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Purpose: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis.Experimental Design: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL–TFE3 fusion and, hence, confirm the aCGH observations.Results: FISH analysis identified the ASPL–TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation.Conclusion: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS. Clin Cancer Res; 20(6); 1521–30. ©2014 AACR.

PDF file, 143K, Characteristics for all men and by ERG-overexpression status among 90 men diagnosed with prostate cancer during transurethral resection of the prostate (TURP)a, PHS and HPFS cohorts 1982-2011.

XLS file, 43K, List of studies reviewed for but excluded from the meta-analysis.

PDF file, 130K, Selection process for the study inclusion in the meta-analysis.

Background: Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.Methods: Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes.Results: The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78–1.26] or lethal disease (HR, 0.93; 95% CI, 0.61–1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)≥T3 vs. T2, 1.23; 95% CI, 1.16–1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86–1.17) or lethal disease (RR, 0.99; 95% CI, 0.47–2.09).Conclusions: These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy.Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(9); 1497–509. ©2012 AACR.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. Cell-of-origin classification in DLBCL has identified activated B cell (ABC) and germinal center B cell (GCB) as two major subtypes. Patients with the ABC subtype show reduced overall survival with standard therapies. Development of a quantitative RT-PCR-based lymphoma cell-of-origin (LCOO) assay to determine ABC, GCB, and unclassifiable subtypes in formalin-fixed, paraffin-embedded tissue (FFPET) DLBCL samples is reported. The LCOO classifier was trained on two DLBCL cohorts with validation performed by using an analytical grade assay in an independent cohort of 60 FFPET DLBCL samples. In the validation cohort, LCOO classification was 88.1%, 84.7%, and 84.7% concordant with microarray, immunohistochemistry (Hans classification), and Lymphoma Subtyping Test, respectively. Importantly, LCOO and Lymphoma Subtyping Test assays commonly assigned subtypes in 17 (94.4%) of 18 ABC samples and 34 (89.5%) of 38 GCB DLBCL samples from this cohort. Progression-free survival and overall survival of ABC and GCB subtypes, as classified by all platforms, were not significantly different in the validation cohort. LCOO classification using publicly available microarray gene expression from two independent data sets (414 fresh frozen and 474 FFPET DLBCL biopsies) revealed a significantly worse outcome for the ABC subtype compared with that of the GCB subtype. Thus, a sensitive, reproducible, LCOO assay developed on an easy to standardize quantitative RT-PCR platform may be an important clinical tool for DLBCL cell-of-origin classification.

The mechanism of high-grade transformation in gastrointestinal stromal tumors (GISTs) remains to be clarified. We aim to discover the key progression events by studying biphasic GISTs. The study group included 101 GISTs. Nineteen of these had been screened from 263 GISTs to represent the early stage of GIST high-grade transformation, characterized by juxtaposed low-grade and high-grade regions in the same tumor (so-called biphasic GISTs). Mutational analyses, fluorescence in situ hybridization (FISH), NanoString analyses, telomere analysis, and gene expression profiling were carried out, followed by in silico analyses, cell line study, and immunohistochemical validation. Using gene expression analysis, downregulation of SFRP1 was revealed to be the main event in GIST high-grade transformation (p = 0.013), accompanied by upregulation of EZH2. In silico analyses revealed that downregulation of SFRP1 was a common feature in GIST progression across several different series. Immunohistochemically, the expression of SFRP1 was validated to be significantly lower in high-grade GISTs (WHO risk group 3a or higher) than in low-grade GISTs (p 0.001), and attenuation/loss of SFRP1 was associated with GIST tumor progression (p 0.001). By NanoString and FISH analyses, chromosomal 9/9p loss was the only recurrent large-scale chromosome aberration in biphasic GISTs, with a correlation with SFRP1 downregulation. Subclones containing chromosome 9/9p loss could be appreciated in the low-grade parts of biphasic GISTs. TP53 mutation, RB1 loss, KIT/PDGFRA mutation, and alternative lengthening of telomeres did not play a significant role in GIST high-grade transformation. In conclusion, high-grade transformation of GISTs features SFRP1 downregulation and chromosome 9/9p loss.

