Independent Predictive Factor For Response Research Articles

Obinutuzumab plus bendamustine for relapsed/refractory chronic lymphocytic leukemia and predictive and prognostic impact of genetic alterations: the phase II GABRIELL study

GABRIELL was a phase II single-arm study to evaluate the efficacy and safety of obinutuzumab plus bendamustine for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Seventy-two patients with active disease received treatment for up to six 28-day cycles. Overall response rate was 78.6% with a median progression-free survival (PFS) of 26 months, and overall survival (OS) not reached at the end of follow-up (36 months). Undetectable measurable residual disease (≤0.01%; 36.4% in bone marrow and 53.4% in peripheral blood) correlated with a significantly longer PFS and OS (vs. >0.01). Common grade ≥3 adverse events (76.4%) were neutropenia (58.3%), thrombocytopenia (26.4%) and febrile neutropenia (11.1%). TP53 disruption was the only independent predictive factor for response (Hazard ratio; HR: 0.228). Unmutated immunoglobulin heavy chain variable region (HR: 16.061) was a negative prognostic factor for PFS. In conclusion, the combination of obinutuzumab plus bendamustine is an active and generally adequately-tolerated treatment for R/R CLL.

Predictive clinico-pathological factors to identify BCG, unresponsive patients, after re-resection for T1 high grade non-muscle invasive bladder cancer.

Seventy-five percent of bladder cancers are non-muscle invasive. The treatment strategy includes the transurethral resection of bladder tumor (TURB) followed by intravesical immunotherapy with the bacillus of Calmette-Guerin (BCG) or chemotherapy, depending on the grade of bladder tumor. Despite a proper BCG intravesical instillations schedule, up to 40% of patients present a failure within 2 years. The aim of this retrospective study was to investigate the predictive factors in the response to BCG in patients with a high-grade non-muscle invasive bladder cancer diagnosis. Patients with non-muscle invasive bladder cancer from 13 hospitals and academic institutions were identified and treated, from January 1, 2002, until December 31, 2012, with TURB and a subsequent re-TURB for restaging before receiving BCG. Follow-up was performed with urine cytology and cystoscopy every 3 months for 1 year and, successively every 6 months. Univariate and multivariate Cox regression models addressed the response to BCG therapy. Kaplan-Meier overall survival (OS) and cancer-specific survival (CSS) estimates were determined for BCG responsive vs. BCG unresponsive patients. A total of 1,228 patients with non-muscle invasive bladder cancer were enrolled. Of 257 (20.9%) patients were BCG unresponsive. Independent predictive factors for response to BCG were: multifocality (HR: 1.4; 95% CI 1.05-1.86; P = 0.019), lymphovascular invasion (HR: 1.75; 95% CI 1.22-2.49; P = 0.002) and high-grade on re-TURB (HR: 1.39; 95% CI 1.02-1.91; P = 0.037). Overall survival was significantly reduced in BCG-unresponsive patients compared to BCG-responsive patients at 5 years (82.9% vs. 92.4%, P < 0.0001) and at 10 years (44.2% vs. 74.4%, P < 0.0001). Similarly, cancer-specific survival was reduced in BCG-unresponsive patients at 5 years (90.6% vs. 97.3%, P < 0.0001) and at 10 years (72.3% vs. 87.2%, P < 0.0001). Multifocality, lymphovascular invasion, and high-grade on re-TURB were independent predictors for response to BCG treatment. BCG-unresponsive patients reported worse oncological outcomes.

Factors associated with the outcomes in ulcerative colitis patients undergoing granulocyte and monocyte adsorptive apheresis as remission induction therapy: A multicenter cohort study.

Ulcerative colitis (UC) patients harbor activated myeloid leukocytes, which exacerbate and perpetuate UC by releasing inflammatory cytokines. Granulocyte and monocyte adsorptive apheresis (GMA) with an Adacolumn depletes elevated myeloid leukocytes, inducing efficacy with favorable safety. To understand how the clinical outcome with GMA is affected by prior corticosteroid treatment or concomitant immunomodulators, a retrospective multicenter study in 102 UC patients, who had not responded well to first-line medications was undertaken. The remission rates after a course of GMA therapy were significantly higher in corticosteroid-naïve patients compared with those with prior corticosteroid exposure. Absence of corticosteroid background was an independent predictive factor of response to GMA. Further, in corticosteroid-naïve patients, the 1-year cumulative sustained remission rate in patients who did not receive immunomodulators was significantly higher than in patients who received immunomodulators. Accordingly, multivariate analysis revealed that immunomodulator was associated with higher risk of relapse. In conclusion, GMA was an effective treatment for corticosteroid-naïve patients and the efficacy sustained longer in those not receiving immunomodulators during GMA. GMA fulfills the notion that apheresis is to induce disease remission by removing from the body factors known to perpetuate disease. In therapeutic settings, these findings should help better decision making and avoid futile use of medical resources.

