In many longitudinal studies, we observe two correlated processes: a repeated measures process and a recurrent events process, both subject to a dependent terminal event. For example, in the 'Terry ...Beirn community programs for clinical research on AIDS' (CPCRA) study, higher CD4 cell counts are associated with lower risk of recurrent opportunistic diseases. They are also correlated with mortality, e.g. higher CD4 cell repeated measures and a lower rate of opportunistic disease imply better survival for patients infected with the human immunodeficiency virus. We propose a joint random-effects model for the three correlated outcomes. The correlation is modelled by conditioning on shared random effects. Covariate effects can be taken into account in the model. Maximum likelihood estimation and inference are carried out through a Gaussian quadrature technique, assuming piecewise constant baseline hazards for recurrent events and death. The model can be fitted conveniently by Gaussian quadrature tools, e.g. SAS procedure NLMIXED. Simulation studies show that the estimation method yields satisfactory results. We apply this method to the CPCRA data.
Reverse-phase protein arrays (RPPAs) are widely used in biological and biomedical fields of study. One of the most popular analytic methods in RPPA data analysis is the SuperCurve method, which ...requires estimation of the background fluorescence level. This estimation is usually not accurate and has sample bias and spatial bias. Here, we propose a taking-the-difference method to overcome this problem. Briefly, for each two consecutive RPPA cycles, we subtract the later cycle from the earlier cycle, transforming the m-cycle data into m-1 cycle of data. This removes most of the background fluorescence noise. We then use the m-1 cycle of data to fit a new model accordingly derived from the SuperCurve model. To evaluate our proposed method, we compare the accuracy and precision between our proposed model and the original SuperCurve model by testing them on both real and simulated datasets. For both situations, our modified model shows improved results. The modified SuperCurve method is easy to perform and the taking-the-difference idea is recommended for application to all current methods of RPPA data analysis.
Since 2000, the National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of breast ...cancer. Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts.
Survivin, a member of the inhibitors of apoptosis protein family, plays important roles in cell proliferation and survival and is highly expressed in various malignancies, including leukemias. To ...better understand its role in acute myeloid leukemia (AML), we profiled survivin expression in samples obtained from 511 newly diagnosed AML patients and in CD34+38− AML stem/progenitor cells using a validated reverse-phase protein array; we correlated its levels with clinical outcomes and with levels of other proteins in the same sample set. We found that survivin levels were higher in bone marrow than in paired peripheral blood leukemic cells (n = 140, P = .0001) and that higher survivin levels significantly predicted shorter overall (P = .016) and event-free (P = .023) survival in multivariate Cox model analysis. Importantly, survivin levels were significantly higher in CD34+38− AML stem/progenitor cells than in bulk blasts and total CD34+ AML cells (P < .05). Survivin expression correlated with the expressions of multiple proteins involved with cell proliferation and survival. Particularly, its expression strongly correlated with HIF1α in the stem/progenitor cell compartment. These results suggest that survivin is a prognostic biomarker in AML and that survivin, which is overexpressed in AML stem/progenitor cells, remains a potentially important target for leukemia therapy.
What's known on the subject? and What does the study add?
Several lymph node staging strategies have been proposed as a response to the high morbidity seen after standard inguinal lymphadenectomy for ...penile cancer. A video‐endoscopic (laparoscopic and robotic) approach has been proposed as a less morbid procedure in several retrospective studies. To date, none has evaluated the oncological adequacy with regard to whether all relevant nodes have been removed.
To the authors’ knowledge this is the first prospective study of a robotic or laparoscopic inguinal lymphadenectomy that evaluates the oncological adequacy of this approach for penile cancer. The study shows that robotic inguinal lymphadenectomy allowed adequate staging of disease in the inguinal region by removing all relevant lymph nodes as assessed by an independent evaluating urological oncologist.
Objective
To prospectively determine the oncological adequacy of robotic assisted video‐endoscopic inguinal lymphadenectomy (RAVEIL).
Patients and Methods
Patients with T1‐3N0 penile cancer were enrolled into a prospective phase I trial at a tertiary care institution from March 2010 to January 2012. All patients underwent an initial RAVEIL approach.
Verification of adequacy of dissection was performed by an independent surgeon via a separate open incision at the conclusion of the RAVEIL procedure.
Out of 10 patients, if more than two superficial inguinal fields with ≥2 nodes or more than four with ≥1 node remained within the superficial dissection field, the study would not proceed to phase II.
Results
Of 10 enrolled patients two had inguinal metastases and all positive nodes were detected by RAVEIL. The remaining eight patients had no metastases, with a mean of nine (range 5–21) left and nine (range 6–17) right nodes removed. One inguinal field RAVEIL was converted to an open dissection.
The verifying surgeon confirmed that 18 of 19 inguinal fields (94.7% in nine patients) had an adequate dissection. Two benign nodes were found just beneath Scarpa's fascia above the inguinal dissection field.
