Lower Progression-free Survival Research Articles

Clinical impact of bulky mass in the patient with primary extranodal diffuse large B cell lymphoma treated with R-CHOP therapy

Although numerous studies about primary extranodal diffuse large B cell lymphoma (DLBCL) were reported sporadically, the literature of clinical value of immunophenotype and bulky diameter in rituximab era is limited. Ninety-six patients with primary extranodal DLBCL receiving R-CHOP therapy were analyzed to evaluate whether immunophenotype and size of bulky disease are significantly important. The International Prognostic Index was still an important prognostic factor for progression-free survival (PFS) and overall survival (OS; p = 0.003, p = 0.027). Difference of survival between germinal center (GC) type and non-GC type was not different (PFS: p = 0.192; OS: p = 0.197). In two separated groups according to extranodal maximum tumor diameter (EN-MTD) 7.5 cm as cutoff value for survival, the group of EN-MTD > or =7.5 cm had lower PFS and OS than <7.5 cm (PFS: p = 0.001; OS: p = 0.008). In four divided subgroups according to EN-MTD combined with immunophenotype, the subgroup of non-GC type with EN-MTD > or = 7.5 cm had lower PFS and OS compared with the other subgroups (PFS: p < 0.001; OS: p = 0.008). Multivariate analysis revealed that non-GC with EN-MTD > or = 7.5 cm was an independent prognostic parameter (PFS: HR = 5.407, 95%CI = 2.378-12.294, p < 0.001; OS: HR = 4.136, 95%CI = 1.721-9.941, p = 0.002). Bulky primary extranodal DLBCL would be associated with unfavorable outcome especially in non-GC type.

Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma

CHOP-like regimen combined with rituximab is a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). The relative dose intensity (RDI) was proposed as an index of the dose and administration interval of agents. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. However, few studies regarding RDI have reviewed patients receiving combination therapy with CHOP and rituximab. We investigated the influence of RDI maintenance, involving combination therapy with rituximab, on therapeutic effects in patients with DLBCL. We retrospectively examined 152 DLBCL patients who were treated with CHOP-like regimen combined with rituximab in whom the RDI could be followed up. Multivariate analysis revealed that international prognosis index (IPI) high intermediate-high (HI-H) (p = 0.005) and RDI of less than 70% (p = 0.007) were independent prognostic factors for low progression free survival. Concerning overall survival, IPI HI-H (p = 0.027) and an RDI of less than 70% (p = 0.002) were involved in an unfavorable prognosis. In addition, age over 60 years (p = 0.003), R-THPCOP (p = 0.034), or the presence of febrile neutropenia (p = 0.004) made RDI maintenance difficult, and prophylactic G-CSF therapy (p = 0.026) was useful for maintaining the RDI. Maintaining the RDI is important even in the era of rituximab-combined chemotherapy for DLBCL.

Abstract 5720: Chromosomal instability predicts the progression of premalignant oral lesions

Abstract A major dilemma in the management of patients with precursor lesions of the oral mucosa lies in deciding which lesions will progress into carcinoma. Because a strong association between histological differentiation and clinical prognosis is lacking, the aim of this study was to evaluate the value of chromosomal instability (CIN) detected by fluorescence in situ hybridization (FISH) for the identification of oral premalignant lesions at risk for progression. We examined a series of premalignant oral mucosa lesions of 106 patients by means of FISH on paraffin-embedded tissue sections using biotin- and digoxigenin-labeled probes specific for the centromeric regions of chromosomes 1 and 7. CIN was indicated by the presence of chromosome imbalances and/or polyploidization for chromosomes 1 and 7. Results were correlated with histopathological data as well as with clinical follow up data. The 5-year progression-free survival rate was 83%. Outcome of routine histopathology did only predict malignant progression when comparing severe dysplasia with lower stage precursor lesions (hyperplasia, mild en moderate dysplasia) (p&amp;lt;0.001). CIN was detected in all different subgroups of histopathological differentiation. Moreover, the percentage of precursor lesions harboring CIN increased with progressing histopathological stage. CIN was significantly associated with a lower progression-free survival as compared with lesions without CIN (p&amp;lt;0.001). In conclusion, tumorigenesis of the oral mucosa is associated with the development of CIN, which can reliably identify lesions at risk for progression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 5720.

Influence of low absolute lymphocyte count of patients with nongerminal center type diffuse large B-cell lymphoma with R-CHOP therapy

BackgroundRituximab has dramatic impact on outcome of patients with diffuse large B-cell lymphoma (DLBCL), especially nongerminal center (non-GC) type. A low absolute lymphocyte count (ALC) before rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone (R-CHOP) therapy as a surrogate marker of immune status is associated with poor clinical outcome in DLBCL. Therefore, we hypothesized that low ALC before R-CHOP would have effect on the survival in non-GC type. Patients and methodsOne hundred and thirty-six DLBCL patients who were treated with R-CHOP from 2003 to 2007 were analyzed in the present study. ResultsALC ≥1.0×109/l predicted a longer 3-year progression-free survival (PFS) and 3-year overall survival (OS) versus ALC <1.0×109/l (82.6% versus 60.0%, P=0.005 and 87.2% versus 62.0%, P<0.001, respectively). Non-GC type had similar PFS and OS to germinal center type (68.2% versus 80.0%, P=0.074 and 72.7% versus 82.9%, P=0.111, respectively). However, considering clinical influence of the ALC according to immunophenotype, low ALC in non-GC type DLBCL was associated with lower PFS and OS compared with others (PFS, P=0.002; OS, P<0.001). Multivariate analysis revealed that low ALC in non-GC type had lower PFS [hazard ratio (HR)=3.324, P=0.001] and OS (HR=4.318, P<0.001), independent of international prognostic index. ConclusionA low ALC in non-GC type DLBCL counteracted the beneficial effect of rituximab on survival.

