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Background: The indications, implementation and reporting of liver biopsies for deceased organ donation are not mandatory or regulated. Reliable data on outcome quality and prognostic relevance are therefore not available. Defined standards are thus required to enable meaningful studies and to ensure high data quality of a national transplantation registry. Objective: Presentation of a synopsis of available studies and literature-based recommendations. Results and conclusion: Against the background of an organ shortage and a growing number of older donors, pretransplantation liver histology is of significant relevance to guide clinical decision making. With the joint recommendations of the German Transplantation Society (DTG), the German Society of Pathology (DGP) and the German Organ Transplantation Foundation (DSO) standardized procedures are defined for the first time. [ABSTRACT FROM AUTHOR]

Background: Routine use of multigene RT-PCR based assays as Recurrence Score (RS) vs. single markers (grade, uPA/PAI-1, HR, HER2, Ki-67) is controversially discussed in early BC. Several definitions of luminal A/B subtypes have been proposed by St. Gallen guidelines and individual researchers (grade 1/2 vs. 3, Ki-67 cut-offs 14 or 20%). Recently, integration of PR>20% was proposed as an immunhistochemical luminal A subtype definition (Ki-67<14%). Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and the first prospective comparison of central and local pathology IHC/FISH assessment, RT-PCR for single markers, impact of central/local grade regarding allocation of patients to luminal A/B subtypes. Methods: planB trial (04/09 to 11/11: n=2,449 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2-BC; n=3197 registered; n=3072 available for central tumor bank). RS was used as selection criterion for chemotherapy (CTx) omission in HR+ BC (if RS<11 in pN0/pN1). Risk assessment by grade, HR, HER2 (IHC/FISH), Ki-67 was evaluated locally and centrally by an independent trial pathologist in all tumors. Clinical risk was estimated using AdjuvantOnline 8.0 (cut-off of 88% of breast cancer specific survival after 10 years without therapy in HR+ disease). Results: RS distribution in 2569 HR+ tumors: 0-11 (18%), 12-25 (60%), >25 (22%) (RS1853%/34%/13%). Luminal A subtype based on Ki-67 cut-off of <14%/<20%: 50.4%/68.8%. If PR>20% was included in the luminal A/Ki-67<14% definition: 37.6%. Luminal A/B based on local/central grade: 79%/21%; 67.9%/32.1%. In 354 pN0-1 patients, CTx was omitted based on low RS (88% compliance). In this group, 62% were high-risk by clinical-pathological criteria. Allocation to luminal A/B subtypes based on local/central grade varied substantially: overall concordance was 72%, but 40% of locally luminal B (HR+/G3) were luminal A (HR+/G1/2) by central and 60% of centrally luminal B were luminal A locally. Moderate correlations were found between RS and central grade (Spearman correlation rs=0.317; p < 0.001), local grade (0.321; p < 0.001) and Ki-67 (rs = 0.374; p < 0.001), particularly due to poor correlations in the RS group <26. Correlations between groups were: RS12 and luminal A/B Ki-6714 (rs = 0.26; p < 0.001). Inclusion of PR>20% moderately improved the correlation between luminal subtypes and RS to rs=0.34; p < 0.001. Data on allocation to luminal subtypes by local/central Ki-67 will be presented at the meeting. Conclusions: Our results represent the first prospective correlation of different luminal A/B definitions vs. a guideline mentioned gene signature (RS). High RS usually implies high grade and luminal B classification, the converse is not true. There is substantial heterogeneity in risk assessment by luminal A/B classification and grade in low/intermediate RS groups. Concordance for central/local assessment of grade and luminal A/B status was limited. There is strong need for standardization of molecular subtype's immunhistochemical/clinical definition prior to implementation into daily routine. Clinical significance of these findings will be addressed by further follow up of the WSG-planB trial. [ABSTRACT FROM AUTHOR]