Increased CD3+ T cells with a low FOXP3+/CD8+ T cell ratio can predict anti-PD-1 therapeutic response in non-small cell lung cancer patients

To determine whether tumor microenvironments affect the clinical response to anti-PD-1 therapy in non-small cell lung cancer, we investigated the expression level of PD-L1 and tumor infiltrating lymphocytes and elucidate their predictive role. Thirty-eight pretreatment and two post-treatment specimens from 36 advanced, treatment-refractory non-small cell lung cancer patients who underwent PD-1 blockade therapy were analyzed. PD-L1 expression by tumor cells and the distribution of CD3, CD8, CD4, FOXP3 and PD-1 positive tumor infiltrating lymphocytes were immunohistochemically assessed and counted using digital image analyzer. CD3+ and CD8+ T cells were distributed more in PD-L1 positive group compared to PD-L1 negative group. Conversely, EGFR mutant group showed fewer CD3+ T cells than EGFR-naïve group. The patients in the clinical benefit group with PD-1 blockade showed a higher number of CD3+, CD8+ T cells and a higher CD8+/CD3+ T cell ratio (p = 0.003, p = 0.001, and p = 0.042) and a lower FOXP3+/CD8+ T cell ratio compared to non-responders (p = 0.001). In multivariate logistic regression analysis, increased CD3+ T cell infiltration and low FOXP3+/CD8+ T cell ratio were found to be independent predictors of clinical benefit with PD-1 blockade (p = 0.014 and p = 0.03, respectively). Using receiver operating characteristic curves, levels of CD3+ T cells and FOXP3+/CD8+ T cell ratio that provide the best distinguishing point between responder versus non-responder to PD-1 blockade were 617.5/mm2 and 25%, respectively (p = 0.007 and p = 0.003). Considering that 1 mm2 is about 5 high power fields (HPF), a good response to the PD-1 blockade can be expected when the number of CD3 T cells is observed to be 120 per HPF and when CD8+ T cells and FOXP3+ T cells are present at a ratio greater than 4:1. Tumor infiltrating lymphocytes might become a promising biomarker as an independent predictive factor of response to PD-1 blockade that may also guide therapeutic decisions.

P501 High TNF-production of CD14+ cells and short disease duration are independent predictive factors for response to Infliximab treatment

P501 High TNF-production of CD14+ cells and short disease duration are independent predictive factors for response to Infliximab treatment

Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma.

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A receiver operating characteristic curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but, on the other hand, predicted a poor response to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.

ERCC1_202 Is A Prognostic Biomarker in Advanced Stage Non-Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

Purpose: To develop a qPCR method to examine the 202 isoform of excision repair cross-complementation group 1 (ERCC1_202) and to evaluate its clinical utility as a predictive biomarker for platinum-based chemotherapy in non-small cell lung cancer (NSCLC).Methods: The relative complementary DNA (cDNA) quantification for ERCC1_202 was conducted using a fluorescence-based, real-time detection method and β-actin was used as a reference gene.Results: A strong correlation was observed between ERCC1_202 mRNA and ERCC1 mRNA levels in NSCLC cells (P < 0.001). 28 patients completed this research. Our results implied that as ERCC1_202 levels increased, the risk of progression (HR = 4.296, P = 0.011) and death (HR = 6.503, P = 0.001) increased. At multivariate analysis, high expression of ERCC1_202 was shown to be an independent predictive factor for time to progression (P = 0.047), and progression-free survival (P = 0.014). However, the high expression of ERCC1_202 was not an independent predictive factor for response (P = 0.324).Conclusions: This study suggests that the efficacy of platinum-based chemotherapy can be improved when customized according to the expression of ERCC1_202.

Impact of Telaprevir in HCV Patients with Cirrhosis and RVR: Real-Life Data from Boceprevir or Telaprevir based "Triple Therapy" Experience in Southern Italy.

