julilili42/papers huggingface dataset:
Addition of darbepoetin alfa to sequential high-dose VIP chemotherapy for patients with advanced metastatic germ cell cancer.
2012-05-20

e15026 Background: High-dose VIP chemotherapy plus ABSCT given as first line treatment might be a strategy in patient with advanced germ cell tumors (GCT) with poor prognosis. The objective of the trial was to investigate the addition of darbepoetin alfa to HD-VIP in order to reduce anemia/red blood cell (RBC) transfusions. Methods: This was a randomized, open-label multicenter phase 2 study conducted in 20 hospitals. Darbepoetin 2.25 mcg/kg weekly or 500 mcg Q3W s.c., started with high dose VIP (dose level 6) was applied in arm B (arm A: HD-VIP alone). The primary objective was freedom from blood transfusions (FFT). Secondary objectives included objective remission rate (ORR) after chemotherapy, 24 mos PFS and OS, median course of hemoglobin (Hb) levels during 3 HD-VIP cycles as well as drug safety. Results: Between 7/2003 and 11/2008 108 pts were allocated to the study, and 106 were included in the intention-to-treat (ITT) analysis. By March 2011 the median follow-up time after randomization was 20 mos. Localisation of primary was gonadal in 66%, retroperitoneal in 19% and mediastinal in 14%s. A favourable treatment outcome (CR/NED/PR m-) in conjunction with secondary surgery (n = 76 pts) was achieved in 58% of pts with no difference between arms A and B. Overall FFT occurred in 2 pts (4.2%) in arm A and 3 pts (5.6%) in arm B, and in 23%/15%/15% and 15%/17%/19% of pts during cycles 1-3, respectively. No differences in baseline Hb, severity of anemia, no of RBC transfusions and area under the curve of Hb levels during HD-VIP was observed. Pts assigned to darbepoetin had similar treatment toxicity compared to those assigned to HD-VIP alone. 24-mos OS in arm A was 86.3% compared to 67.8% (p=.064) in Arm B. 2-year RFS was 66.8% in arm A vs 55.5% in Arm B (p=0.45). Darbopoetin was generally well tolerated with 2 pts discontinuing treatment due to thrombosis. Since compliance to study protocol was generally poor (6 out of 55 pts never received study drug during HD-VIP) a per-protocol analysis is in preparation. Conclusions: Based on ITT analysis, the addition of darbepoetin alfa to the high dose regimen compared to HD-VIP alone does not appear to impact on FFT, ORR, and 2-year survival rate in poor prognosis GCT pts (NCT00204633).
Detection of disseminated tumor cells in bone marrow as an independent prognostic factor in primary ovarian cancer patients.
2012-05-20

5042 Background: Detection of disseminated tumor cells (DTC) in the bone marrow (BM)of breast cancer patients is associated with poor outcome. Recent studies demonstratedthat DTC may serve as a prognostic factor in ovarian cancer.The aim of our study was to evaluate the impact of BM status on survival in a large cohort of ovarian cancer patients. Methods: 365 patients with primary ovarian cancer were included into this three-center prospective study. BM aspirates were collected preoperatively from iliac crest. Disseminatedtumor cells were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and by cytomorphology. Patient outcomes were evaluated using a multivariable Cox regression model. Results: Disseminated tumor cells were detected in 28% of all BM aspirates. The number of CK-positive cells ranged from 1 to 42 per 2x10 6 mononuclear cells. DTC status did not correlate with any of the established clinicopathogical factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 mo, 95% CI: 35 – 67 mo versus 32 mo, 95% CI: 22 – 42 mo; p = 0.003). However, disease-free survival was not related to DTC-positivity. In the multivariable analysis, BM status, FIGO stage, nodal status, resection status and age were independent predictors of reduced overall survival. Interestingly, a subset of DTCs may have stem cell properties since a subset of these cells (128 out of 228 cases) were SOX2 positive, which is an embryonic stem cell marker. Conclusions: Tumor cell dissemination into bone marrow is a common phenomenon in ovarian cancer. DTC detection has the potential to become an important biomarker for prognostication and may be included as a therapeutic target in future concepts.
CNS-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation (HD-ASCT) for CNS relapse of aggressive lymphomas: Final analysis of a phase II study.
2012-05-20

