Surgery for Stage IIIA Non-Small-cell Lung Cancer: Lack of Predictive and Prognostic Factors Identifying Any Subgroup of Patients Benefiting From It.

Although a trimodality regimen for patients with stage IIIA/pN2 non-small-cell lung cancer (NSCLC) has been variably used owing to limited evidence for its benefits, it remains unknown whether any patient subgroup actually receives benefit from such an approach. To explore this question, the published data were reviewed from 1990 to 2015 to identify the possible predictors and prognosticators in this setting. Overall survival was the endpoint of our study. Of 27 identified studies, none had studied the predictors of improved outcomes with trimodality treatment. Of the potential patient- and tumor-related prognosticators, age, gender, and histologic type were the most frequently formally explored. However, none of the 3 was found to influence overall survival. The most prominent finding of the present review was the substantial lack of data supporting a trimodality treatment approach in any patient subgroup. As demonstrated in completed prospective randomized studies, the use of surgery for stage IIIA NSCLC should be limited to well-defined clinical trials.

Diagnostic and Prognostic Impact of pc-ASPECTS Applied to Perfusion CT in the Basilar Artery International Cooperation Study

BACKGROUND AND PURPOSE The posterior circulation Acute Stroke Prognosis Early CT Score (pc-APECTS) applied to CT angiography source images (CTA-SI) predicts the functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). We assessed the diagnostic and prognostic impact of pc-ASPECTS applied to perfusion CT (CTP) in the BASICS registry population. METHODS We applied pc-ASPECTS to CTA-SI and cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) parameter maps of BASICS patients with CTA and CTP studies performed. Hypoattenuation on CTA-SI, relative reduction in CBV or CBF, or relative increase in MTT were rated as abnormal. RESULTS CTA and CTP were available in 27/592 BASICS patients (4.6%). The proportion of patients with any perfusion abnormality was highest for MTT (93%; 95% confidence interval [CI], 76%-99%), compared with 78% (58%-91%) for CTA-SI and CBF, and 46% (27%-67%) for CBV (P < .001). All 3 patients with a CBV pc-ASPECTS < 8 compared to 6/23 patients with a CBV pc-ASPECTS ≥ 8 had died at 1 month (RR 3.8; 95% CI, 1.9-7.6). CONCLUSION CTP was performed in a minority of the BASICS registry population. Perfusion disturbances in the posterior circulation were most pronounced on MTT parameter maps. CBV pc-ASPECTS < 8 may indicate patients with high case fatality.

Prognostic Relevance of Palliative Primary Tumor Removal in 37,793 Metastatic Colorectal Cancer Patients: A Population-Based, Propensity Score-Adjusted Trend Analysis

OBJECTIVE To assess whether palliative primary tumor resection in colorectal cancer patients with incurable stage IV disease is associated with improved survival. BACKGROUND There is a heated debate regarding whether or not an asymptomatic primary tumor should be removed in patients with incurable stage IV colorectal disease. METHODS Stage IV colorectal cancer patients were identified in the Surveillance, Epidemiology, and End Results database between 1998 and 2009. Patients undergoing surgery to metastatic sites were excluded. Overall survival and cancer-specific survival were compared between patients with and without palliative primary tumor resection using risk-adjusted Cox proportional hazard regression models and stratified propensity score methods. RESULTS Overall, 37,793 stage IV colorectal cancer patients were identified. Of those, 23,004 (60.9%) underwent palliative primary tumor resection. The rate of patients undergoing palliative primary cancer resection decreased from 68.4% in 1998 to 50.7% in 2009 (P < 0.001). In Cox regression analysis after propensity score matching primary cancer resection was associated with a significantly improved overall survival [hazard ratio (HR) of death = 0.40, 95% confidence interval (CI) = 0.39-0.42, P < 0.001] and cancer-specific survival (HR of death = 0.39, 95% CI = 0.38-0.40, P < 0.001). The benefit of palliative primary cancer resection persisted during the time period 1998 to 2009 with HRs equal to or less than 0.47 for both overall and cancer-specific survival. CONCLUSIONS On the basis of this population-based cohort of stage IV colorectal cancer patients, palliative primary tumor resection was associated with improved overall and cancer-specific survival. Therefore, the dogma that an asymptomatic primary tumor never should be resected in patients with unresectable colorectal cancer metastases must be questioned.