Morphology of Bone Marrow Plasma Cells (BMPC) and Its Relationship with Interphase Cytogenetics and Prognosis in Multiple Myeloma (MM).

Abstract 1822Poster Board I-848 BackgroundBMPC number is important for diagnostic purposes in monoclonal gammopathies whereas BMPC morphology may be used as a prognostic factor in MM. So far, presence of plasmablasts or of BMPC displaying irregular nuclear outline have been related to adverse prognosis in MM. Interphase FISH demonstrates several cytogenetic changes (CG) in MM, and 17p deletion (del17p) and t(4;14) translocation have been recently shown as both major adverse prognostic factors. Up to 70% pts, however, lack both these CG changes, and prognostic parameters, easy-to-perform in routine practice, are needed for these patients. Our aim in this study was to ascertain whether BMPC morphology displayed prognosis in pts who did not demonstrate both adverse CG changes.Methods. We performed a retrospective analysis of BMPC morphology from 245 patients with MM, uniformly treated within the IFM 99 trials based on presence or absence of high serum beta-2 microglobulin level and 13q- deletion, including IFM 99-02, 99-03, and 99-04. Interphase FISH was performed using previously published methods on sorted BMPC to look for del13q, t(11;14), del17p, and t(4;14) (one to four sets of probes tested in each pt, according to the number of PC sorted in each instance). BM smears were analyzed by at least two out of a group of five morphologists (from different University centers): in each case 100 BMPC were observed, analyzed, and computerized. Comparison between results from observers was performed next: in all instances, if discordance occurred, computerized images were observed by all five morphologists (meeting sessions and Email sessions) leading to consensus. ResultsMedian age was 55, and 38% of patients had ISS 2 and 3 in the overall cohort. 72.3%, 6.8% and 20.9% patients came from the 99-02, 99-03, and 99-04 trials, respectively. Pts were classified according to five morphological subgroups: Mature (>66% of PC displaying mature morphology) [n=74 (30.2%)], Small Plasmacytic (>15% of PC displaying mature morphology but high N/C ratio) [n=14 pts (5.7%)], Plasmablastic (>=1% plasmablasts) [n=48 (19.6%)], Irregular Nucleus (>5% PC displaying irregular nuclear outline, PCIN) [n=32 pts (30.2%)], Activated (one nucleolus in >33% PC and/or immature chromatin network in >10% PC) [n=76 (31%)]. Del13 was found in 125 pts (51%), t(11;14) in 43pts (17.6%), del17p in 16 pts (7.0%), and t(4;14) in 52 pts (21.2%). Del17p and t(4;14) were both absent in 181 pts (73.9%). This group had no clinic-biological difference with the overall population of the trials. The median follow up was 49 months (+/-se 0.74). Median Progression Free Survival (PFS) and Overall Survival (OS) were lower in the adverse CG group [displaying either del17p or t(4;14)] as compared to other pts: 21 vs 43 months (p<0.0001) and 42 months vs median not reached (p<0.0001), respectively.33 pts (51.5%) with adverse CG changes displayed also adverse morphology [either plasmablastic or irregular nucleus]. Combination of adverse CG and adverse morphology led to dismal prognosis: median PFS were 20 months for pts with both adverse CG and morphology prognostic factors, and 36 months for pts with adverse morphology solely (p=0.0001), and median OS were 37 months and not reached (p=0.002), respectively.For pts without adverse CG changes, presence of plasmablasts or/and of irregular nucleus was related to adverse prognosis [median PFS and OS for both subgroups were 36 months (p=0.034) and 49 months (p=0.039)]. In contrast, mature and activated MM groups both showed better prognosis (median PFS were 45 and 49 months and median OS were not reached).Small plasmacytic MM group was peculiar, displaying t(11;14) in 85% cases but almost never del17p or t(4;14) (1.6% cases). This subgroup demonstrated here lower PFS and OS [34 months and 45 months, respectively] as compared to the Mature group, but also as compared to the whole t(11;14) population tested [43 months and median not reached, respectively]. ConclusionAdverse morphological changes and adverse CG changes together lead to dismal prognosis. For pts who do not display del17p and t(4;14) we show here that plasmablasts and irregular nucleus are morphological changes which remain of adverse prognosis. T(11;14) is associated with high number of small PC and is related to intermediate prognosis, whereas quite good prognosis is associated with mature or activated BMPC. Modulation of therapy according to CG but also to BMPC morphology is stressed. DisclosuresNo relevant conflicts of interest to declare.

Alternative Donor Hematopoietic Cell Transplantation (HCT) After Reduced Intensity (RIC) or Nonmyeloablative (NST) Conditioning in Advanced Non-Hodgkin Lymphoma (NHL).