125 (70%) patients were treated with telaprevir, and 51(30%) with boceprevir. There were no differences in demographic characteristics between the groups. The degree of Liver Fibrosis (LF) was evaluated according to Liver Biopsy (LB) and/or Transient Elastography (TE). 53/176 patients (30%) had liver cirrhosis. Sixteen patients (9%) were treatment naïve, and the remaining were not: 92 were non-responders (52, 84%), 63 relapsed (35,79%), and 5 discontinued treatment (2, 8%). Overall, the rapid Virological Response (RVR) rate was 67.6%. Of the 103 patients who had follow-up for at least 12 weeks after the end of treatment, 61 (59, 2%) achieved a Sustained Virological Response (SVR). According to multivariate analysis for SVR, RVR was the only independent predictive factor of SVR, irrespective of the degree of LF and the type of response to previous treatments. In telaprevir-treated patients, the rate of RVR was similar in patients with F0-F2, F3 and F4 fibrosis (85%, 84%, 78%, respectively), and the SVR rates among RVR patients was similar irrespective of LF. Data from this real-life study confirm the efficacy reported in clinical trials, although cirrhosis appears to play a smaller role in influencing treatment efficacy. Moreover, RVR is the only independent predictive factor of response regardless of cirrhosis. Based on RVR and for patients with cirrhosis, a shorter therapy might be considered, at least with telaprevir-based therapy.

Alteration of circulating endothelial progenitor cell counts could be an independent predictive factor for response to neoadjuvant chemotherapy in patients with breast cancer

Alteration of circulating endothelial progenitor cell counts could be an independent predictive factor for response to neoadjuvant chemotherapy in patients with breast cancer

Prognostic significance of BRCA1, ERCC1, RRM1, and RRM2 in patients with advanced non-small cell lung cancer receiving chemotherapy.

The aim of this study was to examine the prognostic value of breast cancer susceptibility gene 1 (BRCA1), excision repair cross-complementation 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), and ribonucleotide reductase subunit M2 (RRM2) in patients with advanced non-small cell lung cancer (NSCLC) who received platinum-based chemotherapy. A total of 214 patients with histologically or cytologically confirmed advanced NSCLC were enrolled in this study. The relative complementary DNA (cDNA) quantification for BRCA1, ERCC1, RRM1, and RRM2 was conducted using a fluorescence-based, real-time detection method, and β-actin was used as a reference gene. A strong correlation was observed between ERCC1 and RRM1 messenger RNA (mRNA) levels (P = 0.0385). There were inverse significant correlations between BRCA1 and ERCC1 (P < 0.0001) or RRM1 (P < 0.0001) mRNA levels. As BRCA1 levels increased, the probability of response increased (odds ratio [OR] = 0.49; P < 0.001) and the risk of progression (hazard ratio [HR] = 1.52; P = 0.034) and death (HR = 1.45; P = 0.024) decreased. As ERCC1, RRM1, and RRM2 levels increased, the probability of response decreased (ERCC1, OR = 0.42, P < 0.001; RRM1, OR = 0.85, P = 0.083; RRM2, OR = 0.42, P = 0.005) and the risk of progression (ERCC1, HR = 1.59, P = 0.002; RRM1, HR = 1.48, P = 0.039; RRM2, HR = 1.49, P = 0.041) and death (ERCC1, HR = 1.62, P = 0.008; RRM1, HR = 1.52, P = 0.023; RRM2, HR = 1.48, P = 0.017) increased. At multivariate analysis, low expression of ERCC1 was shown to be an independent predictive factor for response to chemotherapy (P = 0.018), time to progression (P = 0.025), and overall survival (P = 0.038). Furthermore, concomitant low expression levels of ERCC1, RRM1, and RRM2 and the high expression level of BRCA1 were predictive of a better outcome (P = 0.014). This study suggests that the efficacy of platinum-based chemotherapy can be improved when customized according to the mRNA expression of BRCA1, ERCC1, RRM1, and RRM2.

AB0298 High level of anti-ccp antibodies is predictive of good response to rituximab in patients with active rheumatoid arthritis.

BackgroundIn the current era, where the number of new biologic targets and related therapies for rheumatoid arthritis (RA) is rapidly increasing, identification of factors that predicts the response to biologic...

