Reduction In Overall Survival Research Articles

Expression of activated type I receptor tyrosine kinases in early breast cancer

Overexpression of EGFR, HER2 and HER3 are known to be associated with poor outcome in breast cancer. Few studies have examined the clinical impact of activation of these proteins. In the present study, we evaluated EGFR, HER2 and HER3 and the activated (phosphorylated) forms of these proteins in patients with early breast cancer. EGFR, HER2, HER3, pEGFR, pHER2 and pHER3 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully-documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate overexpression of HER2 and pHER2 to be associated with a significant reduction in overall survival (OS) (HR: 1.66, 95 % CI 1.22-2.26, p = 0.001 and HR: 1.57, 95 % CI 1.22-2.03, p = 0.001, respectively) and distant relapse-free survival (DRFS) (HR: 1.63, 95 % CI 1.23-2.18, p = 0.001 and HR: 1.55, 95 % CI 1.23-1.97, p = 0.0002, respectively). Paradoxically, expression of pEGFR was associated with a significantly improved OS (HR: 0.67 95 % CI 0.50-0.91, p = 0.01) and DRFS (HR: 0.73, 95 % CI 0.56-0.96, p = 0.025). Expression of activated EGFR/HER2 provides additional information on ER positive breast cancer patients and suggests alternative treatment for those in this subgroup.

High extracellular matrix metalloproteinase inducer/CD147 expression is strongly and independently associated with poor prognosis in colorectal cancer

As in most solid tumors, colorectal cancer prognosis strongly depends on the extent of local invasion and lymph node and distant metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) is a transmembrane glycoprotein that activates matrix metalloproteinases, a group of enzymes that play an important role in tumor invasion and metastasis formation. This study investigates the EMMPRIN expression in a large cohort of patients with colorectal cancer. Immunohistochemical analysis of tissue microarrays from 285 patients shows that increased EMMPRIN protein expression does not correlate with clinicopathologic parameters and is an independent prognostic factor of poor survival, with mean survival times of 103 months in EMMPRIN negative/low versus 57 months in EMMPRIN intermediate/high patients (P < .001). This pronounced association of increased EMMPRIN levels and--on average--a 45% reduction in overall survival could help improve the risk stratification in patients with colorectal cancer; moreover, the lack of correlations with classical measures of cancer invasion/spreading may suggest the relevance of alternative EMMPRIN pathways beyond matrix metalloproteinase activation.

Prognostic significance of low volume sentinel lymph node disease in early-stage cervical cancer

ObjectiveEvaluate prognostic significance of low volume disease detected in sentinel nodes (SN) of patients with early stages cervical cancer. Although pathologic ultrastaging of SN allows for identification of low volume disease, including micro-metastasis and isolated tumor cells (ITC), in up to 15% of cases, prognostic significance of these findings is unknown. MethodsA total of 645 records from 8 centers were retrospectively reviewed. Enrolled in our study were patients with early-stage cervical cancer who had undergone surgical treatment including SN biopsy followed by pelvic lymphadenectomy and pathologic ultrastaging of SN. ResultsMacrometastasis, micrometastasis, and ITC were detected by SN ultrastaging in 14.7%, 10.1%, and 4.5% patients respectively. False negativity of SN ultrastaging reached 2.8%. The presence of ITC was not associated with significant risk, both for recurrence free survival and overall survival. Overall survival was significantly reduced in patients with macrometastasis and micrometastasis; hazard ratio for overall survival reached 6.85 (95% CI, 2.59–18.05) and 6.86 (95% CI, 2.09–22.61) respectively. Presence of micrometastasis was an independent prognostic factor for overall survival in a multivariable model. ConclusionPresence of micrometastasis in SN in patients with early stage cervical cancer was associated with significant reduction of overall survival, which was equivalent to patients with macrometastasis. No prognostic significance was found for ITC. These data highlight the importance of SN biopsy and pathologic ultrastaging for the management of cervical cancer.