8031 Background: The outcome of patients with CNS relapse of aggressive lymphoma (secondary CNS lymphoma, SCNSL) is poor with no standard therapy established thus far. Here we present the final analysis of a prospective multicenter phase II study using an intensive induction regimen followed by high-dose chemotherapy and autologous stem-cell transplantation. Methods: Adult immunocompetent patients ≤65 years with SCNSL were eligible. Induction chemotherapy consisted of two cycles MTX/IFO (methotrexate 4g/m 2 iv. d1, ifosfamide 2g/m 2 iv. d3-5 and i.th. liposomal cytarabine 50mg d6) and one cycle AraC/TT (cytarabine 3g/m 2 d1-2, thiotepa 40mg/m2 iv. d 2 and i.th. liposomal cytarabine 50mg d3). Then, patients without progression received high-dose chemotherapy with carmustine 400mg/m2 iv. d -5, thiotepa 2x5mg/kg iv. d -4 to -3 and etoposide 150mg/m 2 iv. d -5 to -3 followed by ASCT d0. Results: Thirty eligible patients (median age 58 years) were enrolled. Three patients had T-cell and 27 aggressive B-cell lymphoma. Pre-treatment was CHOP-like in 29 patients, including rituximab in 26. CNS relapse occurred after a median of 8.5 (3-80) months and was intracerebral in 23 and meningeal in13 patients (combined in 7); 6 had concomitant systemic lymphoma. After induction therapy CNS response was found in 22 (73%) patients (8xCR, 14xPR), 3 patients had SD, 4 patients PD and 1 patient no response evaluation. HD-ASCT was performed in 24 patients; resulting in 15 CR (63%), 2 PR (8%) and 7 PD (29%). Myelotoxicity was the most frequent WHO grade 3-4 adverse event with infections in 8/30 pts on MTX/IFO (27%), 5/23 (22%) on AraC/TT and 11/20(55%) on HD-ASCT. One patient died due to septic diverticulitis and one developed persisting fecal incontinence. The median follow up was 21 months. The median PFS was 12.1 months (95% CI 6.4-17.7) in all patients and 30.4 (95%CI 2.5-58.3) months after HD-ASCT, the median overall survival was 27.4 months and not reached, respectively. Conclusions: This first prospective study on SCNSL demonstrates that lasting remissions can be achieved with CNS-directed HD-ASCT in a large proportion of patients and probably cure in some.
Do children, adolescents, and young adults with soft tissue sarcoma benefit from early detection of recurrences? Results of a population-based study.
2012-05-20

9573 Background: Most patients with pediatric soft tissue sarcoma (PSTS) achieve a 1 st remission with primary therapy, but recurrences are frequent and drive mortality. Relapse detection (RD) is the foundation of post-treatment surveillance. The rationale for frequent follow-up investigations is RD in an early stage with better salvage options. There is however little evidence regarding the value of early asymptomatic RD and it was not investigated by any larger or population-based study in PSTS. We determined whether early radiographic RD in asymptomatic patients improves post-relapse outcome. Methods: Patients aged &lt; 18 years at first reference-reviewed PSTS-diagnosis registered with CWS were enrolled if a 1 st relapse occurred between 1/2003 and 7/2010. The methods of RD and their impact on outcome were evaluated. The data were correlated with the German Childhood Cancer Registry (GCCR), which receives all information about cancer patients &lt; 18 years. Results: 235 patients from Germany (n = 212) and Sweden/Switzerland (n = 23) were eligible. In 2010 all German PSTS-patients were registered both with the GCCR and CWS. The most common PSTS-histiotypes were embryonal (n = 76) and alveolar (n = 74) rhabdomyosarcoma. 156 patients had primary nonmetastatic PSTS. The median time to relapse diagnosis (TTRD) was 1.4 years. 118 recurrences were locoregional, 38 combined and 79 metastatic. In 229 patients, the methods leading to RD could be evaluated. 139 recurrences were detected because of clinical signs and symptoms, primarily observed by patients and/or parents in 72%. 90 RDs were radiographic in asymptomatic patients. TTRD did not differ between symptomatic and asymptomatic patients. As of 12/2011, 77/235 patients are currently alive with a median follow-up of 5.4 years. Overall survival from primary surgery at 3-, 5-, and 10-years for all 235 patients was 49%, 34% and 22%. It was 43%, 29% and 23% for the symptomatic and 59%, 40% and 21% for the asymptomatic group (p = 0.05). Conclusions: In this series, early radiographic RD in asymptomatic PSTS-patients had no significant impact on TTRD or post-relapse survival, although asymptomatic patients tended to survive longer.
Elderly patients with primary CNS lymphoma: Results from the G-PCNSL-SG-1 trial.
2012-05-20