Aims: Marrow fibrosis (MF) is an unfavourable, often lethal complication of haematological neoplasms. Although biopsy technique and staining procedure are standardized, the prestaining processing of bone marrow biopsies (BMBs) varies markedly without any existing data on its significance for the diagnosis of MF. Methods and results: In this study on 712 BMBs from 296 patients with chronic idiopathic myelofibrosis (CIMF), chronic myeloid leukaemia (CML), or healthy bone marrow, MF was a characteristic complication of CML and CIMF. However, diagnosis and quantification of MF and detection of its prognostic significance were significantly biased by fixation, decalcification, embedding, marrow tissue shrinkage during biopsy processing and the thickness of marrow sections ( P < 0.000005). The relevance of these influences was explained by their effect on the marrow volume to which the fibre content was related, whereas the stainability of fibres was not affected. Semiquantitative grading of fibrosis and measurements of fibre density could not be adjusted to various methods of processing of bone marrow biopsies ( P < 0.003). Conclusions: Evaluations of MF and its prognostic significance should consider the bias due to the prestaining processing of BMBs and the necessity of an adjustment to the thickness of tissue sections and the degree of marrow tissue shrinkage. [ABSTRACT FROM AUTHOR]

Individualization and optimization of risk-adapted therapy in breast cancer requires molecular profiling of individual cancer specimens. In tissues of heterogeneous cellular composition, such as mammary tissue, cancer prognostic markers and potential therapeutic target molecules are preferentially detected by in situ techniques such as immunohistochemistry. The more therapy decisions are based on immunohistochemical findings, the more histopathologists are confronted with the demand to establish standardized procedures that enable reproducible evaluation independent from the investigating laboratory. Disappointing results of recent national and international immunohistochemistry trials for steroid receptor and HER-2 analysis in breast cancer underline the need to act now beyond recommendations and well-formulated guidelines for standardization. In order to ensure staining quality in every individual immunohistochemical analysis, we have developed an on-slide control with standardized samples which are placed on every slide of a therapy-decisive stain together with the tissue of interest. Novel mini tissue microarrays were constructed comprising cell lines as standardized controls, indicating the sensitivity and reliability of the staining procedure. Standardized control material on the same slide as the patient's specimen require neither additional reagents nor time and are automatically archived on the diagnostic slide to prove the quality of staining even after years. [ABSTRACT FROM AUTHOR]

Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period. • Adjuvant abemaciclib combined with ET improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, high-risk early breast cancer. • Abemaciclib benefit extended beyond the 2-year treatment period. • Ki-67 ≥20% was prognostic and may be used with clinicopathological features to identify patients at high risk of recurrence. • Adjuvant abemaciclib + ET benefited patients with high-risk clinicopathologic features regardless of Ki-67 index. • Safety data were consistent with the known abemaciclib risk profile. [ABSTRACT FROM AUTHOR]

Background: Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT HER2+/HR— trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy. Patients and methods: Female patients with HER2+/HR— EBC (M0) were randomized (5:2) to 12 weeks of T+P±weekly paclitaxel (pac) at 80 mg/m². Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T+P arm versus all chemotherapy-treated patients. Results: From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T+P and 42 to T+P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T+P per protocol and 92.9% T+P+pac. The pCR rate in the T+P+pac arm was 90.5%, compared with 36.3% in the T+P arm as a whole. In the T+P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population. Conclusion: Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR— EBC compared with dual blockade alone, even within early responders to dual blockade. Early nonresponse under dual blockade strongly predicts failure to achieve pCR. [ABSTRACT FROM AUTHOR]

A letter to the editor, which reports on a series of four chronic myelomonocytic leukemia cases that evolved to myeloproliferative neoplasm, is presented.

Introduction: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/ predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide- docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). Methods: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). Results: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors. In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor. In multivariate interaction analysis (including central and genomic grade), luminal-Blike subtype [HR+ and (Ki-67 =20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. Conclusion: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) tissue biopsy evaluation, including trephine biopsy and clot section, is an integral part of BM investigation and is often followed by ancillary studies, in particular immunohistochemistry (IHC). IHC provides in situ coupling of morphological assessment and immunophenotype. The number of different IHC tests that can be applied to BM trephine biopsies and the number of indications for IHC testing is increasing concurrently with the development of flow cytometry and molecular diagnostic methods. An international Working Party for the Standardization of Bone Marrow IHC was formed by the International Council for Standardization in Hematology (ICSH) to prepare a set of guidelines for the standardization of BM IHC based on currently available published evidence and modern understanding of quality assurance principles as applied to IHC in general. The guidelines were discussed at the ICSH General Assemblies and reviewed by an international panel of experts to achieve further consensus and represent further development of the previously published ICSH guidelines for the standardization of BM specimens handling and reports. [ABSTRACT FROM AUTHOR]

