Summary Background Recommendations for management of cancer‐related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low‐quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies. Methods Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression. Results We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low‐molecular‐weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11–0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45–2.63). The bleeding rate did not increase significantly with dose escalation. Conclusion Morbidity and mortality are high after recurrence of cancer‐related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

TF and CP are elevated in patients with cancer. The highest values of both procoagulants are in the genitourinary cancer group in agreement with the greater presence of thrombosis observed in this group. Clinical follow up is important in order to determine the potential value of these procoagulants and the tendency to develop thrombosis in patients with cancer.

Multiple Myeloma (MM) is an incurable plasma-cell disorder progressing from indolent monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) to relapse MM and finally plasma cell leukemia (PCL). Alterations affecting TP53 are among the principal genetic progression events associated with disease progression. We analyzed results from gene expression profiling (GEP), array-based comparative genomic hybridization (aCGH), fluorescent in situ hybridization (FISH) and mutational data on the largest cohort published to date of 806 patients from all MM stages and 48 human myeloma cell lines (HMCLs). The prevalence of monoallelic TP53 deletions by aCGH is 1.4%, 3.7%, 8.9% and 25%, in MGUS, SMM, newly diagnosed and relapsed MM respectively. It reaches 53% in HMCLs and 75% in secondary PCL. No biallelic TP53 deletion were observed in patients and only 8% in HMCLs. In relapsed MM, the prevalence of TP53 deletions increases from 12/75 patients (16%) at first, to 9/31 patients (29%) in second and 5/7 patients (71%) in third relapse or more. We studied by FISH the status of TP53 in 113 patients from early stages progressing to relapse. Overall 15/113 patients had TP53 deletion, we confirmed that 10/15 patients acquired TP53 deletion at late stages. Next, we investigated the mutational status of TP53 in 59 relapsed MM patients, 5/59 samples (8.5%) had TP53 mutations, 4/5 mutations were located in the DNA binding domain. Presence of TP53 deletion conferred poor overall survival in relapsed MM patients (4.2 vs. 37.8 months, p = 0.015). A cohort of 239 patients had GEP-aCGH paired analysis we used a validated 70-gene model to stratify patients based on calculations obtained by GEP. The cohort was divided into quartiles and we observed the prevalence of TP53 in the low and high-risk groups. TP53 deletion was observed in 33/239 patients (14%) by aCGH, 2/33 (6%) had GEP values in the low-risk and 13/33 (39%) in the high-risk group. Next, we used a previously proposed cut-off value predicting TP53 deletion when GEP values are less than 733. We tried to validate this value as a surrogate for direct detection of TP53 deletion, and used the positive predictive value (PPV) of such level as a potential clinically useful marker. The fact that aCGH is the gold standard approach to define copy-number alterations, the proposed cut-off value failed to predict TP53 deletion as the PPV was low at 18% and the sensitivity of 69%. Finally, we studied by aCGH the status of MDM2 and CDKN2A, two key regulators of TP53. MDM2 gain and CDKN2A loss were infrequent events in patients even in advanced disease. In 48 HMCLs, only one had MDM2 copy gain (2%) while 14 cell lines had CDKN2A loss (29%). In MM, emergence of TP53 deletion/mutations in MM and its increase in aggressive stages of disease remain the overriding genetic factor for poor prognosis determination and a marker of progressive genetic events. Based on GEP, the 733 cut-off value did not accurately predict TP53 deletion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 219. doi:10.1158/1538-7445.AM2011-219