Simvastatin targets the IL-6 signalling cascade in human melanoma cells

Background In the last years the number of melanoma patients has increased markedly. High plasma levels of interleukin-6 (IL-6) are associated with bad prognosis and reduction in overall survival of these patients. Statins, HMG-CoA reductase inhibitors, are well-tolerated therapeutics for hypercholesterolemia. We have recently shown that simvastatin triggers apoptosis in 518A2 human melanoma cells which is paralleled by concentration-dependent changes in autocrine IL-6 secretion. Here, we investigated the impact of simvastatin on the IL-6 pathway.

Increased incidence of endometrioid tumors caused by aberrations in E-cadherin promoter of mismatch repair-deficient mice.

Loss of E-cadherin expression is a critical step in the development and progression of gynecological tumors. Study of the precise role of E-cadherin has been hampered by the lack of satisfactory mouse model for E-cadherin deficiency. Likewise, DNA mismatch repair (MMR) is implicated in gynecological tumorigenesis, but knockout of MMR in mice predominantly causes hematologic neoplasms. Here, we show that combined disruption of E-cadherin and DNA MMR pathways increases incidence of endometrioid tumors in mice. Twenty percent of mice knockout for Msh2 enzyme and hemizygous for E-cadherin [Msh2(-/-)/Cdh1(+/-)] developed endometrioid-like tumors in the ovary, uterus and genital area. Characteristic of these tumors was a complete loss of E-cadherin expression. Sequence analysis of E-cadherin promoter region demonstrated that the loss of E-cadherin expression is caused by inactivating mutations, implying that E-cadherin is a mutational target in Msh2-deficient mice. In addition, Msh2(-/-)/Cdh1(+/-) mice showed a reduction in overall survival as compared with their Msh2(-/-) counterparts due to the development of more aggressive lymphomas, suggesting a specific role of E-cadherin in lymphomagenesis. In conclusion, Msh2(-/-)/Cdh1(+/-) mice provide a good model of gynecological tumorigenesis and may be useful for testing molecular target-specific therapies.

Multidrug Resistance in Breast Cancer: FromIn VitroModels to Clinical Studies

The development of multidrug resistance (MDR) and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. Numerous studies have aimed to establish the role of drug transporter pumps in MDR and to link their expression to response to chemotherapy. The ATP-binding cassette (ABC) transporters are central to breast cancer MDR, and increases in ABC expression levels have been shown to correlate with decreases in response to various chemotherapy drugs and a reduction in overall survival. But as there is a large degree of redundancy between different ABC transporters, this correlation has not been seen in all studies. This paper provides an introduction to the key molecules associated with breast cancer MDR and summarises evidence of their potential roles reported from model systems and clinical studies. We provide possible explanations for why despite several decades of research, the precise role of ABC transporters in breast cancer MDR remains elusive.

HLA-G and CD86 Expression on Malignant Plasma Cells Convey a Poor Prognosis and Immunoregulate T Cells In Patients with Myeloma

