The Prognostic Role of Para-Aortic Lymph Nodes in Patients with Colorectal Cancer: Is It Regional or Distant Disease?

Introduction

Visible para-aortic lymph nodes of ≥2 mm in size are common metastatic patterns of colorectal cancer (CRC) seen on imaging. Their prognostic value, however, remains inconclusive. We aimed to assess the prognostic role of visible para-aortic lymph nodes (PALNs).

Methods

Patients with confirmed pathologic diagnosis of CRC were enrolled. Correlations among clinicopathologic variables were analyzed using the χ² test. The Cox proportional hazards model was applied for univariate and multivariate analyses. Survival was estimated using the Kaplan-Meier method and log-rank test. A prognostic model for visible PALNs in CRC patients was established.

Results

In total, 4527 newly diagnosed CRC patients were enrolled. Patients with visible PALNs had inferior overall survival compared to those without visible PALNs (5-year overall survival, 67% vs. 76%, P = 0.015). Lymphovascular invasion (LVI) (hazard ratio = 1.865, P = 0.015); nodal disease (pN+) status (hazard ratio = 2.099, P = 0.006); elevated preoperative serum carcinoembryonic antigen (CEA) levels (hazard ratio = 2.263, P < 0.001); and visible PALNs ≥10 mm (hazard ratio = 1.638, P = 0.031) were independent prognostic factors for patients with visible PALNs. If each prognostic factor scored one point, 5-year overall survival of lower- (prognostic score 0–1), intermediate- (prognostic score 2), and high- (prognostic score 3–4) risk groups were, 78%. 54%, and 25% respectively (P < 0.001).

Conclusions

The prognostic model, which included LVI, pN+ status, preoperative serum CEA level, and the size of visible PALNs, could effectively distinguish the outcome of patients with visible PALNs.     

The Role of Estrogen Receptor β in Prostate Cancer

Although androgen receptor (AR) signaling is the main molecular tool regulating growth and function of the prostate gland, estrogen receptor β (ERβ) is involved in the differentiation of prostatic epithelial cells and numerous antiproliferative actions on prostate cancer cells. However, ERβ splice variants have been associated with prostate cancer initiation and progression mechanisms. ERβ is promising as an anticancer therapy and in the prevention of prostate cancer. Herein, we review the recent experimental findings of ERβ signaling in the prostate.     

The Role of Arginine–Nitric Oxide Pathway in Patients with Alzheimer Disease

There is a reciprocal regulation of arginase and nitric oxide synthase in l-arginine-metabolizing pathways. There are various evidences of the role of nitric oxide in several neuropsychiatric disorders including Alzheimer’s disease. However, there is no study that has investigated the role of arginase as an important part of the arginine regulatory system affecting nitric oxide synthase activity in Alzheimer’s disease. This study aims to investigate arginase, manganese (a cofactor of arginase), and total nitrite levels (a metabolite of NO) and their relationship to the arginine–NO pathway in patients with Alzheimer’s disease. Arginase activities, Mn, and total nitrite levels were measured in plasma from 47 patients with Alzheimer’s disease and 43 healthy control subjects. Plasma arginase activities and manganese were found to be significantly lower and total nitrite level higher in patients with Alzheimer’s disease compared with controls. Our results suggest that the arginine–NO pathway is involved in the pathogenesis of Alzheimer’s disease.     

The Role οf Ion Channels in the Development and Progression of Prostate Cancer

Molecular Diagnosis & Therapy - Ion channels have major regulatory functions in living cells. Apart from their role in ion transport, they are responsible for cellular electrogenesis and...     

Prognostic Value of Tumor Size in Patients with Remnant Gastric Cancer: Is the Seventh UICC Stage Sufficient for Predicting Prognosis?

Background

The 7th UICC N stage may be unsuitable for remnant gastric cancer (RGC) because the original disease and previous operation usually cause abnormal lymphatic drainage. However, the prognostic significance of the current TNM staging system in RGC has not been studied.

Methods

Prospective data from 153 RGC patients who underwent curative gastrectomy from Jan 1995 to Aug 2009 were reviewed. All patients were classified according to tumor size (<3 cm as N0;>3&≤5 cm as N1;>5&≤7 cm as N2; and>7 cm as N3). The overall survival was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using the Cox proportional hazard model.

