Significant Predictor Of Progression-free Survival Research Articles

Value of volume-based early metabolic response in patients with unresectable thymic epithelial tumor

ObjectiveWe conducted this study to investigate the value of early metabolic responses assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in predicting prognosis and monitoring treatment response in patients with unresectable thymic epithelial tumors (TETs). Patients and methodsStudy subjects were selected from the prospective dataset of a phase II clinical trial for cisplatin plus Cremorphor EL-free paclitaxel. A total of thirty patients with unresectable TETs who underwent baseline and early post treatment scan after two cycles of chemotherapy were enrolled (22 Male; mean age 55.0±15.0years). Metabolic parameters including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of the tumor lesions were measured. ResultsMultivariate analysis using Cox proportional hazards regression model showed that percent decrease of MTV (HR=0.995 by 1% decrease, P=0.037) and TLG (HR=0.996 by 1% decrease, P=0.044) were significant predictors of progression-free survival (PFS). Receiver operating characteristic curve identified an 88.0% decrease in MTV and a 92.0% decrease in TLG as the optimal cut-off value for disease progression. Responders with ≥88% of ΔMTV and ≥92% of Δ TLG had significantly longer PFS than non-responders (P=0.012, 0.026, respectively). ConclusionThe percent decrease in MTV and TLG of tumor lesions measured by early post treatment FDG PET/CT significantly associated with disease progression in this study. Early metabolic response based on these volumetric parameters has the potential to monitor treatment response and predict prognosis in patients with unresectable TETs.

GLI2 expression levels in radical nephrectomy specimens as a predictor of disease progression in patients with metastatic clear cell renal cell carcinoma following treatment with sunitinib.

The aim of the present study was to investigate the role of the Hedgehog signaling pathway in the progression of metastatic clear cell renal cell carcinoma (m-ccRCC) as well as the molecular targets of sunitinib, an inhibitor of multiple tyrosine kinases. A total of 39 patients subjected to radical nephrectomy who were diagnosed with m-ccRCC and were subsequently treated with sunitinib were enrolled in the present study. The expression levels of the Hedgehog signaling proteins (GLI1, GLI2, cyclin D1, cyclin E and transforming growth factor-β) and major molecular targets of sunitinib [vascular endothelial growth factor receptor (VEGFR)-1 and −2, and platelet-derived growth factor receptor-α and -β] in primary RCC specimens were assessed by immunohistochemical staining. The expression levels of GLI2, VEGFR-1, VEGFR-2 and pre-treatment C-reactive protein as well as the Memorial Sloan-Kettering Cancer Center risk were identified as significant predictors of progression-free survival (PFS). Of these, only GLI2 expression was independently correlated to PFS according to multivariate analysis. Furthermore, treatment with sunitinib resulted in a marked inhibition of GLI2 expression in the parental human RCC ACHN cell line, but not in ACHN cells with acquired resistance to sunitinib. These findings suggested that GLI2 may be involved in the acquisition of resistance to sunitinib in RCC; thus, it may be useful to consider the expression levels of GLI2 in addition to conventional prognostic parameters when selecting m-ccRCC patients likely to benefit from treatment with sunitinib.

CT-based texture analysis potentially provides prognostic information complementary to interim fdg-pet for patients with hodgkin\u2019s and aggressive non-hodgkin\u2019s lymphomas