AbstractAbstract 983HLA-G is a “non-classical” HLA class I molecule which is considered to be responsible for the immune tolerance of the fetus, allografts or tumors by inhibiting the antigen-specific cytotoxic T lymphocyte response and decreasing NK cell function. CD86 is a costimulatory molecule which binds to a T cell counter receptor (eg CD28) during antigen stimulation and T cell receptor engagement. T cells do not express CD86mRNA but can acquire CD86 and HLA-G by trogocytosis. We have studied the incidence and prognostic significance of HLA-G and CD86 on malignant plasma cells, the incidence of HLA-G and CD86 on T cells and the immunosuppressive function of HLA-G on malignant plasma cells and T cells. HLA-G and CD86 expression were determined on T cells (CD3+) and plasma cells (CD38++) of patients with myeloma (MM). Flow-sorted CD3+ HLA-G- cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) and stimulated with anti-CD3/CD2/CD28 beads in the presence and absence of either HLA-G+ T cells or HLA-G+ plasma cells. Suppression of the proliferation of CFSE-tracked HLA-G- T cells by HLA-G+ T cells or plasma cells was determined by flow cytometry. CD86+ plasma cells are present in 54% of patients and are associated with a poor prognosis (χ2=4.6;p<0.03) (Blood 96:1274). We now report that the incidence of HLA-G expression on plasma cells was heterogeneous (0.2 to 96%; mean = 21.3%) and that the clinical relevance of HLA-G+ plasma cells was demonstrated by a significant reduction in overall survival (13 months vs median not achieved) for the 11/46 patients with HLA-G+ plasma cells (>5% CD38++ cells and expressing >12% HLA-G; χ2=12.4; p<0.0004) who had no difference in β2M, age or M protein isotype. Biotinylated cell membrane protein transfer from plasma cells to T cells (trogocytosis) was demonstrated using flow cytometry and confocal microscopy. Trogocytosis was unidirectional, common in MM but not from CLL or WM cells and there was with a significantly greater acquisition of biotinylated proteins by CD3+ cells (mean=13.6%) than B cells (mean=2.4%; t=2.80; p<0.05) or NK cells (mean=3.1%; t=2.57; p<0.05). Low HLA-G expression was found on both CD4 and CD8 normal T cells (n=15; mean=0.19%). Twenty six % of MM patients had HLA-G-expressing CD3+ T cells above the normal range (χ2=4.9;p<0.03). There was a significant acquired expression of CD86 by T cells (t=6.06; p<0.004) after T cell activation (CD3/2/28 beads) and exposure to the CD86+ cell line RPMI8226. Trogocytosis of HLA-G has been reported by others (Blood 109:2040). Increased CD86 surface (but not mRNA) expression was found on the CD3+ cells of 32% of patients (n=98; F=38.6; p<0.0001). Flow-sorted HLA-G+ T cells significantly reduced the proliferation of CFSE-labeled T cells in 4 day cultures. Inhibition by HLA-G T cells was greater than the inhibition due to HLA-G+ plasma cells (t=3.03; p=0.039) and was neutralised by anti HLA-G. HLA-G+ T cells were both CD4 and CD8 but were CD25- and thus were not Treg cells. In conclusion, HLA-G and CD86 expression on plasma cells and T cells are clinically relevant in patients with myeloma. Tumor escape in patients with myeloma may be due to the inhibition of normal T cell proliferation by distinct T cell cohorts which develop novel immunoregulatory functions following the acquisition and ectopic expression of antigens which include HLA-G and CD86. Disclosures:No relevant conflicts of interest to declare.

Lactate dehydrogenase as prognostic factor in limited and extensive disease stage small cell lung cancer – A retrospective single institution analysis

The aim of this retrospective study is to present data on clinical significance of lactate dehydrogenase (LDH) serum levels in an unselected contemporary patient population with small cell lung cancer (SCLC) in limited disease (LD) and extensive disease stage (ED). From June 2004 to June 2008, our electronic database including all in-patient and out-patient contacts was searched for patients with newly diagnosed LD and ED SCLC. 397 cases were identified. We collected data on patient characteristics including clinical performance status and LDH serum levels, metastatic sites, efficacy of first line chemotherapy and survival. In both limited and extensive disease SCLC, elevated LDH serum levels resulted in significantly shorter median survival. The effect was most pronounced if levels were 300U/l or higher. In patients with limited disease and normal LDH levels, median survival was 18.0months. If LDH was higher than 300U/l, overall survival was reduced to 12 months. In cases with extensive disease, overall survival was significantly lower in patients with elevated LDH serum levels with an additional reduction in overall survival in patients with LDH levels above 300U/l. (7.0 vs. 12.0 months, p=<0.001). Multivariate Cox regression analyses revealed LDH levels to be an independent predictor of mortality after adjustment for age and Performance Status in LD and ED SCLC (HR 1.003, p=0.017; HR 1.001, p=0.002 respectively). However, categorizing LDH levels revealed no significant difference in LD SCLC. In our contemporary comprehensive patient population, LDH is proved to be a strong, independent predictive factor of median survival in patients with LD and ED SCLC.