Limitations of the study include an inability to determine decisively what specific wound complications were related to RAVEIL because of the protocol‐specified creation of a small inguinal incision for verification of adequate dissection.
Conclusion
RAVEIL allowed adequate staging of disease in the inguinal region among patients with penile cancer at risk for inguinal metastases.
We previously reported using statins was correlated with improved metastasis-free survival in aggressive breast cancer. The purpose of this study was to examine the effect of statins on metastatic ...colonization by triple-negative breast cancer (TNBC) cells. TNBC cell lines were treated with simvastatin and then studied for cell cycle progression and proliferation in vitro, and metastasis formation in vivo, following injection of statin-treated cells. Reverse-phase protein assay (RPPA) analysis was performed on statin-treated and control breast cancer cells. RNA interference targeting
FOXO3a
was used to measure the impact of simvastatin on FOXO3a-expressing cells. The prognostic value of
FOXO3a
mRNA expression was examined in eight public breast cancer gene expression datasets including 1479 patients. Simvastatin increased G1/S-phase arrest of the cell cycle and inhibited both proliferation and migration of TNBC cells in vitro. In vitro pre-treatment and in vivo treatment with simvastatin reduced metastases. Phosphorylated FOXO3a was downregulated after simvastatin treatment in (RPPA) analysis. Ectopic expression of
FOXO3a
enhanced mammosphere formation and migratory capacity in vitro. Knockdown of
FOXO3a
attenuated the effect of simvastatin on mammosphere formation and migration. Analysis of public gene expression data demonstrates
FOXO3a
mRNA downregulation was independently associated with shorter metastasis-free survival in all breast cancers, as well as in TNBC breast cancers. Simvastatin inhibits in vitro endpoints associated with metastasis through a FOXO3a mechanism and reduced metastasis formation in vivo. FOXO3a expression is prognostic for metastasis formation in patient data. Further investigation of simvastatin as a cancer therapy is warranted.
B-cell receptor (BCR) signaling has been inferred as an important mechanism for disease progression in chronic lymphocytic leukemia (CLL) and other B-cell malignancies. In response to BCR activation, ...CLL cells secrete the chemokine CCL3, which fosters interactions between CLL cells and the leukemia microenvironment. CCL3 secretion correlates with expression of the 70-kDa ζ-associated protein (ZAP-70) and responsiveness of the CLL clone to BCR stimulation. Here, we measured CCL3 plasma levels by enzyme-linked immunosorbent assay (ELISA) in 351 CLL patients and examined CCL3 levels for associations with established prognostic markers and time from diagnosis to initial therapy. We found that CCL3 plasma concentrations were strongly associated with established prognostic markers. In a Cox proportional hazards regression model, CCL3 as well as established prognostic markers (immunoglobulin heavy chain variable-region mutation status, CD38 or ZAP-70 cytogenetics, clinical stage) were significantly associated with time to treatment. Multivariable analysis revealed that CCL3 (hazard ratio HR = 2.33, P < .0001), advanced clinical stage (HR = 2.75, P = .0025), poor risk cytogenetics (del 17p, HR = 2.38; del11q, HR = 2.36, P = .001), and CD38 expression (HR = 1.43, P = .023) were independent prognostic markers. Collectively, CCL3 is a novel, robust, and independent prognostic marker in CLL that can easily and reliably be measured by ELISA. CCL3 therefore should become useful for risk assessment in patients with CLL.
Recent studies suggested that AKT activation might confer poor prognosis in acute myelogenous leukemia (AML), providing the rationale for therapeutic targeting of this signaling pathway. We, ...therefore, explored the preclinical and clinical anti-AML activity of an oral AKT inhibitor, MK-2206. Experimental Methods: We first studied the effects of MK-2206 in human AML cell lines and primary AML specimens in vitro. Subsequently, we conducted a phase II trial of MK-2206 (200 mg weekly) in adults requiring second salvage therapy for relapsed/refractory AML, and assessed target inhibition via reverse phase protein array (RPPA).
In preclinical studies, MK-2206 dose-dependently inhibited growth and induced apoptosis in AML cell lines and primary AML blasts. We then treated 19 patients with MK-2206 but, among 18 evaluable participants, observed only 1 (95% confidence interval, 0%-17%) response (complete remission with incomplete platelet count recovery), leading to early study termination. The most common grade 3/4 drug-related toxicity was a pruritic rash in 6 of 18 patients. Nevertheless, despite the use of MK-2206 at maximum tolerated doses, RPPA analyses indicated only modest decreases in Ser473 AKT (median 28%; range, 12%-45%) and limited inhibition of downstream targets.
Although preclinical activity of MK-2206 can be demonstrated, this inhibitor has insufficient clinical antileukemia activity when given alone at tolerated doses, and alternative approaches to block AKT signaling should be explored.
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