ObjectivesThe purpose of this study was to investigate the ability of computed tomography texture analysis (CTTA) to provide additional prognostic information in patients with Hodgkin's lymphoma (HL) and high-grade non-Hodgkin's lymphoma (NHL).MethodsThis retrospective, pilot-study approved by the IRB comprised 45 lymphoma patients undergoing routine 18F-FDG-PET-CT. Progression-free survival (PFS) was determined from clinical follow-up (mean-duration: 40 months; range: 10-62 months). Non-contrast-enhanced low-dose CT images were submitted to CTTA comprising image filtration to highlight features of different sizes followed by histogram-analysis using kurtosis. Prognostic value of CTTA was compared to PET FDG-uptake value, tumour-stage, tumour-bulk, lymphoma-type, treatment-regime, and interim FDG-PET (iPET) status using Kaplan-Meier analysis. Cox regression analysis determined the independence of significantly prognostic imaging and clinical features.ResultsA total of 27 patients had aggressive NHL and 18 had HL. Mean PFS was 48.5 months. There was no significant difference in pre-treatment CTTA between the lymphoma sub-types. Kaplan-Meier analysis found pre-treatment CTTA (medium feature scale, p=0.010) and iPET status (p<0.001) to be significant predictors of PFS. Cox analysis revealed that an interaction between pre-treatment CTTA and iPET status was the only independent predictor of PFS (HR: 25.5, 95% CI: 5.4-120, p<0.001). Specifically, pre-treatment CTTA risk stratified patients with negative iPET.ConclusionCTTA can potentially provide prognostic information complementary to iPET for patients with HL and aggressive NHL.Key Points• CT texture-analysis (CTTA) provides prognostic information complementary to interim FDG-PET in Lymphoma.• Pre-treatment CTTA and interim PET status were significant predictors of progression-free survival.• Patients with negative interim PET could be further stratified by pre-treatment CTTA.• Provide precision surveillance where additional imaging reserved for patients at greatest recurrence-risk.• Assists in risk-adapted treatment strategy based on interim PET and CTTA.

Adjuvant Radiotherapy for Stages II and III Resected Thymoma

The role of adjuvant radiation for Masaoka stages II and III thymoma remains controversial. The aim of this study was to evaluate the clinical benefit of radiation therapy for resected stages II and III thymoma patients. We retrospectively reviewed the medical records of 175 thymoma patients treated from July 1996 to January 2013 at University of Washington Medical Center; 88 patients with adequate follow-up and who met histologic criteria were included. We evaluated progression-free survival (PFS) and overall survival (OS), and compared these outcomes in patients treated by surgery (S) alone versus surgery plus radiotherapy (S+RT). Cox regression models and log-rank tests were used to compare PFS and OS for S versus S+RT, and they were further assessed by margin-positive versus margin-negative subgroups using Kaplan-Meier curves. Among the 88 thymoma patients, 22 were stage II and 18 were stage III. For all stages II and III patients, adjuvant radiation was not identified as a significant predictor for PFS (P=0.95) or OS (P=0.63). A positive surgical margin predicted for a worse OS (hazard ratio=7.1; P=0.004). Further investigation revealed for resection margin-positive patients; S+RT had higher OS than S alone (P=0.006). For stages II and III thymoma, postoperative adjuvant radiation was not associated with statistically significant differences in PFS or OS in this study. Our results indicated a potential OS benefit of adjuvant RT in patients with positive resection margins, and therefore may be considered in this patient population.

Management of pediatric intracranial low-grade gliomas: long-term follow-up after radiation therapy.

The treatment of pediatric intracranial low-grade gliomas (LGG) generally begins with maximal safe resection. Radiation therapy (RT) and chemotherapy are typically reserved for patients with incomplete resection and/or disease progression. We report long-term treatment outcomes and toxicities in a cohort of pediatric patients with LGG after RT. Thirty-four patients <21years old with intracranial LGG who were treated with RT at the Johns Hopkins Hospital were included in this retrospective analysis. Patients were evaluated for overall survival (OS), progression-free survival (PFS), recurrence patterns, and treatment toxicities using descriptive statistics, Kaplan-Meier curves, and Cox proportional hazard regressions. The mean age at diagnosis was 7.9years (range 1.2-18.3years) and mean age at RT was 9.8years (range 3.0-28.9years). The median follow-up time was 9.8years after radiation (range 0.8-33.3years). The estimated 10-year OS and PFS after RT were 92 and 74%, respectively. Twelve patients had disease progression after RT, and all recurrences were local. Two patients died due to disease progression 2.3 and 9.1years after RT. One patient had malignant transformation of LGG to high-grade glioma. No significant predictors of PFS were identified on uni- or multivariate analysis. Late effects of LGG and treatment seen were endocrine deficiencies in 16 patients, visual problems in 10 patients, hearing loss in 4 patients, special education requirements for 5 patients, and a vascular injury/demyelination secondary to RT in 1 patient. Our study suggests that the use of radiation in patients with intracranial LGG results in excellent OS and PFS with acceptable toxicity at long-term follow-up.

The prognostic value of lactate dehydrogenase levels in colorectal cancer: a meta-analysis.