Abstract 1754: Transforming growth factor beta as potential prognostic biomarker of breast cancer: Evidence of ‘TGF-β switch’

Abstract Purpose: Transforming growth factor-beta (TGF-β1, β2, β3) and its receptors, potent inhibitors of normal epithelial cell proliferation also play a dual role from suppressor to promoter during later stages of breast neoplasia and metastases. No clinical studies have reported the levels of circulatory and tumor tissue TGF-β/TβR/SMAD markers to correlate TGF-β pathway in breast cancer progression. Multifactorial analysis is likely to offer a better predictability and identify patients likely to benefit from anti TGF-β strategies. Experimental Design: This prospective study was designed to evaluate prognostic value of TGF-β, TβR and SMAD in 120 randomly enrolled pre-therapeutic breast cancer patients from Gujarat Cancer &amp; Research Institute, India. Circulating TGF-β levels (β1, β2, β3) were evaluated from patients with known clinicopathologic prognosticators compared to 87 healthy individuals. Gene expression of TGF-β (1, 2, 3), their cognate receptors (TβR-I, II, III) and signaling mediators SMAD (3, 4, 7) from breast tumors and non-involved tissue were determined by Real Time PCR. Kaplan-Meier Survival analysis with a median follow-up of 49 months was performed. Comparisons were made between early and advanced breast cancer to correlate with ‘TGF-β switch’. Results: Circulatory TGF-β1 was higher in advanced stage patients than early stage. Higher levels of TGF-β1 correspond with patients in category of &amp;gt;40-≤60 age, premenopausal, grade-I tumors, ductal carcinomas, moderate + poor differentiated tumors, lymphatic permeation, lymphocytic infiltration, absence of vascular permeation, necrosis and stromal involvement. Reduced overall survival was associated with high TGF-β1. TGF-β1 expression was higher in advanced (31.6%) than early stages (16.7%). TGF-β2 mRNA was higher in 47.6% early and 39.5% advanced stage. Serum TGF-β3 was higher in patients than control. TGF-β3 was downregulated in 97.6% early and 92.1% advanced tumors. TβR-I downregulation of early 85.71%, decreased to 76.32% in advanced stage. TβR-I upregulation correlated reduction in overall survival. TβR-II was downregulated in early tumors and 6.58% advanced tumors showed upregulation. Advanced tumor patients with lower TβR-II relapsed faster than early stage. Notably, TβR-III was downregulated in 30.95% early tumors while 69.05% exhibited an upregulation. TβR-III upregulation was associated with reduced RFS in advanced than early stage patients. All SMAD were downregulated in 88% patients. ERα was upregulated in 44.5% and ERβ downregulated in 97.3% patients. TGF-β2 showed 1.49 fold upregulation in ER negative tumors. Conclusions: The present comprehensive study is the first clinical report of Indian breast cancer patients, indicating the dual role of TGF-β and suggests its potential as a prognostic marker for breast cancer. [Support: ICMR, GCS to ST, Fulbright-Nehru India DPR Fellowship #15094403 to HD] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1754.

Abstract 2954: Overexpression of specific genes in surgical margins of head and neck squamous cell carcinoma patients may predict a significantly increased risk of recurrence

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is a high incidence and mortality disease. Despite significant improvements in therapeutic strategies, the overall survival rate in 5 years is around 50%. The presence of microscopic tumor in surgical margins is associated with treatment failure, locoregional recurrence and reduction of overall survival. For this reason, it is vital to ensure tumor-free surgical margins in these patients. Commonly, the extension of surgical resection is determined during the surgery through a low sensitivity histological exam of frozen tissue stained with Hematoxylin and Eosin. Since genetic alterations precede histological alterations, molecular markers may be useful to identify cells that have already started malignant transformation without having developed a histological phenotype that could be detected through conventional histopathological techniques. Also, novel molecular techniques make possible to obtain molecular data of surgical margins in a period of time compatible with the surgery, helping the surgeon in the resection of positive molecular margins in the same surgery and thereby reducing the risk of local recurrence. This study aimed to determine the gene expression pattern of specific markers in HNSCC surgical margins and verify the utility of these markers in detecting the presence of tumor cells in these tissues and predict tumor recurrence. Nine selected genes were evaluated and a panel of 5 genes showed a high specificity and good sensibility. Overexpression of at least one of these genes was found in 50% (23/46) of histologically free surgical margins analyzed and was associated with local recurrence. Patients with positive molecular margins were 7.3-fold more likely to have local recurrence. These preliminary results suggest that the approach used in this analysis is more sensible than traditional histopathological exams and could be useful for the intraoperative diagnosis of the presence of tumor cells in HNSCC surgical margins and as an informative tool to identify and monitor subsets of HNSCC patients with an increased risk of recurrence and consequently reduced survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2954.