Abstract 3380Poster Board III-268For adult allogeneic HCT candidates lacking a matched family donor, an alternative donor (unrelated or mismatched family) remains the most feasible option. Lower intensity conditioning using RIC or NST regimens is increasingly used in NHL to lower transplant related mortality (TRM) while retaining graft vs. lymphoma effect. We analyzed the outcomes of 248 (61% male) adult recipients of HCT for NHL from alternative donors after RIC/NMA conditioning reported to the CIBMTR from 1997 to 2004. Recipients of any prior transplants and those in first complete remission from follicular NHL were excluded. Outcomes of TRM, progression, progression-free survival (PFS) and overall survival (OS) were analyzed in multivariate regression models adjusting for key pre-transplant variables.Median age was 52 (range, 18-72 yrs); 36% having a Karnofsky performance score ≤90. Follicular NHL (43%) was the major histology with 75% in stages III and IV, 47% with chemotherapy resistant disease and only 18% in CR2. Patients received BM (43%) or PBSC (57%) grafts from unrelated well matched/partially matched/mismatched (61% /19% /9% respectively) or related mismatched (10%) donors. Conditioning included fludarabine with either melphalan (20%), TBI (11%), cyclophosphamide (25%), or busulfan (12%); busulfan/cyclophosphamide (RIC) (2%); BEAM (6%); CBV (8%); and others (16%). Use of RIC/NMA regimens increased yearly during the study period from 7 in 1997 to 121 in 2003. Cumulative incidence of grade II-IV acute GVHD (aGVHD) was 43%; and chronic GVHD (cGVHD) was 36% at 1 year and 44% at 3 years. The TRM at 28 and 100 days was 11% and 24%, respectively. Outcomes at a median follow-up of 44 months summarized in Table 1, Figure 1 and Figure 2.Table 1Probability (95% CI)Outcomes1 year3 years5 yearsTRM31 (25 - 37)%39 (32 - 45)%43 (36 - 50)%Relapse/Progression26 (20 - 31)%30 (24 - 36)%31 (26 - 38)%PFS43 (37 - 50)%32 (26 - 37)%26 (19 - 32)%OS55 (48 - 61)%41 (34 - 47)%35 (28 - 42)%In multivariate analysis (Table 2) the use of ATG and HLA mismatch were associated with an increased TRM. Higher age (≥ 60), non-follicular histology, advanced disease status at HCT and later year of HCT were associated with higher risk of relapse. High-grade histology, the use of ATG, and chemotherapy resistant disease at HCT were associated with higher risk of treatment failure or lower PFS. Higher age, shorter interval from diagnosis to HCT, non-TBI conditioning regimens or T-cell depletion and HLA mismatched unrelated donors were associated with lower risk of survival. Acute or chronic GVHD did not influence TRM or PFS. Common causes of death were disease recurrence (n=40), organ failure (n=29), GVHD (n=23). In NHL patients without sibling donor options, alternative donor HCT with RIC/NMA conditioning results in favorable long-term survival although advanced age, histology and resistant disease status remain concerning. Higher grade NHL, use of ATG or T-cell depletion and HLA mismatch were associated with inferior outcomes. Lack of an available sibling donor should not be a barrier to allogeneic HCT in the appropriate patient.Table 2VariablesRelative Risk (95% CI)P-valueTRMATG: No vs. Yes2.13 (1.40 - 3.25)<0.001Donor type: Unrelated well matched vs. mismatched2.07 (1.17 - 3.84)0.02RelapseAge: ≤ 60 vs. >601.93 (1.07 - 3.48)0.028Histology: Follicular vs. Diffuse Large B Cell3.46 (1.80 - 6.34)<0.001Status: CR2+ vs. REL Resistant5.05 (2.13 - 11.99)<0.001Risk of Treatment FailureHistology: Follicular vs. Lymphoblastic/Burkitts/Burkitt-like2.11 (1.40 - 3.18)<0.001Status: CR2+ vs. REL Resistant2.54 (1.50 - 4.31)0.001ATG: No vs. Yes1.50 (1.07 - 2.10)0.020Time from diagnosis to transplant: ≥ 24 vs. 12 – 24 months1.58 (1.09 – 2.31)0.017Risk of MortalityAge: ≤ 60 vs. > 601.77 (1.16 - 2.70)0.009Time from diagnosis to transplant: ≥ 24 vs. 12 – 24 months2.26 (1.56 - 3.27)<0.001TBI: Yes vs. No2.17 (1.36 - 3.48)0.001Donor type: Unrelated well matched vs. mismatched2.20 (1.24 - 3.90)0.007GVHD prophylaxis: FK506/MTX vs. T-cell depletion6.0 (2.68 - 13.45)<0.001 [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Second-line therapy in bladder cancer

To review new developments in second-line treatment for transitional cell carcinoma of the urinary bladder focusing on advances and findings within the last year. So far no standard therapy has been established for pretreated patients with transitional cell carcinoma. Prognostic and predictive factors for response and outcome in pretreated patients have been studied retrospectively and will help to identify those who might benefit from intensive therapy and those who would rather improve their quality of life with best supportive care. Single-agent chemotherapy in this setting provided low response rates, short progression-free and overall survival. Vinflunine, a novel vinca-alkaloid, and best supportive care had a modest, but still significant benefit at a very moderate toxicity rate in a randomized phase III trial. As for second-line combination chemotherapy, response rates as well as potential toxicities are higher and the progression-free survival and overall survival benefits are still poorly understood. New chemotherapeutics and approaches like metronomic chemotherapy and novel agents are under investigation. With vinflunine there is reasonable hope for a new standard chemotherapy in second-line management of transitional cell carcinoma. However, due to the reported results with single agents and combination chemotherapy, treatment within clinical trials is still the best choice in patients progressing after first-line chemotherapy.

