Diagnostic Performance of Kwak, EU, ACR, and Korean TIRADS as Well as ATA Guidelines for the Ultrasound Risk Stratification of Non-Autonomously Functioning Thyroid Nodules in a Region with Long History of Iodine Deficiency: A German Multicenter Trial

Germany has a long history of insufficient iodine supply and thyroid nodules occur in over 30 % of the adult population, the vast majority of which are benign. Non-invasive diagnostics remain challenging, and ultrasound-based risk stratification systems are essential for selecting lesions requiring further clarification. However, no recommendation can yet be made about which system performs the best for iodine deficiency areas. In a German multicenter approach, 1211 thyroid nodules from 849 consecutive patients with cytological or histopathological results were enrolled. Scintigraphically hyperfunctioning lesions were excluded. Ultrasound features were prospectively recorded, and the resulting classifications according to five risk stratification systems were retrospectively determined. Observations determined 1022 benign and 189 malignant lesions. The diagnostic accuracies were 0.79, 0.78, 0.70, 0.82, and 0.79 for Kwak Thyroid Imaging Reporting and Data System (Kwak-TIRADS), American College of Radiology (ACR) TI-RADS, European Thyroid Association (EU)-TIRADS, Korean-TIRADS, and American Thyroid Association (ATA) Guidelines, respectively. Receiver Operating Curves revealed Areas Under the Curve of 0.803, 0.795, 0.800, 0.805, and 0.801, respectively. According to the ATA Guidelines, 135 thyroid nodules (11.1%) could not be classified. Kwak-TIRADS, ACR TI-RADS, and Korean-TIRADS outperformed EU-TIRADS and ATA Guidelines and therefore can be primarily recommended for non-autonomously functioning lesions in areas with a history of iodine deficiency.

C20orf94 deletion Is Strongly Associated with TEL/AML1 Rearrangement and Links Illegitimate V(D)J Recombination with Gender Bias In Childhood Acute Lymphoblastic Leukemia

Abstract 1718 Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent structural and/or numeric genetic aberrations and has been consistently reported to occur with a 20% higher incidence in males relative to females. We performed 100k Affymetrix SNP-array analysis in a selected set of 20 ALL samples. In five out of these 20 patients, a previously described deletion of the 5' region of C20orf94 – a gene coding for an uncharacterized DNA repair-associated protein – was observed. The results were validated by high-resolution custom-made CGH array analysis. As the breakpoints within C20orf94 were defined to recurrent positions, we next applied a PCR assay to screen diagnostic leukemic specimens of a representative cohort of 513 patients enroled into the German multicenter trial ALL-BFM 2000 on treatment of childhood ALL. Here, C20orf94 deletions were detected in 164 patients (32.0%). None of 134 available remission samples exhibited the deletion as well as none of 145 healthy blood donors. Sequencing analysis in 40 patients revealed specific breakpoint junctions with typical characteristics of illegitimate V(D)J recombination in all samples. When analyzing the association of C20orf94 deletion with clinical characteristics in the entire screening cohort, the most significant interrelationships were observed for male gender (75.6% of positives; P < 0.001) and TEL/AML1-rearranged ALL (43.3% of positives; P < 0.001). A negative association was observed for a DNA index of ≥1.16 (3.0% of positives; P < 0.001). In contrast, C20orf94 deletion did not show any effect on treatment outcome. Additional screening of an independent cohort of 232 TEL/AML1-rearranged ALLs identified 145 positive samples and not only confirmed the high incidence of C20orf94 deletion in this subgroup, but also allowed validation of its specific association with male gender (55.9% of positives; P = 0.049). In 21 of 22 (17 TEL/AML1-positive and 5 other pre B cell ALLs) paired initial and relapse leukemic samples C20orf94 deletions were maintained at relapse. Breakpoint sequencing of paired initial and relapse leukemic samples revealed a stable monoclonal breakpoint sequence in 9 patients indicating stability of C20orf94 deletions during disease progression. The remaining samples either developed heterogeneity of C20orf94 breakpoints at relapse after monoclonality at initial diagnosis or initially already showed a polyclonal pattern. Backtracking of C20orf94 deletions to birth in seven TEL/AML1-positive patients using material derived from Guthrie cards did not yield any positive results. In conclusion, we describe the frequent and uniform deletion of the 5' part of C20orf94 in childhood ALL - particularly in males and the TEL/AML1-rearranged subtype. These findings suggest a potential role for C20orf94 deletion in the pathogenesis of childhood ALL and point to differences in illegitimate V(D)J recombination as one potential explanation for the observed and currently only poorly understood gender bias in childhood ALL. Disclosures: No relevant conflicts of interest to declare.

