Significant Decrease In Overall Survival Research Articles

Radiotherapy protocol deviations and clinical outcomes: A meta-analysis of cooperative group clinical trials.

181 Background: Several reports have linked noncompliance with radiotherapy (RT) protocol guidelines with inferior clinical outcomes. Here we perform a meta-analysis of prospective cooperative group trials to determine the impact of RT quality assurance (QA) deviations on disease control and overall survival (OS). Methods: We searched MEDLINE and the Cochrane Central Register of Controlled Trials for multi-institutional trials that reported clinical outcomes in relation to RT quality assurance (QA) results. Hazard ratios (HRs) describing the impact of RT protocol noncompliance on outcomes were extracted directly from the original studies or calculated from survival curves. Analyses were performed to assess the impact of RT QA deviations on OS and secondary outcomes (local/locoregional control, event-free survival, relapse), which were grouped together. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p<0.10 using Q test). Results: Eight studies met all inclusion criteria and were incorporated into this analysis. Four were pediatric trials (POG 8346, SFOP.TC 94, POG 9031, SIOP/UKCC PNET-3), and four studied adult patients (RTOG 73-01, SWOG 7628, TROG 02.02, RTOG 97-04). Six of these trials reported the impact of RT QA deviations on overall survival, and six described the effects of RT QA deviations on secondary endpoints. The frequency of RT QA deviations ranged from 8% to 71% (median: 40%). Using a random effects model, RT deviations were associated with a significant decrease in OS (HR = 1.74, 95% CI: 1.28 to 2.35, p<0.001). A similar effect was seen for secondary endpoints (HR = 1.79, 95% CI: 1.15 to 2.78, p=0.009). No evidence of publication bias was detected using the Egger test (p=0.361 for OS, p=0.468 for secondary endpoints). Conclusions: In clinical trials, RT protocol deviations are associated with increased risk of treatment failure and overall mortality. The magnitude of these effects demonstrates that RT QA results should be considered in the interpretation of clinical trial results. More importantly, the delivery of high-quality RT is critical for the successful treatment of cancer patients.

Evidence That Activated Hedgehog Signaling Predicts for Poor Clinical Outcome in Acute Myeloid Leukemia

AbstractAbstract 1441▪▪This icon denotes a clinically relevant abstract Introduction:Hedgehog (Hh) signaling is essential in many developmental pathways and a growing body of evidence supports a role for aberrant activation of the Hh pathway in a variety of hematological malignancies including Acute Myeloid Leukemia (AML). Primary CD34+ myeloid blasts and cell lines preferentially demonstrate active Hh signaling suggesting that the Hh pathway may be involved in leukemic stem cell maintenance and survival (Bai et al. Leukemia. 2008;22(1):226-8). In addition, disruption of Hh signaling by targeted agents in this setting results in cell death and confers sensitivity to Ara-C in chemoresistant CD34+ leukemic cell lines (Kobune et al. Cancer Science. 2009;100(5):948-55). These findings provide a rationale for targeted disruption of the Hh pathway in AML and imply that the identification of Hh signaling in AML could correlate with disease that is refractory to standard induction therapy. Methods:To extend these previous findings, the presence of Hh signaling was assessed by the identification of nuclear GLI1 by immunofluorescence in tissue microarrays (TMA) prepared from a large cohort of primary human AMLs and the data correlated with clinical outcome. Presentation bone marrow trephine samples from patients diagnosed with AML between 1994 and 2005 were retrieved from the histopathology archives at Manchester Royal Infirmary. These biopsy samples were routinely processed, formalin-fixed, paraffin-embedded, and EDTA-decalcified. All material used for preparation of the TMA was residual diagnostic tissue, anonymized and consented for its use in research. Each TMA core contained at least 20% leukemic blasts and was representative of the whole biopsy sample. A specific and highly sensitive human GLI1 immunofluorescence assay was developed to visualize nuclear GLI1in four micron thick TMA sections. Human embryonic palatal mesenchymal (HEPM) cells stimulated with SHH and treated with the Hh antagonist saridegib (IPI-926) were used as staining controls to demonstrate assay specificity. To determine the cellular context of GLI1 staining in AML, a GLI1/CD34 double immunoflourescence assay was also developed. All samples were scanned in using the TissueGnostics TissueFAXS 2.0 system. The Cy5 channel was used to detect nuclear GLI1 and the Texas Red channel was used to detect CD34 when double staining was employed. A nuclear algorithm was developed to analyze the GLI1 staining using the TissueQuest version 2.0 software. Results:Of the 160 patient samples stained, 71 samples were evaluable after filtering on the basis of the presence of adequate tissue cores on the TMA and a full set of clinical follow-up data. All patients (36 male, 34 female, 1 unknown; age range 17 to 83 years at diagnosis with a median age of 53 years) received intensive chemotherapy according to standard UK MRC AML protocols and had follow-up data for up to 5124 days. Nuclear GLI1 as a function of total marrow cells showed a wide range of expression (0.0–32.0%) with a mean of 4.8% and a median of 3.1%. In a subset of cases with CD34 positive blasts, nuclear GLI1 co-expression could be readily identified as coexpressed in the CD34 positive cells. The degree of GLI1 expression did not correlate with AML subtype or cytogenetics. Correlation of GLI1 positivity with clinical features was performed and while no association with overall survival was observed in the total population, there was a significant decrease in overall survival in patients with secondary AML that had GLI1 levels above the median (HR = 0.18; p value = 0.0112). In addition, there was a significant correlation between GLI1 either above or below the median and remission status (i.e. complete remission, partial remission or refractory disease) with higher GLI1 levels observed in patients with refractory disease (p value = 0.045) and a more significant correlation with GLI1 values as a continuous variable and remission status (p value = 0.026). Conclusions:These data suggest that high levels of GLI1 predict for poor remission status in patients with AML and poor overall survival in patients with secondary AML. The presence of high levels of nuclear GLI1 in AMLs that are refractory to chemotherapy supports a role for Hh signaling in chemoresistance, particularly in patients with secondary AML, and provides a rationale for targeted inhibition of the Hh pathway in selected AML patients. Disclosures:Campbell:Infinity Pharmaceuticals, Inc.: Employment. Quigley:Infinity Pharmaceuticals, Inc.: Employment. Keilty:Infinity Pharmaceuticals, Inc.: Employment. Kelly:Infinity Pharmaceuticals, Inc.: Employment. McGovern:Infinity Pharmaceuticals, Inc.: Employment. Read:Infinity Pharmaceuticals, Inc.: Employment. Kutok:Infinity Pharmaceuticals, Inc.: Employment.