Table 1. Samples to p53 deletions p 53 deletion FISH aCGH FISH and aCGH MGUS 142 - - SMM 108 - - Newly diagnosed MM - 182 - Relapsed/refractory MM 62 156 19 HMCLs - 48 - Total 312 386 19 Background: Inactivation of p53 by mutation or allelic loss is a rare event in multiple myeloma (MM) at the time of disease diagnosis and believed to be more common in the late stages of the disease. Here we defined the prevalence of p53 deletions in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed MM, relapsed MM and human myeloma cell lines (HMCLs). Indirect mechanisms of p53 inactivation such as amplification of MDM2, or deletion of CDKN2A (p14ARF) were also investigated. Patients and Methods: A total of 631 MM samples and 48 HMCLs were analyzed for p53 abnormalities (Table 1) and compared with a cohort of plasma cell leukemia (PCL) previously published by us. Interphase fluorescence in situ hybridization (FISH) and highresolution array-based comparative genomic hybridization (aCGH) were used to detect p53 deletions. MDM2 amplification and p14ARF loss were evaluated by aCGH. Overall survival (OS) was estimated through Kaplan Meier method. Results: The prevalence of p53 deletions was 1.4%, 3.7%, 8.9%, 20% and 87.5% in MGUS, SMM, newly diagnosed MM, relapsed MM and HMCLs respectively (Figure 1). Of interest patients in first relapse showed a p53 deletion prevalence of 18% in comparison with 33% for patients in second relapse or more. We obtained p53 deletion status in 8 patients noted to have deletion at the time of relapse and in whom we had previous samples stored. In 7 of 8 cases deletions had been acquired (absent in the previous samples). The median OS for relapsed MM patients with or without p53 deletion were 4.2 months and 37.8 months respectively (p <0.001). MDM 2 amplification and p14ARF loss was detected in 0.4% and 2% of new diagnosed MM, 0.6% and 5.1% of relapsed MM and 2% and 29% of HMCLs respectively. Discussion: Emergence of p53 deletion/mutations denotes progression genetic events in MM. Importantly we show for the first time the overriding importance of p53 deletions as prognostic markers in relapsed MM. A molecular staging system that is based on the presence of p53 inactivation may be more powerful than classifying patients based on the loss of p53. Other abnormalities involving p53 pathway regulators like MDM2 gain and p14ARF loss are infrequent events in MM, even in advanced disease. Figure 1. Prevalence of p53 deletions Figure 1. Prevalence of p53 deletions

Background: Two procoagulant factors are associated with the tumor cell: tissue factor (TF) and cancer procoagulant (CP). The activation of the coagulation system can cause thrombosis and it has also been involved in the development of metastasis. Aims: 1- to establish the relationship between the presence and the levels of both procoagulants and the development of thrombosis or disease progression. 2- to analyse if the treatment with chemotherapy increases the levels of TF or CP. Methods: Patients with recent diagnosis of cancer were included in this prospective study. TF and CP determinations were done at diagnosis, at three months after chemotherapy, and at either event of progression or thrombosis. TF evaluation was done through ELISA test (normal value 159 pg/ml) and CP evaluation by a coagulometric method (Gordon et al, Thromb Res1989;56:431–40). In the last test negative values indicate high CP activity. Statistical analysis of the data was performed by two-tailed Fisher exact test and Mann-Withney/Wilcoxon test. Results: 31 patients, 61% female sex, age median 54 years. Digestive cancer 49%, breast 32%, genitourinary 13%, lung 2%. Stages of the disease were: early (I and II) 48% and advanced (III and IV) 52%. Median follow-up was 11.6 months. High levels of TF and CP at diagnosis were seen in 48% and 84% respectively. No patients developed thrombosis. Nine patients had disease progression (29%) and 4 (13%) died. Eigthy eight percent patients of this last group had advanced stages of the disease. The type of tumor more frequently associated with the event was digestive cancer (45%) and genitourinary cancer (33%). TF and CP values were increased by 40% and 50% respectively during chemotherapy treatment. Level of CP at diagnosis predicted progression (-26 sec versus -8 sec in patients with and without progression p 0.006) and also mortality (-34 sec versus -10 sec p0.003). TF at diagnosis predicted neither progression nor mortality. All patients who had progressive disease showed increased levels of TF (388 pg/ml vs 217 pg/ml p0.002) and CP (-63 sec vs -23 sec p.006) with respect to the values at diagnosis. Conclusions: Higher levels of CP at diagnosis are associated with a greater frequency of progression and mortality. No patients developed thrombosis. TF and CP levels were increased at the time of progression with respect to the values obtained at diagnosis. Chemotherapy increases the values of both procoagulants. A larger follow-up and a large number of patients could clarify the role of these procoagulants in the development of disease progression (metastasis).