BackgroundThe prognostic value of lactate dehydrogenase levels in the prognosis of colorectal cancer patients has been assessed for years, although the results remain controversial and heterogeneous. Thus, we comprehensively reviewed the evidence from studies that evaluated lactate dehydrogenase levels in colorectal cancer patients to determine their effect.MethodsThe following databases were searched in September 2014 to identify studies that evaluated the prognostic value of lactate dehydrogenase levels in colorectal cancer: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. We extracted hazard ratios (HRs) and the associated 95 % confidence intervals (CIs) from the identified studies, and performed random-effects model meta-analyses on the overall survival (OS) and progression-free survival (PFS). Thirty-two studies with a cumulative sample size of 8,261 patients were included in our analysis.ResultsOur meta-analyses revealed that high levels of lactate dehydrogenase were associated with poor OS (HR, 1.75; 95 % CI, 1.52–2.02) in colorectal cancer patients. However, this effect was not obvious in the OS of non-metastatic colorectal cancer patients (HR, 1.21; 95 % CI, 0.79–1.86). The prognostic value of lactate dehydrogenase levels on PFS was also not confirmed (HR, 1.36; 95 % CI, 0.98–1.87). Subgroup analyses revealed that the prognostic significance of lactate dehydrogenase was independent of study location, patient age, number of patients, metastasis, chemotherapy with anti-angiogenesis drugs, study type, or risk of bias.ConclusionsOur results indicate that high lactate dehydrogenase levels are associated with poor OS among colorectal cancer patients, although these levels are not significant predictors of PFS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2276-3) contains supplementary material, which is available to authorized users.

Identifying the association between contrast enhancement pattern, surgical resection, and prognosis in anaplastic glioma patients.

Contrast enhancement observable on magnetic resonance (MR) images reflects the destructive features of malignant gliomas. This study aimed to investigate the relationship between radiologic patterns of tumor enhancement, extent of resection, and prognosis in patients with anaplastic gliomas (AGs). Clinical data from 268 patients with histologically confirmed AGs were retrospectively analyzed. Contrast enhancement patterns were classified based on preoperative T1-contrast MR images. Univariate and multivariate analyses were performed to evaluate the prognostic value of MR enhancement patterns on progression-free survival (PFS) and overall survival (OS). The pattern of tumor contrast enhancement was associated with the extent of surgical resection in AGs. A gross total resection was more likely to be achieved for AGs with focal enhancement than those with diffuse (p = 0.001) or ring-like (p = 0.024) enhancement. Additionally, patients with focal-enhanced AGs had a significantly longer PFS and OS than those with diffuse (log-rank, p = 0.025 and p = 0.031, respectively) or ring-like (log-rank, p = 0.008 and p = 0.011, respectively) enhanced AGs. Furthermore, multivariate analysis identified the pattern of tumor enhancement as a significant predictor of PFS (p = 0.016, hazard ratio [HR] = 1.485) and OS (p = 0.030, HR = 1.446). Our results suggested that the contrast enhancement pattern on preoperative MR images was associated with the extent of resection and predictive of survival outcomes in AG patients.

Impact of Polymorphic Variations of Gemcitabine Metabolism, DNA Damage Repair, and Drug-Resistance Genes on the Effect of High-Dose Chemotherapy for Relapsed or Refractory Lymphoid Malignancies