Introduction Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence. Methods We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated. Results Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up. Conclusion In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

Background Irish Health Research Regulations (HRRs) were introduced following the commencement of the General Data Protection Regulation (GDPR) in 2018. The HRRs set out supplementary regulatory requirements for research. A legal analysis presented under the auspices of the Irish Academy of Medical Sciences (IAMS) on April 8 and November 25, 2019 at the Royal College of Surgeons in Ireland welcomed the introduction of GDPR and the HRRs. The analysis found the GDPR “explicit consent” introduced by the HRRs is problematic. A call was made to regulate informed consent in line with the common law as an achievable alternative safeguard, bringing Ireland in line with other EU Member States. Aims This article aims to review academic papers, legal opinion, EU opinion and advice and data protection law in relation to research and explicit consent, in order to examine the legal burden of GDPR and the HRRs on health research in Ireland and to determine whether the analysis presented at the IAMS meetings is reflected more widely in legal text. Methods Legal literature review of academic papers, legal opinion, EU opinion and advice and data protection legislation. Results The legal literature review overwhelmingly supports the concerns raised. Conclusions Our results confirm the GDPR explicit consent requirement of the HRRs is having had a significantly negative and far-reaching impact on the conduct of health research in Ireland. Urgent review of the HRRs and meaningful engagement between the health research community and legislators in healthcare is required.

Monomorphic posttransplant lymphoproliferative disorders have been defined as lymphoid or plasmacytic proliferations that fulfill criteria for one of the B-cell or T/NK-cell neoplasms recognized in immunocompetent hosts in the current WHO Classification. Low-grade B-cell neoplasms have historically been excluded from this category, although rare reports of marginal zone lymphoma (MZL) have been described. We report 9 cases of posttransplant Epstein-Barr virus-negative MZL, all arising in solid organ transplant recipients (4 renal, 3 liver, 1 cardiac, and 1 liver, pancreas, and small bowel). Seven were extranodal MZL of mucosa-associated lymphoid tissue type, all of which had gastrointestinal involvement (4 colon, 1 duodenum, 1 stomach, and 1 oropharynx/base of tongue). Notably, the preferential involvement of intestine distinguishes posttransplant extranodal MZL from sporadic cases. Immunoglobulin light-chain restriction was seen in all cases, with polymerase chain reaction showing a monoclonal pattern in 7 of 8 cases with successful amplification of polymerase chain reaction products. A clonally unrelated recurrence was seen in one case. Next-generation sequencing identified recurrent mutations previously reported in MZL in 3/5 cases. MZL was diagnosed at least 1 year after solid organ transplant (median time to presentation, 84 mo; range, 13 to 108 mo). The median age was 44 (range, 9 to 73 y); the male: female ratio was 5:4. The mean follow-up was 33.4 months, with an indolent clinical course observed. A subset responded to reduction in immunosuppression and anti-CD20 therapy alone. These data support the designation of Epstein-Barr virus-negative MZL as an uncommon form of monomorphic posttransplant lymphoproliferative disorders.

Immune Checkpoint Inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and Tumour Mutational Burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

Lymphoma diagnosis is complex, requiring a wide array of adjunctive tests to reach accurate diagnoses. We retrospectively examined the rates of concordance between referral and review lymphoma diagnoses on cases referred to St James’s Hospital, Dublin for multidisciplinary team review between 2013 and 2016. Frequency and cost of adjunctive diagnostic tests performed were also analysed. The overall discordance rate was 7.8% (14/179), compared with rates of 6%–48% in the published literature. 13 discordant cases required a change in clinical management following review of the referred diagnosis. Of all referred cases, 33.5% (60/179) required extra analyses to reach a final diagnosis, costing the reference laboratory €35463.40. We conclude that establishment of centralised haematopathology diagnostic networks would help reduce the rate of revision made to lymphoma diagnoses by providing specialist haematopathologist input and access to ancillary testing.