Contemporary Outcomes in Infants With Congenital Heart Disease and Bochdalek Diaphragmatic Hernia

Fifteen percent of infants with congenital diaphragmatic hernia (CDH) are born with a coexisting cardiac anomaly. The purpose of this study was to evaluate contemporary outcomes in this patient population and to identify potential risk factors for in-hospital mortality. Data from all CDH neonates with congenital heart disease managed at a single pediatric tertiary care referral center between 1997 and 2011 were retrospectively analyzed. Forty (18%) of 216 CDH patients had a cardiac anomaly. This group was associated with a significant decrease in overall survival when compared with patients without cardiac anomaly (55% versus 81%; p = 0.001). There was no association between type of cardiac anomaly and mortality based on risk stratification according to the Risk Adjustment for Congenital Heart Surgery and The Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery scoring systems (p = 0.86 and p = 0.87, respectively). Birth weight was similarly no different between survivors and nonsurvivors (2.8 ± 0.6 kg versus 2.8 ± 0.9 kg, respectively; p = 0.98). There was a trend toward increased extracorporeal membrane oxygenation use among nonsurvivors (p = 0.13). Infants with hemodynamic stability enabling subsequent cardiac repair were associated with lower mortality (p = 0.04). Survivors had a wide spectrum of long-term morbidity, but most had some evidence of neurodevelopmental impairment. This large single-institution series suggests that the overall prognosis of infants with concomitant CDH and congenital heart disease can be quite variable, regardless of the type of heart anomaly. Hemodynamic instability and need for extracorporeal membrane oxygenation correlate with higher mortality. Although some long-term survivors have excellent outcomes, most suffer from chronic, long-term morbidities.

Zinc-finger protein 545 is a novel tumour suppressor that acts by inhibiting ribosomal RNA transcription in gastric cancer

ObjectiveZinc-finger protein 545 (ZNF545) is a member of the family of Krüppel-associated box-containing zinc-finger proteins. The aim of this study was to clarify its biological function as a tumour suppressor...

Long‐Term Prognosis and Significance of the Sentinel Lymph Node in Head and Neck Melanoma

To report the long-term significance of sentinel lymph node (SLN) biopsy on prognosis, determine false-negative SLN occurrences, and determine risk factors for death and recurrence in a large series of patients with head and neck melanoma. Case series with tumor registry review. Academic tertiary care medical center. A database review was performed of all patients who underwent SLN biopsy for head and neck melanoma from 1994 to 2009. End points assessed were SLN status, recurrence, false-negative SLN results, and survival comparing SLN-positive and SLN-negative patients and different locations. Survival curves and multivariate analyses were performed. SLN biopsy was performed in 365 patients. SLNs were identified in 98.6% of patients with a mean of 3.7 nodes removed from 1.6 nodal basins per patient. Median follow-up was 8 years. The SLN was positive in 40 (11%) patients. SLN-positive patients had significantly thicker melanomas, higher recurrence (P < .0001), and a significant decrease in overall survival compared with SLN-negative patients (P < .002). Scalp melanoma patients had significantly thicker melanomas and an elevated risk of SLN positivity, recurrence, and death compared with other sites. Seventeen of 365 SLN-negative patients developed regional nodal disease for a false-omission rate of 5.2% and a negative predictive value of a negative SLN to be 94.8%. Risks for false negative-SLN occurrences included thick melanomas and scalp melanomas. SLN biopsy is accurate in head and neck melanoma and provides significant prognostic data. Scalp melanoma patients present with thicker tumors with an increase in SLN positivity and false-negative SLN occurrences.