WSG EC-Doc is a prospective randomized trial comparing sequential taxanes versus taxane-free control involving more than 2000 early breast cancer patients at intermediate risk of recurrence (pN1). Addition of taxanes improves significantly event-free and overall survival rates. In hormone-sensitive disease only, patients with luminal B-like tumors as identified by high Ki-67 benefit from EC-Doc.Background Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only. Patients and methods A total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. Results Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). Conclusion EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. Clinical Trial number ClinicalTrials.gov, NCT02115204. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation is one curative treatment for hematological malignancies, but is compromised by life-threatening complications, such as severe acute graft-versus-host disease (aGvHD). Prediction of severe aGvHD as early as possible is crucial to allow timely initiation of treatment. Here we report on a multicentre validation of an aGvHD-specific urinary proteomic classifier (aGvHD_MS17) in 423 patients. Samples (n=1106) were collected prospectively between day +7 and day +130 and analyzed using capillary electrophoresis coupled on-line to mass spectrometry. Integration of aGvHD_MS17 analysis with demographic and clinical variables using a logistic regression model led to correct classification of patients developing severe aGvHD 14 days before any clinical signs with 82.4% sensitivity and 77.3% specificity. Multivariate regression analysis showed that aGvHD_MS17 positivity was the only strong predictor for aGvHD grade III or IV (P<0.0001). The classifier consists of 17 peptides derived from albumin, β2-microglobulin, CD99, fibronectin and various collagen α-chains, indicating inflammation, activation of T cells and changes in the extracellular matrix as early signs of GvHD-induced organ damage. This study is currently the largest demonstration of accurate and investigator-independent prediction of patients at risk for severe aGvHD, thus allowing preemptive therapy based on proteomic profiling. [ABSTRACT FROM AUTHOR]

BRCA1 is a major gatekeeper of genomic stability. Acting in multiple central processes like double-strand break repair, centrosome replication, and checkpoint control, BRCA1 participates in maintaining genomic integrity and protects the cell against genomic instability. Chromosomal instability (CIN) as part of genomic instability is an inherent characteristic of most solid tumors and is also involved in breast cancer development. In this study, we determined the extent of CIN in 32 breast cancer tumors of women with a BRCA1 germline mutation compared to 62 unselected breast cancers. We applied fluorescence in situ hybridization (FISH) with centromere-specific probes for the chromosomes 1, 7, 8, 10, 17, and X and locus-specific probes for 3q27 (BCL6), 5p15.2 (D5S23), 5q31 (EGR1), 10q23.3 (PTEN), and 14q32 (IGH@) on formalin-fixed paraffin-embedded tissue microarray sections. Our hypothesis of an increased level of CIN in BRCA1-associated breast cancer could not be confirmed by this approach. Surprisingly, we detected no significant difference in the extent of CIN in BRCA1-mutated versus sporadic tumors. The only exception was the CIN value for chromosome 1. Here, the extent of CIN was slightly higher in the group of sporadic tumors. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents a study which illustrates a third documented case of systemic mastocytosis (SM)-chronic myelogenous leukemia (CML) with unusual phenotypic and genotypic findings. The researchers also emphasized the use of immunohistochemical markers of diagnosis. A total of 98 formalin-mixed and paraffin-embedded bone marrow samples from 95 patients have been evaluated. It was found out that bone marrow evaluation of a CML may incidentally reveal the presence of an SM.

The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in ∼5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm). A series of primary and secondary acute myeloid leukaemias (AML) with megakaryoblastic phenotype and myelofibrosis unrelated to PMF (n=12) was analysed for the MPLW515K/L mutation by pyrosequencing. In three cases (25%), MPLW515L was found and in two of these a combination with trisomy 21 or the Philadelphia chromosome occurred. None of the secondary AML cases evolving from pre-existing PMF showed MPLW515K/L (n=4). We conclude that MPLW515L occurs in a considerable proportion of acute megakaryoblastic leukaemias with myelofibrosis unrelated to PMF.Leukemia (2009) 23, 852–855; doi:10.1038/leu.2008.371; published online 5 February 2009 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to the chronic myeloproliferative diseases with the presence of a Philadelphia chromosome/BCR-ABL fusion in the November 1, 2007 issue.

