroendocrine carcinomas (G-NECs) are rare. This study aimed to explore the feasibility and clinical efficacy of laparoscopic surgery in patients with advanced G-NECs. METHODS: The clinicopathological data of 175 G-NECs patients who underwent radical gastrectomy in a high-volume centre were collected. One hundred fifty-one cases with advanced G-NECs (laparoscopic gastrectomy [LG] = 30, open gastrectomy [OG] = 121) were finally selected for comparison of the short-term outcomes and oncologic efficacy. RESULTS: In the postoperative recovery, when comparing the OG group, the time to ambulation (3.2 d vs. 2.6 d, respectively, p = 0.049), the time to first flatus (4.1 d vs. 3.6 d, respectively, p = 0.050), the time to first soft diet (7.9 d vs. 6.7 d, respectively, p = 0.007), and the postoperative hospital stay (13.1 d vs. 11.4 d, respectively, p = 0.047) of the LG group were shorter. There was no significant difference in the postoperative complication rates between the OG and LG groups (19.8% vs. 23.3%, p = 0.671). The 3-year overall survival (OS) rate was 57.0% in the OG group and 64.4% in the LG group (p = 0.349). The 3-year disease-free survival (DFS) rate was 51.7% in the OG group and 57.4% in the LG group (p = 0.357). There was no significant difference in the 3-year OS and DFS rates between the LG and OG groups at each stage. The recurrence rate was 35.5% in the OG group and 33.0% in the LG group (p = 0.821). CONCLUSIONS: The short-term outcomes and oncologic efficacy of laparoscopic gastrectomy and open gastrectomy for advanced G-NECs are comparable.

Tai Chi can prevent cardiovascular disease and improve cardiopulmonary function of adults with obesity aged 50 years and older: A long-term follow-up study.

To research the possible role of Tai Chi in preventing cardiovascular disease and improving cardiopulmonary function in adults with obesity aged 50 years and older.Between 2007 and 2012, 120 adults with obesity, aged 50 years and older, were divided into a Tai Chi group and a control group, with 60 participants in each group. The 2 groups were evaluated for weight, waist circumference, hip circumference, blood pressure (BP), body mass index, and incidence of chronic disease during follow-up monitoring.Two- and 6-year follow-up showed that the average BP in the Tai Chi group along with either the systolic or diastolic pressure decreased significantly compared to those in the control group (P < .001). Waist and hip circumference, weight, and body mass index in the Tai Chi group were significantly reduced compared to those in the control group (P < .001). The cardiopulmonary function of the control group and the Tai Chi group changed, with the cardiac index significantly higher in the Tai Chi group than in the control group (P < .05). The Tai Chi group had significantly higher levels of lung function, including vital capacity, maximal oxygen uptake, and total expiratory time, than the control group. The total incidence of complications and mortality in the Tai Chi group were much lower than those in the control group (P < .001). The incidence of cardiovascular and cerebrovascular disease in the Tai Chi group (16.67%) was lower than that in the control group (38.33%).Tai Chi is not only a suitable exercise for elderly people with obesity, but it can also help to regulate BP, improve heart and lung function in these individuals, as well as reduce the incidence of cardiovascular disease and other chronic diseases, helping to improve their quality of life.

Aerobic exercise repairs neurological function after cerebral ischaemia by regulating the nitric oxide.

To investigate the mechanism of different exercise patterns on neurological function after focal cerebral ischaemia in rats. Rats with focal cerebral cerebral ischaemia were randomly divided into an aerobic exercise group, an exhaustive exercise group and a control group, with 8 rats in each group. A score for nerve function in each group was calculated, and the ultrastructure of nerve cells was observed. Levels of NO and NOS in the brain motor area of the ​​rats were measured in each group. The aerobic exercise group had lower nerve function scores than the exhaustive exercise group and higher scores than the control group (P<0.05). Under transmission electron microscopy, irregular shapes and organs were observed in nerve cells in the control group, while regular cell shapes and organs were observed in the aerobic exercise group. The aerobic exercise group and exhaustive exercise group had higher measures of NO content, NOS activity and eNOS, nNOS and iNOS gene expression than the control group, but eNOS expression in the aerobic exercise group and iNOS expression in the exhaustive exercise group were clearly higher according to RT-PCR (P<0.05). Aerobic exercise can promote the expression of NOS, mainly in eNOS, which can promote nerve repair.

Clinicopathological features and prognosis of patients with gastric neuroendocrine tumors: A population-based study.

BACKGROUND: Despite its rarity, studies have shown the incidence of gastric neuroendocrine tumors (G-NETs) is increasing. This study investigated the risk factors affecting the survival of G-NETs patients and their prognosis over time. METHOD: A retrospective analysis of 506 G-NETs patients who underwent surgery for nonmetastatic disease from the Surveillance, Epidemiology and End Result database from 1988 to 2011 was conducted. Multivariate Cox regression analyses identified the prognostic factors affecting overall survival (OS) and disease-specific survival (DSS). Three-year conditional survival (COS3 and CDS3) estimates at "x" year after treatment were calculated as follows: COS3 = OS(x + 3)/OS(x) and CDS3 = DSS(x + 3)/DSS(x). RESULTS: The 1-, 3-, and 5-year OS rates of all patients after surgery were 90.2%, 77.3%, and 68.8%, respectively. The 1-, 3-, and 5-year DSS rates after surgery were 93.9%, 84.5%, and 80.9%, respectively. In the multivariate analysis, age, tumor grade, and T stage were independent prognostic factors of OS and DSS (all P < 0.05). With 1-, 3-, and 5-year survivorship, the COS3 improved by +5.2 (82.2%), +7.2 (84.4%), and +8.5 (85.5%), respectively, and the CDS3 improved by +4.4 (89.4%), +9.1 (94.1%), and +12.5 (97.5%), respectively. Notably, the CDS3 improved dramatically among patients with advanced stage disease (eg, N0 stage: 93.0%-98.9%, Δ5.9% vs N1 stage: 52.0%-95.7%, Δ43.7%). CONCLUSION: For G-NETs patients, age, tumor grade, T stage, and N stage were the clinicopathological factors significantly associated with prognosis. There were excellent outcomes for most G-NETs patients, with a CDS3 of greater than 90% across all independent prognostic factors after 5 years of survival.