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PubMed2005

Cyclin E expression in breast cancer: predicting germline BRCA1 mutations, prognosis and response to treatment.

BACKGROUND: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, p27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. PATIENTS AND METHODS: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(Kip1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. RESULTS: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P <0.001] and low p27(Kip1) protein levels (OR 2.8; P=0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P=0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P <0.001] and low p27(Kip1) protein levels (RR 2.3; P=0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P=0.002). CONCLUSIONS: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.

Adult↗
PubMed2003

Thymidylate synthase expression in advanced colorectal cancer predicts for response to raltitrexed.

PURPOSE: The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS) and other genes for response to raltitrexed (RTX). EXPERIMENTAL DESIGN: Twenty-five patients with metastatic colorectal cancer received RTX 3 mg/m(2) 3-weekly. Pretreatment tumor biopsies were analyzed for TS, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), folylpolyglutamate synthetase, and reduced folate carrier mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody. RESULTS: Twenty patients were evaluable for response and gene expression. Six of 20 (30%) achieved a partial response. Median TS/beta-actin was 5.7 x 10(3) (range, 2.2-42 x 10(3)). Median TS/beta-actin was 3.7 x 10(3) in responding patients and 6.1 x 10(3) in nonresponders (P = 0.048). Five of 6 patients with TS/beta-actin </=4.1 x 10(3) and 1 of 14 with higher values responded (P = 0.002). Overall survival was 21.7 months in patients with TS/beta-actin </=4.1 x 10(3) and 5.7 months in patients with higher values (P = 0.013). No correlations were seen between expression of TP, DPD, reduced folate carrier, or folylpolyglutamate synthetase mRNA and response or survival. Weak TS staining was seen in 10 of 21 tumors evaluable for immunohistochemistry, including 5 responders All 4 of the patients with both weak staining and TS/beta-actin </=4.1 x 10(3) responded. CONCLUSIONS: High TS mRNA expression predicts nonresponse to RTX. By contrast with 5-fluorouracil, high levels of TP and DPD mRNA are not associated with RTX resistance. Limited genomic fingerprinting could optimize single-agent therapy, allowing combinations to be reserved for high TS-expressing patients or for treatment failures, with potential reductions in toxicity and cost.

Antimetabolites, Antineoplastic↗
PubMed2007

Discovering biomarkers from gene expression data for predicting cancer subgroups using neural networks and relational fuzzy clustering.

BACKGROUND: The four heterogeneous childhood cancers, neuroblastoma, non-Hodgkin lymphoma, rhabdomyosarcoma, and Ewing sarcoma present a similar histology of small round blue cell tumor (SRBCT) and thus often leads to misdiagnosis. Identification of biomarkers for distinguishing these cancers is a well studied problem. Existing methods typically evaluate each gene separately and do not take into account the nonlinear interaction between genes and the tools that are used to design the diagnostic prediction system. Consequently, more genes are usually identified as necessary for prediction. We propose a general scheme for finding a small set of biomarkers to design a diagnostic system for accurate classification of the cancer subgroups. We use multilayer networks with online gene selection ability and relational fuzzy clustering to identify a small set of biomarkers for accurate classification of the training and blind test cases of a well studied data set. RESULTS: Our method discerned just seven biomarkers that precisely categorized the four subgroups of cancer both in training and blind samples. For the same problem, others suggested 19-94 genes. These seven biomarkers include three novel genes (NAB2, LSP1 and EHD1 - not identified by others) with distinct class-specific signatures and important role in cancer biology, including cellular proliferation, transendothelial migration and trafficking of MHC class antigens. Interestingly, NAB2 is downregulated in other tumors including Non-Hodgkin lymphoma and Neuroblastoma but we observed moderate to high upregulation in a few cases of Ewing sarcoma and Rabhdomyosarcoma, suggesting that NAB2 might be mutated in these tumors. These genes can discover the subgroups correctly with unsupervised learning, can differentiate non-SRBCT samples and they perform equally well with other machine learning tools including support vector machines. These biomarkers lead to four simple human interpretable rules for the diagnostic task. CONCLUSION: Although the proposed method is tested on a SRBCT data set, it is quite general and can be applied to other cancer data sets. Our scheme takes into account the interaction between genes as well as that between genes and the tool and thus is able find a very small set and can discover novel genes. Our findings suggest the possibility of developing specialized microarray chips or use of real-time qPCR assays or antibody based methods such as ELISA and western blot analysis for an easy and low cost diagnosis of the subgroups.