Background Splenectomy is a surgical intervention for a variety of indications; benign and malignant. Complications of this procedure include Venous thromboembolism (VTE) and infection. The incidence of VTE post-surgery has been reported between 0.8%–3% depending on the type of surgery. A higher incidence of abdominal VTE was reported post splenectomy (6–11%). However, there is limited literature regarding the risk factors for post splenectomy VTE and the optimal strategy for thromboprophylaxis. Objective The primary objective of the study was to evaluate the incidence of VTE post splenectomy and to identify the pre-operative, intra-operative and post-operative risk factors. The secondary objective was to assess the local compliance with post-splenectomy prophylactic antibiotics and vaccination protocols. Methods We conducted a retrospective observational study. All patients who had a splenectomy in St James's Hospital between January 2007 and June 2017 were included and reviewed. Statistical analysis was carried out using SPSS statistical package. Results 85 patients were involved in the study. The main indications for splenectomy were benign haematology, malignant haematology, solid tumours, traumatic and spontaneous rupture. 6/85 patients developed VTE (7.06%). High BMI ≥ 30 was associated with increased risk of VTE (p = 0.007), while the use of post-operative prophylactic anticoagulation was associated with reduced risk (p = 0.005). Other factors including age >50 years, female gender, presence of active malignancy and splenomegaly were associated with increased VTE risk with no statistical significance. All VTE's occurred in elective versus emergency splenectomy. Laparoscopic splenectomy was associated with higher risk of VTE than open splenectomy. 97% of patients were prescribed prophylactic antibiotics on discharge, but only 88% had received recommended vaccinations. Conclusion Venous thromboembolism is common post splenectomy. Our data showed that BMI ≥30 was associated with a statistically significant increased risk of VTE, while the use of prophylactic anticoagulation was associated with reduced risk. Further prospective studies with larger samples are warranted and a splenectomy care plan may be helpful., Highlights • Venous thromboembolism is common post splenectomy procedure. • High Body Mass Index can increase the risk of venous thromboembolism post splenectomy surgery. • The use of extended prophylactic anticoagulation post splenectomy can reduce the venous thromboembolism complications. • Many other factors can contribute to the venous thrombosis risk post splenectomy at variable extents.

Background Central nervous system (CNS) lymphoma is rare, representing 2% of all brain tumors. The commonest subtype is diffuse large B-cell lymphoma (DLBCL), with primary T-cell lymphomas (PCNSTL) accounting for ~ 2%. Objective To determine the frequency and describe the key features of CNS lymphoma over a 10-year period in an Irish population. Materials and methods This retrospective review was carried out using the neuropathology database in Beaumont hospital, the largest of two national neurosurgical centers, to identify all cases of CNS lymphoma from 2007 to 2017. Clinical, radiological, morphological, immunophenotype, and molecular information was recorded where available. Results We identified 149 cases of CNS lymphoma from 2007 to 2017, which equated to a cumulative incidence rate of 0.4/100,000 persons. Median age at diagnosis was 66 years, and 46% were male. 86% were classified as DLBCL (n = 128), 10% immunodeficiency-associated CNS lymphoma (n = 15), 3% PCNSTL (n = 4), and 1% (n = 2) cases of intravascular large B-cell lymphoma. Location in declining frequency was as follows: supratentorial (n = 125), infratentorial (n = 22), spinal (n = 1), and orbital (n = 1). Conclusion This is the first study in an Irish population to determine a cumulative incidence rate of CNS lymphoma, which is in line with larger international population-based registries. No significant trends in incidence rate have been observed from 2007 to 2017. DLBCL is the commonest subtype encountered. Rare variants including PCNSTL can pose a significant diagnostic challenge, and in this setting, molecular studies can be useful to confirm diagnoses.