Prognostic value of serum vascular endothelial growth factor in Egyptian females with metastatic triple negative breast cancer

Objectives The aim of this work was to explore the value of serum vascular endothelial growth factor-A (VEGF-A) in patients with metastatic triple negative breast cancer (TNBC) treated with chemotherapy. The primary end point was overall survival (OS). Secondary end points were response rate (RR), progression-free survival (PFS) and VEGF-A level at baseline, mid-therapy and at the end of therapy. Design and methods Female patients aged 18 years or above with histologically proven metastatic TNBC were included. Serum VEFG-A levels were measured at baseline, after the 3rd and 6th cycles of FAC chemotherapy regimen (Fluorourcil, Adriamycin, and Cyclophamide). Results The overall RR was 57%. The median PFS and OS were 7 and 11.2 months, respectively (95% CI: 4.3–9.7 and 3.8–18.5 months, respectively). Patients whose disease progressed despite therapy had a significantly higher baseline VEGF-A level than those who did not progress. VEGF-A level did not drop with continuation of therapy. Patients with high VEGF-A level had a significantly lower PFS but not OS than patients with low levels. Conclusion The outcome of metastatic TNBC is poor with FAC chemotherapy regimen. Alternative chemotherapeutic regimens and novel therapeutic approaches including targeting of VEGF and/or its receptors are warranted.

Comparison of patterns of relapse in thymic carcinoma and thymoma

Thymic carcinomas are considered to be more aggressive than thymomas and carry a worse prognosis. We reviewed our recent experience with the surgical management of thymic tumors and compared the outcomes and patterns of relapse between patients with thymic carcinoma and those with thymoma. We performed a single-institution retrospective cohort study. Data included patient demographics, stage, treatment, pathologic findings, and postoperative outcomes. During the period 1995-2006, 120 patients with thymic tumors underwent surgical intervention, including 23 patients with thymic carcinoma and 97 patients with thymoma, as classified according to the World Health Organization 2004 histologic classification. The overall 5-year survival was significantly different between patients with thymic carcinoma and those with thymoma (thymic carcinoma, 53%; thymoma, 89%; P = .01). Data on relapse were available for 112 patients. The progression-free 5-year survival was also significantly different between patients with thymic carcinoma and those with thymoma (thymic carcinoma, 36%; thymoma, 75%; P < .01). Using multivariate analysis, thymic carcinoma and incomplete resection were found to be independent predictors of progression-free survival. Relapses in patients with thymic carcinoma tended to occur earlier, and occurred significantly more frequently at distant sites than in patients with thymoma (60% vs 13%, P = .01). Patterns of relapse differ significantly between patients with thymic carcinoma and those with thymoma, with lower progression-free survival, earlier onset, and more distant relapses in patients with thymic carcinoma. Given the greater propensity for distant failures, the inclusion of systemic therapy in the treatment of thymic carcinoma might take on greater importance. Despite significantly higher rates of distant relapse, good overall survival in patients with thymic carcinoma can be achieved.

Pre-treatment serum lactate dehydrogenase level is an important prognostic factor in high-grade extremity osteosarcoma

Treatment of high-grade osteosarcoma remains a challenge. The prognostic significance of the pre-treatment serum lactate dehydrogenase (LDH) level is currently controversial. We reviewed records from all patients diagnosed with conventional high-grade osteosarcoma at our institution over a 25-year period and analysed the prognostic significance of LDH in high-grade localised extremity osteosarcomas treated with chemotherapy. Between June 1977 and March 2003, 66 patients for whom follow-up was available were diagnosed with localised high-grade extremity osteosarcoma and treated with chemotherapy. The median age was 15 years, with only 3% older than 40 years, and the median follow-up was 100 months. The median progression-free survival (PFS) was 67 months and the median overall survival (OS) was 113 months. The absence of a response to chemotherapy was correlated with a trend toward lower PFS and OS. High serum pre-treatment LDH level was associated in multivariate analyses with a poorer prognosis for both PFS (HR=8.623, 95%CI: 1.71-43.37; p=0.009) and for OS (HR=9.38; 95%CI: 1.73-50.74; p=0.009). In this series, the pre-treatment serum LDH level had an independent prognostic value for both PFS and OS in patients with high-grade localised extremity osteosarcoma. This measurement should be included in a large prospective prognostic series.