Biomarkers, Tumor↗
PubMed1992

[Postoperative infection with methicillin-resistant Staphylococcus aureus and its control measures in patients with esophageal cancer--prediction of high risk patients].

Whether or not compromised host defense prior to surgical treatment is related to development of infection with methicillin-resistant staphylococcus aureus (MRSA) following major surgery was examined. Of 22 patients undergoing esophagectomy for cancer between 1989 and 1990, 5 were free from MRSA colonization and infection (group I) while 8 had MRSA colonization without infection (group II) and 9 had MRSA infection (group III). Levels of neutrophil cytocidal functions, complements, immunoglobulins and cell-mediated immunity were not significantly different among these three groups. The mean of anti pneumococcal polysaccharide (PPS)-IgG was significantly lower in group III than in group I (p < 0.05) and tended to be lower than in group II (P = 0.08). All infected patients showed a titer < 600 EU while all but one non-infected patient did so > 600 EU. Serum IgG2 levels positively correlated with anti-PSS IgG levels. Thus, we concluded that a preoperative evaluation of antibody response against polysaccharides and serum IgG2 levels can serve to predict development of MRSA-related infection following esophageal surgery.

Esophageal Neoplasms↗
PubMed1999

Prostate cancer: prediction of extracapsular extension with endorectal MR imaging and three-dimensional proton MR spectroscopic imaging.

PURPOSE: To determine if the addition of three-dimensional (3D) proton magnetic resonance (MR) spectroscopic imaging to endorectal MR imaging helps diagnose extracapsular extension (ECE) of prostate cancer. MATERIALS AND METHODS: Endorectal MR imaging and 3D MR spectroscopic imaging were performed in 53 patients with prostate cancer before radical prostatectomy. MR imaging studies were evaluated by two independent readers unaware of histopathologic findings. The presence of ECE was graded on a five-point scale. At 3D MR spectroscopic imaging, cancer was diagnosed if the ratio of choline plus creatine to citrate was 2 or more SDs above normal. The accuracy of MR imaging alone was compared with that of combined MR imaging and 3D MR spectroscopic imaging, with use of the step-section histopathologic results as the standard of reference. RESULTS: For the less experienced reader, the addition of 3D MR spectroscopic imaging to MR imaging significantly improved accuracy (area under the receiver operating characteristic curve [Az] = 0.75 vs Az = 0.62, P < .05). For the more experienced reader, the addition improved accuracy but not significantly (Az = 0.86 vs Az = 0.78). The addition also reduced interobserver variability (Az = 0.86 vs Az = 0.75). CONCLUSION: The addition of 3D MR spectroscopic imaging to MR imaging improves accuracy for less experienced readers and reduces interobserver variability in the diagnosis of ECE of prostate cancer.

Cross-Sectional Studies↗
PubMed2001

Low proliferative rate of invasive node-negative breast cancer predicts for a favorable outcome: a prospective evaluation of 669 patients.