Results

Tumor sizes ranged from 1.0 to 15.0 cm (median 5.0 cm). Tumor size, depth of invasion and lymph node (LN) metastasis were significant prognostic factors based on both the univariate and multivariate analyses (P<0.05). In the survival analysis, the seventh edition UICC-TNM classification provided a detailed classification; however, some subgroups of the UICC-TNM classification did not have significantly different survival rates. The combination of the seventh edition T classification and the suggested N classification, with ideal relative risk (RR) results and P value, was distinctive for subgrouping the survival rates except for the IA versus IB and II A versus IIB. A modified staging system based on tumor size, predicted survival more accurately than the conventional TNM staging system.

Conclusions

In RGCs, tumor size is an independent prognostic factor and a modified TNM system based on tumor size accurately predicts survival.     

The Practicability of a Novel Prognostic Index (PI) Model and Comparison with Nottingham Prognostic Index (NPI) in Stage I–III Breast Cancer Patients Undergoing Surgical Treatment

Background

Previous studies have indicated the prognostic value of various laboratory parameters in cancer patients. This study was to establish a prognostic index (PI) model for breast cancer patients based on the potential prognostic factors.

Methods

A retrospective study of 1661 breast cancer patients who underwent surgical treatment between January 2002 and December 2008 at Sun Yat-sen University Cancer Center was conducted. Multivariate analysis (Cox regression model) was performed to determine the independent prognostic factors and a prognostic index (PI) model was devised based on these factors. Survival analyses were used to estimate the prognostic value of PI, and the discriminatory ability of PI was compared with Nottingham Prognostic Index (NPI) by evaluating the area under the receiver operating characteristics curves (AUC).

Results

The mean survival time of all participants was 123.6 months. The preoperative globulin >30.0g/L, triglyceride >1.10mmol/L and fibrinogen >2.83g/L were identified as risk factors for shorter cancer-specific survival. The novel prognostic index model was established and enrolled patients were classified as low- (1168 patients, 70.3%), moderate- (410 patients, 24.7%) and high-risk groups (83 patients, 5.0%), respectively. Compared with the low-risk group, higher risks of poor clinical outcome were indicated in the moderate-risk group [Hazard ratio (HR): 1.513, 95% confidence interval (CI): 1.169–1.959, p = 0.002] and high-risk group (HR: 2.481, 95%CI: 1.653–3.724, p< 0.001).

Conclusions

The prognostic index based on three laboratory parameters was a novel and practicable prognostic tool. It may serve as complement to help predict postoperative survival in breast cancer patients.     

Identification of Risk Factors for Locoregional Recurrence in Breast Cancer Patients with Nodal Stage N0 and N1: Who Could Benefit from Post-Mastectomy Radiotherapy?

Introduction

The locoregional recurrence (LRR) rate was reported as high as approximately 20% in stage I-II breast cancer following mastectomy. To investigate the risk factors for LRR in pT1–2N0-1 breast cancer patients treated with mastectomy but not radiation, and to define a subgroup of patients at high risk of LRR who may benefit from postmastectomy radiotherapy (PMRT).

Methods and Materials

In total, 390 patients with pT1-2N0M0 (n = 307) and pT1-2N1M0 (n = 83) breast cancer who underwent total mastectomy without adjuvant radiotherapy from 2002 to 2011 were enrolled in the study.

Results

After a median follow-up period of 5.6 years (range, 0.6–11.3 years), 21 patients had 18 systemic relapses and 12 LRRs including six in the chest wall and eight in the regional nodal area. The 5-year LRR-free survival (LRRFS) rates were 97.0% in pN0, 98.8% in pN1, and 97.4% in all patients. Multivariate analysis revealed that age < 50 years (Hazard Ratio, 11.4; p = 0.01) and no adjuvant chemotherapy (Hazard Ratio, 10.2; p = 0.04) were independent risk factors for LRR in pN0 patients. Using these factors, the 5-year LRRFS rates were 100% without any risk factors, 96.4% with one risk factor, and 86.7% with two risk factors. In pN1 patients, multivariate analysis revealed that having a hormone receptor negative tumor (Hazard Ratio, 18.3; p = 0.03) was the only independent risk factor for LRR. The 5-year LRRFS rates were 100.0% for luminal type, and 92.3% for non-luminal type cancer.

Conclusion

Patients with pT1-2N0-1 breast cancer who underwent total mastectomy without PMRT could be stratified by nodal stage and risk factors for LRR. PMRT may have of value for node negative patients aged less than 50 years and who are not treated with adjuvant chemotherapy, and for non-luminal type patients with one to three positive nodes.     