Marrow fibrosis (MF) has rarely been studied in myelodysplastic syndromes (MDS). There are no data on occurrence and significance of MF in the context of the World Health Organization (WHO) classification of disease. In total, 349 bone marrow biopsies from 200 patients with primary MDS were examined for MF and its prognostic relevance. MF correlated with multilineage dysplasia, more severe thrombopenia, higher probability of a clonal karyotype abnormality, and higher percentages of blasts in the peripheral blood (P<0.002). Its frequency varied markedly between different MDS types ranging from 0 (RARS) to 16% (RCMD, RAEB, P<0.007). Two patients with MF showed a Janus kinase-2 mutation (V617F). Patients with MF suffered from marrow failure significantly earlier with shortening of the survival time down to 0.5 (RAEB-1/-2), and 1–2 (RCMD, RA) years in median (P<0.00005). The prognostic relevance of MF was independent of the International Prognostic Scoring System and the classification of disease. Conclusion: The risk of MF Differs markedly between various subtypes of MDS. MF indicates an aggressive course with a significantly faster progression to fatal marrow failure and should therefore be considered in diagnosis, prognosis and treatment of disease.Leukemia (2008) 22, 313–322; doi:10.1038/sj.leu.2405030; published online 22 November 2007 [ABSTRACT FROM AUTHOR]

In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF). Whether the unfavorable prognosis of MF is also reversed and whether imatinib guarantees against evolution of MF are unclear as yet. Fifty-nine patients with Ph+ CML treated with 400 mg imatinib/day were examined for MF in 6- to 12-month intervals. Imatinib effectively reversed initial MF (P<0.0005). However, during a follow-up period of up to 4.8 years, small foci with abnormal fiber increase (FFI) emerged in 8 of 30 pretreated and 6 of 29 non-pretreated patients. Patients with FFI showed a significantly lower probability of achieving a complete cytogenetic or major molecular response (36 versus 81%; P<0.007). During the further follow up, 57% of patients with FFI but none of the other patients suffered from full-blown MF (P=0.00005). None of the patients with FFI or MF showed a Janus kinase-2 mutation (V617F). Evolutions of FFI and MF were independent significant predictors of imatinib failure (P=0.0031), accelerated phase and death of patients (P=0.0001; multivariate analyses). Imatinib effectively reverses initial MF in CML, but neither eliminates its unfavorable prognosis nor guarantees completely against new evolution of MF.Leukemia (2007) 21, 2420–2427; doi:10.1038/sj.leu.2404917; published online 6 September 2007 [ABSTRACT FROM AUTHOR]

Three consecutive polycythemia vera (PV) patients were analyzed before and during pegylated-interferon (rIFNalpha) treatment for the following markers: (1) granulocyte and CD34(+) cell clonality, (2) Jak2V617F expression, (3) PRV-1 mRNA overexpression, and (4) Epo-independent colony (EEC) growth. Before rIFNalpha therapy, all patients displayed clonal hematopoiesis, 100% Jak2V617F expression as well as PRV-1 overexpression, and EEC growth. After rIFNalpha treatment, all three patients demonstrated polyclonal hematopoiesis. Nonetheless, Jak2V617F expression, PRV-1 overexpression, and EEC-growth remained detectable, albeit at lower levels. We conclude that reemergence of polyclonal hematopoiesis after rIFNalpha treatment may be achieved in a substantial proportion of patients. However, this does not constitute elimination of the PV clone. These data demonstrate the usefulness of novel markers in monitoring minimal residual disease and caution against discontinuation of rIFNalpha treatment after hematologic remission. Long-term follow-up of large patient cohorts is required to determine whether rIFNalpha treatment can cause complete molecular remissions in PV. [ABSTRACT FROM AUTHOR]

Bone marrow fibrosis (MF) has been shown to indicate therapy failure in Ph+ chronic myeloid leukemia (CML). However, the results on the development of MF during interferon-a therapy of CML are controversial. The significance of the interferon dose has not been considered as yet. In total, 627 bone marrow biopsies taken prospectively from 200 patients with CML recruited in two studies using different doses of interferon-a ± low-dose cytosine arabinoside were examined for MF before and during therapy. The results showed that the risk of MF depended significantly on the interferon-a dose applied (P<0.000005). MF progressed during low-dose therapy (3 × 5 × 106?IU/week), but was prevented from progression when applying high dose (5 × 106?IU/m2/per day). MF disappeared when high-dose interferon-a was combined with low-dose cytosine arabinoside (P<0.000005). The risk of death markedly increased when MF occurred or progressed (P<0.0009), independent of all other prognostic factors evaluated including the cytogenetic response. In conclusion, the effectiveness of interferon-a on MF depends on the treatment intensity. MF reverses when combining high-dose interferon-a with low-dose cytosine arabinoside, but progresses when applying low-dose interferon-a. MF appears to be a significant early indicator of ineffective therapy in CML.Leukemia (2004) 18, 1460-1467. doi:10.1038/sj.leu.2403451 Published online 29 July 2004 [ABSTRACT FROM AUTHOR]

