ALBERT

Description: Introduction The American Cancer Society anticipates the diagnosis of 80,000 new cases of lymphoma in the US in 2013. Cancer Research UK estimates that more than 80% of Hodgkin Lymphoma (HL) patients and more than 60% of Non-Hodgkin Lymphoma (NHL) patients will be alive 5 or more years after diagnosis. As survival rates improve, focus shifts to ensuring quality of life in survivors and decreasing potential toxicity. Radiological procedures play a prominent role in diagnosis, staging and assessment of treatment response. Exposure to ionizing radiation has been linked to an increased risk of malignancy (Pearce et al 2012, Miglioretti et al 2013, Mathews et al 2013). Cumulative exposure in excess of 75mSv has been estimated to increase cancer mortality by 7.3% (Cardis et al 2007). There is a paucity of data in the literature regarding cumulative radiation exposure in patients with lymphoma. In cancer treatment, the aim is individualized management strategies. This should also be the goal for diagnostic procedures (O' Neill et al 2011, Fletcher et al 2012). Methods A retrospective review of all patients on a prospectively maintained database with biopsy proven HL or NHL between January 2009 and July 2012 was conducted in a University hospital group. The cumulative effective radiation dose (CED) was calculated using standardized procedure-specific radiation dose levels. Results Four hundred and eighty six patients were included in the study. Mean (SD) age at diagnosis was 59 (17) years and 15% were aged 〈 40. Fifty-nine percent were men. Sixteen percent had HL; 84% had NHL. There were a total of 1127 patient-years of follow-up, with 15% having 75mSv and 14% had a total CED 〉150mSv – SeeFigure 1. CT contributed 89% of the radiation dose and PET-CT contributed 8%. Patients aged

Description: Background Evidence based consensus guidelines for venous thromboembolism (VTE) prevention are broadly accepted to be effective and safe for more than three decades (Clagett GP et al, 1992). However VTE continues to be associated with a major global burden of disease with 3.9 million cases of HAT during one year among 1.1 billion citizens of high income countries (Jha AK et al, 2013). Therefore prevention is the key to reduce death and disability resulting from VTE (Kahn S et al, Gould MK et al & Falck-Yitter Y et al, 2012). Ireland like many other countries has yet to implement a mandatory risk assessment tool and thromboprophylaxis (TP) policy nationally. Aims The aim of this study was to calculate the proportion of inpatients who had a VTE risk assessment performed and received appropriate TP in a large tertiary referral hospital. This information will be vital for baseline data for implementation of a new national policy for prevention of HAT. Methods This audit was performed at Cork University Hospital on 4 pre specified days between November 2014 to February 2015. All adult inpatients (Medical and Surgical) excluding maternity and psychiatric were included. Patients on therapeutic anticoagulation were also excluded. The patients' medical chart and drug prescription chart were reviewed to determine whether or not a VTE risk assessment was documented for each patient and if they had received appropriate TP. If no risk assessment had been performed, trained researchers applied the National Institute for health and Care Excellence (NICE) guidelines 92 (Jan 2010) for VTE risk assessment and prevention. Following the risk assessment patients were divided into three categories, high risk of VTE with low risk of bleeding; high risk of VTE with significant risk of bleeding and low risk of VTE. From this the proportion of patients in each group that received appropriate TP were calculated. Results A total of 1019 patients were enrolled the majority were medical patients 63.5% (n=648). The mean age of patients was 69 years. Females accounted for 52% of patients. Average length of hospitalisation for each patient at the time of the audit was 6 days (range 1-664 days). Overall, a formal TP risk assessment was documented in only 24% (n=244) of all charts reviewed however TP was prescribed in 43.2% (n=441) of patients. See table.Table 1.High Risk of VTE low risk of bleedingHigh risk of VTE significant risk of bleedingLow risk of VTENo. of pts80.3% (n=819)16.6% (n=170)2.9% (n=30)VTE risk assessment documented21.9% (n=180)28.2% (n=55)30% (n=9)Received TP46.3% (n=380)28.8% (n=49)40% (n=12) Within the high risk category patients, 64.3% (n=526) medical. TP was only administered to 46.3% (n=380) of patients in the high risk category. This was almost evenly distributed between surgical 50.1% (n=147) and medical 43.4% (n=233) patients. Conclusion This audit was done as the initial step to develop a national policy to prevent HAT. As suspected, this audit highlights that a large proportion of hospitalised patients, both surgical and medical, continue to be at high risk for VTE despite the availability of preventative measures. There is clear illustration of under prescription of safe, effective and recommended means of VTE prevention. The current overall figure of less than 50% prescription of VTE thromboprophylaxis in high risk patients is a major patient safety concern. There are numerous recognised international guidelines for prevention of VTE, and an efficient method to implement these guidelines needs to be developed. Beyond developing national guidelines for TP, we need a co-ordinated approach to implement and monitor compliance with guidelines. Once the preliminary results of this audit were available to us in March 2015, urgent measures were taken to reduce the identified risk such as the establishment of a Hospital Thrombosis Group which developed a user friendly VTE risk assessment tool and TP policy. The VTE risk assessment tool was incorporated into the patients drug prescription chart and included a pre printed prescription for TP. It is now mandatory for the all patients to have a VTE risk assessment tool and TP prescribed if appropriate within 24hrs of admission. This was successfully piloted for four weeks in the acute medical assessment unit and is now incorporated into each patients drug chart throughout the hospital. This audit will be replicated in 6 months from introduction of this initiative, with an aim of 〉90% compliance. Disclosures No relevant conflicts of interest to declare.