Soluble α-Klotho as a Novel Biomarker in the Early Stage of Nephropathy in Patients with Type 2 Diabetes

Objective

Although α-klotho is known as an anti-aging, antioxidant, and cardio-renal protective protein, the clinical implications of soluble α-klotho levels in patients with diabetes have not been evaluated. Therefore, this study evaluated whether plasma and urinary α-klotho levels are associated with albuminuria in kidney disease in diabetes.

Research Design and Methods

A total of 147 patients with type 2 diabetes and 25 healthy control subjects were enrolled. The plasma and urine concentrations of α-klotho were analyzed by enzyme-linked immunosorbent assay.

Results

Plasma α-klotho (572.4 pg/mL [95% CI, 541.9–604.6 pg/mL] vs. 476.9 pg/mL [95% CI, 416.9–545.5 pg/mL]) and urinary α-klotho levels (59.8 pg/mg creatinine [95% CI, 43.6–82.0 pg/mg creatinine] vs. 21.0 pg/mg creatinine [95% CI, 9.7–45.6 pg/mg creatinine]) were significantly higher in diabetic patients than non-diabetic controls. Among diabetic patients, plasma α-klotho concentration was inversely associated with albuminuria stages (normoalbuminuria, 612.6 pg/mL [95% CI, 568.9–659.6 pg/mL], microalbuminuria, 551.8 pg/mL [95% CI, 500.5–608.3 pg/mL], and macroalbuminuria, 505.7 pg/mL [95% CI, 439.7–581.7 pg/mL] (p for trend  = 0.0081), while urinary α-klotho levels were remained constantly high with increasing urinary albumin excretion.

Conclusions

Soluble α-klotho levels in plasma and urine may be novel and useful early markers of diabetic renal injury.     

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF POLIOMYELITIS—The Management of Patients in the Hospital Admitting Room

Because of the great variety of early symptoms of poliomyelitis and their similarity to the symptoms of a number of other diseases, in times of epidemic many patients are admitted to hospital on suspicion of poliomyelitis. At such times the prime purpose of the hospital admitting room staff is to distinguish between patients with poliomyelitis (or other diseases requiring immediate treatment) and those who may be referred into other channels.This presentation (1) points out the superficial similarities of the clinically observable signs and symptoms and of laboratory data in poliomyelitis and in other diseases, and (2) discusses the more occult dissimilarities which aid in differentiation.     

CONGENITAL ABNORMALITIES—The Timing and Management of Surgical Reconstruction in Infancy and Childhood

The proper timing of corrective and reconstructive surgical operations for the management of congenital abnormalities in infancy and childhood is exceptionally important. Although no hard and fast rules apply, each deformity should be evaluated in the light of specific features of local and general relationship. Correlation to growth and development must be stressed as an important feature. Evaluation of the congenital abnormality in the light of its many relationships provides for a basis of better complete handling, follow-up, and ultimate result with the aim directed toward elimination of tumor threat, restoration of function and esthetic improvement.     

Activating Mutations in β-Catenin in Colon Cancer Cells Alter Their Interaction with Macrophages; the Role of Snail

Background

Tumor cells become addicted to both activated oncogenes and to proliferative and pro-survival signals provided by the abnormal tumor microenvironment. Although numerous soluble factors have been identified that shape the crosstalk between tumor cells and stroma, it has not been established how oncogenic mutations in the tumor cells alter their interaction with normal cells in the tumor microenvironment.

Principal Findings

We showed that the isogenic HCT116 and Hke-3 cells, which differ only by the presence of the mutant kRas allele, both stimulate macrophages to produce IL1β. In turn, macrophages enhanced Wnt signaling, proliferation and survival in both HCT116 and Hke-3 cells, demonstrating that signaling by oncogenic kRas in tumor cells does not impact their interaction with macrophages. HCT116 cells are heterozygous for β-catenin (HCT116^WT/MT), harboring one wild type (WT) and one mutant (MT) allele, but isogenic lines that carry only the WT (HCT116^WT) or MT β-catenin allele (HCT116^MT) have been generated. We showed that macrophages promoted Wnt signaling in cells that carry the MT β-catenin allele, but not in HCT116^WT cells. Consistent with this observation, macrophages and IL1β failed to stabilize Snail in HCT116^WT cells, and to protect these cells from TRAIL-induced apoptosis. Finally, we demonstrated that HCT116 cells expressing dominant negative TCF4 (dnTCF4) or HCT116 cells with silenced Snail failed to stimulate IL1β production in macrophages, demonstrating that tumor cells activate macrophages via a Wnt-dependent factor.

Significance

Our data demonstrate that oncogenic β-catenin mutations in tumor cells, and subsequent activation of Wnt signaling, not only trigger cell-intrinsic alterations, but also have a significant impact on the crosstalk of tumor cells with the tumor associated macrophages.     