The goal of this study was to determine whether single nucleotide polymorphisms (SNPs) in genes involved in gemcitabine metabolism, DNA damage repair, multidrug resistance, and alkylator detoxification influence the clinical outcome of patients with refractory/relapsed lymphoid malignancies receiving high-dose gemcitabine/busulfan/melphalan (Gem/Bu/Mel) with autologous stem cell support. We evaluated 21 germline SNPs of the gemcitabine metabolism genes CDA, deoxycytidine kinase, and hCNT3; DNA damage repair genes RECQL, X-ray repair complementing 1, RAD54L, ATM, ATR, MLH1, MSH2, MSH3, TREX1, EXO1, and TP73; and multidrug-resistance genes MRP2 and MRP5; as well as glutathione-S-transferase GSTP1 in 153 patients with relapsed or refractory lymphoma or myeloma receiving Gem/Bu/Mel. We studied the association of genotypes with overall survival (OS), progression-free survival (PFS), and nonhematological grade 3 or 4 toxicity. CDA C111T and TREX1 Ex14-460C>T genotypes had a significant effect on OS (P = .007 and P = .005, respectively), and CDA C111T, ATR C340T, and EXO1 P757L genotypes were significant predictors for severe toxicity (P = .037, P = .024, and P = .025, respectively) in multivariable models that adjusted for clinical variables. The multi-SNP risk score analysis identified the combined genotypes of TREX1 Ex14-460 TT and hCNT3 Ex5 +25A>G AA as significant predictors for OS and the combination of MRP2 Ex10 + 40GG/GA and MLH1 IVS12-169 TT as significant predictor for PFS. Polymorphic variants of certain genes involved in gemcitabine metabolism and DNA damage repair pathways may be potential biomarkers for clinical outcome in patients with refractory/relapsed lymphoid tumors receiving Gem/Bu/Mel.

Abstract A10: Soluble CD25 and C-reactive protein predict overall survival in melanoma patients receiving anti-CD40 monoclonal antibody CP-870,893 (αCD40) and anti-CTLA4 monoclonal antibody tremelimumab

Abstract Purpose: Identifying baseline patient biomarkers that predict clinical outcomes to cancer immunotherapy is a major goal for the field. In a phase I dose escalation study of αCD40 CP-870,893 (0.1-0.2 mg/kg) and tremelimumab (6-15 mg/kg) for patients (pts) with metastatic melanoma, we determined associations between pre-treatment clinical (stage, LDH) and immune variables and tumor response, progression-free survival (PFS) and overall survival (OS). Methods: Twenty-two metastatic melanoma pts (6 stage 4a, 6 stage 4b and 10 stage 4c) enrolled and contributed serum specimens for immunologic evaluation, which included: soluble CD25 (sCD25), C-reactive protein (CRP), EGF, HGF, VEGF, IFNα, IFNγ, TNFα, G-/GM-CSF, MIP1A/1B, MIG, MCP1, IL1B, IL1RA, IL2, IL4, IL5, IL6, IL8, IL10, IL12 and IL13. There were 6 responders (2 CR, 4 PR) and 16 nonresponders (3 SD, 13 PD). With a median follow-up of 26 months (mos), 13 pts have died. Median PFS and OS were 2.5 and 26.1 mos, respectively. Associations with continuous and binary immune variables were tested, cut points for the latter were determined by median or classification and regression tree (CART) analysis. Univariate logistic or Cox regression analyses determined predictors for response or PFS and OS, respectively. Variables with univariate significance &amp;lt;0.05 were then tested in multivariable models using stepwise regression. Results: Tumor Response. Response was associated with stage (50% in 12 stage 4a/b pts vs 0% in 10 stage 4c pts, p=0.02). Baseline LDH was not associated with response or PFS. No immune variables predicted response. Overall Survival. sCD25 (p=0.01), CRP (p=0.005), LDH (p=0.006) and stage (p=0.01) were highly significant predictors of OS. Natural log transformed sCD25 was highly correlated with CRP (r=0.56, p=0.006) and moderately correlated with LDH (r=0.41, p=0.06) and stage (rho=0.32, p=0.09). CART analysis identified sCD25 &amp;gt;110 and CRP &amp;gt;7 as the optimal cut points for OS. Accordingly, binary sCD25 (&amp;gt;110 vs &amp;lt;110, HR=13.4, p&amp;lt;0.001) and binary CRP (&amp;gt;7 vs &amp;lt;7, HR=7.2, p=0.003) were highly significant predictors. These cut points defined very similar risk groups. Of 6 pts with sCD25 &amp;gt;110, 5 had CRP &amp;gt;7 and of 16 pts with sCD25 &amp;lt;110, 14 had CRP &amp;lt;7. Thus, these CART-defined binary variables were strongly associated (p=0.004). In multivariate modeling, only binary sCD25 remained statistically significant since it was slightly superior to binary CRP, although both variables produced identical estimates of median OS. For pts with sCD25 &amp;lt;110 (or CRP &amp;lt;7), median OS was 27.1 mos while for pts with sCD25 &amp;gt;110 (or CRP &amp;gt;7), median OS was 4.6 mos. Moreover, binary sCD25 remained highly significant (HR=11.2, p=0.002) after adjusting for LDH (p=0.06). Progression-free Survival. Stage (p=0.01) and sCD25 (p=0.02), but not CRP (p=0.10), were significant predictors of PFS. Binary sCD25 defined by median (&amp;gt;60 vs &amp;lt;60, HR=3.1, p=0.02) and binary CRP (&amp;gt;7 vs &amp;lt;7, HR=3.1, p=0.02) were also significant predictors. Binary CRP (p=0.001), but not binary sCD25 (p=0.20), was associated with stage. In multivariable modeling, only stage remained significant. For stage 4a/b pts, median PFS was 4.8 mos while for stage 4c pts, median PFS was 2.3 mos. sCD25, CRP and IL6. IL6 was not correlated with sCD25 (p=0.99) or CRP (p=0.83) nor was it associated with response (p=0.26), PFS (p=0.48) or OS (p=0.74). Conclusion: sCD25 and CRP are both highly significant predictors for OS, although they are not independent predictors due to their strong co-linearity. sCD25 remains a significant predictor for OS after adjusting for baseline LDH. To confirm these findings, sCD25 and CRP should be investigated as possible predictive biomarkers in future studies of immune checkpoint inhibitors. Citation Format: Rosemarie Mick, David Bajor, Lee Richman, Robert Vonderheide. Soluble CD25 and C-reactive protein predict overall survival in melanoma patients receiving anti-CD40 monoclonal antibody CP-870,893 (αCD40) and anti-CTLA4 monoclonal antibody tremelimumab. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A10.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