Prognostic significance of IGF-1R expression in patients treated with breast-conserving surgery and radiation therapy

Background Insulin-like growth factor (IGF) receptor is a key receptor in apoptotic protection, cell adhesion, longevity, and transformation into a cancerous cell and can induce malignant changes in the presence of the IGF ligand. Over-expression of IGF-1R has been associated with resistance to radiation. Inhibitors of IGF-1R have been shown to enhance tumor radiation sensitivity and amplify radiation therapy-induced apoptosis. The purpose of this study is to evaluate the prognostic significance of IGF-1R expression in patients with breast cancer treated with breast conserving therapy. Materials and methods Paraffin specimens from 345 women with early stage breast cancer treated with BCT were constructed into tissue microarrays and stained for IGF-1R, COX-2 and p53. The molecular profiles were correlated with clinical-pathologic factors, overall, local, and distant relapse-free survival. The association between IGF-1R, other co-variables, and outcome was assessed. Results IGF-1R over-expression was identified in 197 cases (57%). IGF-1R over-expression was found to be correlated with African-American race ( p = 0.0233), p53 status ( p = 0.0082) and COX-2 expression ( p < 0.0001). While IGF-1R over-expression was associated with lower overall survival ( p = 0.0224) in node-negative patients, there was no impact of IGF-1R expression on local control. Conclusions In node-negative patients, patients with high levels of IGF-1R were found to have a significant reduction in overall survival, but no apparent effect on local control. Given the limited published data on IGF-1R in early stage, conservatively treated patients, further studies investigating IGF-1R expression in this cohort are necessary.

The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma

The study aimed to examine the tolerability of the combination of radiotherapy and tamoxifen and the effect on median and event free survival as well as collecting data on the use of steroids in this population. 31 patients with diffuse intrinsic pontine glioma, diagnosed on clinical and radiological criteria, were treated with high-dose oral tamoxifen (120 mg/m(2)/day) given concomitantly with standard dose radiotherapy (54 Gy in 1.8 Gy fractions over 6 weeks). Results Tamoxifen was well tolerated with no grade 3 or 4 CTC toxicity reported. At 1 year, the progression free and event free survival were 3.2% (95% CI: 0.2-14.1%), and at 6 months 19.4% (CI: 7.9% to 34.6%). The overall survival at 1 year was 16.1% (CI: 5.9-30.9%) with median survival 6.32 months. In this study, in which tamoxifen was used in conjunction with radiotherapy, progression free survival was shown to be less good when compared with historical data HR = 3.1 (CI: 1.7-5.7). There was no significant reduction in overall survival. The addition of high-dose tamoxifen, although well tolerated, confers no clinical benefit to patients treated with diffuse intrinsic pontine glioma treated with standard radiotherapy.

Study and Treatment of Locally Advanced Melanoma

Locally advanced melanoma is characterized clinically by the appearance of in-transit or satellite metastases, and is considered stage IIIB or IIIC according to the 2002 classification of the American Joint Committee on Cancer. Despite the absence of distant metastases, the management of locally advanced melanoma is complicated and the disease is associated with a reduction in overall survival. The initial step in the approach to the patient with locally advanced melanoma involves restaging in order to exclude the presence of distant metastases. Positron emission tomography-computed tomography is currently accepted as the most accurate restaging technique. Surgical excision of the metastases continues to be the treatment of choice for locally advanced melanoma. In the case of unresectable metastases, hyperthermic isolated limb perfusion with melphalan with or without tumor necrosis factor has achieved complete responses in up to 60% of patients treated, with very rare severe locoregional and systemic toxic effects. Radiation therapy, chemotherapy, and biochemotherapy are options that, even though they have not been tested in patients with only in-transit metastases, may have a role in unresectable, locally advanced melanoma without distant metastases. In any case, therapeutic options for locally advanced melanoma should be individualized, and should take into consideration the availability of each of these techniques as well as the experience of the health care team.