Description: During the last decade the frequency of therapy-related acute leukemia (t-leuk) and myelodysplastic syndrome (t-MDS) has been increasingly observed. Over the past 15 years, we treated 56 patients with t-leuk who had received prior chemotherapy (39%), radiotherapy (11%), or both (45%). The drugs received included alkylating agents and topoisomerase II inhibitors. The primary tumors included hematological malignancies (49%) and solid tumors such as breast or ovarian cancer. The median age at diagnosis of the primary tumor was relatively young (43 years +/- 18). Twelve patients had more than one primary tumor and 31 patients had a family history of malignancy. Karyotypic abnormalities were found in 91% of the patients. Prognosis was uniformly poor, with an overall median survival of 10 months. Twelve of the 18 patients examined (67%) had a multidrug resistance phenotype. P53 genes of the leukemic cells, as well as the original tumors, were analyzed in 21 patients using polymerase chain reaction (PCR) with single-stranded conformation polymorphism analysis followed by sequencing. P53 mutations were identified in 38% of these patients, a relatively high prevalence compared with other forms of MDS or de novo acute myeloid leukemia. Mutations were nongermline and restricted to the leukemic cells. We identified different p53 mutations in the various primary tumors of individual patients. The presence of a mutator phenotype was assessed by PCR analysis of microsatellites in eight loci (one trinucleotide repeat sequence, four dinucleotide, and three mononuclear repeat sequences). Microsatellite instability in two to seven loci were found in 15 of 16 (94%) of the patients. This instability is compatible with a mutator phenotype, which predisposes the patients to the development of malignancies including t-leuk.

Description: During the last decade the frequency of therapy-related acute leukemia (t-leuk) and myelodysplastic syndrome (t-MDS) has been increasingly observed. Over the past 15 years, we treated 56 patients with t-leuk who had received prior chemotherapy (39%), radiotherapy (11%), or both (45%). The drugs received included alkylating agents and topoisomerase II inhibitors. The primary tumors included hematological malignancies (49%) and solid tumors such as breast or ovarian cancer. The median age at diagnosis of the primary tumor was relatively young (43 years +/- 18). Twelve patients had more than one primary tumor and 31 patients had a family history of malignancy. Karyotypic abnormalities were found in 91% of the patients. Prognosis was uniformly poor, with an overall median survival of 10 months. Twelve of the 18 patients examined (67%) had a multidrug resistance phenotype. P53 genes of the leukemic cells, as well as the original tumors, were analyzed in 21 patients using polymerase chain reaction (PCR) with single-stranded conformation polymorphism analysis followed by sequencing. P53 mutations were identified in 38% of these patients, a relatively high prevalence compared with other forms of MDS or de novo acute myeloid leukemia. Mutations were nongermline and restricted to the leukemic cells. We identified different p53 mutations in the various primary tumors of individual patients. The presence of a mutator phenotype was assessed by PCR analysis of microsatellites in eight loci (one trinucleotide repeat sequence, four dinucleotide, and three mononuclear repeat sequences). Microsatellite instability in two to seven loci were found in 15 of 16 (94%) of the patients. This instability is compatible with a mutator phenotype, which predisposes the patients to the development of malignancies including t-leuk.