Pomalidomide is a distinct oral IMiD(®) immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30.

Identifying the association of contrast enhancement with vascular endothelia growth factor expression in anaplastic gliomas: a volumetric magnetic resonance imaging analysis.

Contrast enhancement is a crucial radiologic feature of malignant brain tumors, which are associated with genetic changes of the tumor. The purpose of the current study was to investigate the potential relationship among tumor contrast enhancement with MR imaging, vascular endothelial growth factor (VEGF) expression, and survival outcome in anaplastic gliomas. MR images from 240 patients with histologically confirmed anaplastic gliomas were retrospectively analyzed. The volumes of T2 hyperintense, contrast enhanced regions and necrotic regions on postcontrast T1-weighted images were measured. The ratio of the enhanced volume to necrotic volume was compared between patients with high versus low levels of VEGF expression and was further used in the survival analysis. The volumetric ratio of enhancement to necrosis was significantly higher in patients with low VEGF expression than in those with high VEGF expression (Mann-Whitney, p = 0.009). In addition, the enhancement/necrosis ratio was identified as a significant predictor of progression-free survival (Cox regression model, p = 0.004) and overall survival (Cox regression model, p = 0.006) in the multivariate analysis. These results suggest that the volumetric ratio of enhancement to necrosis could serve as a noninvasive radiographic marker associated with VEGF expression and that this ratio is an independent predictor for progression-free survival and overall survival in patients with anaplastic gliomas.

(18)F-Fluorocholine PET/CT for early response assessment in patients with metastatic castration-resistant prostate cancer treated with enzalutamide.

We investigated the role of (18)F-methylcholine (FCH) PET/CT in the early evaluation of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide. The study group comprised 36 patients with a median age of 72 years (range 48-90 years) who were treated with enzalutamide 160 mg once daily after at least one chemotherapeutic regimen with docetaxel. Patients were evaluated monthly for serological prostate-specific antigen (PSA) response. FCH PET/CT was performed at baseline and repeated after 3-6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 24.2 months (range 1.8-27.3 months), 34 patients were evaluable for early FCH PET/CT evaluation of response, and of these 17 showed progressive disease (PD) and 17 had stable disease or a partial response. A decrease in PSA level of more than 50% was observed in 21 patients. Early FCH PET/CT PD predicted radiological PD 3 months in advance of CT in 12 of 18 patients (66%) and was discordant with the decrease in PSA level in 13 patients. In 6 of these, biochemical PD was confirmed in 2 months. In multivariate analysis, only decrease in PSA level and FCH PET/CT were significant predictors of PFS (p = 0.0005 and p = 0.029, respectively), whereas decrease in PSA level alone was predictive of OS (p = 0.007). This is one of the first studies to evaluate the role of FCH PET/CT as an early predictor of outcome in mCRPC patients treated with enzalutamide. Our preliminary results suggest that the combination of FCH PET/CT and decrease in PSA level could be a valid tool to predict PFS in mCRPC patients. PSA remains the single most important prognostic factor, while FCH PET/CT does not add more information on OS beyond that obtained from PSA. Further studies in larger populations are needed to confirm these data and to clarify the role of FCH PET/CT in predicting response to enzalutamide in mCRPC patients.