Two prognostic factors in breast cancer: Novel functions of EGFR and beta-catenin

In this study, we demonstrated the novel functions of two important prognostic markers in breast cancer, EGFR and b -catenin in proliferation and/or other transformation phenotype. ^ First we demonstrated that EGFR could be detected in the nucleus in highly proliferating tissues, including primary breast cancer samples and a breast cancer cell line. We found that EGFR contained a strong transactivation domain, complexed with an AT-rich consensus DNA sequence and activated promoters containing this sequence, including cyclin D1 promoter. Therefore, EGFR may function as a transcription factor to activate genes required for highly proliferating activity such as cyclin D1 in breast cancer. ^ In the second part of this study, we identified b -catenin as an important prognostic factor in breast cancer. We found that cyclin D1 was one of the genes regulated by b -catenin in breast cancer cells. The transactivation activity of b -catenin correlated significantly with cyclin D1 expression in both breast cancer cell lines and in breast cancer patient samples, in which high b -catenin activity correlated with poor prognosis of the patients. Moreover, blockage of b -catenin activity significantly inhibited transformation phenotypes in breast cancer cells. Therefore, our results indicate that b -catenin can be involved in breast cancer formation and/or progression and may serve as a target for breast cancer therapy. ^

Analysis of prognostic factors for the development of metastases and survival in renal cell carcinoma patients

Introduction and objective. A number of prognostic factors have been reported for predicting survival in patients with renal cell carcinoma. Yet few studies have analyzed the effects of those factors at different stages of the disease process. In this study, different stages of disease progression starting from nephrectomy to metastasis, from metastasis to death, and from evaluation to death were evaluated. ^ Methods. In this retrospective follow-up study, records of 97 deceased renal cell carcinoma (RCC) patients were reviewed between September 2006 to October 2006. Patients with TNM Stage IV disease before nephrectomy or with cancer diagnoses other than RCC were excluded leaving 64 records for analysis. Patient TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were analyzed in relation to time to metastases. Time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from metastases to death. Finally, analysis of laboratory values at time of evaluation, Eastern Cooperative Oncology Group performance status (ECOG), UCLA Integrated Staging System (UISS), time from nephrectomy to metastasis, TNM staging, Furhman Grade, age, tumor size, tumor volume, histology and patient gender were tested for significance in relation to time from evaluation to death. Linear regression and Cox Proportional Hazard (univariate and multivariate) was used for testing significance. Kaplan-Meier Log-Rank test was used to detect any significance between groups at various endpoints. ^ Results. Compared to negative lymph nodes at time of nephrectomy, a single positive lymph node had significantly shorter time to metastasis (p<0.0001). Compared to other histological types, clear cell histology had significant metastasis free survival (p=0.003). Clear cell histology compared to other types (p=0.0002 univariate, p=0.038 multivariate) and time to metastasis with log conversion (p=0.028) significantly affected time from metastasis to death. A greater than one year and greater than two year metastasis free interval, compared to patients that had metastasis before one and two years, had statistically significant survival benefit (p=0.004 and p=0.0318). Time from evaluation to death was affected by greater than one year metastasis free interval (p=0.0459), alcohol consumption (p=0.044), LDH (p=0.006), ECOG performance status (p<0.001), and hemoglobin level (p=0.0092). The UISS risk stratified the patient population in a statistically significant manner for survival (p=0.001). No other factors were found to be significant. ^ Conclusion. Clear cell histology is predictive for both time to metastasis and metastasis to death. Nodal status at time of nephrectomy may predict risk of metastasis. The time interval to metastasis significantly predicts time from metastasis to death and time from evaluation to death. ECOG performance status, and hemoglobin levels predicts survival outcome at evaluation. Finally, UISS appropriately stratifies risk in our population. ^

Prognostic factors in desmoid tumors

Purpose. To evaluate the prognostic factors in desmoid tumors in the light of its possible use in standardizing the treatment strategy of an individual patient. ^ Patients and methods. A retrospective review of 189 consecutive patients who were treated at MD Anderson Cancer Center (MDACC) from January 1995 to December 2005 was done. Univariate and multivariate analysis of different prognostic factors was done on all patients, patients treated with surgery alone, subset of patients who came to MDACC with primary tumor. The median follow up was 63 months. Also the analysis of 189 desmoid patients treated at MDACC between 1995 and 2005 was compared to results of 189 desmoid patients treated at MDACC from 1965-1994 using data retrieved from a 150 field prospective relational soft tissue tumor database. ^ Results. 5-, and 10-year overall survival rate were 0.976 (95%CI 0.952, 0.999), and 0.966 (95% CI 0.935, 0.996), respectively. 5-, and 10-year recurrence free rate were 0.803 (95%CI 0.738, 0.868), and 0.793 (95% CI 0.726, 0.860), respectively. 5 year recurrence free survival for surgery alone, radiotherapy alone, chemotherapy alone and combination regimen were 0.759, 0.625, 0.933, and 0.802 respectively. Age (>30 vs. <=30) and primary tumor site (extremity vs visceral) were two prognostic factors significantly associated with local recurrence in all of the patients. ^ Conclusion. An increased awareness of the complex multidisciplinary management needed for successful control of desmoid tumor may underlie a significantly increased number of desmoid referrals, especially primary untreated desmoids, to UTMDACC. The careful prospective integration of multiple therapies has led to a significant recent improvement in desmoid patient outcome. These trends should be supported, particularly if personalized molecular-based therapies are to be rapidly and effectively deployed for the benefit of those afflicted by this rare and potentially devastating disease.^