Long-term clinical outcomes for patients with lower limb ischemia implanted with G-CSF-mobilized autologous peripheral blood mononuclear cells

BackgroundMany studies have described the clinical effects of treating critical limb ischemia with granulocyte colony-stimulating factor-mobilized autologous peripheral blood mononuclear cells (M-PBMNC); however, there are no long-term data available on survival, limb salvage, or prognostic factors. MethodsTo investigate the long-term clinical outcomes of M-PBMNC implantation, we reviewed data for 162 consecutive patients with limb ischemia who were treated with M-PBMNC implantation at 6 hospitals between 2001 and 2006. A subset of 123 patients with homogenous clinical profiles was selected for prognostic factor analysis. ResultsOf the 162 patients, 50 died during the follow-up period. The median follow-up time for surviving patients was 26.4 months. The 2-year survival rate was 65% for the 140 patients with arteriosclerosis obliterans (ASO), and 100% for the 11, 4 and 7 patients with thromboangiitis obliterans (TAO), diabetic gangrene (DG) and connective tissue disease (CTD), respectively. The 1-year amputation-free rates for ASO, TAO, DG and CTD were 70%, 79%, 75% and 83%, respectively. Common serious adverse events included heart failure (15 cases), myocardial infarction (15 cases), serious infection (13 cases), stroke (10 cases), and malignant tumor (9 cases). Significant negative prognostic factors associated with overall survival were ischemic heart disease and collection of a small number of CD34-positive cells. Factors associated with time-to-amputation and amputation-free survival were a combination of Fontaine classification and lower limb gangrene, and history of dialysis. ConclusionsCollection of a small number of CD34-positive cells and ischemic heart disease were associated with a reduction in overall survival.

Concepts and techniques of intraoperative radiotherapy (IORT) for breast cancer

The standard treatment for early breast cancer comprises wide local excision, sentinel lymph node biopsy or axillary lymph node dissection, adjuvant medical treatment and radiotherapy to the whole breast. Many studies suggest that local control plays a crucial role in overall survival. The local recurrence rate is estimated to be 1% per year and varies between 4 and 7% after 5 years and up to 10 to 20% in the long-term follow up. On the basis of low local recurrence rates the concept of whole breast irradiation comes up for discussion, and partial breast irradiation (PBI) is increasingly under consideration. Intraoperative radiotherapy (IORT) is referred to as the delivery of a single high dose of irradiation directly to the tumor bed (confined target) during surgery. PBI (limited field radiation therapy, accelerated partial breast irradiation APBI) is the irradiation exclusively confined to a breast volume, the tumor surrounding tissue (tumor bed) either during surgery or after surgery without whole breast irradiation. Various methods and techniques for IORT or PBI are under investigation. The advantage of a very short radiation time or the integration of the complete radiation treatment into the surgical procedure convinces at a first glance. The promising short-term results of those studies must not fail to mention that local recurrence rates could probably increase and furthermore give rise to distant metastases and a reduction in overall survival. The combination of IORT in boost modality and whole breast irradiation has the ability to reduce local recurrence rates. The EBCTCG overview approves that differences in local treatment that substantially affect local recurrence rates would avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

Impact of mandibular condyle preservation on patterns of failure in head and neck cancer

To determine the role of native condyle preservation in local recurrence after segmental mandibulectomy in patients with head and neck squamous cell carcinoma. Retrospective chart review with main outcome measuring local control of cancer. Between 1994 and 2003, 72 patients (48 men, 24 women) with an average age of 73.5 years without previous treatment underwent segmental mandibulectomy. Fifty-four cases (n = 54) involved the mandible posterior to the mental foramen and are the subject of this review. In 36 patients, the condyle was preserved and mandibular continuity was restored. In 18 patients, condyle and ramus were resected without mandibular reconstruction. Reconstructive modalities included primary closure (3), split-thickness skin graft (3), pedicle flap (19), and free tissue reconstructions (29). Overall local-regional recurrence rate was 22 percent (12 of 54); no recurrences were identified in patients who underwent condylar resection. Recurrences were observed in patients with mandibular reconstruction by both plate and pedicle flap (5 of 9) or (osteo) myocutaneous free flap (7 of 27). Condylar preservation may predispose patients to local recurrence after segmental mandibulectomy. This does not translate into overall reduction in survival.