Prognostic superiority of the National Comprehensive Cancer Network International Prognostic Index over pretreatment whole-body volumetric-metabolic FDG-PET/CT metrics in diffuse large B-cell lymphoma.

This study aimed to determine the prognostic value of whole-body maximum standardized uptake value (SUVmax ), whole-body metabolic tumor volume (MTV), and whole-body total lesion glycolysis (TLG) at pretreatment (18) F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Seventy-three patients with newly diagnosed DLBCL who had undergone FDG-PET/CT before rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone (R-CHOP) immunochemotherapy were retrospectively included. All FDG-avid lesions in each patient were segmented using semi-automated software to calculate whole-body SUVmax , whole-body MTV, and whole-body TLG values. Cox regression analyses were used to determine the associations of whole-body SUVmax , whole-body MTV, whole-body TLG, and dichotomized National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) risk group (low risk vs. high risk) with progression-free survival (PFS) and overall survival (OS). On univariate Cox regression analysis, only the NCCN-IPI was a significant predictor of PFS (P=0.024), and only the NCCN-IPI and whole-body MTV were significant predictors of OS (P=0.039 and P=0.043, respectively). In the multivariate Cox proportional hazards model, only the NCCN-IPI remained an independent predictive factor of PFS (P=0.024) and OS (P=0.039). Whole-body SUVmax , whole-body MTV, and whole-body TLG do not provide any prognostic information in DLBCL beyond that which can already be obtained by the NCCN-IPI. Therefore, the NCCN-IPI remains the most important prognostic tool in this disease.

High neutrophil-to-lymphocyte ratio persistent during first-line chemotherapy predicts poor clinical outcome in patients with advanced urothelial cancer.

Increased neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation, is associated with poor outcome for various types of cancers. We assessed the role on outcome prediction of NLR at baseline and persistent during first-line chemotherapy in patients with advanced urothelial cancer. We retrospectively reviewed 292 patients with unresectable or metastatic urothelial cancer treated with first-line chemotherapy between January 2003 and December 2012. The cutoff values of NLR (>3 vs. <3) were evaluated before therapy and at day 1 of the second and third cycle (follow-up NLR). After univariate analysis, a multivariate analysis was carried out by Cox regression model and included the following variables: Eastern Cooperative Oncology Group (ECOG) performance status (≥ 2 vs. 0-1), visceral disease (present vs. absent), hemoglobin (<12 g/dL vs. >12 g/dL), pretherapy NLR (>3 vs. <3), and follow-up NLR (>3 vs. ≤ 3). Patients with pre- and follow-up NLR of >3 had a median progression-free survival of 3.2 months and a median overall survival of 5.7 months. In multivariate analysis, visceral metastases, pretherapy hemoglobin, and follow-up NLR were significant predictors of progression-free survival [hazard ratio (HR) 1.75, P = 0.0001; HR 1.57, P = 0.0015; HR 2.77, P < 0.0001, respectively], and of overall survival (HR 1.60, P = 0.0023; HR 1.59, P = 0.0024; HR 2.89, P < 0.0001, respectively); whereas pretherapy NLR remained as predictor of overall survival only (HR 1.53, P = 0.0101). An increased NLR persistent during first-line chemotherapy is an independent predictive factor for patients with advanced urothelial cancer.

Asphericity of pretherapeutic tumour FDG uptake provides independent prognostic value in head-and-neck cancer.