Prognostic risk group classification for patients (pts.) with platinum-refractory metastatic urothelial cancer (UC) treated with second-line chemotherapy

5078 Background: Second-line chemotherapy in pts. with platinum-refractory metastatic UC is associated with low objective response rates and short progression-free and overall survival. Prognostic risk groups in this setting have not been reported. Methods: We studied 151 pts. with platinum-refractory metastatic UC treated with second-line vinflunine (VFL) (Vaughn, GU Cancer Symposium. 2008). Using progression at 6 months as the primary endpoint, baseline patient characteristics were examined in univariate and multivariate analyses. Multivariate logistic regression was used to identify independent predictors of progression at 6 months, and the variable selection result was validated by nonparametric bootstrap. Risk scores were generated from summing the relative importance of the factors identified on multivariate analysis. Patients were classified into risk groups and compared. Results: Of the 151 pts., 80% were male, 54% were aged &gt; 65 years, and 68% had Karnofsky performance status (KPS) &gt; 90%. 115 pts. (76%) progressed or died by 6 months after initiating VFL. The factors associated with an increased odds ratio (OR) for disease progression at 6 months were presence of visceral metastases (OR 8.08; p &lt; 0.001; 2 points), KPS &lt; 90% (OR 6.63; p = 0.002; 2 points), and age &lt; 65 years (OR 3.53; p = 0.008; 1 point). Only 41% of the low-risk group (score 0–1) progressed by 6 months compared to 74% of the intermediate-risk group (score 2) and 91% of the high-risk group (score 3–5). Compared to the low-risk group, the intermediate-risk group had OR for disease progression at 6 months of 4.01 (p = 0.006) and the high-risk group had OR of 15.5 (p &lt; 0.001). Conclusions: We identified risk factors and developed a scoring system that classifies pts. with platinum-refractory UC treated with second-line chemotherapy into risk groups based upon probability of disease progression at 6 months. Similar to the first-line setting, the presence of visceral metastases and decreased KPS predict a worse prognosis. This system should be validated in other independent populations. [Table: see text]

A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer

To evaluate the response to lapatinib, an inhibitor of epidermal growth factor receptors 1 and 2, in patients with advanced bilary tree cancer (BTC) and hepatocellular cancer (HCC). Lapatinib was dosed at 1,500 mg/day orally continuously. Fifty-seven patients were accrued (BTC 17, HCC 40). Therapy was well tolerated. The response in BTC was 0% and in HCC was 5%. The progression free survival (PFS) for BTC and HCC patients was 1.8 (95% CI: 1.7-5.2) months and 2.3 (95% CI: 1.7-5.6) months. The median survival for BTC and HCC patients was 5.2 (95% CI 3.3-infinity) months and 6.2 (95% CI: 5.1-infinity) months. EGFR genotyping indicated HCC patients with <20 repeats have the lowest PFS. The occurrence of any skin rash significantly prolonged PFS and survival. Lapatinib was well-tolerated. There was evidence of activity in HCC, but therapy with lapatinib did not meet the predefined efficacy rate.

Junctional Adhesion Molecule: An Expression in Human Endometrial Carcinoma

Junctional adhesion molecule A (JAM-A) is involved in cell-cell contact and tight junction formation. Loss of cell adhesion molecules may be associated with high histologic grade and invasiveness of endometrial carcinoma. We attempted to determine JAM-A expression in human endometrial carcinoma and its correlations with pathologic features, stage, and survival. Junctional adhesion molecule A expression in human endometrial carcinoma was evaluated by immunohistochemistry. In addition, we cultured human well and poorly differentiated endometrial adenocarcinoma cell lines, Ishikawa cells, and KLE in 3-dimensional basement membrane preparation, and JAM-A expression in these cells was assessed by real-time reverse transcription-polymerase chain reaction and immunohistochemistry. Junctional adhesion molecule A immunostaining intensity was negatively correlated with histologic grade (tau = -0.420, P < 0.0001), myometrial invasion (tau = -0.306, P < 0.01), and stage (tau = -0.383, P < 0.0001). Low JAM-A immunostaining intensity was associated with positive vascular space involvement (P < 0.01). Moreover, low immunostain intensity was significantly (P < 0.0001) related to low overall survival rate and progression-free survival rate. Additionally, in our 3-dimensional epithelial cell culture, JAM-A expression in poorly differentiated adenocarcinoma was significantly lower than that in well-differentiated adenocarcinoma (P < 0.001). Junctional adhesion molecule A expression seems to be reduced in high-grade or advanced endometrial carcinoma and may be a prognostic factor.

Allogeneic Stem Cell Transplantation Results in a Low Relapse Rate in Patients with Peripheral T-Cell Lymphoma.

