Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components ...of this pathway. However the prognostic value of these aberrations is unclear.
PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation PIK3CA, lack of phosphatase and tensin homolog PTEN expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model.
Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42-3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13).
Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway.
Inflammation influences cancer development and progression. An elevated platelet to lymphocyte ratio (PLR), a marker of inflammation, has been linked to poor prognosis in several malignancies. Here, ...we quantify the prognostic impact of this biomarker.
A systematic review of databases was conducted to identify publications exploring the association of blood PLR and overall survival (OS) in solid tumors. Data were pooled in a meta-analysis. Pooled HRs for OS by disease group and by PLR cutoff groups were computed and weighted using generic inverse-variance and random-effect modeling.
Twenty studies comprising 12,754 patients were assessed. Cutoffs for PLR defining risk groups ranged from 150 to 300 and were dichotomous (12 studies; group 1) or split into three groups (<150/150-300/>300, 8 studies; group 2). Higher PLR was associated with significantly worse OS in group 1 HR = 1.87; 95% confidence interval (CI, 1.49-2.34); P < 0.001 and with a nonsignificant association in group 2 (HR per higher category = 1.21; 95%CI, 0.97-1.50; P = 0.10). The size of effect of PLR on OS was greater for metastatic disease (HRgroup 1 = 2.0; 95% CI, 1.6-2.7; HRgroup 2 = 1.6; 95% CI, 1.1-2.4) than for early-stage disease (HRgroup 1 = 1.5; 95% CI, 1.0-2.2; HRgroup 2 = 1.0; 95% CI, 0.8-1.3). A significant association was observed for colorectal, hepatocellular, gastroesophageal, ovarian, and pancreatic carcinoma in group 1 and for colorectal cancers in group 2.
A high PLR is associated with worse OS in various solid tumors. Further research of its regulation and relevance in daily practice is warranted.
PLR is a readily available and inexpensive biomarker with independent prognostic value in solid tumors.
Women with multifocal or multicentric breast tumors (multifocality henceforth) have been reported to have greater probability of nodal metastasis and relapse and worse survival than women with ...unifocal tumors. However, these associations have been inconsistent and multifocality is not taken into account by staging guidelines and prognostic models. A systematic review of electronic databases identified publications exploring the association between multifocality and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and loco-regional relapse (LRR). The hazard ratios (HRs) for OS and DFS for multifocal compared to unifocal tumors were extracted from multivariable analyses and included in a meta-analysis. For studies not reporting multivariable analyses, odds ratios (OR) were estimated from Kaplan–Meier curves for all endpoints at 5 and 10 years. Twenty-two studies comprising 67,557 women were included. Multifocality was reported in 9.5 % of patients. Classical prognostic factors were well balanced between unifocal and multifocal populations. In multivariable analyses, multifocality was associated with significantly worse OS (HR 1.65;
P
= 0.02), and a non-significant association with worse DFS (HR 1.96;
P
= 0.07). In univariable analyses, multifocality was associated with worse OS, DFS, DSS, and LRR at 5 years (OR 1.39,
P
= 0.02; OR 1.52,
P
= 0.02; OR 1.56,
P
= 0.03; and OR 3.23,
P
= 0.02, respectively). Similar estimates were observed at 10 years, but statistical significance was only reached for DSS and LRR. Mutifocality appears to be associated with a worse prognosis, however, substantial inter-study heterogeneity limits the precise determination of increased risk. Further validation of the independent prognostic impact of multifocality is warranted.
Ovarian dysgerminomas are rare entity and account for only about 2% of all malignant ovarian neoplasm. The aim of this study was to evaluate the clinicopathologic characteristics, treatment, ...long-term survival, and fertility outcome of women diagnosed with ovarian dysgerminoma at our institution. Sixty-five women with histologically proven pure ovarian dysgerminoma were identified in this retrospective study. They were treated at King Faisal Specialist Hospital, Riyadh; Saudi Arabia between 1976 and 2010. The median age was 20 years. The most frequent symptoms at presentation were abdominal pain and abdominal/pelvic mass. Thirty-three patients (50.7%) presented with stage I, 2 (3.1%) had stage II, 22 (33.8%) had stage III, and 4 (6.2%) had stage IV (4 unknown stage). Unilateral oophorectomy was performed in 50 patients (76.9%) while bilateral oophorectomy ± hysterectomy was done in 12 patients (18.4%). Three patients had biopsy only. Forty patients (61.5%) received only chemotherapy, and 4 patients (6.2%) received radiotherapy alone. Recurrence was observed in 6 patients (9.2%). With median follow-up of 54 months, the 5-year disease-free survival (DFS) and overall survival (OS) were 88 and 95%, respectively. On univariate analysis, adjuvant chemotherapy was independent better prognostic factor for DFS (HR, 0.09; 95% CI, 0.01–0.84;
P
= 0.034). Of the 50 patients treated with fertility-sparing surgery, 16 patients (32%) achieved pregnancy with 14 live births. Patients with pure ovarian dysgerminoma have excellent long-term outcome. There is no difference at outcome between fertility-sparing and nonconservative surgeries. Adjuvant chemotherapy was associated with significant improvement in DFS. It is possible to maintain good reproductive function after conservative surgery followed by chemotherapy in our series.
Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such ...recurrence, but the optimal duration of endocrine therapy remains unclear.
We conducted a systematic review and meta-analysis to quantify the benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (5 years of therapy). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for disease recurrence, death and adverse events. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried.
Five trials comprising 21,554 patients were included. Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76-1.05, p = 0.17). There was no association between extended adjuvant tamoxifen and all-cause death (OR:0.99, 95% CI 0.84-1.16, p = 0.88). There was an apparent reduction in risk of recurrence occurring after completion of extended adjuvant tamoxifen with little evidence of effect during therapy, however, this difference was not significant (p for difference 0.10). Subgroup analysis suggested that a greater effect size among lymph node positive patients compared with those who are lymph node negative (NNT: 25 vs. 49). There was no apparent difference in the effect between pre- and post-menopausal patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65-2.58, p<0.001, number needed to harm:89).
In unselected patients, extended adjuvant tamoxifen is not associated with a significant reduction in recurrence, or a reduction in all-cause death. Patients with lymph node positive breast cancer may derive some benefit. Reduction in the risk of recurrence appears to occur only after completion of extended adjuvant therapy.
Earth materials have been used in construction as safe, healthy and environmentally sustainable. It is often challenging to develop an optimum soil mix because of the significant variations in soil ...properties from one soil to another. The current study analyzed the soil properties, including the grain size distribution, Atterberg limits, compaction characteristics, etc., using multilinear regression (MLR) and artificial neural networks (ANN). Data collected from previous studies (i.e., 488 cases) for stabilized (with either cement or lime) and unstabilized soils were considered and analyzed. Missing data were estimated by correlations reported in previous studies. Then, different ANNs were designed (trained and validated) using Levenberg-Marquardt (L-M) algorithms. Using the MLR, several models were developed to estimate the compressive strength of both unstabilized and stabilized soils with a Pearson Coefficient of Correlation (R
) equal to 0.2227 and 0.766, respectively. On the other hand, developed ANNs gave a higher value for R
than MLR (with the highest value achieved at 0.9883). Thereafter, an experimental program was carried out to validate the results achieved in this study. Finally, a sensitivity analysis was carried out using the resulting networks to assess the effect of different soil properties on the unconfined compressive strength (UCS). Moreover, suitable recommendations for earth materials mixes were presented.
Abstract
Earth materials have been used for thousands of years and are considered as one of the oldest construction materials. Recently, due to energy crises and the need to adopt energy-conservative ...solutions in construction sectors, earth buildings have drawn attention worldwide and reemerged since the 1950s. The materials, which are mixtures of natural soils and possible stabilizing materials, are considered as one of the foremost solutions to develop structures that are environmentally friendly due to several properties like low CO2 emission and thermal comfort. Also, the availability of such materials makes them the perfect solution for load-bearing residential house construction and no major processes are required prior to construction. However, understanding the behavior of such materials is challenging due to the large variation in their properties which is attributed to several factors like the sensitivity to water, density, curing conditions, etc. Therefore, in this paper, earth materials (both stabilized and unstabilized) are discussed in different terms including soil suitability, strength, and assessment methods or criterions. The effect of different parameters on the soil performance is analyzed based on previous studies and recommendations are presented, and a number of correlations are prepared based on the data of previous studies. Moreover, the criteria presented by many studies and standards to assess the earth performance are discussed thoroughly. Finally, numerical modeling of such materials is discussed. Such a study is expected to help both engineers and researchers to understand the role of different features on the earth materials and how to utilize them to come up with the optimum performance. Also, the study reveals the lack of development of a classification system that helps in selecting proper materials for earth construction in future.
The androgen receptor (AR) is expressed frequently in breast cancer, but its prognostic significance is unclear. Preclinical data suggest that expression of AR may modify clinical outcomes in early ...breast cancer with improved prognosis in estrogen receptor (ER)-positive disease and poorer prognosis in ER-negative disease.