Assessing the improved discriminatory power of a new biomarker in prognostic models

Although the area under the receiver operating characteristic (AUC) is the most popular measure of the performance of prediction models, it has limitations, especially when it is used to evaluate the added discrimination of a new biomarker in the model. Pencina et al. (2008) proposed two indices, the net reclassification improvement (NRI) and integrated discrimination improvement (IDI), to supplement the improvement in the AUC (IAUC). Their NRI and IDI are based on binary outcomes in case-control settings, which do not involve time-to-event outcome. However, many disease outcomes are time-dependent and the onset time can be censored. Measuring discrimination potential of a prognostic marker without considering time to event can lead to biased estimates. In this dissertation, we have extended the NRI and IDI to survival analysis settings and derived the corresponding sample estimators and asymptotic tests. Simulation studies were conducted to compare the performance of the time-dependent NRI and IDI with Pencina’s NRI and IDI. For illustration, we have applied the proposed method to a breast cancer study.^ Key words: Prognostic model, Discrimination, Time-dependent NRI and IDI ^

CHARACTERIZATION OF DIFFERENTIATION AND PROGNOSTIC BIOMARKERS ON CD8+ TUMOR-INFILTRATING LYMPHOCYTES IN METASTATIC MELANOMA

CD8+ cytotoxic T lymphocytes (CTL) frequently infiltrate tumors, yet most melanoma patients fail to undergo tumor regression. We studied the differentiation of the CD8+ tumor-infiltrating lymphocytes (TIL) from 44 metastatic melanoma patients using known T-cell differentiation markers. We also compared CD8+ TIL against the T cells from matched melanoma patients’ peripheral blood. We discovered a novel subset of CD8+ TIL co-expressing early-differentiation markers, CD27, CD28, and a late/senescent CTL differentiation marker, CD57. This CD8+CD57+ TIL expressed a cytolytic enzyme, granzyme B (GB), yet did not express another cytolytic pore-forming molecule, perforin (Perf). In contrast, the CD8+CD57+ T cells in the periphery were CD27-CD28-, and GBHi and PerfHi. We found this TIL subset was not senescent and could be induced to proliferate and differentiate into CD27-CD57+, perforinHi, mature CTL. This further differentiation was arrested by TGF-β1, an immunosuppressive cytokine known to be produced by many different kinds of tumors. Therefore, we have identified a novel subset of incompletely differentiated CD8+ TIL that resembled those found in patients with uncontrolled chronic viral infections. In a related study, we explored prognostic biomarkers in metastatic melanoma patients treated in a Phase II Adoptive Cell Therapy (ACT) trial, in which autologous TIL were expanded ex vivo with IL-2 and infused into lymphodepleted patients. We unexpectedly found a significant positive clinical association with the infused CD8+ TIL expressing B- and T- lymphocyte attentuator (BTLA), an inhibitory T-cell receptor. We found that CD8+BTLA+ TIL had a superior proliferative response to IL-2, and were more capable of autocrine IL-2 production in response to TCR stimulation compared to the CD8+BTLA- TIL. The CD8+BTLA+ TIL were less differentiated and resembled the incompletely differentiated CD8+ TIL described above. In contrast, CD8+BTLA- TIL were poorly proliferative, expressed CD45RA and killer-cell immunoglobulin-like receptors (KIRs), and exhibited a gene expression signature of T cell deletion. Surprisingly, ligation of BTLA by its cognate receptor, HVEM, enhanced the survival of CD8+BTLA+ TIL by activating Akt/PKB. Our studies provide a comprehensive characterization of CD8+ TIL differentiation in melanoma, and revealed BTLA as a novel T-cell differentiation marker along with its role in promoting T cell survival.