Immunosuppression has recently been proposed for low-risk myelodysplastic syndromes (MDS) to reverse bone marrow failure by inhibiting intramedullary secretion of proapoptotic cytokines. We treated 35 MDS patients (24 refractory anaemia (RA), 10 RA with excess blasts and one chronic myelomonocytic leukaemia) with either horse antithymocyte globulin 15?mg/kg/day or rabbit antithymocyte globulin 3.75?mg/kg/day, each for 5 days. Median age was 63 years (range: 41-75). After 1 to 34+ months of follow-up (mean: 15+), four patients experienced complete haematological responses (CR), six good responses (GR) and two minor responses. All CRs and GRs occurred in patients with RA, in whom both horse and rabbit ATG yielded five responses out of 12 (42%). Time to response varied between 1 and 10 (mean: 3) months. The median duration of response was 9+ (1-17+) months; five patients are in continuing response. In all, 23 patients suffered side effects >°II WHO (the degree of toxicity encountered according to the internationally accepted WHO toxicity grading); one patient died 2 weeks after rabbit ATG from rhinocerebral mucormycosis. Parameters that correlated with response were duration of disease and RA subgroup. In our experience, immune-modulating therapy with either horse or rabbit ATG is feasible in patients with RA and short duration of disease.Leukemia (2004) 18, 460-465. doi:10.1038/sj.leu.2403239 Published online 08 January 2004 [ABSTRACT FROM AUTHOR]

Marrow fibrosis (MF) has rarely been considered in therapy studies on chronic myeloid leukemia (CML), and there is a lack of long-term observations on the basis of sequential bone marrow biopsies (BMBs) taken prospectively during the course of disease. A total of 848 BMBs from 400 patients with Ph+ CML recruited in the German randomized CML study I were examined for MF before and during therapy. In total, 110 patients had been randomized to receive interferon (IFN)-a, and 290 to receive chemotherapy (hydroxyurea (HU): 154, busulfan: 136). During IFN-a and HU medication, MF was reduced or did not increase for about 2 years. Evolving or progressive MF was an independent and early predictor of therapy failure about 2 years earlier than indicated by changes in the peripheral blood, spleen size, marrow blast count and cytogenetics (P<0.00005), resulting in a significant shortening of the survival times of patients independent of the type of therapy applied including allografting (multivariate analyses; P<0.00005). The analyzed long-term observations strongly indicate that MF is an independent poor prognostic complication of CML, allowing an early prediction of therapy failure. Consideration of the fiber content in marrow may therefore significantly improve the prediction of therapy efficacy and outcome of disease.Leukemia (2003) 17, 2444-2453. doi:10.1038/sj.leu.2403172 Published online 16 October 2003 [ABSTRACT FROM AUTHOR]

The important cell cycle regulatory gene p15[SUPNK4b] has been shown to be inactivated in acute myeloid leukemia and myelodysplastic syndrome. Little is known about the expression and epigenetic modification of this gene in chronic myelomonocytic leukemia (CMML) that belongs to the myelo-dysplastic/myeloproliferative disorders (MDS/MPD) with a high proportion of blastic transformation. Analysis of bone marrow trephines in a series of 33 CMML cases showed an aberrant p15&[SUPINK4b] gene methylation in up to 58% of cases. Methylation was analyzed employing different methylation-specific PCR and genomic sequencing protocols. It turned out to be spread over a broad area of the 5′ region and exhibited substantial heterogeneity between cases and even in individual patients. The degree of aberrant methylation was correlated with a reduced mRNA as well as reduced protein expression, and was associated with a higher expression of DNA methyltransferase DNMT 3A. We conclude that aberrant gene methylation is a frequent event in CMML that might contribute to the pathogenesis of this MDS/MPD. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in which association of SRSF2 and U2AF1 mutations in primary myelofibrosis with JAK2 and MPL without calreticulin mutation that may independently reoccur after allogeneic stem cell transplantation is being discussed.

Investigates the reconstitution of squamos epithelium in Barrett's oesophagus after argon plasma coagulation (APC). Characterization of Barret's oesophagus; Identification of Barrett's mucosa; Use of the method in reducing the risk of adenocarcinoma.