High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM

Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500IU/L received DAR 500μg once every 2weeks for 12weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56% at 12 and 24weeks, respectively. Addition of G-CSF rescued 22% of non-responders. In 48% of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12weeks, and its most discriminant cutoff value was 100IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70%, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.

Low-Dose Radiotherapy in Patients with Non Hodgkin Lymphoma

AbstractAbstract 4875 Background:Some studies have showed high activity for low-dose radiotherapy (LDRT) in low-grade Non-Hodgkin Lymphoma (NHL). However, this therapeutic approach is often forgotten and other approaches are used - chemotherapy and/or conventional radiotherapy - associated with greater toxicity. The efficacy of total body LDRT (1.5–2 Gy, fractions 0.1–0.25 Gy in 2 – 5 times a week) in disseminated disease is associated with 10 year progression free survival (PFS) of 15 – 25%, with response rates of 70 – 90% (Gérard et al., IJ Radiation Oncology 2010; 78), despite hematologic toxicity and leukemogenic effects. Although its mechanism of action is unknown, its effectiveness has been confirmed (Jones et al., Cancer 1973; 32) suggesting that low dose radiation induces localized lymphocytes apoptosis that can trigger local and systemic benefits. More recently, LDRT was used in palliative treatment for patients with localized disease (4Gy into two fractions, for 3 days) with a low toxicity, and with an objective response (partial or complete) in 24/37 patients, 89% (G Ganem et al., Hematol Oncol1997; 42). Objectives:To assess the response to treatment with LDRT. Explore the predictive factors of response. Determine the progression-free survival (PFS) after LDRT. We will present PFS after LDRT and compare PFS in second line treatment: LDRT vs convencional chemotherapy. Methods:Retrospective study of 44 patients with new or recurrent NHL, treated with LDRT (4Gy in 2 fractions) in 1stor more lines, in a cancer care centre between 2004 and 2011.All transformed lymphomas were excluded (4 patients), as well all diagnosis that weren't centrally reviewed. Patients with complete resolution of the disease according to clinical and/or image studies were considered to have achieved complete response (CR). Results:We identified 40 patients undergoing LDRT, with a median follow-up of 69,5 months after LDRT ([28–87]). 52,5% (n = 21) were male, median age at the time of LDRT was 69 years ([31–85]). 75% of patients (n = 30) had follicular NHL, 12,5% (n = 5) Mantle cell NHL, 10% (n = 4) Marginal Zone NHL and 2,5% (n = 1) lymphoplasmacytic lymphoma.The median numbers of lines of chemotherapy completed before LDRT were 2 lines ([0–5]). There wasn’t any impact on PFS on using Rituximab containing regimens after LDRT (p> 0,05). The overall response rate to LDRT was 92,5% (n = 37): 42,5% (n = 17) achieved complete response (CR), 50% (n = 20) partial response (PR) and 7,5% (n = 3) had disease progression. There weren’t any treatment related toxicities, nor was histological transformation recorded after treatment with LDRT. The logistic regression analysis showed that irradiated areas with dimension <40mm are an independent predictive factor of response (p <0,031, 95% CI [1,268-133,285]). We find a median PFS of 4 months ([0–72]) for patients that went on LDRT, and 50% of these patients relapsed after a median 5 months ([0–35]). 56,5% (n = 13) showed relapse at the same location of the irradiated area. Patients who have completed one chemotherapy scheme after relapsing following LDRT, showed a rate of 6 months-PFS of 50% such as the patients that have done a second LDRT treatment.Concerning follicular NHL patients who relapsed after 1st line conventional chemotherapy, 43,8% (n = 7) were treated with LDRT and 56,2% (n = 9) were treated with conventional 2nd line chemotherapy. Comparing these two groups of patients, there weren’t any difference for PFS for both groups (mean 9,5 vs 9 months p> 0,05, for LDRT vs 2ndline chemotherapy), for equal overall survival. Conclusion:LDRT is an effective treatment for patients with relapsed or recurrent advanced stage NHL. We can obtain high response rates with negligible toxicity. In the treatment of first relapse, PFS is similar when using LDRT or 2nd line chemotherapy. Considering that Rituximab promotes a synergistic effect with LDRT-induced apoptosis and decrease the cell turnover (Skvortsova I et al., J Radiat Res (Tokyo) 2006), comparative studies with conventional chemotherapy regimens should be promoted. Treatment with conventional radiotherapy should be used in patients with relapsed low-stage and localized disease, having curative intention or locally controlling involved areas. Disclosures:No relevant conflicts of interest to declare.