Using Pre-radiation PET Parameters to Predict Survival in Adenocarcinoma of the Pancreas Treated With Gemcitabine and Single Fraction Stereotactic Body Radiation Therapy

Although positron emission tomography (PET) scanning has been influential in radiation treatment planning and target delineation, tumor metabolic activity has not been studied as a prognostic factor in predicting individual patient outcomes in pancreatic cancer. In a cohort of 35 patients treated with stereotactic body radiation therapy (SBRT) we analyzed whether pretreatment PET scan parameters could predict for patient survival. This study consists of 35 patients with pancreatic cancer (29 locally advanced and 6 metastatic disease) who had a pre-treatment PET scan and at least 4 months of follow-up. All PET scans were carried out on our GE Discovery-ST CT-PET scanner. PET images were imported into RT_Image (an application developed in our laboratory) for analysis. Pancreatic tumor volume, Maximum SUV, Mean SUV, Minimum SUV and integrated SUV over the tumor volume were calculated for each patient. Survival times from date of pathologic diagnosis were available for all patients. Stereotactic radiation doses of 25 Gy in a single fraction were administered. Among the various PET parameters, maximum SUV (SUVmax) demonstrated the greatest correlation with patient survival. Patients were sorted into two groups based on their SUVmax values. The Hi-SUV group consisted of patients with SUVmax values above the median and the Low-SUV group consisted of patients with SUVmax values below the median. Mean survival from diagnosis was 221 days (stdev 112) in the Hi-SUV group and 469 days (stdev 267) in the Low-SUV group (p value of 0.12 by t-test). Kaplan-Meier survival curves for all patients (Figure 1-Left) and locally advanced patients only (Figure 1-Right) are below. Neither reached significance by log-rank testing (p = 0.63 and 0.20 respectively). Our preliminary data demonstrates a trend between greater maximum SUV on pre-treatment PET scan and a reduction in overall survival. A larger sample size and longer follow-up will be available at time of presentation.

Single Nucleotide Polymorphisms in the NOD2/CARD15 Gene Are Associated With an Increased Risk of Relapse and Death for Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation With Unrelated Donors

Hematopoietic stem cell transplantation (HSCT) is an important option in the management of acute leukemia, but the risk of disease relapse and death remains appreciable. Recent studies have suggested that nucleotide-binding oligomerization domain 2 (NOD2)/caspase recruitment domain 15 (CARD15) gene single nucleotide polymorphisms (SNPs), implicated in innate immunity and Crohn's disease, may also affect immune function post-HSCT. NOD2/CARD15 genotypes were analyzed in 196 patients diagnosed with acute leukemia and their unrelated donors. The pairs are part of a previously well-characterized cohort with a median follow-up of 2.2 years (range, 0.42 to 6.61 years). T-cell depletion was used in 83% of pairs. NOD2/CARD15 SNPs were associated with a reduction in overall survival (44% v 22%; log-rank P = .0087) due to an increase in disease relapse (32% v 54%; Gray's test P = .001) as compared with wild-type pairs. In multivariate analyses, the two most significant factors impacting outcome were transplantation in relapse and the presence of SNPs. The incidence of acute graft-versus-host disease was low and there was no significant difference due to the presence of SNPs. These data indicate an unrecognized role for the NOD2/CARD15 gene in unrelated donor HSCT for acute leukemia. The increased risk of disease relapse suggests that the wild-type gene product may contribute to a graft-versus-leukemia effect. These data suggest that NOD2/CARD15 genotyping before transplantation may contribute to prognosis and influence clinical management.