Patients (pts) suffering from mature (peripheral) T-cell lymphoma are known to have a poor outcome compared to pts with aggressive B-cell lymphoma when receiving conventional therapies. However, case reports and single centre experiences show promising results of allogeneic stem cell transplantation (allo SCT) for these pts. We here present a retrospective analysis of 103 pts with mature T-cell lymphoma who received an HLA-identical allo SCT in EBMT centres between 2000 and 2005. Histological subtypes of the patients were anaplastic large cell lymphoma (n=25; 4 anaplastic lymphoma kinase [ALK] positive, 11 ALK negative, 10 ALK unknown), peripheral T-cell lymphoma unspecified (n=51), angioimmunoblastic T-cell lymphoma (n=18) and aggressive T-cell lymphoma unspecified (n=9). Patients with primary cutaneous T-cell lymphoma or T-lymphoblastic lymphoma were excluded. Median follow up for surviving patients was 40 months (6–98), median age at allo SCT 42 years (18–68) and median time to allo SCT 17 months (3–233). 39 pts had failed a prior autologous SCT; 68 pts had chemosensitive disease at allo SCT (of these 15 in CR1) and 30 pts had chemorefractory or untested relapsed or progressive disease. Donors were HLA identical siblings for 73 and matched unrelated donors for 30 pts; 82 pts received peripheral blood stem cells. 54 pts were treated with reduced intensity conditioning before SCT. The cumulative incidence (CI) of acute graft versus host disease (GvHD) 100 days after SCT was 52% and had no effect on non-relapse mortality (NRM) or relapse rate (RR). 34 of 74 evaluable pts experienced chronic GvHD (14 limited, 20 extensive), CI 46% at 2 years. Introducing chronic GvHD as a time dependent covariate, this factor was associated with a higher NRM (p<0.001) and a lower RR (statistically not significant), resulting in a lower progression free survival (PFS) (p=0.001). For all patients CI of NRM and RR at 3 years were 36.7% and 24.9%, respectively, resulting in 41.4% PFS and 46.9% OS. Median time to relapse / progression was 4 (1–18) months. In multivariate COX analysis for PFS refractory disease (relative risk 3.4, p=0.001), prior failed auto SCT (relative risk 2.6, p=0.001) and poor performance status at SCT (relative risk 2.5, p=0.04) were significant adverse factors. Additionally, there were trends for T-cell depleted grafts (p=0.1), CMV status other than negative-negative (p=0.1) and reduced intensity conditioning (p=0.2) to be adverse factors. A subgroup of 39 good risk pts (good performance status, chemosensitive disease, no prior autologous SCT) had a PFS of 59%.This retrospective analysis on allo SCT in peripheral T-cell lymphoma shows an encouraging low RR but efforts have to be made to reduce NRM. Prospective studies are warranted to further define pts who will profit from an early allo SCT.

Autologous Hematopoietic Stem Cell Transplantation (HSCT) for Autoimmune Diseases: 10 Years Experience from the European Group for Blood and Marrow Transplantation (EBMT) Working Party on Autoimmune Diseases

Introduction Since 1996 a joint collaborative effort from the European Group for Blood and Marrow Transplantation (EBMT) and League against Rheumatism (EULAR) collected cases of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for patients (pts) with severe autoimmune diseases (AD). This retrospective observational study was designed to assess patients outcome and analyse the determinants of treatment responses after AHSCT.Methods All consecutive AD pts treated by AHSCT from 1996 to 2007 according to the EBMT-EULAR consensus statement with ethics committee approved protocol were included. Data were reported yearly via the electronic EBMT data management system PROMISE and outcomes updated as December 2007. Standard AHSCT techniques used either bone marrow (BM), peripheral blood stem cells (PBSC) or both. PBSC were collected with cyclophosphamide CY (CY 4 g/m2) + granulocyte-colony stimulating factor (G-CSF), or with G-CSF alone if cardiac function prevented CY.Cell selection used either CD34+ selection with or without monoclonal antibodies, particularly anti-CD52, anti-CD3, anti- CD19 or anti-CD20. Conditioning regimen used either Total Body Irradiation (TBI) or chemotherapy alone, with various combinations of CY, Busulfan, BEAM ± Antithymocyte Globulins (ATG), which were then subgrouped arbitrarily intohigh intensity regimen, including Busulfan or TBI,low intensity restricted to CY alone, Melphalan alone and Fludarabine-based regimens, orintermediate regimen with all the other combinations.Primary outcome measure was Progression Free Survival (PFS) defined as survival without evidence of relapse or progression. Secondary outcomes were the Overall Survival (OS) defined as time to death, irrespective of the cause and Transplant Related Mortality (TRM) at day 100, defined as death without ADs relapse or progression. Cumulative incidence curves were used for TRM, considering relapse or progression within 100 days as a competing event and compared using the Gray's test. Kaplan-Meier estimate was used to calculate PFS Probabilities and the log-rank test for univariate comparisons. For all pronostic analyses, continuous variables were categorised and the median was used as a cut-off point. Associations of patient, disease and graft characteristics with outcomes were evaluated in multivariate analyses, using Cox proportional hazards for PFS, and proportional hazard regression model of Fine and Gray for NRM. Results: From 1996 to December 2007, 900 AD pts (64 % female, median 35 years) from 171 teams in 27 countries treated by AHSCT were reported to the EBMT data base, mainly multiple sclerosis (MS, n=345), systemic sclerosis (SSc, n=175), systemic lupus erythematosus (SLE, n=85), rheumatoid arthritis (RA, n=89), juvenile idiopathic arthritis (JIA, n=65), vasculitis (VASC, n=26) and hematological immune cytopenia (HIC, n=37). PSC were used as stem cell source for 92% of the pts; 42 % of the pts had in vitro cell selection, mostly with CD34+ selection. All types of conditioning regimens were used in all disease categories with very few patients (7%) with TBI. On the overall population, the 5 years PFS was 43 ± 2 % and OS was 85 ± 1 %. Three years after AHSCT:PFS was 61±5 % for SSc, 55±3 % for MS, 54±6 % for SLE, 52±7 % for JIA, 53±15 % for PMDM, 47±11 % for VASC, 34±9 % for HIC and 23±5 % for RA,);OS was 98 ± 2 % for RA, 93 ± 2 % for MS, 82 ± 5 % for JIA, 83 ± 5 % for SLE and 77 ± 4 % for SSc, depending primarily on AD type (p<0.001).By multivariate analysis, the age > 35 yrs (HR 0.73, 95%CI (0.59–0.89), p=0.002), AHSCT performed before December 2000 (HR 0.69, 95%CI (0.55–0.85), p=0.008) and number of AHSCT for ADs per centre £ 13 (HR 0.82, 95%CI (0.67–0.99, p=0.05) were associated with a lower PFS. The day 100 TRM was 5 ± 1% overall and appeared significantly lower for a number of patients per centre > 13 (HR 0.45, 95% CI (0.21–0.99), p=0.05).ConclusionThe EBMT registry allowed to collect 900 ADs pts with AHSCT after 10 years of collaborative effort. Although retrospective, this largest cohort studied worldwide so far showed that patient age, AD type and number of AHSCT per centre are important determinants of the response. AHSCT appeared a good therapeutic alternative for severe Ads unresponsive to conventional treatment, supporting the ongoing European and north American phase 3 trials comparing AHSCT to standard therapies in SSc, MS, SLE and Crohn's disease.