This study was designed to compare outcome in terms of disease-free survival (DFS) in women with histologically negative axillary lymph nodes and documented low proliferative rate cancer to other well-defined prognostic factors including type of adjuvant treatment. Between 1988 and 1998, we studied 669 patients with invasive node-negative breast cancer up to 5 cm in size and low proliferative rate measured by flow cytometry to determine S-phase fraction (SPF) or by histochemistry (Ki67/MIB1). At a median follow-up of 53 months, 5-year DFS for the entire group was 94% and did not differ significantly by type of systemic adjuvant treatment: none (133 patients, 95% DFS), tamoxifen (441 patients, 94% DFS), or chemotherapy with doxorubicin and cyclophosphamide (95 patients, 92% DFS). In a multivariate prognostic factor analysis, only tumor size was significant; 5-year DFS was 96% for T1N0 cancer versus 89% for T2N0 cancer (P = 0.01). We have prospectively confirmed that a low rate of proliferation as measured by SPF or MIB1 determination confers an excellent prognosis in invasive node-negative breast cancer up to 5 cm in size, regardless of adjuvant treatment.

Adult↗
PubMed2005

Can pathological complete response in the primary tumour following pre-operative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for sterilisation of pelvic lymph nodes, a low risk of local recurrence and the appropriateness of local excision?

INTRODUCTION: Local excision is considered inappropriate treatment for T3-T4 rectal adenocarcinomas, as it cannot provide prognostic information regarding lymph node involvement and has a high risk of pelvic recurrence. Preoperative chemoradiation (CRT) studies in rectal cancer suggest that a pathological complete response (pCR) in the primary tumour provides an excellent long-term outcome. If downstaging to stage pT0 predicts a tumour response within the perirectal and pelvic lymph nodes, this may allow local excision to be performed without increased risk of pelvic recurrence. This retrospective study aimed to determine the incidence of involved lymph nodes following pCR (ypT0) after preoperative CRT and total mesorectal excision. METHOD: The outcome and treatment details of 211 patients undergoing preoperative CRT for clinically staged T3-T4 unresectable rectal adenocarcinomas between 1993 and 2003 at Mount Vernon Hospital were reviewed. RESULTS: Data were recorded from the 143 patients who completed treatment with a median follow-up of 25 months. Twenty-three patients (18%) were found to have had a pCR. Four out of 23 patients (17%) had involved lymph nodes. No pelvic recurrences developed after a ypCR. Overall survival was similar for patients with ypT0 or residual tumour. CONCLUSION: Pathological complete response in the primary tumour failed to predict a response in the perirectal lymph nodes (p=0.08). The degree of response predicted a lymph node response (p=0.02). The detection of ypCR identified patients with a low rate of pelvic recurrence. This may in the future allow selection of patients for whom local excision can be performed without a higher risk of local relapse.

Adenocarcinoma↗
PubMed1999

Combination and multivariate analysis of PSA-based parameters for prostate cancer prediction.

The aim of this study was to evaluate the ability of prostate-specific antigen (PSA)-based parameters including PSA density (PSAD), PSAD of the transition zone (PSA-TZ), percent free PSA, PSA velocity, and their combination to enhance the specificity of PSA for prostate cancer detection in men with serum PSA levels between 4 and 10 ng/mL. We evaluated prospectively 559 consecutive men referred for early detection of prostate cancer who had serum PSA levels between 4 and 10 ng/mL. All men underwent prostatic ultrasonography and sextant biopsy with two additional TZ biopsies. In all cases, if first biopsies were negative an additional set of biopsies was obtained within 6 weeks. The ability of PSAD, PSA-TZ, PSA velocity, percent free PSA, and their combination to improve the detection of prostate cancer was evaluated by univariate and multivariate analysis as well as receiver operating characteristic (ROC) curves. In this prospective study of 559 patients, 217 had prostate cancer and 342 had histologically confirmed benign prostatic hyperplasia. Multivariate analysis and ROC curves showed that PSA-TZ and percent free PSA (f/t PSA) were the most powerful and highly significant predictors of prostate cancer. Areas under the ROC curve (AUC) for PSA-TZ and percent free PSA were 0.827 and 0.778, respectively (p = .01). Combination of f/t PSA with PSA-TZ (AUC = 88.1%) significantly increased AUC as compared to each of the other parameters alone as well as their combination (p = .02). The next best combinations were PSA-TZ + PSAD, PSA-TZ + PSA, and f/t PSA + PSA. PSA-TZ followed by f/t PSA and PSAD were the most powerful predictors of prostate cancer in referred patients with a serum PSA between 4 and 10 ng/mL. f/t PSA + PSA-TZ was the most effective combination. When volume-independent PSA parameters were taken into consideration, f/t PSA + PSA clearly outperformed the other options.