Abstract 721: Expression of Aurora A and Phospho-Aurora-A is predictive of survival in patients with head and neck cancer

Abstract Introduction: The Aurora kinases represent a family of serine/threonine kinases important in regulating cell cycle progression. Aurora-A is required for centrosome function and mitotic spindle assembly. Aurora-A phosphosphorylation supports the activity of many proteins involved in cell proliferation and survival, including important EGFR effectors such as AKT and RAS. High expression of Aurora A has been shown in patients with breast, lung, gastrointestinal, genitourinary, and gynecological cancers. The Aurora kinases are known to promote tumor formation and progression, which has led investigators to develop multiple inhibitors of Aurora kinases for clinical use. The expression of Aurora-A kinase in head and neck cancers is not well understood. We assessed the overall survival (OS) for a cohort of patients with squamous cell carcinoma of the head and neck (SCCHN) based upon Aurora-A and phospho-Aurora-A kinase expression (reflecting active Aurora-A). We also related this to SCCHN subtype, using p16 expression as a surrogate for human papillomavirus association, because of the recognition that p16 + cancers have far superior prognosis. Methods: Tumor tissue from 89 patients with SCCHN operated on at the Fox Chase Cancer Center was analyzed for Aurora-A and phospho-Aurora-A expression. Aurora kinase expression was determined using AQUATM, with the median values used to distinguish over-expressers. Aurora-A and phospho-Aurora-A expression was correlated with T and N stage and OS, in p16+ versus p16- tumors The p16 status was determined by immunohistochemistry. Results: T stage was inversely related to Aurora-A expression when adjusted for p16 status (Spearman's rho -0.24, p = 0.04). Aurora-A expression was not related to N stage (Spearman's rho -0.03, p = 0.79). OS was 36 months for over-expressers of Aurora-A and 92 months for patients with low levels of Aurora-A expression (HR 1.9, 95% CI 1.05-3.46). 20 patients were positive for p16 by IHC. There was no difference in survival amongst p16 positive patients based on Aurora-A expression (53.3 months vs 57.2 months, p = 0.679). Amongst the 69 p16 negative patients, OS was 93.6 months for patients with low levels of Aurora-A expression and 35.9 months for those with elevated levels of Aurora-A (HR 1.84, 95% CI 0.89-3.79). There was a trend towards improved survival in patients with lower levels of phospho-Aurora-A expression (63.9 vs 57.6 months, p = 0.129). Conclusions: Increased expression of Aurora-A in this cohort of SCCHN patients is associated with a significant decrease in OS. Increased expression of Aurora-A in patients with p16 positive tumors does not seem to impact survival, though the number of patients was small. Aurora-A represents a possible therapeutic target in patients with SCCHN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 721. doi:1538-7445.AM2012-721

Triple-negative breast cancer: the impact of guideline-adherent adjuvant treatment on survival—a retrospective multi-centre cohort study

Triple-negative breast cancer (TNBC) (ER-/PGR-/erb-2-) constitutes an aggressive subtype in breast cancer because it is accompanied by a significant decrease in overall survival (OAS) and recurrence-free survival (RFS) compared with hormone receptor positive breast cancers. This retrospective cohort study investigates the following issues: (1) Is there an impact of guideline-adherent treatment on RFS and OAS in TNBC? (2) Which adjuvant treatment has the most important impact on RFS and OAS in TNBC? This German retrospective multi-centre cohort study included 3,658 patients with primary breast cancer recruited from 2000 to 2005. The definition of guideline adherence was based on the German national S3 guideline for diagnosis and treatment of breast cancer (2004). A total of 371 patients (10.1%) had TNBC. Compared with HR+/erb-2- breast cancer (P = 0.001; HR = 1.75; 95% CI: 1.27-2.40), the recurrence rate of TNBC was significantly higher (P < 0.001; HR = 2.86; 95% CI: 2.17-3.76). Furthermore, the 5-year RFS and OAS was significantly lower in TNBC (RFS: 74.8% [95% CI: 68.8-80.8%] vs. 86.5% [95% CI: 84.6-88.4%] [log-rank P = 0.0001]) (OAS: 75.8% [95% CI: 69.9-81.8%] vs. 86.0% [95% CI: 84.1-87.9%] [log-rank P = 0.0001]). The most important parameters predicting RFS and OAS in TNBC after receiving guideline-conform chemotherapy are guideline-adherent surgery, radiotherapy, nodal status and grading. Overall, 66.8% TNBC were found with one or more (18%) guideline violations, which subsequently impaired OAS and RFS. The most important impact on OAS and RFS in TNBC patients was because of guideline violations (GV) concerning adjuvant radiotherapy and GV concerning adjuvant chemotherapy. Patients with TNBC primarily have a worse prognosis in terms of RFS and OAS than patients of a primarily non-TNBC phenotype. There is a strong association between guideline-adherent adjuvant treatment and improved survival outcome in TNBC. The outcome significantly decreases with the number of guideline violations.

