PURPOSE The classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) plays a pivotal role in the management of metastatic germ cell tumors but relies on data of patients treated between 1975 and 1990. MATERIALS AND METHODS Data on 9,728 men with metastatic nonseminomatous germ cell tumors treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Europe, North America, and Australia. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS). The survival estimates were updated for the current era. Additionally, a novel prognostic model for PFS was developed in 3,543 patients with complete information on potentially relevant variables. The results were validated in an independent data set. RESULTS Compared with the original IGCCCG publication, 5-year PFS remained similar in patients with good prognosis with 89% (87%-91%) versus 90% (95% CI, 89 to 91), but the 5-year OS increased from 92% (90%-94%) to 96% (95%-96%). In patients with intermediate prognosis, PFS remained similar with 75% (71%-79%) versus 78% (76%-80%) and the OS increased from 80% (76%-84%) to 89% (88%-91%). In patients with poor prognosis, the PFS increased from 41% (95% CI, 35 to 47) to 54% (95% CI, 52 to 56) and the OS from 48% (95% CI, 42 to 54) to 67% (95% CI, 65 to 69). A more granular prognostic model was developed and independently validated. This model identified a new cutoff of lactate dehydrogenase at a 2.5 upper limit of normal and increasing age and presence of lung metastases as additional adverse prognostic factors. An online calculator is provided ( https://www.eortc.org/IGCCCG-Update ). CONCLUSION The IGCCCG Update model improves individual prognostication in metastatic nonseminomatous germ cell tumors. Increasing age and lung metastases add granularity to the original IGCCCG classification as adverse prognostic factors.

PURPOSE The classification of the International Germ-Cell Cancer Collaborative Group (IGCCCG) has been a major advance in the management of germ-cell tumors, but relies on data of only 660 patients with seminoma treated between 1975 and 1990. We re-evaluated this classification in a database from a large international consortium. MATERIALS AND METHODS Data on 2,451 men with metastatic seminoma treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2013 were collected from 30 institutions or collaborative groups in Australia, Europe, and North America. Clinical trial and registry data were included. Primary end points were progression-free survival (PFS) and overall survival (OS) calculated from day 1 of treatment. Variables at initial presentation were evaluated for their prognostic impact. Results were validated in an independent validation set of 764 additional patients. RESULTS Compared with the initial IGCCCG classification, in our modern series, 5-year PFS improved from 82% to 89% (95% CI, 87 to 90) and 5-year OS from 86% to 95% (95% CI, 94 to 96) in good prognosis, and from 67% to 79% (95% CI, 70 to 85) and 72% to 88% (95% CI, 80 to 93) in intermediate prognosis patients. Lactate dehydrogenase (LDH) proved to be an additional adverse prognostic factor. Good prognosis patients with LDH above 2.5× upper limit of normal had a 3-year PFS of 80% (95% CI, 75 to 84) and a 3-year OS of 92% (95% CI, 88 to 95) versus 92% (95% CI, 90 to 94) and 97% (95% CI, 96 to 98) in the group with lower LDH. CONCLUSION PFS and OS in metastatic seminoma significantly improved in our modern series compared with the original data. The original IGCCCG classification retains its relevance, but can be further refined by adding LDH at a cutoff of 2.5× upper limit of normal as an additional adverse prognostic factor.

Antiangiogenic drugs are currently tested in haematological malignancies. As these drugs target different angiogenic regulators, and as cancers are inherently heterogeneous, a detailed characterization of angiogenesis in individual cancers is needed. Hence, we measured bone marrow microvessel density (MVD), plasma concentrations of eight angiogenesis-related parameters and the expression in blood mononuclear cells of 40 angiogenesis-related mRNAs in 93 patients with haematological neoplasias (acute myeloid leukaemia; chronic lymphatic leukaemia; multiple myeloma (MM); or non-Hodgkin's lymphoma (NHL)) before start and after completion of cancer therapy. Compared with healthy individuals, the patients had significantly increased bone marrow MVD, especially patients with advanced stage disease. A novel finding was that patients with NHL also had increased bone marrow MVD. The plasma levels of vascular endothelial growth factor (VEGF), interleukin (IL)-6 and IL-8 were significantly increased. VEGF levels were highest in those who did not achieve complete remission after cancer therapy. The mRNA expression of IL-8 was upregulated 15-fold. Our data show that patients with haematological malignancies have increased bone marrow MVD; hence, supporting the notion that bone marrow angiogenesis plays a role in the pathogenesis and progression of these cancers. VEGF, IL-6 and IL-8 seem to contribute to the malignant phenotype.