2007 Background: Age is the most important therapy-independent prognostic factor in patients with primary central nervous system lymphoma (PCNSL). Here we aimed at providing an analysis of the impact of higher age on response to therapy, toxicity, and survival in the largest PCNSL trial ever performed to date. Methods: Response to therapy, toxicity and survival of PCNSL patients enrolled in the G-PCNSL-SG-1 trial evaluating the role of radiotherapy after high-dose methotrexate (HD-MTX)-based chemotherapy were monitored. Subjects aged 70 or more were compared to younger patients. Results: Of all eligible patients (n=526), 126 (24%) were aged 70 or more. In the per protocol population, 66 of 318 patients (21%) were at least 70 years old. Among the eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly compared to 57% in the younger patients (p=0.016). A higher rate of grade III/IV leukopenia was observed in the elderly (34% versus 21%, p=0.007). Also, death on therapy was more frequent (18% versus 11%; p=0.027) in these patients. In contrast, there was no other major age-dependent toxicity. Survival analyses revealed shorter progression-free survival (PFS) (4.0 versus 7.7 months, p=0.014) and overall survival (OS) (12.5 versus 26.2 months, p&lt;0.001) in the elderly population. The PFS of CR patients was 35.0 months in younger patients compared to 16.1 in the elderly (p=0.024). Salvage therapy was used less commonly in elderly patients. When salvage WBRT was applied in patients who had failed on HD-MTX-based chemotherapy, there was no association between age and survival (p=0.633). Conclusions: Elderly PCNSL patients have a lower response rate and higher mortality on HD-MTX-based chemotherapy. Their PFS is shorter and they receive less salvage therapy which may contribute to the poor prognosis.
Serum HER2 in the context of circulating tumor cells in patients with metastatic breast cancer.
2012-05-20

10599 Background: Circulating tumor cells (CTC) reflect an aggressive tumor behavior by hematogenous tumor cell dissemination. Overexpression of HER2 in breast cancer (BC) is associated with increased angiogenesis and therefore potentially linked to increased hematogenous tumor cell spread. The aim of the analysis was to investigate whether concentrations of serum HER2 (sHER2) deliver prognostic information in the context of CTC detection in metastatic BC patients. Methods: Blood was obtained in a prospective multicenter setting from 254 patients with metastatic BC at the time of disease progression. sHER2 was determined using a commercial ELISA-kit (Wilex). CTC were detected with the CellSearch system (Veridex). Patients received systemic treatment according to national and international guidelines including HER2-targeted treatment. Results: Five or more CTC were detected in 122 of 245 evaluable patients (49.8%).119 of 251 (47%) metastatic patients had serum sHER2 levels above 15ng/mL. Median PFS was 9.2 months (95%-CI: 9.9 – 13.0 mths) with elevated sHER2 versus 11.4 mths (9.9 – 13.0 mths) with non-elevated levels (p=0.07). OS was 17.4 mths (14.6 – 20.3 mths) vs. 26.5 mths (23.1-29.8 mths; p&lt;0.01). In patients with 5 or more CTC, serum levels were above the cut-off for sHER2 in 61% vs. 33% in those with less than 5 CTC (p&lt; 0.01). Patients with elevated sHER and 5 or more CTC hat a PFS of 9.1 mths (7.2 – 11.1 mths) and a OS of 14.5 mths (11.8 – 17.2 mths), those with non-elevated sHER2 and less than 5 CTC a PFS of 12.1 (10.1 – 14.1 mths) and a OS of 29.5 month (25.4 – 33.6 mths) (p=0.15 for PFS and p&lt; 0.01 for OS). Including sHER2, CTC and established prognostic factors in the multivariate analysis, the presence of CTC, line of therapy, ER and HER2 status of the primary tumor remained independent predictors of OS. Conclusions: Elevated serum levels of sHER2 are associated with the presence of CTC and indicate poor clinical outcome. However, sHER2 has no independent prognostic value when presence of CTC were taken into account.
Five years into the national second-opinion project of the German Testicular Cancer Group (GCTSG): Impact on guideline implementation and the quality of care for testicular cancer patients.
2012-05-20