Laparoscopic liver resection – a substantial progress towards multimodal treatment of metastases

Multidisciplinary strategies are commonly used to treat liver metastases of various origins, especially colorectal cancer. Progress in surgical techniques and the use of appropriate devices have opened the fields for a laparoscopic approach to increasingly complex procedures, like liver resection. Patients benefit from shorter hospital stay, less postoperative pain, reduced postoperative morbidity and better cosmetic results. According to a meta-analysis, delaying initiation of adjuvant chemotherapy after curative surgery for stage III colorectal cancer was associated with a statistically significant decrease in overall survival. It is tempting to assume that these results may be assignable to metastatic disease. Therefore, laparoscopic liver resection offers a substantial contribution to multimodal treatment of liver metastases.

Triple-negative breast cancer: The effect of guideline-adherent adjuvant treatment on the cumulative survival—A retrospective multicenter cohort study of 3,658 patients.

1063 Background: Triple negative breast cancer (TNBC) constitutes an aggressive subtype in breast cancer accompanied with a significant decrease in overall survival (OAS) and disease free survival (RFS). This retrospective cohort study investigates the following queries: (1) Is there an impact of guideline adherent treatment on RFS and OAS in TNBC? (2) Which adjuvant treatment has the most important impact on RFS and OAS in TNBC? Methods: This German multi-center [16 participating hospitals all are certified as breast centers] retrospective cohort study included 3658 patients from 2000 until 2005. The definition of guideline adherence was based on the German national S3 guideline (2004). Results: 371(10.1%) were TNBC [median age(years): 60(range 28-97)]. 13.8% premenopausal/ 9.3% postmenopausal of the patients were TNBC. 90.3% of TNBC-patients were intermediate-/high-risk (Nottingham-prognostic index) and 76.5% were GIII. Compared to HR-pos./HER2-neg.-BC as reference, RFS of TNBC was significantly worse (HR=2.86; 95%CI: 2.17-3.76; p<0.001). Furthermore 5 years RFS (OAS) is significantly lower in TNBC vs. non-TNBC [RFS: 74,8% (95%CI:68.8%-80.8%) vs. 86.5%(95%CI:84.6%-88,4%); logrank p<0.001)] (OAS:75.8%(95%CI:69.9%-81.8%) vs. 86.0%(95%CI:84.1%-87.9%); logrank p<0.001)]. The most important parameters predicting RFS or OAS in TNBC are nodal status, grading, guideline adherent surgery, radiotherapy and chemotherapy. Overall 66.9% TNBC had one or more guideline violations, which subsequently impaired RFS and OAS (Ranking of guideline violations with respect to RFS: Radiotherapy (HR=2.92;95%CI(2.24-3.81); p<0.001), chemotherapy(HR=2.16;95%CI(1.70-2.74); p<0.001), initial surgical intervention(HR=2.03;95%CI(1.36-3.04); p=0.001) and lymph node dissection(HR=1.54;95%CI(1.05-2.25); p=0.027). Conclusions: Patients with TNBC have primarily a worse prognosis in terms of RFS and OAS than patients with primarily non-TNBC phenotype. There is a strong association between guideline adherence and RFS/OAS of patients with TNBC. The outcome decreases significantly with the number of guideline violations.

Abstract P4-10-01: Twenty-Five Year Results in the Treatment of Early Breast Carcinoma with Mastectomy Versus Breast Conservation Therapy: The National Cancer Institute Randomized Trial