Background Irish Health Research Regulations (HRRs) were introduced following the European Union (EU) General Data Protection Regulation (GDPR) in 2018. The HRRs described specific supplementary regulatory requirements for research regarding governance, processes and procedure that impact on several facets of research. The numerous problems that the HRRs and particularly “explicit consent” inadvertently created were presented under the auspices of the Irish Academy of Medical Sciences (IAMS) on November 25, 2019, at the Royal College of Surgeons in Ireland. Aims The objective of this review was to obtain feedback and to examine the impact of GDPR and the HRRs on health research in Ireland in order to determine whether the preliminary feedback, presented at the IAMS meetings, was reflected at a national level. Methods Individuals from the research community were invited to provide feedback on the impact, if any, of the HRRs on health research. Retrospective patient recruitment and consent outside a hospital setting for a multi-institutional Breast Predict study (funded by the Irish Cancer Society) were also analysed. Results Feedback replicated the issues presented at the IAMS with additional concerns identified. Only 20% of the original target population (n = 1987) could be included in the Breast Predict study. Conclusions Our results confirm that the HRRs have had a significantly negative impact on health research in Ireland. Urgent meaningful engagement between patient advocate groups, the research community and legislators would help ameliorate these impacts.

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7–59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18–3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82–3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54–2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.

A composite lymphoma is the rare simultaneous occurrence of two or more distinct lymphomas within a single tissue or organ. Herein, we describe a case of a 51-year-old man presenting with a history of lower limb rash, fatigue, and bulky abdominopelvic lymphadenopathy. An excisional left iliac lymph node biopsy was notable for the composite presence of two distinct lymphoid neoplasms, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), and follicular lymphoma (FL). Multiplex PCR and FISH analyses failed to demonstrate a t(14;18)(q32;q21) translocation in either composite lymphoma component. A clonal light-chain kappa (V/JC intron-kde) gene rearrangement was detected in the FL component only.

Brain biopsy in patients presenting with subacute encephalopathy is never straightforward, and only undertaken when a ‘treatable condition’ is a realistic possibility.This 63 year old right handed, immunocompetent Caucasian woman presented with an 8 month history of rapidly progressive right-sided hearing impairment, a 4 month history of intermittent headaches, tinnitus, ‘dizziness’, dysphagia, nausea and vomiting, with the subsequent evolution of progressive gait ataxia and a subacute global encephalopathy. The possibility of CJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. She died 9 days later and autopsy brain examination confirmed widespread subacute infarction due to an EBV positive atypical NK/T-cell infiltrate with positivity for CD3, CD56, granzyme B, perforin and EBER with absence of CD4, CD5 and CD8 expression. Molecular studies for T-cell clonality were attempted but failed due to insufficient DNA quality. Serology was consistent with past EBV infection (EBV VCA and EBNA IgG Positive). There was no evidence of disease outside the CNS. Primary central nervous system NK/T-cell lymphoma is extremely rare. The rare reported cases all present with a discrete intracranial mass, unlike the diffuse infiltrative pattern in this case. Whilst the diffuse interstitial pattern is reminiscent of chronic active EBV infection (CAEBV) seen in other organ systems such as the liver and bone marrow, the clinical presentation and epidemiologic profile are not typical for CAEBV.

Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness. Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death. Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6–16.6; P < 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8–5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04). Conclusions: These data support the hypothesis that perineural invasion creates a microenvironment that promotes cancer aggressiveness. Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. Cancer Epidemiol Biomarkers Prev; 26(5); 719–26. ©2017 AACR.