Aged↗
PubMed2005

The maximum standardized uptake values on positron emission tomography of a non-small cell lung cancer predict stage, recurrence, and survival.

OBJECTIVE: We sought to assess whether the standard uptake value of a pulmonary nodule is an independent predictor of biologic aggressiveness. METHODS: This is a retrospective review of a prospective database of patients with non-small cell lung cancer. Patients had dedicated positron emission tomography scanning with F-18 fluorodeoxyglucose, with the maximum standard uptake value measured. All suspicious nodal and systemic locations on computed tomographic and positron emission tomographic scanning underwent biopsy, and when indicated, resection with complete lymphadenectomy was performed. RESULTS: There were 315 patients. Multivariate analysis showed patients with a high maximum standard uptake value (>/=10) were more likely to have poorly differentiated tumors (risk ratio, 1.5; P = .005) and advanced stage (risk ratio, 1.9; P = .010) and were less likely to have their disease completely resected (risk ratio, 3.7; P = .004). Maximum standard uptake value was the best predictor of disease-free survival (hazard ratio, 2.5; P = .039) and survival (hazard ratio, 2.8; P = .001). Stage-specific analysis showed that patients with stage IB and stage II disease with a maximum standard uptake value of greater than the median for their respective stages had a lower disease-free survival at 4 years ( P = .005 and .044). The actual 4-year survival for patients with stage Ib non-small cell lung cancer was 80% versus 66% ( P = .048), for stage II disease it was 64% versus 32% ( P = .028), and for stage IIIa disease it was 64% versus 16% ( P = .012) for the low and high maximum standard uptake value groups, respectively. CONCLUSIONS: The maximum standard uptake value of a non-small cell lung cancer nodule on dedicated positron emission tomography is an independent predictor of stage and tumor characteristics. It is a more powerful independent predictor than the TNM stage for recurrence and survival for patients with early-stage resected cancer. This information might help guide treatment strategies.

Adult↗
PubMed1998

Loss of p120ctn in human colorectal cancer predicts metastasis and poor survival.

The p120ctn protein (formerly p120CAS) is an armadillo family member that associates directly with the cytoplasmic tail of E-cadherin and participates in the junctional complex responsible for cell-cell adhesion. Since reduced cell-cell adhesion is associated with metastasis in colorectal cancer and other neoplasms, we hypothesize that reduced expression of p120ctn may be related to metastasis in colorectal tumors. Here we describe a study of p120ctn expression in 44 primary human colorectal adenocarcinomas. As detected by immunohistochemical methods, we find altered p120ctn staining patterns in 86% of the cases. Regional complete loss of expression is seen in 18% of the cases, and it correlates with high stage disease and nodal metastasis as well as decreased survival. Although this is a preliminary study, it suggests that downregulation of p120ctn in colon cancer may be associated with metastasis and poor clinical outcome.

Adult↗
PubMed1996

Simultaneous detection of genetic and immunological markers in non-small cell lung cancer: prediction of metastatic potential of tumor.