Abstract Background: Breast conservation therapy (BCT) has become an accepted treatment in women with early stage breast cancer due to multiple randomized trials showing equivalent mortality rates when compared to modified radical mastectomy (MRM). Results of the National Cancer Institute's prospective randomized trial comparing MRM to BCT are now reported at a median follow up of 25.4 years. Methods: Between 1979 and 1987, 237 evaluable patients with biopsy proven clinical Stage I or Stage II primary breast cancer were randomized to receive a MRM or a lumpectomy followed by definitive radiation to the entire breast followed by a boost to the tumor bed. An axillary dissection was performed in both arms. Negative margins were not required. Patients with node positive disease in either arm were treated with adriamycin and cytoxan. The primary endpoints were overall survival and disease-free survival. Results: At a median follow-up of 25.4 years, there was no statistical difference in overall survival between either arm, with 45.7% of patients alive in the MRM group and 38.0% alive in the BCT group (p=0.43). Although disease-free survival was significantly worse in patients randomized to BCT (57% vs 82%, P&amp;lt;0.001), the additional treatment failures in the BCT group were primarily isolated ipsilateral breast tumor recurrences (IBTR's) which were salvaged by MRM. 22.3% of BCT patients experienced an IBTR but those patients had no significant decrease in overall survival. There were no differences in distant metastasis between the groups. Clinical factors associated with a worse prognosis include the presence of nodal disease (HR 2.46, 95% CI 1.71-2.71, P&amp;lt;0.05) and tumor size (HR 1.91, 95% CI 1.346-2.711, P&amp;lt;0.05). Conclusion: The 25 year survival rate among women receiving BCT vs MRM in the National Cancer Institute randomized trial appears to be equivalent and is consistent with findings across multiple trials. In patients receiving BCT there is an increased incidence of IBTR's. Despite a higher risk of local failure in the BCT group, there is no increased risk of distant failure or mortality. The risk of local failure however, should be discussed when counseling patients regarding their treatment options. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-10-01.

Adrenocortical carcinoma: The influence of large vessel extension

The impact of large vessel extension (LVE) as a prognostic factor for adrenocortical carcinoma (ACC) is not fully understood. This study aimed to assess outcome of ACC in the presence and absence of LVE. A retrospective review of 57 patients undergoing curative intent resection for ACC over 10 years is presented comparing those with and without LVE. LVE was defined as vascular wall invasion or intraluminal extension of the neoplasm into the inferior vena cava or renal vein. Preoperative diagnostics, operative details, pathology, overall survival (OS), and recurrence-free survival (RFS) were analyzed. Multivariable regression analysis showed a significant association for decreased survival with Stage III and IV disease and LVE. Patients with LVE had more functional neoplasms, greater preoperative serum hormone levels, and more positive margins than those without LVE. Median OS was 6 years and RFS 3 years. Kaplan-Meier analysis demonstrated a significant decrease in OS and RFS with LVE. Median OS with and without LVE was 18 vs 111 months and median RFS was 11 vs 64 months. Three-year OS with and without LVE were 29% vs 93% and 3 year RFS was 15% vs 67%. In addition to systemic and lymph node metastases, LVE is associated with poorer OS and RFS.

The impact of preoperative erectile dysfunction on survival after radical prostatectomy

Erectile dysfunction (ED) and cardiovascular disease (CVD) share etiology and pathophysiology. The underlying pathology for preoperative ED may adversely affect survival following radical prostatectomy (RP). We examined the association between preoperative ED and survival following RP. Between 1983 and 2000, a single surgeon performed RP on 2511 men, with preoperative ED (ED group, n= 231, 9.2%) or without ED (No ED group, n= 2280, 90.8%). We retrospectively analysed their CVD-specific survival (CVDSS), prostate cancer-specific survival (PCSS), non-PCSS (NPCSS) and overall survival (OS) from time of surgery. With median follow-up of 13 years after RP, 449 men (18%) died (140 from prostate cancer, 309 from other causes). Kaplan-Meier analyses demonstrated significant differences in CVDSS (P < 0.001), NPCSS (P < 0.001) and OS (P < 0.001), but not in PCSS (P= 0.12), between the ED group vs No ED group. In univariate proportional hazards analyses, preoperative ED was associated with a significant decrease in OS, hazard ratio (HR), 1.71 (95% CI, 1.34-2.23), P < 0.001. However, in multivariable analyses, the association of ED with survival became non-significant (HR, 1.25 (95% CI, 0.97-1.66), P= 0.111) after adjusting for other prognostic factors, such as age, preoperative prostate-specific antigen (PSA) level, Gleason score, pathologic stage, body mass index and Charlson Comorbidity Index. Preoperative ED is associated with decreased overall survival and survival from causes other than prostate cancer following RP. However, preoperative ED was not an independent predictor of overall survival after adjusting for other predictors of survival. Urologists should carefully assess pretreatment ED status to enhance appropriate treatment recommendation for men with prostate cancer.

Diabetes, obesity, and survival in a large cohort of early-stage breast cancer patients.