PURPOSE Using complete information regarding testicular cancer (TC) treatment burden, this study aimed to investigate cause-specific non-TC mortality with impact on previous treatment with platinum-based chemotherapy (PBCT) or radiotherapy (RT). METHODS Overall, 5,707 men identified by the Cancer Registry of Norway diagnosed with TC from 1980 to 2009 were included in this population-based cohort study. By linking data with the Norwegian Cause of Death Registry, standardized mortality ratios (SMRs), absolute excess risks (AERs; [(observed number of deaths − expected number of deaths)/person-years of observation] ×10,000), and adjusted hazard ratios (HRs) were calculated. RESULTS Median follow-up was 18.7 years, during which non-TC death was registered for 665 (12%) men. Overall excess non-TC mortality was 23% (SMR, 1.23; 95% CI, 1.14 to 1.33; AER, 11.14) compared with the general population, with increased risks after PBCT (SMR, 1.23; 95% CI, 1.07 to 1.43; AER, 7.68) and RT (SMR, 1.28; 95% CI, 1.15 to 1.43; AER, 19.55). The highest non-TC mortality was observed in those < 20 years at TC diagnosis (SMR, 2.27; 95% CI, 1.32 to 3.90; AER, 14.42). The most important cause of death was non-TC second cancer with an overall SMR of 1.53 (95% CI, 1.35 to 1.73; AER, 7.94), with increased risks after PBCT and RT. Overall noncancer mortality was increased by 15% (SMR, 1.15; 95% CI, 1.04 to 1.27; AER, 4.71). Excess suicides appeared after PBCT (SMR, 1.65; 95% CI, 1.01 to 2.69; AER, 1.39). Compared with surgery, increased non-TC mortality appeared after 3 (HR, 1.47; 95% CI, 0.91 to 2.39), 4 (HR, 1.41; 95% CI, 1.01 to 1.99), and more than four (HR, 2.04; 95% CI, 1.25 to 3.35) cisplatin-based chemotherapy cycles after > 10 years of follow-up. CONCLUSION TC treatment with PBCT or RT is associated with a significant excess risk of non-TC mortality, and increased risks emerged after more than two cisplatin-based chemotherapy cycles after > 10 years of follow-up.

Using complete information on total treatment burden, this population-based study aimed to investigate second cancer (SC) risk in testicular cancer survivors (TCS) treated in the cisplatin era. The Cancer Registry of Norway identified 5,625 1-year TCS diagnosed 1980-2009. Standardized incidence ratios (SIRs) were calculated to evaluate the total and site-specific incidence of SC compared to the general population. Cox regression analyses evaluated the effect of treatment on the risk of SC. After a median observation time of 16.6 years, 572 TCS developed 651 nongerm cell SCs. The SC risk was increased after surgery only (SIR 1.28), with site-specific increased risks of thyroid cancer (SIR 4.95) and melanoma (SIR 1.94). After chemotherapy (CT), we observed 2.0to 3.7-fold increased risks for cancers of the small intestine, bladder, kidney and lung. There was a 1.6to 2.1-fold increased risk of SC after ≥2 cycles of cisplatin-based CT. Radiotherapy (RT) was associated with 1.5to 4.4-fold increased risks for cancers of the stomach, small intestine, liver, pancreas, lung, kidney and bladder. After combined CT and RT, increased risks emerged for hematological malignancies (SIR 3.23). TCS treated in the cisplatin era have an increased risk of developing SC, in particular after treatment with cisplatin-based CT and/or RT.Additional Supporting Information may be found in the online version of this article.

Background Reports on perioperative complications after Post-Chemotherapy Retroperitoneal lymph node dissection (PC-RPLND) for Non-Seminoma Germ Cell Tumour (NSGCT) are from experienced single centres, with a lack of population-based studies. Objective To assess the complications of bilateral and unilateral PC-RPLND. Design, Setting, Participants Prospective, population-based observational multicentre study that included all patients with NSGCT that underwent PC-RPLND in Norway and Sweden 2007 to 2014. In total 318 patients, 87 underwent bilateral PC-RPLND and 231 unilateral PC-RPLND. Median follow-up 6 years.Outcome measurements and statistical analysis Bilateral and unilateral PC-RPLND were compared for the outcome intra-and postoperative complications (graded by Clavien-Dindo) and retrograde ejaculation (with or without nerve-sparing surgery). Complications were reported as absolute counts and percentages. The x 2 -test was used for comparisons Results and LimitationsThe incidence of intraoperative complications was higher for bilateral PC-RPLND compared to unilateral PC-RPLND (14% vs. 4.3%, p=0.003), with ureteral injury as the most frequent reported complication (2% of the patients). Postoperative complications were more common after bilateral than unilateral PC-RPLND (45% vs 25%, p=0.001) with Clavien ≥3b reported in 8.3% and 2.2% respectively (p=0.009). Lymphatic leakage was the most common complication occurring in 11% of the patients. Retrograde ejaculation occurred more frequently after bilateral than unilateral surgery (59% vs 32%, (p<0.001). Limitation of the study include reporting of retrograde ejaculation, which was based on chart review. Conclusions Intraoperative complications and postoperative complications includingretrograde ejaculation are more frequent after bilateral PC-RPLND compared to unilateral PC-RPLND.