Retrospective study to evaluate the outcome of patients with transformed follicular lymphoma (tFL) treated with rituximab-containing chemotherapy and consolidation. Patients diagnosed with tFL from 2003 to 2013 treated with consolidation therapy with last follow-up in December 2015 were identified from the institutional lymphoma database and included in this study. Data collected included age, gender, stage, interval to tFL diagnosis, R-IPI score, histological diagnosis and therapy. The treatment algorithm used was stratified for age, performance status (PS) and sibling donor availability using R-chemotherapy induction followed by consolidation with allogeneic stem cell transplant (SCT), autologous SCT, Zevalin or rituximab maintenance (RM). Patients with B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt’s lymphoma (BCL-U), with FISH-proven t(14;18) and t(8;14) and their variants were excluded. Four hundred patients were diagnosed with FL of whom 26 (7%) developed histologically proven tFL. The group was predominantly male (73%) with a median age at transformation of 53 (range 27–72) years and 85% presented with stage III/IV disease. Thirteen (50%) patients presented with de novo tFL and the remainder had previously diagnosed FL, with a median time to transformation of 5.7 (range 1–15) years. The median follow-up time from tFL diagnosis to December 2015 is 8 (range 4–14) years. All patients received immuno-chemotherapy achieving an overall response rate (ORR) of 100%. Fourteen (54%), patients were transplant eligible and based on donor availability, six had an auto-SCT only, five had an allo-SCT only and three had a matched unrelated allo-SCT for a post-auto-SCT relapse. The 12 patients (46%) who were not transplant eligible were consolidated with rituximab maintenance (RM) in nine (35%) and Zevalin in three (11%) cases. The overall survival (OS) and progression-free survival (PFS) for the series at 5 years were, 92 and 73%, respectively. This consecutively treated series of 26 patients with tFL have had a better outcome than expected which may be due to the use of rituximab-chemotherapy and a consolidation strategy based on age, PS and availability of a sibling donor.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma. While many patients will be cured with Rituximab-CHOP, 30%–50% will either relapse or have disease refractory to treatment.1 The International Prognostic Index is not sufficiently accurate to stratify these patients into prognostic subgroups, thus gene expression profiling (GEP) and the identification of gene rearrangements (R) involving Myc , Bcl-2 and Bcl-6 are instead used for risk stratification. GEP or more commonly immunohistochemistry (IHC)-based algorithms are used to stratify patients according to their cell of origin (COO), broadly dividing them into germinal centre B (GCB), and non-GCB subgroups. The latter group incorporates the activated B-cell (ABC) subtype, which is associated with significantly worse outcomes when treated with standard chemotherapy regimens, as compared with the GCB subgroup.2 Double hit (DH) lymphomas are characterised by the presence of a Myc gene R with a concurrent Bcl-2 or Bcl-6 gene R, while triple hit (TH) lymphomas have all three. The rearrangement status of these lymphomas is reflected in the updated WHO classification of lymphoid neoplasms in 2017. DH/TH lymphomas account for 5%–10% of (morphologic) DLBCL.2 Interestingly, 80% of DH lymphomas have concurrent Myc and Bcl-2 R and are associated with the GCB subtype, while dual translocations of Myc and Bcl-6 are more commonly linked to the ABC phenotype.3 Overexpression of c-myc protein (defined as >40% positive neoplastic …

Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence.We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated.Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up.In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

Thrombocytopenia is one of the most common hematological abnormalities observed during pregnancy, and in rare cases, this may be the first indicator of an underlying hematological malignancy. Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder of which thrombocytopenia is a recurrent presenting feature. A case of pancytopenia presenting in pregnancy is described in which the thrombocytopenia persisted postpartum coincidental with a vesicular, pustular rash characterised as Sweet’s syndrome. Hematological, histological, immunophenotypic, and molecular investigations confirmed the presence of HCL. The patient was treated with cladribine resulting in resolution of Sweet’s syndrome, hematological remission from HCL, and achievement of a normal platelet count. This case highlights the need to maintain a wide differential diagnosis for presentations of pancytopenia or thrombocytopenia in pregnancy and the requirement for follow-up investigation of unusual cases with a lack of response to steroids or immunoglobulin.