Description: Introduction The TP53 gene encodes the tumour suppressor and cell cycle regulatory protein and is found to be mutated in a variety of carcinomas. Mutation in TP53 gene is associated with resistance to conventional therapy, disease progression and overall poor prognosis in solid tumours and haematological malignancies including Myelodysplastic Syndromes (MDS). TP53 mutated sub-clones in MDS have been demonstrated by deep sequencing technology in prior studies. Strong nuclear staining of p53 protein by immunohistochemistry has been used as a surrogate marker for TP53 gene mutation in haematological and other malignancies. Methods We analysed sequential marrow samples for p53 expression on 35 patients with MDS from a single institution pre and post Azacitidine therapy. Formalin fixed, paraffin embedded marrow biopsies were stained with DO-7 mouse p53 monoclonal antibody. 1000 haematopoietic cells were examined under the high power and p53 expression was determined as per Modified Quick Score. Results Median age of the patients was 70 and WHO subgroups were identified as follows: 7 RCMD, 1 5q-syndrome, 1 MDS/MPN, 8 CMML, 6 RAEB-1, 6 RAEB-2 and 6 t-MDS. Cytogenetic risk as per IPSS-R/CPSS showed 17 (50%) lower risk, 4(12%) intermediate risk and 13(38%) higher risk groups. Patients received a median 13 cycles of Azacitidine. Marrows were assessed prior to treatment and after 3-6 cycles. Median overall survival of the study group was 20 months and transformation to AML occurred in 13 patients (37%). At diagnosis, 27 patients (77%) were p53 negative and 8 patients (23%) were p53 positive. At reassessment, 24 patients (69%) remained p53 negative while 6 patients (17%) remained p53 positive. Two patients (6%) became p53 negative and 3 (8%) became p53 positive following Azacitidine treatment. Median overall survival of patients who remained p53 negative during Azacitidine treatment was 28 months compared to 11 months in patients who remained p53 positive, p=0.005. Similarly, median overall survival of patients who remained or became p53 negative was 28 months compared to 18 months for those who remained or became p53 positive during Azacitidine therapy, p=0.012. p53 expression at diagnosis or changes in p53 expression during Azacitidine treatment did not correlate with transformation to Acute Myeloid Leukaemia (AML) or time to progression to AML. Among the p53 positive group, patients who had more than 10% p53 expression had lower overall survival compared to those who were 10% at DiagnosisPositive p53

Description: Background: Cytoreductive therapy with hydroxyurea (HU) has been considered first line therapy for patients with high risk polycythemia vera (PV) and essential thrombocythemia (ET) since the results of the PVSG-08 trial demonstrated thrombotic risk reduction (Fruchtman SM et al 1997) for PV and PT1 for ET (Harrison CN et al 2005). Although HU is well tolerated by most patients and has been shown to reduce thrombotic risk in this setting, concern regarding the leukemogenic potential of this oral ribonucleotide reductase inhibitor balanced by the observation of molecular responses with interferon-α (IFN-α) led us to compare the clinical response and tolerability of pegIFN-α (PEG) and HU in a global, randomized, phase III trial. Methods : MPD-RC 112 trial (NCT01258856) enrolled patients with high risk (age 〉60 years, history of thrombosis, extreme thrombocytosis, symptomatic splenomegaly, uncontrolled cardiovascular risk factors), newly diagnosed (

Description: Background Interferons are recognized as active agents in the treatment of patients with high risk essential thrombocythemia (ET) or polycythemia vera (PV), both in the upfront setting as well as beyond. Several trials have shown high rates of hematologic and molecular responses with the use of interferons, however, data on direct comparison of interferon activity in patients with early disease in comparison to patients refractory or resistant to prior therapies, such as hydroxyurea (HU) are lacking. We conducted a controlled analysis of the activity of pegylated interferon alfa-2a (PEG) in two prospective parallel clinical trials conducted in these two unique patient populations. Methods The MPD-RC 111 (NCT01259817) was an international, multicenter, phase 2 open-label clinical trial that evaluated PEG therapy in patients with high risk PV and high-risk ET who were either refractory or intolerant (R/I) to HU by modified ELN criteria. The MPD-RC 112 trial (NCT01258856) enrolled patients with high risk ET/PV who were treatment-naïve (TN) (HU