Anaemia is Associated with Poor Overall Survival but not with Inferior Local Control in Patients with Muscle Invasive Bladder Carcinoma Treated by Radical External Beam Radiotherapy. A Retrospective Study

Aims The treatment of muscle invasive transitional cell carcinoma of the bladder with radiotherapy allows organ preservation and is frequently used in the UK, especially in patients not medically fit for cystectomy. Anaemia is known to be an indicator of a poor response to radiotherapy in head and neck and cervical carcinomas. Here we describe the prevalence and type of anaemia in patients with transitional cell carcinoma of the bladder and determine the effect anaemia has on treatment outcome. Materials and methods A retrospective review of notes was carried out on patients treated radically between 1992 and 1997. Potential patient, tumour and treatment prognostic indicators were reported. Patients were labelled as being anaemic if their pre-treatment haemoglobin level was below the normal range (below 13.5 g/dl for men and below 11.5 g/dl for women). The time to local failure, metastases and overall survival were recorded. Recurrence-free survival and overall survival actuarial estimations were carried out using the Kaplan–Meier method and compared by Log-rank testing. A multivariate analysis was carried out using the Cox regression method. Results Data on 100 patients were available for analysis. Most of the patients were not adequately staged by today's standards. Fifty-two patients were anaemic, with 75% of them having a normochromic, normocytic anaemia. The univariate analysis showed no significant difference in the time to local recurrence, a trend towards a shorter time to metastases and a significant reduction in overall survival in anaemic patients ( P = 0.001). Two-year survival was 43% and 22% for non-anaemic and anaemic patients, respectively. A multivariate analysis using the covariates tumour stage, grade and serum creatinine found anaemia to be a poor prognostic indicator for overall survival ( P = 0.005). Conclusion Anaemia is highly prevalent in patients with bladder cancer. This retrospective study showed anaemic patients to have a worse outcome with radiotherapy treatment than patients with a normal haemoglobin level. This was not accounted for by a difference in local control, which may be expected from hypoxic radiobiological principles. Anaemia may be indicative of more aggressive malignancy or subclinical metastases.

Anaemia in patients with transitional cell carcinoma (TCC) of the bladder treated with radiotherapy

14569 Background: Treatment of muscle invasive TCC of the bladder with radiotherapy allows organ preservation and is frequently used in the UK especially in patients not medically fit for cystectomy. Anaemia is known to be an indicator of poor response to radiotherapy in head and neck and cervical carcinomas. This study describes the prevalence and type of anaemia in patients with TCC of the bladder and looks at the impact anaemia has on treatment outcome. Methods: Retrospective review of notes was performed on patients treated radically between 1992 and1997. Potential patient, tumour and treatment prognostic indicators were reported. Patients were labelled as being anaemic if their pre treatment haemoglobin level was below the normal range (below 13.5g/dl for men and below 11.5g/dl for women). Time to local recurrence, metastases and overall survival was recorded. Recurrence free survival and overall survival actuarial estimations were done using the Kaplan Meier method and compared by log rank testing. Multivariate analysis was carried out using Cox Regression method, correcting for potential confounding factors. Results: Data on 100 patients were available for analysis. 52 patients were anaemic with 75% of these having a normochromic, normocytic anaemia. Univariate analysis showed no significant difference in time to local recurrence, a trend to shorter time to metastases, and a significant reduction in overall survival in anaemic patients (p = 0.04). Two year survival was 43% and 22% for non anaemic and anaemic patients respectively. Multivariate analysis using covariates tumour stage, grade, and serum creatinine found anaemia to be poor prognostic indicator for overall survival (p = 0.005) and time to metastases (p = 0.003). Conclusions: Anaemia is highly prevalent in patients with bladder cancer. This retrospective study shows anaemic patients to have a worse outcome with radiotherapy treatment than patients with a normal haemoglobin level. This is not accounted for by a difference in local control which may be expected from hypoxic radiobiological principles. Anaemia may be indicative of more aggressive malignancy or sub clinical metastases. No significant financial relationships to disclose.