To propose a novel measure, namely the 'asphericity' (ASP), of spatial irregularity of FDG uptake in the primary tumour as a prognostic marker in head-and-neck cancer. PET/CT was performed in 52 patients (first presentation, n = 36; recurrence, n = 16). The primary tumour was segmented based on thresholding at the volume-reproducible intensity threshold after subtraction of the local background. ASP was used to characterise the deviation of the tumour's shape from sphere symmetry. Tumour stage, tumour localisation, lymph node metastases, distant metastases, SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were also considered. The association of overall (OAS) and progression-free survival (PFS) with these parameters was analysed. Cox regression revealed high SUVmax [hazard ratio (HR) = 4.4/7.4], MTV (HR = 4.6/5.7), TLG (HR = 4.8/8.9) and ASP (HR = 7.8/7.4) as significant predictors with respect to PFS/OAS in case of first tumour manifestation. The combination of high MTV and ASP showed very high HRs of 22.7 for PFS and 13.2 for OAS. In case of recurrence, MTV (HR = 3.7) and the combination of MTV/ASP (HR = 4.2) were significant predictors of PFS. ASP of pretherapeutic FDG uptake in the primary tumour improves the prediction of tumour progression in head-and-neck cancer at first tumour presentation. Asphericity (ASP) characterises the spatial heterogeneity of FDG uptake in tumours. ASP is a promising prognostic parameter in head-and-neck cancer. ASP is useful for identification of high-risk patients with head-and-neck cancer.

Prognostic significance of heme oxygenase-1, S100 calcium-binding protein A4, and syndecan-1 expression in primary non-muscle-invasive bladder cancer.

We investigated the prognostic significance of heme oxygenase-1 (HO-1), S100 calcium-binding protein A4 (S100A4), and syndecan-1 (SYND1) expression in patients with primary non-muscle-invasive bladder cancer (NMIBC). Immunohistochemical studies were performed on tissue specimens from 109 patients diagnosed with primary NMIBC following complete transurethral resection, with the expression dichotomized as negative/mild ("low") versus moderate/strong ("high") according to scores based on staining area and intensity. The effect of each biomarker on recurrence-free survival (RFS) and progression-free survival (PFS) was analyzed. The predictive accuracy for RFS and PFS in multivariate Cox regression models with or without (the baseline model) biomarkers was estimated using the Harrell concordance index. High HO-1, S100A4, and SYND1 expressions were observed in 33.0%, 36.7%, and 63.3% cases, respectively. High HO-1 and S100A4 expressions were significantly associated with various adverse pathological characteristics (high T stage and grade); SYND1 expression was inversely correlated with these characteristics (all, P < .05). In the baseline multivariate model, multifocality, intravesical therapy, and T stage were significant predictors for RFS, whereas intravesical therapy and T stage had marginal statistical significance in predicting PFS. In the multivariate model with the biomarkers, the 3 biomarkers were significant predictors for RFS; and HO-1 expression was a significant predictor for PFS. Addition of the 3 biomarkers to the baseline model significantly increased the predictive accuracy for RFS from 0.754 to 0.828 (P = .043). Our findings suggest that HO-1, S100A4, and SYND1 expressions have prognostic value in primary NMIBC; thus, their evaluation might be useful for determining treatment strategies.

Prognostic significance of the epithelial-to-mesenchymal transition markers e-cadherin, vimentin and twist in bladder cancer.

The goal of this study was to utilize long-term patient follow-up to determine whether epithelial-to-mesenchymal transition (EMT)-related markers can predict bladder cancer patient survival and progression of disease. This study included 121 patients with bladder cancer. Sixty-four of these patients presented with non-muscle invasive (NMI, stage T1) bladder cancer and 57 with muscle invasive (MI, stage T2, T3). The patients were diagnosed and treated between May 1998 and July 2012. The EMT markers E-cadherin, Twist, and Vimentin were detected via immunohistochemistry. Univariate and multivariate/Cox analyses were then utilized to determine whether these EMT markers could be useful prognostic markers for predicting bladder cancer patient outcomes. Analysis of the 121 bladder cancer patients in this study revealed that the frequency of E-cadherin expression was 59.5% (72/121), Twist was 54.5% (66/121), and Vimentin was 24.8% (30/121). Twist and Vimentin were found to have statistically significant correlations with grade, recurrence, and progression but not with stage, whereas E-cadherin was associated with stage but not with the other parameters. In the univariate analysis, grade (p = 0.02) was the only significant predictor for progression-free survival (PFS). Stage, grade, and expression of E-cadherin, Vimentin and Twist were included in the multivariate analysis of predicting PFS. In this analysis, grade (p = 0.01) and Vimentin expression (p = 0.001) were found to be significant prognostic factors in predicting PFS. Grade and Vimentin are potential independent indicators in predicting bladder cancer progression and survival.

VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: The ALICE‐1 study

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.

Presence of intraductal carcinoma of the prostate on needle biopsy as a prognostic factor for prostate cancer in radical prostatectomy patients.

268 Background: Intraductal carcinoma of the prostate (IDCP) is seen with widely invasive, biologically aggressive prostate cancer. A recent study has shown this morphologic pattern is useful for prognostication of biochemical recurrence after radical prostatectomy, whereas there is no paper to report biopsy finding of IDCP to be a positive predictor of progression-free survival (PFS) and cancer-specific survival (CSS). Methods: This retrospective study included men with high-risk prostate cancer treated with radical prostatectomy between 1991 and 2005, and we reviewed slides of biopsy samples. Presence of IDCP was defined using previously published diagnostic criteria by a single genitourinary pathologist. Analyzed factors included age, prostate-specific antigen (PSA), clinical T stage, higher biopsy Gleason score (bGS), presence of Gleason pattern five, and IDCP on biopsy samples. Finally, a total of 205 patients with high-risk prostate cancer were entered in our retrospective clinicopathological analysis. Results: Patient mean age was 68. Baseline characteristics included a PSA greater than 20 ng/ml at diagnosis in 122 cases (60%), clinical stage greater than T2 (cT) in 86 (42%), and bGS ³a8 in 150 (73%) in all patients. Follow-up period was 86 months on average. The presence of IDCP on needle biopsy was in 75 (37%). Forty-four patients showed clinical failure, and 20 patients died of the disease. Patients with IDCP showed a higher increased PSA level, higher increased bGS, and more advanced cT than those without IDCP (p &lt; 0.0001). In univariate analysis, IDCP (p &lt; 0.0001), cT (p &lt; 0.0001), bGS (p = 0.0002), and presence of Gleason pattern five (p=0.004) were significantly associated with PFS; IDCP (p &lt; 0.001) and cT (p = 0.02) were significantly associated with CSS. In multivariate analysis, IDCP (p&lt; 0.0001; hazard ratio (HR), 3.574) and cT (p= 0.004; HR, 3.087) were significantly associated with PFS; IDCP (p = 0.001; HR, 8.405) and PSA level (p = 0.0044; HR, 2.920) were significantly associated with CSS. Conclusions: Presence of IDCP on needle biopsy can be a significant predictor of PFS and CSS when analyzing factors of biopsy samples in high risk prostate cancer.

Radiation therapy with concurrent chemotherapy for locally advanced cervical carcinoma: outcome analysis with emphasis on the impact of treatment duration on outcome.

Objective. To assess the effectiveness and toxicity of carboplatin concurrent with pelvic external beam radiation and low-dose rate brachytherapy and to assess the impact that adherence to the treatment plan has on outcomes. Methods. Retrospective chart review of 56 patients treated from January 2001 to December 2010. Results. Median follow-up was 68 months. Optimal dose of radiation (ORT) was defined as a minimal cervical dose exceeding 70 Gy, point A dose of 80–90 Gy, and duration not exceeding 56 days. Only 50% received ORT. In multivariable analyses we only found ORT to be statistically significant predictor for progression-free survival (PFS) and overall survival (OS) (HR [95% CI] for non-ORT vs. ORT: 2.4 [1.2, 5.1], P = 0.014 for PFS and 2.2 [1.1, 4.6], P = 0.035 for OS). The 5-year PFS in patients who received ORT was better than that in patients who received non-ORT, 56% vs. 22% (95% CI: [36%, 72%] vs. [9%, 39%]). Patients who received ORT had a better 5-year OS as well (59% vs. 33%; 95% CI: [38%, 75%] vs. [16%, 51%]). Conclusion. Patients with locally advanced cervical cancer treated with weakly carboplatin or cisplatin, teletherapy, and low dose-dose rate brachytherapy have poorer outcomes when treatment duration is prolonged.