1503 Background: Diabetes and obesity have risen to epidemic proportions globally. Both conditions, which share overlapping etiologies, are associated with worse breast cancer (BC) outcomes in some but not all studies. To address these inconsistencies, we examined the relationship between diabetes, body mass index (BMI), and survival in a large cohort of early-stage BC patients. Methods: We retrospectively studied patients treated at M.D. Anderson from 1996-2005. For comparison, the patients were divided into diabetic (DM) and non-diabetic (ND) groups and into 3 BMI classes: normal or underweight (N, BMI < 25), overweight (Ov, BMI 25-30), and obese (Ob, BMI ≥ 30). Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier product and compared among groups via the log-rank test. Multivariate analysis was conducted via Cox proportional hazards models. Results: There were 6,106 patients. Median age was 52 (range 19-91). 93% had stage I-II disease, 7% stage III. 77% were hormone-receptor (HR) positive, 18% HER2-positive. 476 patients had DM (7.8%). Patients distributed into BMI classes as follows: N 40%, Ov 31%, Ob 29%. By chi-squared tests, diabetes was associated with increasing age, stage, and BMI; and higher BMI was associated with increasing age, stage, grade, and diabetes. At a median follow-up of 5.4 years, there were 488 recurrences and 921 deaths. RFS and OS were significantly worse in DM vs. ND patients (p < 0.001 and p < 0.001, respectively), and in the high vs. low BMI groups (p < 0.001 and p > 0.002, respectively). After adjustment for DM status, BMI, age, stage, grade, and HR status, DM patients had decreased RFS (hazard ratio [hr], 1.22; 95% CI > 0.99,1.50; p > 0.065) and OS (hr, 1.40; 1.11,1.78; p > 0.005). In the same model, Ob vs N patients had decreased RFS (hr, 1.15; 0.99,1.33; p > 0.065) and OS (hr, 1.26; 1.06,1.50; p > 0.010). Conclusions: In this large cohort of early-stage BC patients, diabetes and obesity each correlated with a significant decrease in OS, as well as a borderline significant decrease in RFS, after adjustment for DM status, BMI, age, stage, grade, and HR status. Further studies to discover the reasons for these poorer outcomes in diabetic and obese breast cancer patients are underway. No significant financial relationships to disclose.

1488 SURGICAL TREATMENT OF BILATERAL SYNCHRONOUS KIDNEY TUMORS: LONG-TERM FUNCTIONAL AND ONCOLOGICAL OUTCOMES

You have accessJournal of UrologyKidney Cancer: Localized V1 Apr 20101488 SURGICAL TREATMENT OF BILATERAL SYNCHRONOUS KIDNEY TUMORS: LONG-TERM FUNCTIONAL AND ONCOLOGICAL OUTCOMES Matthew Simmons, Ricardo Brandina, Adrian Hernandez, and Inderbir Gill Matthew SimmonsMatthew Simmons Cleveland, OH More articles by this author , Ricardo BrandinaRicardo Brandina Los Angeles, CA More articles by this author , Adrian HernandezAdrian Hernandez Cleveland, OH More articles by this author , and Inderbir GillInderbir Gill Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1204AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To assess renal functional and oncologic outcomes after sequential radical (RN) and/or partial nephrectomy (PN) in patients with bilateral synchronous kidneys tumors. METHODS Patients treated from June 1994-July 2008 were retrospectively analyzed. Study endpoints included MDRD2 eGFR <60ml/min/1.73m2, overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). RESULTS 220 patients were treated with sequential PN (PN-PN; n=134), PN followed by RN (PN-RN; n=60), or RN followed by PN (RN-PN; n=26). Postoperatively, cumulative eGFR decreased by 28% in the PN-PN group compared to decreases of 50% and 53% in the PN-RN and RN-PN groups, respectively (p<0.001). Tumor size <4cm and preoperative chronic kidney disease (CKD) stage ≤II correlated with favorable functional outcomes (i.e. eGFR ≥30 ml/min/1.73m2). OS for the entire cohort was 86% at 5y and 71% at 10y, which decreased to 73% at 5y, 51% at 10y for tumors >7cm. After bilateral surgery an eGFR ≤60ml/min/1.73m2 was associated with a significant decrease in OS: 5y and 10y OS was 96% and 93% for patients with CKD stage I-II vs. 80% and 70% in patients with CKD stage ≥III (p=0.02). CSS was 96% at 5y and 96% at 10y. RFS was 73% at 5y and 44% at 10y. CONCLUSIONS In patients with bilateral synchronous kidneys tumors, tumor size >4cm and pre-operative CKD stage ≥III were risk factors for CKD stage progression. Post-operative stage ≥III CKD was strongly associated with decreased 5y and 10y OS. Nephron-sparing surgery should be compulsory for all amenable kidney masses given the negative impact of renal functional decline on overall survival. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e573-e574 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Matthew Simmons Cleveland, OH More articles by this author Ricardo Brandina Los Angeles, CA More articles by this author Adrian Hernandez Cleveland, OH More articles by this author Inderbir Gill Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Impact of pretherapy body mass index on prognosis of nasopharyngeal carcinoma

Given the limited information regarding the impact of BMI on treatment outcomes for nasopharyngeal carcinoma, we sought to examine the relationship between body mass index (BMI) and cancer control after radiotherapy. We compared clinic outcome information across BMI groups from 1,489 patients treated with radiotherapy between 1990 and 2003. Multivariate analysis was used to determine if BMI significantly predicted adverse recurrence. In comparison with normal group, there were statistical difference in age, T staging, N staging, and clinical staging (P<0.0001). In survival analysis, in comparison with under-weight group, we could found the hazard ratio was less than one, in the risk of death, cancer recurrence and local recurrence. Meanwhile, the hazard ratio gradually declined when the body weight increased. In univariate survival analysis, under-weight patient had a significant decrease in overall survival,(P<0.0001). When Cox regression model was applied to multivariate analysis, we could found age, T staging, N staging, and BMI grades could be a significant independent prognosis factors(P<0.05). Under-weight patients had a significant decrease in overall survival rate, distant metastasis failure-free survival, and local relapse-free survival. Pretherapy BMI grades could be a significant independent prognosis factors.