4530 Background: The diagnosis and therapy of testicular germ cell tumors are subject to constant change. Numerous national and international guidelines have been published since the 1990s in order to meet this challenge. It is questionable, however, whether mere publication of guidelines will lead to their implementation. The aim of the present project of the GTCSG was to establish a national second-opinion network in order to improve the implementation of guidelines and the quality of care. Methods: Before determining the primary therapy, participating urologists could communicate with one of 30 second-opinion centers (SOC) via an internet-based platform. The data set comprised the primary clinical, radiological and pathohistological findings, the therapy planned by the advice seeker (first opinion), the therapy recommended by the SOC (second opinion), and the applied therapy as well as the 2-year follow-up data. Primary end points of the study were congruence between the first and second opinion, treatment changes based on the second opinion, and relapse-free 2-year survival. Results: A total of 1722 SOC requests have been submitted since November 2006. At the time of our data analysis 927 cases were evaluated. The response rate was 75.8% for treatment data and 74.4% for 2-year follow-up data. Advice seekers and SOC had discrepant treatment concepts in 43.3% of the cases; this discrepancy was independent of tumor histology and increased in advanced tumor stages (clinical stage ≥IIa: 52.3% vs. &lt;IIa: 34%; p&lt;0.001, Pearson Χ 2 test). The SOC request led to reduction of the applied therapy in 11.4% and intensification in 9.5% of the cases. Progression-free 2-year survival was 92% (112/122) for stage I, 90% (17/19) for stage IIa-IIb, and 65% (17/26) for stage ≥IIc. Conclusions: Guidelines for the treatment of germ cell tumors are inadequately implemented, particularly in advanced tumor stages. Every fifth second opinion resulted in a relevant change in the scope of therapy. Patients whose treatment was congruent with the second opinion had a relapse rate comparable to that of study results in the literature.
Feasibility of 6 months of maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck (HNC).
2012-05-20

e16033 Background: The prognosis for HNC patients (pts) after surgical treatment and adjuvant chemoradiation (CRT) is unsatisfactory in case of close resection margin &lt;5 mm (CM) or extra capsular extent at the lymph nodes (ECE). Therefore we conducted a multicenter phase II study to investigate the toxicity and efficacy of adjuvant radiotherapy (RT) in combination with concurrent cisplatin, 5- fluorouracil (5FU), and cetuximab (CTX) followed by maintenance therapy with CTX for 6 months. Here, we present the preliminary results on feasibility and toxicity. Methods: HNC pts after primary surgery were eligible for the study, if a CM or ECE was detected. Cisplatin [20 mg/m2 d1-5 and d29-33] and 5-FU (CI 600 mg/m 2 d1-d5 + d29-33) were given concurrently to postoperative RT using an integrated boost IMRT-technique (1.8/2.0/2.2Gy QD) to a total dose of 61.6 Gy. CTX started 7 days prior CRT with a loading dose of 400 mg/m 2 followed by weekly CTX (250 mg/m2) during CRT. Maintenance CTX started after completion of CRT plus CTX with 500 mg/m2 every 2 weeks over a 6-month period. Results: 55 of 80 planned pts (46 male, 9 female, mean age 55.6, range 29-70 years) have finished CRT, 50 are evaluable for toxicity. Concurrent CRT plus CTX was associated with grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reaction outside the radiation portals in 46%, 28%, and 14% of pts, respectively. One toxic death occurred (peritonitis at day 57). CTX was terminated in 10% of all pts (allergic reactions) after the first application. In 22% of all pts CTX was discontinued during the last 2 weeks or at the end of CRT. Of those pts embarking on maintenance therapy, 80% were still on CTX after 3 and 63% after 5 months. 48% completed 6 months maintenance therapy. Conclusions: Adjuvant CRT in combination with CTX followed by maintenance CTX is feasible with toxicity in the expected range. Compliance to maintenance CTX was satisfactory during the first 3-5 months.
Aldehyde dehydrogenase activity in serous ovarian carcinoma.
2012-05-20