Composite lymphoma (CL) describes the rare occurrence of 2 or more distinct types of lymphoma in a single anatomical location. We present the case of a 78-year-old man presenting with a 3-month history of weakness, malaise, and increasing dyspnea. A lymph node excised from the posterior triangle of the neck revealed the coexistence of 2 morphologically and phenotypically distinct lymphoid neoplasms consistent with a blastoid variant of mantle cell lymphoma (MCL) occurring in composite with classical Hodgkin lymphoma (cHL), mixed cellularity subtype. A t(11;14)(q13;q32) translocation was demonstrated by fluorescence in situ hybridization in the MCL and Hodgkin Reed-Sternberg cells of the cHL. Multiplex polymerase chain reaction detected clonal Immunoglobulin heavy chain (VFR1-J, VFR2-J, and VFR3-J), clonal immunoglobulin light chain kappa (V-J and V/JC intron-kde) and clonal immunoglobulin light chain lambda (V-J) gene rearrangements in the MCL. This report represents the first case of a blastoid variant of MCL occurring in composite with cHL.

Breast implant–associated lymphoma has recently gained wide recognition. Anaplastic large cell lymphoma (ALCL) is the most frequently diagnosed subtype in this setting but the spectrum is broadening. A 66-year-old woman developed swelling and itch around her saline implant 6 years after its insertion. Imaging revealed a fluid collection surrounding the implant with an adjacent mass. Microscopy showed sclerotic tissue punctuated by discrete cellular nodules comprising small lymphocytes, eosinophils and interspersed large atypical Hodgkin Reed-Sternberg (HRS)-like cells. The HRS-like cells stained positively for CD30 and CD15 by immunohistochemistry. Small T-lymphocytes formed rosettes around HRS-like cells. Appearances were consistent with classical Hodgkin lymphoma (HL). Multiplex polymerase chain reaction demonstrated no clonal rearrangements of immunoglobulin or T-cell receptor genes, however, a t(14;18)(q32;q21)BCL2-JH translocation involving the major breakpoint region of the bcl2 gene was present. Staging positron emission tomography–computed tomography scan revealed FDG-avid masses in the right axilla and pelvis. Subsequent pathological examination identified low-grade follicular lymphoma (FL) with a t(14;18) translocation at these sites. To our knowledge, this is the first case of HL arising adjacent to a breast implant. An awareness of this diagnosis is important as classical HL, with its prominent mixed inflammatory background, may be overlooked as a reactive process when histologically assessing capsulectomy specimens. It is also important in the differential diagnosis for implant-associated ALCL as both contain large atypical CD30-positive cells highlighting the need for full immunohistochemical and molecular workup in such cases. This case also adds to the large body of literature regarding the association between HL and FL.

65 Background: DNA repair genes including BRCA1 are commonly altered in metastatic prostate tumors. However, mutations and copy number aberrations in these genes are rare in primary tumors. Instead, preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. Methods: We undertook a prospective study of tumor BRCA1 protein expression and lethal prostate cancer among men with clinically localized prostate cancer in the Health Professionals Follow-up Study. We performed immunohistochemical staining for BRCA1 on tumor tissue microarrays using a validated antibody and scored expression as positive or negative. We also assessed tumor proliferation by immunostaining for Ki67, angiogenesis by immunostaining for CD34, and apoptosis using a TUNEL assay. Proportional hazards regression was used to evaluate the association between BRCA1 protein expression and development of lethal prostate cancer (metastasis or cancer-specific death). Results: Ten percent of tumors (60 of 589) stained positive for the BRCA1 protein. BRCA1-positive tumors were characterized by higher Gleason scores, a higher proliferative index, and a higher apoptotic index. During a median follow-up of 14.3 years, 18 men (34%) in the BRCA1-positive group and 74 men (14%) in the BRCA1-negative group developed lethal prostate cancer. There was a strong positive association between BRCA1 protein expression and lethal prostate cancer in both unadjusted analyses (HR 2.71, 95% CI 1.73–4.26) and after adjusting for clinical factors (HR 2.00, 95% CI 1.26–3.18). The positive association with BRCA1 protein expression was also independent of proliferation index. Conclusions: Primary prostate tumors expressing the BRCA1 protein have a highly proliferative phenotype and are more likely to progress to lethal disease, independent of its higher proliferative index. Assessing tumor protein expression of BRCA1 may help elucidate the Janus-faced role of DNA repair pathways in prostate cancer progression.[Table: see text]