Predictive factors of response to intravenous ciclosporin in severe ulcerative colitis: the development of a novel prediction formula

When treating patients with severe ulcerative colitis (UC), accurate prediction of drug efficacy contributes to early clinical decision-making. To identify predictive factors and to develop a reliable prediction formula and a decision tree of response to intravenous ciclosporin treatment for severe UC. Patients included in this study were those diagnosed with refractory severe UC who had undergone ciclosporin treatment between December 2004 and March 2011 at a tertiary referral centre in Japan. Demographic and clinical parameters from all patients were analysed by multivariate statistics. Fifty-two patients were included in this study (36.5% men with an average age of ciclosporin initiation of 40.2±15.6years). Thirty-four patients (65.4%) were responders to the treatment with ciclosporin and avoided colectomy, 18 patients (34.6%) were nonresponders and underwent colectomy. Stepwise multiple logistic regression analysis identified four independent predictive factors of response to intravenous ciclosporin: age at hospitalisation (AGE), platelet count (×10(4) /μL) on the first day (PLA), Lichtiger score on the third day (LIC) and total protein (g/dL) on the third day minus total protein on the first day (ΔTP). The calculation formula (8.5 - 0.16 × AGE + 0.21 × PLA - 0.61 ×LIC+2.3×ΔTP<0) predicted colectomy with an accuracy of 88.5% and the decision tree predicted colectomy with an accuracy of 90.4%. The novel calculation formula and the decision tree effectively predict the clinical outcome of ciclosporin treatment for severe ulcerative colitis as early as on day 3 after starting ciclosporin treatment.

277P - Serum Concentration of Estrone (E1), not Estradiol (E2), is the Independent Predictive Factor of Response to Neo-Adjuvant Exemestane Treatment in Postmenopausal Breast Cancer Patients: JFMC 34-0601 TR

ABSTRACT Background Local production of estrogen using aromatase at tumor site was thought to be the direct target of aromatase inhibitor (AI). However recent our works (Honma N, Can Sci 2011, Takada M, Breast 2012) and others (Lonning PE, Clin Can Res 2011) postulated that not local aromatase but whole body aromatase (possibly correlates to serum estrone (E1) level) would be the critical target of this drug. Patients and methods Among the 116 postmenopausal patients who enrolled to the JFMC 34-0601 phase II clinical trial of neo-adjuvant 24 weeks (wks) treatment with AI, exemestane, serums from 60 patients at pre-treatment, at 4wks and at the end of treatment (24wks) were subjected to this study. Estradiol (E2), E1, dehydroepiandrosterone (DHEA) and androstenedione (A) were measured using LC-MS/MS analysis for precise measurement, and E1- sulfate (E1S) was by RIA. Results Mean pre-treatment serum levels of E2, E1 and E1S were 2.29, 12.86 and 198.87 pg/ml, respectively. All these estrogens decreased to under-detection level (0.5 pg/assay for E1 and E2, 5 pg/assay for E1S) at 4wks of treatment, and it maintained to the end of the treatment in almost all patients irrespective of clinical response. Patients with higher concentration of pre-treatment E2 and E1 (cutoff = mean value) had more chance to obtain clinical objective response (p = 0.0245 and p = 0.0448, respectively). However in multivariate analysis, only E1 is the independent predictive factor for objective response (Odds 5.97, p = 0.0113), probably due to positive correlation of E2 to BMI, which is also predictive factor for AI response. When comparing pre-treatment level and those at 24wks (or at termination of treatment), patients with progressive disease showed significant increase of DHEA and A (p = 0.0313 for both), although patients with objective response maintained those at the same level. Conclusion Pretreatment serum concentration of E1, not E2, is the independent predictive factor of clinical response to neo-adjuvant exemestane. Patients with disease progression showed significant increase of androgens during the treatment. Serum steroid concentrations using precise LC-MS/MS analysis may have the informative value for the AI treatment, and the increased androgens would be the important subject to be studied further. (UMIN trial ID; 00345) Disclosure S. Saji: S.S. has a honorarium for lecture from Pfizer. M. Toi: M.T. has a research grant and honorarium for lecture from Pfizer. All other authors have declared no conflicts of interest.