The Prognostic Role of the Class III β-Tubulin in Non-Small Cell Lung Cancer (NSCLC) Patients Receiving the Taxane/Vinorebine-Based Chemotherapy: A Meta-Analysis

Background

A number of studies have examined the relationship between the expression of the class III β-tubulin (TUBB3) and the treatment responses to the taxane/vinorebine-based chemotherapy in patients with non-small cell lung cancer (NSCLC). However, the results of these studies were inconsistent and inconclusive. Therefore, we conducted an up-to-date meta-analysis to evaluate the prognostic role of TUBB3 in the taxane/vinorebine-based chemotherapy.

Methods

A literature search for relevant studies was conducted in PubMed, Embase, and CNKI. The inclusion criteria were the taxane/vinorebine-based chemotherapy in patients with NSCLC and the evaluation of the clinical outcomes in relation to the expression of TUBB3. The clinical outcomes analyzed in this study included the overall response rate (ORR), overall survival (OS), and event-free survival (EFS). Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were calculated to assess the risk associated with the TUBB3 expression in the taxane/vinorebine-based chemotherapy.

Results

A total of 28 studies with 2401 NSCLC patients were qualified for this meta-analysis. We found that the positive or high level of TUBB3 expression was associated with a poorer ORR (OR = 0.24, 95% CI = 0.16–0.36, p<0.001), an unfavorable OS (HR = 1.52, 95% CI = 1.27–1.82, p<0.001), and a worse EFS (HR = 1.47, 95% CI = 1.24–1.74, p<0.001) compared to the negative or low level of TUBB3 expression. The statistically significant associations between TUBB3 and chemotherapy responses were also observed in the stratified subgroup analysis, which included the analysis by ethnic subgroup (Asian and Caucasian), chemotherapy regimen (taxane-based and vinorebine-based), TUBB3 detection method (IHC and PCR), and treatment strategy (surgery plus adjuvant chemotherapy and palliative chemotherapy).

Conclusions

The expression level of TUBB3 may be a useful biomarker to predict the clinical outcomes of the taxane/vinorebine-based chemotherapy in patients with NSCLC.     

Percutaneous Fine-Needle 5% Ethanol-Cisplatin Intratumoral Injection Combined with Second-Line Chemotherapy Improves On the Standard of Care in Patients with Platinum-Pretreated Stage IV Non–Small Cell Lung Cancer

BACKGROUND: Efficacy of second-line chemotherapy in platinum-pretreated non–small cell lung cancer (NSCLC) is poor. This study investigated efficacy of computed tomography–guided percutaneous fine-needle 5% ethanol-cisplatin intratumoral injection (CT-PFNECII) combined with second-line chemotherapy in patients with platinum-pretreated stage IV NSCLC. PATIENTS: Between October 2011 and July 2013, 34 eligible patients were randomly assigned to receive either CT-PFNECII combined with second-line chemotherapy (combination group, n = 17) or second-line chemotherapy alone (chemotherapy group, n = 17). The primary end points were the proportions of patients who achieved an overall response rate (ORR) and disease control rate (DCR). Secondary end points were median survival and progression-free survival (PFS). RESULTS: The ORR and DCR in the combination group were significantly higher than in the chemotherapy group (23.53% vs 11.76% for ORR, P < .01; and 58.82% vs 35.29% for DCR, P < .01). Compared with patients in the chemotherapy group, patients in the combination group had significantly longer PFS (5.4 months vs 3.0 months, P < .01) and median survival (9.5 months vs 5.3 months, P < .01). CONCLUSIONS: CT-PFNECII combined with second-line chemotherapy provided a higher response rate and improved survival than second-line chemotherapy for patients with platinum-pretreated stage IV NSCLC.     

The Role of the Transport System in the Control of the Source–Sink Relations in Pinus sylvestris

Morphophysiological correlations were studied in medium-aged (20- to 60-year-old) Scots pine trees under the northern taiga conditions. Under various ecological conditions, pine trees developed a well-balanced structure, with close linear relationships between needle and root weight and their cross-section areas in all components of the continuous transport network (the coefficient of determination was between 0.88 and 0.999). When the annual cycle of soluble and insoluble carbohydrate contents was followed in various pine tissues, the total concentrations of soluble and insoluble carbohydrates were maintained at constant and tissue-specific levels, except in the growth period. The maximum level of carbohydrates was observed in all tissues at the beginning of rapid growth, and the minimum, at growth cessation. The qualitative composition and amount of carbohydrates matched the phenological phases of development and were not affected by the ecological growth conditions pertinent to the particular environment. The authors conclude that assimilate synthesis and partitioning are related to structural development, and the state of sink centers determines the attracting capacity, whereas the transport network, from roots to needles, and its conducting capacity are essential for the realization of systemic relationships and the control over growth and development in Pinus sylvestris L.     