A systematic review of electronic databases was conducted to identify studies published between 1946 and July 2012 and to explore the association between AR expression and overall survival (OS) and disease-free survival (DFS) in women diagnosed with early breast cancer. The odds ratios (OR) for OS and DFS at 3 and 5 years were calculated and then weighted and pooled in a meta-analysis with Mantel-Haenszel random-effect modeling. All statistical tests were two-sided.
Nineteen studies with a total of 7693 women were included. AR expression was documented in 60.5% of patients. ER-positive tumors were more likely to express AR- than ER-negative tumors (74.8% vs 31.8%, χ(2) P < .001). Compared with tumors without AR expression, those expressing AR were associated with improved OS at both 3 and 5 years (OR = 0.47, 95% confidence interval CI = 0.39 to 0.58, P < .001; and OR = 0.40, 95% CI = 0.29 to 0.56, P < .001). The absolute differences in the probability of OS at 3 and 5 years were 6.7% (95% CI = 3.5% to 9.8%) and 13.5% (95% CI = 7.5% to 19.6%), respectively. Results for 3- and 5-year DFS were similar. Coexpression of the ER did not influence OS at 3 or at 5 years.
Expression of AR in women with breast cancer is associated with better OS and DFS irrespective of coexpression of ER.
The practice of designing load-bearing walls with stabilized earth-based material is currently increasing in most developed countries. Potentialities of earth-based materials have room for more ...exploration, investigation, and promotion among building industry stakeholders globally. This research aims to analyze the compressive strength and durability of “Hamrah” Soil to assess its fitness in construction. Such a study is intended to get international and local (Saudi Arabia) construction practitioners’ confidence about soil usage in the construction industry. To achieve this goal, sufficient soil material was procured from the Al-Hofuf region in eastern Saudi Arabia. Several geotechnical experiments were carried out to characterize and identify Hamrah Soil properties. The soil samples were classified in adherence to both the Unified Soil Classification System (USCS) and the American Association of State Highway and Transportation Officials (AASHTO) system. Stabilizing agents (cement and lime) were added at different percentages (0, 2.5, 5, 7.5, 10, 15% of the dry soil weight) to enhance their structural properties. Based on the acceptance criteria of 2 MPa strength, more than 5% cement maximized the stabilized rammed earth (SRE) sample strength more than 2 MPa (up to 6.3 MPa at 15% cement content), whereas 10% lime reached only1.46 MPa, which proved the efficiency of cement stabilization over lime. Micro-characterization techniques utilizing XRD, SEM, and durability tests also lent credence to the effectiveness of cement in the stabilization regime, giving more fibrous formations and a reduction in weight loss below the acceptable limits compared with the case of lime stabilization.
Abstract only
e11613
Background: Fulvestrant is an endocrine agent which degrades the estrogen receptor, thereby downregulating its signaling. While fulvestrant has been consistently tested in ...postmenopausal women with inoperable locally advanced or metastatic breast cancer, there has been substantial heterogeneity in study populations and drug dosing. The optimal use of fulvestrant in advanced breast cancer is therefore unclear. Methods: A systematic review of electronic databases was conducted to identify randomized trials of fulvestrant versus other endocrine therapy. The hazard ratios (HR) for time to progression (TTP) and the odds ratios (OR) for serious adverse events (SAEs), discontinuation of treatment due to toxicity and commonly reported toxicities (hot flashes, venous thrombosis, gastrointestinal disturbance, arthralgia, and asthenia) were pooled in a meta-analysis. Meta-regression explored heterogeneity in study population and fulvestrant dosing. Results: Eight studies were included in the analysis. Overall, there was no difference in TTP between fulvestrant and control groups (HR:0.94, 95% CI 0.85-1.03, p=0.18). On meta-regression, fulvestrant showed reduced hazards for TTP compared to aromatase inhibitors (AI) if used in first line (p for trend <0.001), in studies where fewer patients received adjuvant endocrine therapy (p for trend <0.001) and at higher doses (p for trend <0.001). Rates of SAEs and treatment discontinuation were similar for fulvestrant and control groups, but fulvestrant monotherapy was associated with significantly less arthralgia (OR:0.73,95% CI 0.57-0.95, p=0.02). The addition of fulvestrant to AI compared with AI alone was not associated with improved TTP (HR:0.88, 0.72-1.09,P=0.25), but led to increased hot flashes (OR: 1.68,95% CI 1.30-2.16, P<0.001) and gastrointestinal disturbances (OR:1.28, , 95% CI 1.01-1.63, p=0.04). Conclusions: In unselected patients, fulvestrant monotherapy is associated with similar efficacy, but reduced arthralgia. Use of high dose fulvestrant monotherapy in first line or in patients with limited prior exposure to adjuvant endocrine therapy may delay progression compared with AI. Fulvestrant combined with AI was not associated with improved efficacy but led to increased toxicity.
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