The restriction fragment length polymorphism of c-Ha-ras-1 and L-myc genes and expression of cell surface effector molecules were studied to determine their potential utility as markers for assessing risk of metastasis in 84 lung cancer patients. We performed a comparative study of primary lung carcinomas, metastases, adjacent tissues and blood samples in a group of patients with lung cancer of different histological types, grade of differentiation and presence of regional and distant metastasis. No differences in the frequency of c-Ha-ras-1 rare alleles were found between lung cancer patients and unaffected controls. The detection of common a4-allele seems to be associated with metastasis and low differentiation of lung carcinomas. S-allele of L-myc was observed in 82.6% of patients with metastatic lesions. Homozygosity of L-allele patients was not evidence for distant metastasis and only 17.4% of these patients have metastatic lesions of the lymph nodes. The expression of HLA class I and receptor of transferrin (TrRec) were tested immunohistochemically in the same patients. In the group of squamous cell carcinomas with regional metastases the expression of HLA class I antigens was decreased [7/21 (33.3%) positive staining tumors versus 13/20 (65.0%) in the group without metastases]. The opposite situation was observed for TrRec. The data of restriction fragment length polymorphism of oncogenes and expression of two cell surface effector molecules, identified in the same patients, were combined. The registration of more than one poor marker, tested in individuals with squamous cell carcinoma, closely correlated with dissemination and advanced stage of the disease. Nearly 90% (20/22) of patients with well and moderately differentiated tumor revealed metastatic lesions versus 6.6% (1/15) of patients with manifestation of a single poor marker. Finally, proposals could be made for the development of a risk group that incorporates both clinical and molecular biology features in the prediction of metastasis.

Adenocarcinoma↗
PubMed2002

Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients.

Akt/PKB is a serine/threonine protein kinase that regulates cell cycle progression, apoptosis and growth factor mediated cell survival in association with tyrosine kinase receptors. The protein is a downstream effector of erbB-2 with implications in breast cancer progression and drug resistance in vitro. We aimed to examine the role of Akt-1 in breast cancer patients, by determining whether the expression (Akt-1) and/or activation (pAkt) were related to prognostic markers and survival. The expression of erbB-2, heregulin beta 1 and Bcl-2 was also assessed by flow cytometry or immunohistochemistry. This study comprised 93 patients, aged <50 who were treated with tamoxifen and/or goserelin. We found that pAkt was associated with lower S-phase fraction (P=0.001) and the presence of heregulin beta 1-expressing stromal cells (P=0.017). Neither Akt-1 nor pAkt was related with other factors. Tumour cells-derived heregulin beta 1 was found mainly in oestrogen receptor negative (P=0.026) and node negative (P=0.005) cases. Survival analysis revealed that pAkt positive patients were more prone to relapse with distant metastasis, independently of S-phase fraction and nodal status (multivariate analysis; P=0.004). The results suggest that activation of Akt may have prognostic relevance in breast cancer.

Adult↗
PubMed2001

Abnormal expression of 17beta-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence.

The 17beta-hydroxysteroid dehydrogenase (17beta-HSD) enzymes are involved in the interconversion of biologically active and inactive sex steroids and are considered to play a critical role in the in situ metabolism of estrogen, especially in estrogen-dependent breast cancer. The gene encoding 17beta-HSD type 2 is located at 16q24.1-2, and earlier studies have shown that allelic loss in this region is an early and frequent event in breast cancer progression. Recurrence of hormone-dependent breast cancer frequently occurs several years after the primary treatment. The aim of this study was to investigate whether the expression of 17beta-HSD types 1 and 2 differs in tumors from patients with late relapses (>5 years) compared with controls without recurrence after long-term follow-up. Using real-time reverse transcription-PCR, we found that the normal mammary gland expressed both 17beta-HSD types 1 and 2, whereas the tumors frequently lacked detectable levels of type 2. Only 10% of the estrogen receptor-positive tumors expressed type 2, whereas 31% of the ER-negative tumors did so (P = 0.031). In a case-control series of 84 patients, a high level of 17beta-HSD type 1 indicated increased risk to develop late relapse of breast cancer (odds ratio, 3.0; 95% confidence interval, 1.0-12.6; P = 0.041), whereas retained expression of type 2 indicated decreased risk (odds ratio, 0.25; 95% confidence interval, 0.05-1.2; P = 0.050). In multivariate analysis of the estrogen receptor-positive patients, the absence of 17beta-HSD type 2 combined with a high expression of type 1 showed prognostic significance (P = 0.016) in addition to DNA aneuploidy (P = 0.0058), whereas progesterone receptor status did not (P = 0.71). These findings suggest that abnormal expression of 17beta-HSD isoforms has prognostic significance in breast cancer and that altered expression of these enzymes may have importance in breast cancer progression.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