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Background Corpora amylacea are amyloid bodies commonly found adjacent to damaged prostate epithelium. Little is known about their formation or function. The current study sought to characterize corpora amylacea in prostate tissue and to describe their relationship with clinical, histological, molecular, and lifestyle factors, especially with chronic inflammation which is associated with aggressive disease. Methods We studied a cohort of 355 men with prostate cancer and tissue specimens from the Health Professionals Follow-Up Study. Pathologists examined H&E slides and undertook a standardized review for histologic data and inflammation. Trained observers counted corpora amylacea within the benign and predominately tumor areas. Immunohistochemistry biomarkers were available from tissue microarrays. We used multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) to assess associations of chronic inflammation, clinical, histological, molecular, and lifestyle factors with the presence of corpora amylacea. Results Corpora amylacea were present in benign tissue area for 298 men (84%). Specimens with moderate-to-severe chronic inflammation were more likely to have corpora amylacea in benign regions (OR = 5.4 95%CI 1.9, 15.6). Moreover, corpora amylacea were more common in men with higher body mass index (OR = 1.13 95%CI 1.01, 1.26). In contrast, Gleason grade (OR = 0.4 95%CI 0.2, 0.8), proliferation index (OR = 0.6 95%CI 0.3, 1.2) and the presence of the TMPRSS2:ERG fusion (OR = 0.4 95%CI 0.2, 0.8) were inversely associated with corpora amylacea presence. TURP specimens were less likely to have corpora amylacea than prostatectomy specimens (OR = 0.12 95%CI 0.03, 0.47). Age, PSA, stage, biomarkers of angiogenesis and PTEN, and vasectomy were not significantly associated with corpora amylacea. Conclusion Corpora amylacea were common among men with prostate cancer and were associated with pro-inflammatory factors, some markers of less aggressive disease, and lack of the TMPRSS2:ERG fusion.

Ovarian cancer is the fifth most common cancer in women worldwide and has the highest mortality amongst gynecological cancers. miRNAs are a class of non-coding RNAs, approximately 22 nt long, that negatively regulate gene expression and have roles in cell growth, differentiation, metabolism, apoptosis and tumorigenesis. Dysregulated miRNA-223 expression has been implicated in a wide range of cancer subtypes. SMARCD1 is an integral protein component of the SWI/SNF complex, which remodels chromatin, and which has important roles in transcriptional control, DNA replication, recombination and repair. In this study, we examined whether the expression levels of miR-223 and SMARCD1 are altered in ovarian serous neoplasia and whether miR-223 functionally regulates the gene and protein expression of SMARCD1 in vivo, as has been predicted by in silico methods. Benign, atypical proliferative serous tumors (borderline) and malignant serous tumors (n = 144) were laser-capture microdissected, and relative expression levels of miR-223 and SMARCD1 were quantified by RT-PCR. Ovarian cancer cell line OC316 was reverse transfected with a miR-223 mimic, and relative expression levels of miR-223 and SMARCD1 were quantified by reverse-transcription polymerase chain reaction; protein expression of SMARCD1 was evaluated by Western blot. miR-223 expression was up-regulated in high-grade ovarian serous carcinoma samples (median RQ = 4.8881, P = .0045), whilst SMARCD1 was down-regulated (median RQ = 0.5107, P = .0492). In OC316 cells transfected with a miR-223 mimic, SMARCD1 gene expression was down-regulated 3-fold (P = .001), and SMARCD1 protein expression was down-regulated 2-fold (P = .002). These results suggest a regulatory role for miR-223 in ovarian serous neoplasia, linking it with SMARCD1.