New Horizons in Chemotherapy: Platforms for Combinations in First-Line Advanced Non-small Cell Lung Cancer

The treatment of advanced non-small cell lung cancer has evolved substantially during the last decade. Chemotherapy with a platinum-based doublet prolongs survival and improves quality of life in patients with good performance status. Recently, the addition of bevacizumab and the use of epidermal growth factor receptor inhibitors in appropriately selected patients have further improved the outcome of patients with advanced non-small cell lung cancer. Newer targeted agents are being developed and tested in the clinical arena at a rapid pace. In addition, the identification by clinical or molecular criteria of patient populations that benefit the most from these agents is under active investigation. In contrast, the development of newer cytotoxic agents, with innovative mechanisms of action, has been comparatively disappointing. Whether standard cytotoxic drugs are required as newer biologic agents are more frequently used or whether a more active and safer chemotherapy can be used as a template for combinations with biologic agents remains an important research topic.

Comparison of patterns of relapse in thymic carcinoma and thymoma

7539 Background: Thymic carcinomas (TC) are considered to be more aggressive than thymomas and carry a worse prognosis. Given their rarity, our knowledge about their clinical behavior and optimal management is limited. We reviewed our recent experience with the surgical management of thymic tumors and compared the outcomes and patterns of relapse between TC and thymoma. Methods: Retrospective review of a single institution surgical database. Data included patient demographics, stage, treatment, pathologic findings, and postoperative outcomes. Results: During the period 1995–2006, 120 patients with thymic tumors underwent surgery, including 24 patients with TC and 96 patients with thymoma by the WHO 2004 histologic classification. At a median follow-up of 41 months (range 6–154), the overall 5 year survival was significantly different between TC and thymoma (TC 57%, thymoma 89%, p=0.01). Data on relapse was available for 112 patients. The progression-free 5 year survival was also significantly different between TC and thymoma (TC 36%, thymoma 75%, p<0.01). Complete macroscopic resection (R0 and R1) resulted in significantly higher progression-free survival in both TC and thymoma. Relapses in TC occurred earlier and more frequently at distant sites than in thymoma. Sites of distant relapse included lung (4), bone (3), brain (1), liver (1) and skin (1), with some patients having multiple sites. Details are listed in the table below. Conclusions: Patterns of relapse differ between TC and thymoma with lower progression-free survival, earlier onset and more distant relapses in TC. Complete macroscopic resection affords significantly longer freedom from disease progression in both TC and thymoma. Despite significantly higher rates of distant relapse, good overall survival in TC can be achieved. Comparison of Patterns of Relapse in Thymoma and Thymic Carcinoma Thymic Carcinoma (n=22) Thymoma (n=90) 5 yr Progression-free Survival by Resection Status 5 yr Progression-free Survival by Resection Status Complete Resection (n=14) 59% p=0.01* Complete Resection (n=81) 87% p<0.01* Incomplete Resection (n=8) 0% Incomplete Resection (n=9) 0% Site of Progression (n=10) Site of Progression (n=14) Locoregional (n=4) 40% Locoregional (n=13) 93% p<0.01** Distant (n=6) 60% Distant (n=1) 7% Time to Progression (mo) Time to Progression (mo) Mean 14.0 Mean 31.1 p=0.05*** Median (Range) 9 (6–33) Median (Range) 21(4–95) * Log-Rank Test, Complete vs. Incomplete; ** Fisher’s Exact Test, TC vs. Thymoma; *** T-test, TC vs. thymoma. No significant financial relationships to disclose.