Impact of number of resected and involved lymph nodes (LN) at the time of surgical resection on the survival of non-small cell lung cancer (NSCLC)

7514 Background: Total number of lymph-nodes has recently proven prognostic in early breast and colorectal cancer. In this study we retrospectively evaluated the prognostic impact of the number of resected and involved lymph-nodes on the survival of stage I-III NSCLC. Methods: A series of 928 consecutive NSCLC pts who underwent complete lobectomy, bilobectomy or pneumonectomy with lymph-nodes dissection from 1/2000 to 11/2007 at Tokyo Medical University was eligible. Log rank and Cox proportional hazard model was used to estimate survival rates and relative risks. Results: Demographics are as follows: median age: 65.0 (22–87yrs), sex: 547 males and 381 females, median follow-up time: 2.5 yrs, clinical stage: 765 stage I, 84 stage II and 76 stage III, histology: 684 adenocarcinoma, 182 squamous cell carcinoma, and 62 others, operation: 870 lobectomy, 42 bilobectomy and 16 pneumonectomy, mean number of resected LN: 15 (1–49), mean number of involved LN: 0.9 (0–22). We observed a statistically significant increasing trend in overall survival (OS) between 0–3 and 4 and more of number of involved LN (P&lt;0.001). Although a significant increasing in OS of 0–9 of number of resected LN cases compared with 10 and more was observed in all stages (P=0.024), no significant differentiation was observed in clinical stage I cases. Conclusions: This data suggests that there is a significant decrease in OS with 10 and more number of resected LN examined at surgery in NSCLC pts. However, there is no significant different in stage I pts, which implies that selected LN sampling is enough in clinical stage I cases. Further study such as LN dissection vs LN sampling in clinical stage I will be needed. No significant financial relationships to disclose.

Methylation of Protocadherin 10, a Novel Tumor Suppressor, Is Associated With Poor Prognosis in Patients With Gastric Cancer

By using methylation-sensitive representational difference analysis, we identified protocadherin 10 (PCDH10), a gene that encodes a protocadherin and is silenced in a tumor-specific manner. We analyzed its epigenetic inactivation, biological effects, and prognostic significance in gastric cancer. Methylation status was evaluated by combined bisulfite restriction analysis and bisulfite sequencing. The effects of PCDH10 re-expression were determined in growth, apoptosis, proliferation, and invasion assays. PCDH10 target genes were identified by complementary DNA microarray analysis. PCDH10 was silenced or down-regulated in 94% (16 of 17) of gastric cancer cell lines; expression levels were restored by exposure to demethylating agents. Re-expression of PCDH10 in MKN45 gastric cancer cells reduced colony formation in vitro and tumor growth in mice; it also inhibited cell proliferation (P < .01), induced cell apoptosis (P < .001), and repressed cell invasion (P < .05), up-regulating the pro-apoptosis genes Fas, Caspase 8, Jun, and CDKN1A; the antiproliferation gene FGFR; and the anti-invasion gene HTATIP2. PCDH10 methylation was detected in 82% (85 of 104) of gastric tumors compared with 37% (38 of 104) of paired nontumor tissues (P < .0001). In the latter, PCDH10 methylation was higher in precancerous lesions (27 of 45; 60%) than in chronic gastritis samples (11 of 59; 19%) (P < .0001). After a median follow-up period of 16.8 months, multivariate analysis revealed that patients with PCDH10 methylation in adjacent nontumor areas had a significant decrease in overall survival. Kaplan-Meier survival curves showed that PCDH10 methylation was associated significantly with shortened survival in stage I-III gastric cancer patients. PCDH10 is a gastric tumor suppressor; its methylation at early stages of gastric carcinogenesis is an independent prognostic factor.