External validation of the Mayo Clinic Stage, Size, Grade and Necrosis (SSIGN) score to predict cancer specific survival using a European series of conventional renal cell carcinoma.

PURPOSE: We validated the Mayo Clinic SSIGN score in an independent European sample of patients who were surgically treated for conventional RCC. MATERIALS AND METHODS: In our kidney cancer database we identified 388 patients who were treated with radical or partial nephrectomy for conventional RCC between 1986 and 2000. Associations of the pathological features studied with death from RCC were evaluated using the log rank test and Cox proportional hazards regression model. The predictive ability of competing models was evaluated using the c index. RESULTS: Median followup in the 290 patients who were alive at last followup was 5 years (range 5 months to 17 years). The estimated cancer specific survival rate 5 years following surgery was 81.3%. All features that comprise the SSIGN score except tumor size were significantly associated with death from RCC in a multivariate setting, resulting in a c index of 0.90. The median SSIGN score in the 388 patients studied was 3 (range 0 to 15). The c index in a model containing the clear cell SSIGN score was 0.88. Five-year cancer specific survival rates in patients with a score of 0 to 2, 3 to 4, 5 to 6, 7 to 9 and 10 or more were 100.0%, 90.5%, 63.6%, 46.8% and 0%, respectively. CONCLUSIONS: We provide the first external validation of the Mayo Clinic SSIGN score for conventional RCC. This simple algorithm resulted in a high degree of prognostic accuracy.

Adult↗
PubMed2002

Coexpression of parathyroid hormone related protein and its receptor in early breast cancer predicts poor patient survival.

PURPOSE: Parathyroid hormone-related protein (PTHRP) is in part responsible for the clinical syndrome of hypercalcaemia of malignancy and has been implicated as an important factor in the development of bone metastases. The aim of this study was to determine the coexpression of PTHRP and its receptor in early breast cancer (EBC) and bone metastases (BM), and correlate these findings to clinical outcome. EXPERIMENTAL DESIGN: Samples of surgically excised EBC (n = 176) and BM (n = 43) were collected and stored in liquid nitrogen. PTHRP protein was determined using immunohistochemistry and receptor mRNA using in situ hybridization (n = 107) or semiquantitative reverse transcription-PCR (n = 69). RESULTS: PTHRP protein was expressed in 115 of 170 (68%) EBC compared with 100% of BM (P < 0.001), whereas its receptor mRNA was expressed in 88 of 176 (50%) EBC compared with 35 of 43 (81%) BM (P < 0.001). Coexpression of both PTHRP and its receptor was present in 62 EBC samples (37%) and in 35 BM samples (81%; P < 0.001). The PTHRP receptor correlated well with increasing patient age, but not with tumor size, grade, estrogen receptor, progesterone receptor, or lymph node status. Individually PTHRP and PTHRP receptor both correlated well with a reduced disease-free survival (P < 0.004) and receptor alone with reduced overall survival (P < 0.003). Coexpression of both PTHRP and receptor predicted the worst clinical outcome at 5 years, with a mortality rate of 20 of 62 (32%) compared with the ligand and receptor-negative group with 2 of 32 (6%; P < 0.004). CONCLUSIONS: Overall these results show that the PTHRP receptor is expressed more frequently in BM than EBC, and is associated with poor clinical outcome and survival.

Aged↗
PubMed1996

Predicting cancer risk from vinyl chloride exposure with a physiologically based pharmacokinetic model.