NEUROLOGICALLY HANDICAPPED CHILDREN—The Role of the Pediatrician in Rehabilitation

In the application of the broad services now available to assist a child having a major neurologic impairment, the pediatrician occupies an important role owing to his ability to consider the problem of the handicapped child in the context of his specialized knowledge of the developmental process. He thus has a large responsibility for interpretation of the problem to the child, to the parents and to his professional colleagues and for guidance of the rehabilitation regimen within the limits of the child''s developmental readiness for new experiences.The pediatrician has the opportunity to contribute significant clinical observations which may provide stimuli for future basic research and to exercise his skill as a practitioner of preventive medicine.Goals for the future achievement of the child having a major neurologic impairment must be set realistically and with great caution.     

Could the Extent of Lymphadenectomy Be Modified by Neoadjuvant Chemotherapy in Cervical Cancer? A Large-Scale Retrospective Study

Background

The effect of neoadjuvant chemotherapy (NACT) on topographical distribution patterns of lymph node metastasis in cervical cancer was unknown.

Methods

Patients with FIGO stage IB1-IIB who underwent radical surgery with or without NACT were enrolled (3527 patients). A matched-case comparison design was used to compare the effects of NACT on lymph node metastasis.

Results

We analyzed groups of 167 and 140 patients who were diagnosed with lymph node metastasis in the matched primary surgery group and NACT group, respectively, and no significant difference was observed (p = 0.081). The incidence of lymph node metastasis was significantly decreased in the NACT-responsive group compared to the non-responsive group (18.4% vs. 38.6%, P<0.001). The metastatic rates for every lymph node group also declined in the NACT-responsive group except for the deep inguinal and the para-aortic lymph node groups. Clinical response, deep stromal, parametrial and lymph vascular invasions were independent risk factors for lymph node metastasis in the NACT group. Furthermore, deep stromal invasion and lymph vascular invasion, but not the response to NACT, were independently associated with upper LNM. The number of lymph nodes involved, response to NACT, tumor histology and a positive vaginal margin were independent prognostic factors affecting DFS or OS rates in node-positive patients treated with NACT plus radical surgery.

Conclusion

The frequency and topographic distribution of LNM are not modified by NACT, and clinical non-responders showed more involved LNs. A systemic and extensive lymphadenectomy should be performed in patients treated with NACT plus surgery regardless of the response to NACT.     

SNPs in the TGF-β Signaling Pathway Are Associated with Increased Risk of Brain Metastasis in Patients with Non–Small-Cell Lung Cancer

Purpose

Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is relatively common, but identifying which patients will develop brain metastasis has been problematic. We hypothesized that genotype variants in the TGF-β signaling pathway could be a predictive biomarker of brain metastasis.

Patients and Methods

We genotyped 33 SNPs from 13 genes in the TGF-β signaling pathway and evaluated their associations with brain metastasis risk by using DNA from blood samples from 161 patients with NSCLC. Kaplan-Meier analysis was used to assess brain metastasis risk; Cox hazard analyses were used to evaluate the effects of various patient and disease characteristics on the risk of brain metastasis.

Results

The median age of the 116 men and 45 women in the study was 58 years; 62 (39%) had stage IIIB or IV disease. Within 24 months after initial diagnosis of lung cancer, brain metastasis was found in 60 patients (37%). Of these 60 patients, 16 had presented with BM at diagnosis. Multivariate analysis showed the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with a significantly higher risk of brain metastasis at 24 months follow-up (hazard ratio [HR] 2.540, 95% confidence interval [CI] 1.204–5.359, P = 0.014; and HR 1.885, 95% CI 1.086–3.273, P = 0.024), compared with the GA or CT/CC genotypes, respectively. When we analyzed combined subgroups, these rates showed higher for those having both the GG genotype of SMAD6: rs12913975 and the TT genotype of INHBC: rs4760259 (HR 2.353, 95% CI 1.390–3.985, P = 0.001).

Conclusions

We found the GG genotype of SMAD6: rs12913975 and TT genotype of INHBC: rs4760259 to be associated with risk of brain metastasis in patients with NSCLC. This finding, if confirmed, can help to identify patients at high risk of brain metastasis.