e15577 Background: Only specific subpopulations of tumor cells, so called cancer stem cells (CSC) may initiate and maintain tumors. The phenotype and molecular properties of ovarian CSC remain elusive. Aldehyde dehydrogenase (ALDH) activity characterizes (cancer) stem cells in different tissues and has been associated with ovarian CSC (Silva et al, 2011; Kryczek et al, 2012). Contradictory results have been reported on ALDH1 expression and prognosis in ovarian carcinoma. In this study, we explore the role of ALDH in serous ovarian carcinoma (SOC). Methods: Aldefluor-staining was used to assess ALDH activity in different ovarian carcinoma cell-lines and patient samples. ALDH+ and ALDH- cells isolated by FACS and ALDH1 versus control siRNA treated cells were analyzed in sphere forming, proliferation, BrdU and cell cycle assays. In vivo tumorigenicity assays including serial re-transplantations were performed in NOD/SCID/IL2Rγ null mice. ALDH1 and Ki67 expression were assessed immunohistochemically on a tissue microarray of 152 SOC samples. Results: ALDH+ cells formed more tumor spheres than ALDH- cells from the OVCAR-3 cell line and primary SOC and larger spheres (&gt; 5.000 μm2) developed solely from ALDH+ cells. However, in vivo both cell fractions gave rise to tumors. Tumors contained both ALDH+ and ALDH- cells irrespective of the starting population. Notably, ALDH+ cells generated tumors more rapidly and induced larger tumors, suggesting a higher proliferative capacity. Immunohistochemical analysis of a larger cohort of SOC patients confirmed association of ALDH1 expression with the proliferation marker Ki67 (p=0.007). Surprisingly, co-stainings revealed that ALDH1 positive cells were mostly Ki67 negative and cell cycle synchronisation experiments using different agents showed ALDH induction in G0-enriched OVCAR-3 cells. However, inhibition of ALDH by treatment with three distinct siRNAs against ALDH1 did not alter cell cycle distribution. Conclusions: Our data suggest that ALDH is a correlative marker indicating, but not actively sustaining a quiescent stem-cell like state in SOC. Upon exit from G0, ALDH+ cells lose ALDH expression and induce a proliferative response.
The prognostic utility of LDH and CRP for survival after melanoma metastasectomy in the urogenital tract.
2012-05-20

e19021 Background: Recent studies suggest that serum lactate dehydrogenase (LDH) and serum C-reactive protein (CRP) are risk factors for survival in patients with metastatic melanoma. However, due to the relatively low tropism of metastatic melanoma lesions in the urogenital tract the clinical benefit of metastasectomy in this highly selective group of patients remains uncertain. The objective of this study was to address the role of LDH and CRP as preoperative serological risk factors for survival in patients with solitary or concomitant metastatic melanoma lesions in the urogenital tract. Methods: All patients who were referred for metastasectomy in the urogenital tract in a tertiary center within 1999-2008 were considered for this analysis. Demographic, disease and survival data were collected. Elevated LDH activity was defined as &gt;250U/l and elevated serum CRP&gt;0.5mg/dl. The primary endpoint was overall survival (OS), calculated using Kaplan-Meier method with log-rank test and multivariate Cox-regression analysis. Results: Of a total of 21 patients,16 (76%) had solitary urogenital metastases and 5 patients (24%) concomittant non-urogenital metastases.Median OS after metastasectomy was 23 months (range: 3-59 months). LDH&gt;250U/l was significantly associated with decreased OS (27.6 vs. 6.0 months; p=0.001), but elevated CRP did not (24.1 vs. 20.7 months; p=0.93). No further significant differences in survival were found for age (p=0.76), gender (p=0.83), number of urogenital metastatic sites (0.97) and preoperative solitary vs. concomitant distant metastases (p=0.48). In multivariate analysis, adjusted for the TNM-stage grouping (M1a-c) and CRP level, elevated LDH maintained significance as negative prognostic factor for overall survival (p=0.0015). Conclusions: To our knowledge, this is the first study addressing the prognostic role of LDH and CRP in patients with melanoma urogenital metastases. If confirmed in large prospective studies, LDH level may be used for preoperative risk stratification in patients scheduled for melanoma metastasectomy in the urogenital tract to identify those patients who profit most from the surgical approach.