Atezolizumab (an anti–PD-L1 antibody) has shown clinical activity alone or in combination with nab-paclitaxel in patients (pts) with first-line metastatic TNBC who have PD-L1 expression on their tumour-infiltrating immune cells (IC). We analysed the performance of 4 PD-L1 IHC assays for PD-L1 IC expression in TNBC. Thirty archival TNBC tissue specimens were selected from a set of 107 based on PD-L1 IC expression per VENTANA SP142 (<1%: 15 cases; 1–5%: 7 cases; >5%: 8 cases), to represent the distribution of PD-L1 IC–positivity in the pivotal atezolizumab studies (Emens et al., SABCS 2018; JAMA Oncol 2019). Serial histologic sections were stained with VENTANA SP142 and SP263, and DAKO 22C3 and 28-8, per manufacturer protocols. Slides were blinded for both assay and sample information and scored by trained readers at 7 sites for PD-L1 IC expression (% per tumour area), as well as tumour cell expression (≥1% vs < 1%), by online virtual microscopy. Adjusted means of PD-L1 IC staining ranged from 3.7% to 7.8% (Table); SP263 stained more IC than the other assays. Pairwise comparison of adjusted means showed small, non-significant differences (–1.2% to 0.6%) between SP142, 22C3 and 28-8, but a significant increase in PD-L1 staining for SP263 vs the other assays (3.0% to 4.2%). Intra-class correlations (ICC) for the assays showed moderate (0.460) to excellent (0.805) reader concordance (Table). Pre-specified allocation to a 1% binary IC cut-off revealed good-to-high inter-reader agreement (Kappa 0.589 to 0.789). Table 359P Table Assay PD-L1 on IC, % (95% CI) * Reader ICC (95% CI) † SP263 7.8 (7.1–8.6) 0.616 (0.477–0.758) SP142 4.3 (3.5–5.0) 0.805 (0.710–0.887) 22C3 3. 7 (2.9–4.4) 0.605 (0.474–0.755) 28-8 4.9 (4.1–5.6) 0.460 (0.319–0.636) * Sample and reader adjusted means; † Between 7 readers The results of this first multicentre PD-L1 assay comparison study in TNBC indicate good-to-high reproducibility and concordance of PD-L1 IC expression between the SP142, 22C3 and 28-8 assays, while higher PD-L1 IC expression levels were detected with SP263. Hence, SP142, 22C3 and 28-8 may be considered analytically interchangeable for PD-L1 IC testing. Roche study ID SL41336. Support for third-party writing assistance for this abstract, furnished by Katie Wilson, PhD, of Health Interactions, was provided by Roche Pharma AG, Grenzach-Wyhlen, Germany. F. Hoffmann-La Roche Ltd. Roche Pharma AG, Grenzach-Wyhlen, Germany. A. Noske: Travel / Accommodation / Expenses: Roche; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. J. Ammann: Full / Part-time employment: Roche Pharma AG, Germany; Shareholder / Stockholder / Stock options: Roche; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. D. Wagner: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. C. Denkert: Honoraria (institution): Teva; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Amgen; Advisory / Consultancy: Daiichi; Advisory / Consultancy: MSD; Shareholder / Stockholder / Stock options: Sividon Diagnostics; Shareholder / Stockholder / Stock options: Myriad; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG. A. Lebeau: Advisory / Consultancy: Roche Pharma AG, Germany; Advisory / Consultancy: Novartis; Research grant / Funding (self): Roche Pharma AG, Germany; Research grant / Funding (self): Sysmex Europe; Research grant / Funding (self): BioNTech Diagnostics; Travel / Accommodation / Expenses: Roche Pharma AG, Germany; Travel / Accommodation / Expenses: Novartis; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. P. Sinn: Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (institution), Travel / Accommodation / Expenses: Nanostring; Honoraria (self), Travel / Accommodation / Expenses: Genomic Health; Research grant / Funding (self): Dietmar-Hopp-Stiftung; Full / Part-time employment: Univ. Heidelberg; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. H. Kreipe: Advisory / Consultancy: Roche Pharma AG, Germany; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genomic Health; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. G. Baretton: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. K. Steiger: Research grant / Funding (institution): Roche; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Bruker Daltonics; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. M. Kiechle: Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Myriad; Research grant / Funding (self): German Cancer Aid; Research grant / Funding (self): DFG; Shareholder / Stockholder / Stock options: Therawis Diagnostics GmBH; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. S. Hieke-Schulz: Full / Part-time employment: Roche Pharma AG, Germany; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. W. Roth: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): Chugai; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. W. Weichert: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Celgene; Speaker Bureau / Expert testimony: Boehringer; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Amgen; Research grant / Funding (institution): Bruker Daltonics; Non-remunerated activity/ies, Support for third-party medical writing assistance: Roche Pharma AG, Germany. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Telomere shortening, clonal evolution and disease progression in myelodysplastic syndrome patients with 5q deletion treated with lenalidomide," published in the online July 29, 2011 issue of the journal "Leukemia" is presented.