Increase in circulating endothelial progenitor cells predicts response in patients with advanced non‐small‐cell lung cancer

Previous reports have shown that circulating endothelial progenitor cells (CEPs) are released in response to cytotoxic chemotherapy. We investigate the relationship between the kinetics of CEPs during one cycle of chemotherapy and the response to cytotoxic chemotherapy and prognostic impacts. Previously untreated patients (n = 38) receiving cytotoxic chemotherapy for non-small-cell lung cancer were included. Blood sampling was carried out on day 1, day 8, and just before the second cycle of chemotherapy. The mononuclear cell fraction was analyzed for CEPs by FACS analysis. We evaluated the relationship between the kinetics of CEPs, each independent clinicopathological variable, the response to chemotherapy, and the risk factors associated with prognosis. On the eighth day after chemotherapy, a significant decrease in CEPs was observed. In contrast, CEP counts before the second cycle of chemotherapy were significantly increased. The high percentage change in CEPs between day 1 and before the second cycle of chemotherapy is an independent predictive factor for response to chemotherapy. However, the change in CEP levels did not predict progression-free survival. These findings indicate that the late release of CEPs is a common phenomenon after chemotherapeutic treatment. The correlation with clinical response to chemotherapy provides further support for the biologic relevance of these cells in patients' prognosis and highlights the potential use of CEPs as therapeutic targets.

Serum-transforming growth factor-α (TGF-α) and response to lapatinib plus capecitabine in HER2-positive (HER2+) metastatic breast cancer (MBC).

1102 Background: Although lapatinib plus capecitabine is effective in trastuzumab-resistant HER2+ MBC, predictive biomarker of the treatment has not been identified. We investigated biomarkers from serum of patients receiving lapatinib and capecitabine. Methods: Patients received lapatinib 1,250 mg once daily and capecitabine 2,000 mg/m2/day, day 1 to 14, every 3 weeks. Serum samples were obtained prior to treatment initiation. Levels of TGF-α, EGF, EGFR-extracellular domain (ECD) and HER2-ECD were measured by ELISA. We analyzed the association between the serum levels and response to the treatment. Besides, the effect of TGF-α on in vitro sensitivity of SK-BR-3 cells to lapatinib was investigated. Results: A total of 64 women were enrolled. All patients had HER2+ MBC and had progressed after trastuzumab containing regimen. The overall response rate was 31.3% and median TTP was 4.5 months in the study population. Among the serum markers, serum TGF-α level was significantly lower in responders (PR) compared to nonresponders (SD or PD) (median, 3.5 vs. 8.2 pg/mL; p=0.005). The EGFR-ECD level tended to be lower in responders than nonresponders (median, 21.9 vs. 24.9 ng/mL; p=0.190). The response rate was significantly higher in patients with low (≤3.75 pg/mL) than high TGF-α [61.1% (11/18) vs. 19.6% (9/46), respectively; p=0.001]. The response rate was also significantly higher in patients with low (≤22.2 ng/mL) than high EGFR-ECD [50.0% (11/22) vs. 21.4% (9/42), respectively; p=0.019]. In multivariate analysis adjusting for baseline characteristics, low serum TGF-α (adjusted OR, 17.1; 95% CI, 3.19 - 91.7) and low EGFR-ECD (adjusted OR, 10.7; 95% CI, 2.07 - 55.1) were independent predictive factors for response. Patients with low TGF-α tended to have longer TTP than those with high TGF-α [median, 6.5 (95% CI, 6.1-6.8) vs. 3.8 months (95% CI, 2.3-5.4); p=.067]. We confirmed that TGF-α diminished the sensitivity of SK-BR-3 cell to lapatinib in vitro, which was restored by cetuximab. Conclusions: These data suggest that TGF-α plays a role in resistance to lapatinib and capecitabine in HER2+ MBC. No significant financial relationships to disclose.