[18F]-FDG-PET in germ cell tumors following chemotherapy: Results of the German multicenter trial

4521 Background: The aim of this study was to evaluate the viability of residual masses following chemotherapy in patients (pts) with germ cell cancer (GCT) using FDG-PET. Methods: Pts with diagnosis of GCT at primary diagnosis or at relapse were included if residual masses (> 1 cm) were present following chemotherapy. 140 pts, 27 with primary extragonadal GCT, aged 15.7–59.2 (mean age: 32.7 years) treated in 18 centers were examined with concurrent FDG-PET and CT. FDG-PET was performed in fasting state. Images were reconstructed by filtered back projection. All PET-scanners were calibrated using the same phantom. The presented data are based on visual scan analysis. All pts underwent surgery for residual masses. Thus, all results were validated by histology. Results: Histology of the primary tumor included 20 seminoma and 109 NSGCT, while 11 pts had no primary histology. 88 pts (63%) had no persistent GCT. 120 pts (86%) demonstrated residual masses in retroperitoneal lymph nodes; in 56 pts (40%) residual masses were localized in the thorax and in 8 pts elsewhere (multiples possible). 40 pts (29%) presented active residual carcinoma and 54 (39%) presented residual teratoma (combination possible) following chemotherapy. Correct classification of the residual mass by FDG-PET was achieved in 79 of 140 (56%), while CT scans were correct in 58 of 140 pts (42%). 46 of 89 patients with a positive FDG-PET turned out to have viable tumor while in 36 out of 52 patients with a negative scan no lymph node metastases were found. FDG-PET turned out to show a sensitivity of 73% and specificity of 44%. Positive and negative predictive value (PPV, NPV) were 48% and 69% and accuracy 56%, respectively. In NSGCT 58 pts had no active tumor and 28 were true negative with FDG-PET resulting in a specificity of 47% and a NPV of 67%. 36 patients were true positive with a PPV of 54% and a sensitivity of 72%. Conclusion: FDG-PET for GCT following chemotherapy has a higher accuracy than CT, but sensitiviy is still too low to avoid subsequent resections in patients with NSGCT. [Table: see text] No significant financial relationships to disclose.

Increased survival using platinum analog combined with gemcitabine as compared to gemcitabine single agent in advanced pancreatic cancer (APC): Pooled analysis of two randomised trials, the GERCOR/GISCAD Intergroup Study and a German Multicenter Study

4003 Background: Two randomized trials (GERCOR/GISCAD: gemcitabine [GEM] plus oxaliplatin versus Gem; German multicenter trial: Gem plus cisplatin versus Gem) indicated superior efficacy in terms of response rate and progression-free survival (PFS) for combined therapy. While a trend for prolonged overall survival (OS) was reported in these underpowered studies, they failed to demonstrate a significant advantage. Methods: We report a pooled analysis of both studies. Standard methods for meta-analysis based on individual patient (pt) data were used. Results: Among 503 evaluable pts, 252 received the combination therapy (GP), while 251 pts were treated with Gem single agent (G). In the GP vs G groups, an ECOG performance status = 0 was observed in 40% vs 35%, distant metastasis in 72% vs 73%, and pathological tumor grading of 3 in 34% vs 38%, respectively. A high degree of homogeneity was noted among the study groups with regard to survival data. For PFS, the pooled univariate analysis indicated a hazard ratio (HR) of 1.34 (95% CI, 1.11–1.63, p=.0030; median PFS 5.5 m vs 3.5 m) in favour of the GP-combination. The benefit of the GP-combination was greatest in the subgroup of pts with PS 0 (HR=1.56; 95% CI, 1.11–2.20, p=.013). OS was significantly superior in the GP pts (HR=1.23; 95% CI, 1.02–1.49, p=.031; median OS 8.3 m vs 6.7m). Again, pts with a PS=0 may have a greater benefit from treatment intensification (HR=1.38; 95% CI, 0.99–1.93, p=.063). Conclusions: This pooled data analysis indicates that combination of gemcitabine with a platinum analog such as oxaliplatin or cisplatin significantly improves PFS and OS as compared to single-agent gemcitabine in APC. [Table: see text]