The article reports on the significant increase of the DNA methylation in patients with myelodysplastic syndrome. It says that epigenetic aberrations are recognized as early events in the process of malignant transformation. It also says that gene specific hypermethylation occurs in the context of global hypomethylation. In addition, in patients with myelodysplastic syndrome, the induction of hypomethylation using DNA methyltransferase inhibitors leads to haematological improvement.

A letter to the editor is presented about a case of an 80-year-old woman diagnosed with polycythemia vera (PV) with clonal granulopoiesis.

The article reports a case of hepatocellular carcinoma (HCC) with a preserved reticulin network. The loss of the reticulin network was demonstrated to be preceded by chromosomal instability and aneuploidy in the present case. This finding has major implications for the diagnosis of well-differentiated HCC for the understanding of hepatocarcinogenesis.

We describe a 35-year old patient with nodular fasciitis, erythema migrans, and gonarthritis four months after a bite of a Borrelia afzelii infected tick. The Borrelia afzelii infection was identified by a polymerase chain reaction and direct sequencing of the amplification product. Borrelia-specific DNA was also detectable in nodular fasciitis tissue. We therefore conclude that Borrelia afzelii can be a causative agent of nodular fasciitis and Lyme arthritis in a highly endemic region of Northern Germany. [ABSTRACT FROM AUTHOR]

The article presents a case-study of a 65-year-old male, who was presented with thrombocytosis, splenomegaly, anemia and signs of hemolysis. Topics discussed include proliferation of all cell lineages displayed by bone marrow histology, myeloproliferative neoplasm showed by splenectomy and massive proliferation of the granulocytic lineage. Also mentioned are mutations in CSF3R gene associated with the transformation of myeloproliferative neoplasm to atypical chronic myeloid leukemia.

Objective: C4d staining in peritubular capillaries (PTC) has been established as an in situ marker of humoral rejection. A definite cut-off for the C4d stain is still under discussion. Few data are available about the incidence of C4d deposition in protocol biopsies (Bx) in comparison to that of indicated biopsies. To test whether center specific factors are influencing the incidence of C4d detection we performed a multicenter study. Methods: Bx were from Hannover, Germany, Barcelona, Spain, and Antwerp, Belgium. 779 paraffin embedded biopsies (501 protocol, 278 indication) were stained by immunohistochemistry using a polyclonal antiserum. C4d results in PTC were recorded in five groups: >50% of PTC/biopsy core area C4d positive, 25-50%, 5-25%, >5%, C4d negative. Staining results were correlated to clinical data. Bx were classified following the updated Banff 2001 criteria. Additionally, the amount of inflammatory cells in PTC were graded according to a proposal made at the recent Banff 2003 meeting. Results: Diffuse C4d deposition (>50% of PTC) was found in 1.6% of protocol Bx and in 11.2% of indication Bx. The incidence in protocol Bx varied from 0.8% to 6.4% between the different centers. A focal C4d stain (25-50% of PTC) was found in 2.0% of protocol Bx and 8.6% of indication Bx. Diffuse C4d staining is more frequent in females, in patients with pre-transplants, or PRA >30%. Inflammatory cells in PTC and acute tubular injury are the most common morphological findings in C4d positive cases. Conclusions: The incidence of C4d staining in protocol Bx is lower than in indication Bx. Diffuse C4d deposition in PTC accompanied by morphological signs of AHR occur in stable renal allografts, suggesting subclinical AHR. Focal C4d detection seems to be related to morphological signs of AHR, too. [ABSTRACT FROM AUTHOR]

Bone Marrow Transplantation (2003) 31, 1071-1072. doi:10.1038/sj.bmt.1704035 [ABSTRACT FROM AUTHOR]