Predictive Factors of Response to Decongestive Therapy in Patients with Breast-Cancer-Related Lymphedema

Many studies have reported the benefits of Decongestive treatment in patients with breast-cancer-related lymphedema (BCRL) but few have study what are the predictive factors of response. We performed a prospective, multicenter controlled cohort study of 171 patients with BCRL to identify independent predictive factors of response to decongestive treatment (CDT). Demographic data and clinical and lymphedema characteristics were collected prospectively. The end point was the "percentage reduction in excess volume (PREV)." Volumes were measured prior and at the end of CDT. Factors associated with response (PREV) were tested in univariate and multivariate analyses using linear regression techniques. Median age was 60.4 years (range 32-84); mean lymphedema chronicity 4 years [95% confidence interval (95% CI): 3.1-5.0]; mean baseline excess volume (EV) was 936 mL (95% CI: 846-1026), and mean percentage EV was 35.3% (95% CI: 32.0-38.7); compliance to bandages was good in 81.3% of patients. PREV was 71.7% (95% CI: 65.2-78.2). After univariate screening, 11 variables were found to be associated with PREV but only 4 variables were independent predictive factors of response to CDT in the multivariate analysis: Venous insufficiency, percentage of EV (the higher the EV, the lower the reduction with CDT); compliance to bandages (a good compliance improved PREV in 25%), and treatment in autumn (better results than during the rest of the year). This study shows that compliance to bandages during CDT is one of the most important predictors of response. Moreover, data support the idea that more severe lymphedemas have a worse response to treatment, and it should be recommended in early stages. The association between the season of treatment and response was also very strong, so weather conditions are an additional factor that must be taken into account in further studies.

Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome

Terlipressin plus albumin is an effective treatment for type 1 hepatorenal syndrome (HRS), but approximately only half of the patients respond to this therapy. The aim of this study was to assess predictive factors of response to treatment with terlipressin and albumin in patients with type 1 HRS. Thirty-nine patients with cirrhosis and type 1 HRS were treated prospectively with terlipressin and albumin. Demographic, clinical, and laboratory variables obtained before the initiation of treatment as well as changes in arterial pressure during treatment were analyzed for their predictive value. Response to therapy (reduction in serum creatinine <1.5 mg/dL at the end of treatment) was observed in 18 patients (46%) and was associated with an improvement in circulatory function. Independent predictive factors of response to therapy were baseline serum bilirubin and an increase in mean arterial pressure of >or=5 mm Hg at day 3 of treatment. The cutoff level of serum bilirubin that best predicted response to treatment was 10 mg/dL (area under the receiver operating characteristic curve, 0.77; P < 0.0001; sensitivity, 89%; specificity, 61%). Response rates in patients with serum bilirubin <10 mg/dL or >or=10 mg/dL were 67% and 13%, respectively (P = 0.001). Corresponding values in patients with an increase in mean arterial pressure >or=5 mm Hg or <5 mm Hg at day 3 were 73% and 36%, respectively (P = 0.037). Serum bilirubin and an early increase in arterial pressure predict response to treatment with terlipressin and albumin in type 1 HRS. Alternative treatment strategies to terlipressin and albumin should be investigated for patients with type 1 HRS and low likelihood of response to vasoconstrictor therapy.

Sex difference in the influence of smoking status on the responsiveness to gefitinib monotherapy in adenocarcinoma of the lung: Okayama Lung Cancer Study Group experience

Gefitinib is effective in patients with lung adenocarcinoma. Smoking status also affects the responsiveness to gefitinib, but it has not been fully evaluated whether a sex difference exists in the influence of smoking on the efficacy of gefitinib in patients with lung adenocarcinoma. We reviewed the clinical records of 260 Japanese patients with lung adenocarcinoma who received gefitinib therapy (250 mg/day), and whose smoking status was known. Tumour response and survival were evaluated and stratified by smoking status and gender. Among the 260 patients, 157 were male (60%). Median pack-years was 40 (range 8-160) and 23 (range 1-74) in male and female smokers, respectively. Objective response was observed in 62 (23.8%) of the 260 patients, and 1-year overall survival and progression-free survival were 45.1 and 24.3%, respectively. Multivariate analysis revealed that smoking status (pack-years) was an independent predictive factor for response to gefitinib [odds ratio (OR) = 0.971, 95% confidence interval (CI) = 0.947-0.995; P = 0.0159] in male patients, but not in female patients (OR = 0.999, 95%CI = 0.957-1.042). Additionally, pack-years significantly influenced the overall survival in males (hazard ratio = 1.010; 95%CI = 1.002-1018, P = 0.0169), while differential survival of females was not significantly predicted by this factor (P = 0.7639). In male patients with lung adenocarcinoma, cumulative smoking significantly affected response and survival following gefitinib treatment, while in female patients, responsiveness to gefitinib was independent of smoking status. These results suggest that the influence of smoking habit on responsiveness to gefitinib is gender specific.