IMP3 Predicts Aggressive Superficial Urothelial Carcinoma of the Bladder

In this study, we investigated whether an oncofetal protein, IMP3, can serve as a new biomarker to predict progression and metastasis of early-stage urothelial carcinoma of the bladder. The expression of IMP3 in 242 patients with primary superficial bladder urothelial carcinoma and metastatic urothelial carcinoma was evaluated by immunohistochemistry. Patients with primary superficial urothelial carcinoma of the bladder were further investigated by use of survival analysis. Twenty percent (42 of 214) of primary superficial urothelial carcinomas and 93% (26 of 28) of metastatic urothelial carcinomas expressed IMP3. Kaplan-Meier plots and log-rank tests showed that patients with IMP3-positive tumors had a much lower progression-free survival (P = 0.0002) and disease-free survival rate (P = 0.0067) than did those with IMP3-negative tumors. The 5-year progression-free and disease-free survival rates were 91% and 94% in IMP3-negative patients versus 64% and 76% in IMP3-positive patients, respectively. Sixty percent of IMP3-positive patients with superficial invasive urothelial carcinoma at initial diagnosis went on to develop metastases, whereas no metastasis was found in IMP3-negative patients (P = 0.0017). In the multivariable Cox analysis, patients with IMP3 expression in their superficial urothelial carcinomas subsequently developed invasive tumors or metastasis at a rate that was about five times greater than cases without expression of IMP3 adjusting for other well-known clinical variables (tumor stage and grade, etc.). Our findings indicate that IMP3 is an independent prognostic marker that can identify a group of patients with a high potential to develop progression and who might benefit from early aggressive therapy.

Transitional Cell Carcinoma of the Ureter: Prognostic Factors Influencing Progression and Survival

ObjectivesWe retrospectively evaluated prognostic factors for progression-free and disease-specific survival in a large cohort of patients with transitional cell carcinoma (TCC) of the ureter. MethodsA single-centre series of 145 consecutive patients treated with partial resection of the ureter or nephroureterectomy between 1975 and 2004 was evaluated. Median follow-up was 96 mo. Routine preoperative laboratory parameters as well as clinical and tumour-specific data were assessed. Univariate and multivariate statistical analyses were performed. ResultsFive-year disease-specific survival ranged from 96.1% for stages pTa to 28.6% for pT4. Grade1 tumours were associated with 5-yr disease-specific survival rates of 100% compared with 84% for G2, and 51.9% for G3 tumours, respectively. Univariate analyses identified pT stage and grade, tumour diameter, cM and pN categories, weight loss, the presence of synchronous tumour in the renal pelvis as well as elevated levels for humoral factors such as serum alkaline phosphatase (AP), white blood cell (WBC) count, platelet count, γ-glutamyl transferase, creatinin, and blood urea nitrogen as prognostic factors. In multivariate analyses, tumour grade and WBC counts were predictive for low progression-free survival rates, whilst simultaneous tumour in the renal pelvis, high AP levels, and WBC counts were correlated with worse disease-specific survival. ConclusionsOur retrospective analysis provides clinical factors to identify patients with TCC of the ureter at high risk for progression and death of disease. Interestingly, humoral factors such as elevated serum AP levels and high WBC counts were demonstrated to be of paramount prognostic significance besides tumour stage, grade and multifocality.

Urokinase-type plasminogen activator and its inhibitor in thyroid neoplasms: a cytosol study

Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. uPA and PAI-1 were expressed in most thyroid carcinomas, as had been measured immunohistochemically. However, no relationship between their expression and clinicopathological parameters were found. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in thyroid cancer. uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined in 23 patients using enzyme-linked immunosorbent assay and correlated to the known prognostic features. Both uPA and PAI-1 concentrations were significantly higher in malignant thyroid tumors (uPA=1.342 +/- 2.944 and PAI-1=17.615 +/- 31.933 ng/mg protein) than in normal tissue (uPA=0.002 +/- 0.009, P=0.011 and PAI-1=2.333 +/- 0.338 ng/mg protein, P=0.001) with positive correlation of the two proteins in the tumors. There were no differences in proteins' levels between benign tumors and normal tissue. Both proteins' concentrations were significantly different among various histological grades (uPA P=0.024 and PAI-1 P=0.017), showing higher values in higher tumor grades (grade I uPA=0.116 +/- 0.247 and PAI-1=4.802 +/- 4.151 ng/mg protein; grade III uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). The uPA and PAI-1 levels showed significant differences among different histological types of thyroid cancer (uPA P=0.049 and PAI-1=0.017). The lowest values were in adenomas (uPA=0.013 +/- 0.025 and PAI-1=2.785 +/- 1.069 ng/mg protein) and the highest in anaplastic carcinomas (uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). uPA and PAI-1 were significantly higher in anaplastic vs. well-differentiated cancers (uPA P=0.014 and PAI-1 P=0.026), if extrathyroidal invasion (uPA P=0.019 and PAI-1 P=0.009) or distant metastases (uPA P=0.006 and PAI-1 P=0.003) had been present, and in tumors whose size exceeded 1 cm in diameter (uPA P=0.009 and PAI-1 P=0.035). Only PAI-1, but not uPA was significantly higher in multicentric vs. solitary tumors (P=0.012) and lymph node positive compared to lymph node negative patients (P=0.042). The differences of uPA and PAI-1 did not reach the significant level when patients with well-differentiated tumors below and above 40 years of age had been compared. Survival analysis revealed the significant impact of both uPA and PAI-1 on the Progression-Free Survival (PFS) (38.84 vs. 3.67 months for patients with low and high uPA, respectively, P<0.001; 38.2 vs. 12 months for patients with low and high PAI-1, respectively, P=0.016). The correlation of high uPA and PAI-1 with the known prognostic factors of poorer outcome and with lower PFS rate in patients with thyroid cancers proved that these proteins could be an additional prognostic parameter.