A physiologically based pharmacokinetic (PBPK) model capable of describing the metabolism of vinyl chloride (VC) in rats, mice, and humans has been developed and validated by comparison with experimental data from experiments not used in model development. This PBPK model has been used to predict measures of delivered dose (reactive VC metabolites produced in the livers of the affected species) hypothesized to be involved in the induction of liver angiosarcoma in rats, mice, and human populations exposed to VC. Measures of delivered dose in rats were fit to an empirical dose-response model (the linearized multistage model of Crump et al.) and used to make predictions of liver angiosarcoma incidence in mice and human populations exposed to VC. This procedure gave a good prediction of angiosarcoma incidence in mice. Predictions of angiosarcoma incidence in humans were more than two orders of magnitude lower than risk estimations which did not utilize pharmacokinetic data, but were still almost an order of magnitude higher than actually observed in exposed human populations.

Animals↗
PubMed2005

Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival?

PURPOSE: This study set out to determine the impact of a positive circumferential resection margin (CRM) (R1-R2) and pathologic downstaging on local recurrence and survival in patients with borderline resectable or unresectable rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy (CRT). METHODS AND MATERIALS: A total of 150 patients with locally advanced rectal cancer were treated with long-course neoadjuvant CRT using low-dose folinic acid and 5-fluorouracil. CRT was followed 6-12 weeks later by surgical excision. The CRM rate and incidence, site, and pattern of local and systemic recurrences were recorded. The median follow-up was 25 months. RESULTS: The overall median survival was 37 months, with a 5-year overall survival rate of 34%. Of the 150 patients, 122 underwent curative resection; 12% had a complete pathologic response, and downstaging to pT1-T2 occurred in an additional 16%. A negative CRM (R0) was achieved in 65% overall (98 of 150). Local recurrence occurred in 10% of those with R0 resection and 62% of those with R1-R2 resections. Distant metastases occurred in 29% of those with R0 resections and 75% of those with R1-R2 resections. The 3-year disease-free and 3-year overall survival rate was 9% and 25% and 52% and 64%, respectively, for patients with and without a histologically positive CRM. CONCLUSION: After 5-fluorouracil-based CRT, a positive CRM predicted for a high risk of subsequent local recurrence and a 3-year disease-free survival rate of only 9%. For this reason, the CRM should be considered a major prognostic factor and should be validated in future trials as an early alternative clinical endpoint.

Adult↗
PubMed2007

Intensity of CNS treatment for pediatric cancer: prediction of social outcomes in survivors.

PURPOSE: To evaluate the association of central nervous system (CNS) treatment intensity and the social functioning of children who have completed treatment for leukemia, lymphoma, and solid tumors outside the CNS. Furthermore, we expected that these associations would be moderated by child age at diagnosis and gender. METHOD: Peer, teacher, and self-report data were obtained for 82 cancer survivors (age 9-17 years) using classroom rating and nomination procedures that are widely used in research on social development. Information regarding cranial radiation therapy (CRT), intrathecal chemotherapy (ITC), and systemic methotrexate were obtained from medical records and used to create a composite index of CNS treatment intensity. RESULTS: Higher scores on the index of CNS treatment intensity were associated with poorer peer acceptance, fewer friendships, greater social sensitivity-isolation, and diminished leadership-popularity based on peer-report. These associations were stronger for boys and children who were younger (<10 years old) at diagnosis. In contrast, CNS treatment intensity was only predictive of teacher-perceptions of aggressive-disruptive behavior and it was unrelated to social self-perceptions. CONCLUSION: These results suggest that children who receive CRT and ITC are at risk for problematic peer relations, particularly if they are male or younger at diagnosis. Given the stability of poor peer relationships and documented linkages between peer problems and subsequent academic and psychiatric difficulties, clinical services should address these issues. Research is needed to identify mechanisms that account for these outcomes and provide direction for prevention and treatment efforts.

Adolescent↗