The Significance of EphB4 and EphrinB2 Expression and Survival in Head and Neck Squamous Cell Carcinoma

To examine the expression of EphB4 and EphrinB2 in tumor tissue and surrounding normal tissue in patients with head and neck squamous cell carcinoma (HNSCC) and to evaluate its association with overall patient survival. Retrospective study. University of Southern California-University Hospital, the Los Angeles County and University of Southern California Medical Center, and the Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles. Fifty patients, 8 with early-stage (stages I and II) and 42 with advanced-stage (stages III and IV) HNSCC, were enrolled into this study. Staging was based on the system of the American Joint Committee on Cancer. EphB4 and EphrinB2 expression was evaluated by Western blot analysis. Overall survival in patients was then compared with EphB4 and EphrinB2 expression. EphB4 and EphrinB2 expression was detected in all normal and tumor samples in patients with HNSCC, with the magnitude of EphB4 overexpression greater than that of EphrinB2 expression compared with normal tissue. There was a statistically significant decrease in overall survival among patients with elevated EphB4 and EphrinB2 expression (P < .001). EphB4 and EphrinB2 overexpression is associated with poor overall survival in patients with HNSCC. Our results are the first to demonstrate an association between decreased survival and elevated expression of the receptor tyrosine kinase EphB4 and its ligand EphrinB2, suggesting that EphB4 and EphrinB2 may be used as biomarkers to predict prognosis and as targets in future HNSCC therapies.

Gefitinib Maintenance in Stage III Non–Small-Cell Lung Cancer

■■■ TOTHEEDITOR:Kellyetal 1 recentlyreportedinJournalofClinical Oncology that gefitinib maintenance after chemoradiotherapy and consolidation chemotherapy was associated with a significant decreaseinoverallsurvival(butonlyaslightdecreaseinprogression-free survival)comparedwithplaceboinstageIIInon‐small-celllungcancer(NSCLC).Theyofferpotentialexplanationsforthis,asdoKeedyet al 2 in an accompanying editorial. We would like to suggest an additional possible reason for this outcome. The flattening of the NSCLC dose-response curve at higher chemotherapy doses suggests that the most important factor in chemotherapy resistance is deficiency of factors required for efficacy. 3 Platinum-resistant cell lines may have decreased expression of a range of transporters that are important for cellular uptake of chemotherapy and nutrients. 4 In patients with a variety of resistant tumor types, we assessed tumor expression (by immunohistochemistry) of the copper transporter CTR1, which is also important in platinum uptake. CTR1 expression was significantly lower in tumors of patients who had received either chemotherapy or targeted therapies withintheprevious3monthsthanintumorsofpatientswithalonger interval off therapy. 5 The correlation with time from last chemotherapy or targeted therapy was stronger than the correlation with time from last cytotoxic therapy alone. This leads us to hypothesize that either chemotherapy or targeted therapy may result in a broad reduction in membrane transporters and that this, in turn, may generate broad cross resistance. This could, in part, explain why adding tyrosine kinase inhibitors to chemotherapy did not improve outcome in chemotherapy-naive advanced NSCLC patients 6 and might also predict that monoclonal antibodies (that do not require uptake across membranes) might add to chemotherapy even if small molecules did not. If correct, this would also predict that most other currentlyavailablesmallmoleculestargetingtumorcellswilladdlittle

Clinical significance of the metastatic lymph-node ratio in patients with D2 gastrectomies for gastric cancer

The Union Internationale Contre le Cancer/Tumor, Node, Metastasis (UICC/TNM, 5th edition) Classification established the number of the lymph nodes with metastatic deposits as the determinant factor for nodal category (N category) in patients with gastric cancer. This may suggest that N category could be influenced by the degree to which specimens are pathologically examined and the extension of lymph node surgical dissection. To correct this problem, the Lymph node ratio (LNR), which is the number of positive nodes divided by total number harvested, has been proposed. This study aims to investigate whether the LNR is a better prognostic factor as compared with N category (5th edition) proposed by the UICC in patients with gastric cancer. A retrospective review of a prospectively collected database of 63 patients with gastric cancer who underwent curative D2 gastrectomy between 2003 and 2007 was performed to determine the effect of the LNR on disease-free survival (DFS) and overall survival (OS). Prognostic factors were identified by univariate and multivariate analyses. Survival curves were constructed using the Kaplan-Meier method. The LNR was divided into four categories using the hazard ratio (HR). LNR categories (LNR 0= 0%; LNR 1= 1%–9%; LNR 2= 10%–25%; LNR 3= >25%) were determined by the best cut-off approach. After a median follow-up of 25.1 months (range, 4–32 months), analyzing the survival time comparing the lymph node ratio categories against the N categories (5th edition) demonstrated that the ratio stands out as the best prognostic factor. The implementation of proposed LNR nodal categories led to the identification of groups of patients prognostically more homogeneous than those classified by the UICC proposed nodal categories. Overall survival data according to LNR proposed nodal categories showed a statistically significant decrease in overall survival and disease free survival with increasing scores, which was more statistically significant than that observed with UICC proposed nodal categories (N categories, 5th edition), the LNR also discriminates different prognostic categories among patients with N1 and N2 lymph node involvement. In conclusion, LNR is a simple and reproducible prognostic tool that can stratify patients with gastric cancer. LNR gave a more accurate prognostic information from nodal involvement than the current N category of the TNM (5th edition). These data may represent the rational for improving the prognostic power of current UICC TNM staging system and ultimately the selection of patients who may most benefit from adjuvant treatments.