Summary.  Background: We have previously found that activation of coagulation in patients with various hematological malignancies was apparently not initiated by tissue factor (TF). Acquired activated protein C (APC) resistance may be another mechanism responsible for such hypercoagulation, and has been demonstrated in patients with solid tumors, but not in patients with hematological malignancy. Objective: To investigate acquired APC resistance in a hypercoagulable cohort of patients with hematological malignancies. Patients/methods: Blood samples from 93 patients with acute myeloid leukemia (AML), chronic lymphatic leukemia, multiple myeloma, or non‐Hodgkin’s lymphoma, were analyzed before start and after completion of cancer therapy. APC resistance was measured using calibrated automated thrombography. The APC sensitivity ratio (APC‐SR) was calculated as the ratio of the endogenous thrombin potential (ETP) determined in plasma probed with either APC or buffer. Results: Untreated patients were found to have higher APC‐SR than healthy controls, and patients with AML had higher APC‐SR as compared to the other diagnoses, both findings being consistent with acquired APC resistance. The acquired APC resistance was partly ameliorated with cancer treatment. Decreased levels of protein S and TF pathway inhibitor were inversely correlated to APC resistance. Conclusions: APC resistance may contribute to the hypercoagulable state in hematological malignancies.

5006 Background: Previous studies have reported an increased risk of premature mortality in testicular cancer (TC) survivors, probably associated with previous platinum-based chemotherapy (PBCT) or radiotherapy (RT). However, complete data regarding PBCT cycles are lacking in available literature. Using complete TC treatment data, this population-based cohort study aimed to investigate non-TC mortality in relation to TC treatment. Methods: Overall, 5,707 men diagnosed with TC 1980-2009 were included, identified from the Cancer Registry of Norway. Clinical parameters and treatment data were abstracted from medical records and linked with the Norwegian Cause of Death Registry. Causes of death were classified by the European Shortlist. Standardized mortality ratios (SMRs) were calculated to compare the cause-specific mortality in the cohort to an age-matched general population. Age-adjusted hazard ratios (HRs) were estimated to evaluate the impact of number of PBCT cycles on non-TC mortality. Results: During a median follow-up of 18.7 years, 665 (12%) men were registered with non-TC death. The overall excess non-TC mortality was 23% (SMR 1.23, 95% CI 1.14-1.33) compared with the general population, with increased risks after PBCT (SMR 1.23, 95% CI 1.06-1.42) and RT (SMR 1.28, 95% CI 1.15-1.43), but not after surgery (SMR 0.95, 95% CI 0.79-1.14). SMRs increased significantly with increasing follow-up time ≥10 years, and the overall risk of non-TC death reached a maximum after ≥30 years follow-up (SMR 1.64, 95% CI 1.31-2.06). The most important cause of death was non-TC second cancer with an overall SMR of 1.53 (95% CI 1.35-1.73). Increased risks appeared after PBCT (SMR 1.43, 95% CI 1.12-1.83) and RT (SMR 1.59, 95% CI 1.34-1.89). Treatment with PBCT was associated with significantly 1.69-6.78-fold increased SMRs for cancers of the oral cavity/pharynx, esophagus, lung, bladder, and leukemia. After RT, significantly 3.02- 4.91-fold increased SMRs emerged for cancers of the oral cavity/pharynx, stomach, liver, pancreas and bladder. Non-cancer mortality was also increased by 15% (SMR 1.15, 95% CI 1.04-1.27), and excesses appeared after PBCT (1.23, 95% CI 1.03-1.47) and RT (SMR 1.17, 95% CI 1.01-1.34). Importantly, we report excess suicides after PBCT (SMR 1.65, 95% CI 1.01-2.69). Long-term overall cardiovascular mortality was not increased in the study cohort nor according to treatment modality. Compared with surgery, the overall non-TC mortality was increased after 4 (HR 1.41, 95% CI 1.00-1.98) and >4 (HR 2.03, 95% CI 1.24-3.33) PBCT cycles after >10 years of follow-up. Conclusions: TC treatment with PBCT or RT is associated with significantly increased long-term non-TC mortality, with non-TC second cancer being the most important cause of death. Significantly elevated risks for non-TC mortality emerged after ≥4 PBCT cycles after >10 years of follow-up.