Derivation and Validation of a Novel Prognostic Scale (Modified–Stroke Subtype, Oxfordshire Community Stroke Project Classification, Age, and Prestroke Modified Rankin) to Predict Early Mortality in Acute Stroke

© 2015 American Heart Association, Inc.

Mutation detection by highly sensitive methods indicates that p53 gene mutations in breast cancer can have important prognostic value.

Human cancer cells with a mutated p53 tumor-suppressor gene have a selective growth advantage and may exhibit resistance to ionizing radiation and certain chemotherapeutic agents. To examine the prognostic value of mutations in the p53 gene, a cohort of 90 Midwestern Caucasian breast cancer patients were analyzed with methodology that detects virtually 100% of all mutations. The presence of a p53 gene mutation was by far the single most predictive indicator for recurrence and death (relative risks of 4.7 and 23.2, respectively). Direct detection of p53 mutations had substantially greater prognostic value than immunohistochemical detection of p53 overexpression. Analysis of p53 gene mutations may permit identification of a subset of breast cancer patients who, despite lack of conventional indicators of poor prognosis, are at high risk of early recurrence and death.

Spectral-domain optical coherence tomography study of macular structure as prognostic and determining factor for macular hole surgery outcome

Purpose: To evaluate postoperative spectral-domain optical coherence tomography findings after macular hole surgery. Methods: Retrospective, interventional, nonrandomized study. Overall, 164 eyes of 157 patients diagnosed with macular hole were operated on by vitrectomy and internal limiting membrane peeling. Preoperative and postoperative best-corrected visual acuity and spectral-domain optical coherence tomography images were obtained. Two groups were considered on the basis of the postoperative integrity of the back reflection line from the ellipsoid portion of the photoreceptor inner segment: group A (disruption of ellipsoid portion of the inner segment line, 60 eyes) and group B (restoration of ellipsoid portion of the inner segment line, 104 eyes). Results: Logarithm of the minimum angle of resolution best-corrected visual acuity improved significantly after the surgery of macular hole from a mean preoperative value of 0.79 ± 0.37 (range, 0.15–2.00) to a mean postoperative value of 0.35 ± 0.31 (range, 0.00–1.30) at the last follow-up visit (P < 0.01). Best-corrected visual acuity improved significantly in the 2 groups analyzed (all P < 0.01). A larger improvement was found in group B than in group A (P < 0.01). Conclusion: Ellipsoid portion of the inner segment line reconstruction seems to be a good prognostic factor for visual rehabilitation after macular hole surgery.

Prognostic Value of Secretoneurin in Critically Ill Patients With Infections.

OBJECTIVES Secretoneurin is produced in neuroendocrine cells, and the myocardium and circulating secretoneurin levels provide incremental prognostic information to established risk indices in cardiovascular disease. As myocardial dysfunction contributes to poor outcome in critically ill patients, we wanted to assess the prognostic value of secretoneurin in two cohorts of critically ill patients with infections. DESIGN Two prospective, observational studies. SETTING Twenty-four and twenty-five ICUs in Finland. PATIENTS A total of 232 patients with severe sepsis (cohort #1) and 94 patients with infections and respiratory failure (cohort #2). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We measured secretoneurin levels by radioimmunoassay in samples obtained early after ICU admission and compared secretoneurin with other risk indices. In patients with severe sepsis, admission secretoneurin levels (logarithmically transformed) were associated with hospital mortality (odds ratio, 3.17 [95% CI, 1.12-9.00]; p = 0.030) and shock during the hospitalization (odds ratio, 2.17 [1.06-4.46]; p = 0.034) in analyses that adjusted for other risk factors available on ICU admission. Adding secretoneurin levels to age, which was also associated with hospital mortality in the multivariate model, improved the risk prediction as assessed by the category-free net reclassification index: 0.35 (95% CI, 0.06-0.64) (p = 0.02). In contrast, N-terminal pro-B-type natriuretic peptide levels were not associated with mortality in the multivariate model that included secretoneurin measurements, and N-terminal pro-B-type natriuretic peptide did not improve patient classification on top of age. Secretoneurin levels were also associated with hospital mortality after adjusting for other risk factors and improved patient classification in cohort #2. In both cohorts, the optimal cutoff for secretoneurin levels at ICU admission to predict hospital mortality was ≈ 175 pmol/L, and higher levels were associated with mortality also when adjusting for Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. CONCLUSIONS Secretoneurin levels provide incremental information to established risk indices for the prediction of mortality and shock in critically ill patients with severe infections.

Horary astrology; the key to scientific prediction, being the prognostic astronomer,

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