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The amended EU Shareholder Rights Directive introduces a comprehensive regime of ex ante review for potentially conflicted transactions between listed companies and 'related parties' (major shareholders, managers, and others). If considered material, these transactions will have to be evaluated in advance by the board of directors, the shareholders' meeting, or the stock market. The most important choice to be made by member states in implementing the directive concerns the definition of 'materiality'. We use hand-collected data based on IAS 24 reporting of related party transactions to estimate the number of German companies affected by quantitative materiality thresholds based on accounting assets, sales, market capitalisation, and other financials. One important recommendation derived from the analysis is to use more than one single quantitative test to define material related party transactions. [ABSTRACT FROM AUTHOR]

Objectives: Domatinostat (4SC‐202) is a selective class I histone deacetylase inhibitor (HDACi). This phase I study investigated safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity in patients with advanced hematological malignancies. Methods: Domatinostat was administered orally once (QD) or twice daily (BID) on days 1‐14 with 7 days off or continuously days 1‐21 in a 3 + 3 design at 7 dose levels from 25 to 400 mg total daily dose (TDD). Twenty‐four patients were treated with domatinostat. Results: No formal maximum tolerated dose (MTD) was determined. One dose‐limiting toxicity (DLT, grade 4 hypercalcemia) occurred during 200 mg BID continuous treatment. Six patients were reported with ≥ grade 3 treatment‐related adverse events (TRAE; grade 3 hematological in three patients, grade 3 and grade 4 liver enzyme increase in 2 patients, grade 4 pulmonary embolism, and grade 4 hypercalcemia in one patient each). Higher grade hepatic TRAE occurred in the 200 mg BID continuous treatment cohort. Out of 24 patients, 1 achieved a complete response, 1 achieved a partial response, and 18 had stable disease as best response. Conclusion: Administration of domatinostat was safe, well tolerated with signs of antitumor activity. Four hundred milligram TDD in a 200 mg BID schedule (14 + 7) is the recommended phase II dose for monotherapy. [ABSTRACT FROM AUTHOR]

Physiological immune checkpoint pathways are important to regulate self-tolerance, limit immune reactions, and moderate autoimmunity. Various cancers are commonly exploiting these mechanisms to evade the host immune system by restraining a durable, efficient antitumor immune response. Immune checkpoints include, but are not limited to, the programmed death 1 (PD1) and the cytotoxic T-lymphocyte-associated protein-4 (CTLA4) axis, which are both druggable by monoclonal antibodies referred to as checkpoint inhibitors (CIs). To date, the anti-PD1 antibodies nivolumab and pembrolizumab are approved for relapsed or refractory classical Hodgkin lymphoma (cHL) due to high response rates with a favorable yet distinct safety profile, and other agents are under investigation. This review summarizes the available preclinical and clinical data including the toxicity and efficacy of different CIs in cHL. It also provides future perspectives based on ongoing clinical trials, potentially synergistic combinatory approaches, and their fit in the therapeutic landscape in cHL. [ABSTRACT FROM AUTHOR]

Cancer in the adolescent and young adult (AYA) is the second leading cause of nonaccidental death with hematological malignancies spiking during this period. Treatment of AYAs with hematological malignancies usually follows either pediatric or adult protocols with sufficient information lacking on subgroup analyses regarding course and outcome. In this review we will outline up-to-date treatment possibilities for AYAs diagnosed with Hodgkin's lymphoma. Early and late toxicities will be addressed and future directions of research suggested. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma ( HL) is a B cell-derived lymphoid malignancy most often affecting young adults. More than 80% of HL patients achieve long-term remission after appropriate first-line treatment consisting of multiagent chemotherapy and/or radiotherapy ( RT). In addition, approximately 50% of patients with disease recurrence remain relapse-free after salvage therapy with high-dose chemotherapy followed by autologous stem cell transplantation ( ASCT). However, patients with multiple relapses are mostly in a palliative situation, and novel drugs for this patient group are needed. Furthermore, novel less toxic but equally effective first-line and second-line approaches are required as therapy-related late sequelae represent a relevant cause of morbidity and mortality in HL survivors. Several antibodies and antibody-drug conjugates ( ADC) targeting CD30 and CD20 have recently been evaluated in HL. Excellent response rates in heavily pretreated patients were observed with the ADC brentuximab vedotin directed against CD30. Thus, ongoing trials investigate brentuximab vedotin in different additional indications. One example is the first-line treatment of advanced HL where the drug is currently being evaluated in combination with variants of the first-line protocols ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone). Anti- CD20 antibodies given either as single agent or in combination with conventional chemotherapy have also been investigated and still undergo investigation in prospective studies including HL patients. This article reviews the available data on treatment approaches including antibodies and ADC in HL patients. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL), a B cell-derived cancer, is one of the most common lymphomas. In HL, the tumor cells -- Hodgkin and Reed-Sternberg (HRS) cells -- are usually very rare in the tissue. Although HRS cells are derived from mature B cells, they have largely lost their B cell phenotype and show a very unusual co-expression of markers of various hematopoietic cell types. HRS cells show deregulated activation of multiple signaling pathways and transcription factors. The activation of these pathways and factors is partly mediated through interactions of HRS cells with various other types of cells in the microenvironment, but also through genetic lesions. The transforming events involved in the pathogenesis of HL are only partly understood, but mutations affecting the NF-κB and JAK/ STAT pathways are frequent. The dependency of HRS cells on microenvironmental interactions and deregulated signaling pathways may offer novel strategies for targeted therapies. [ABSTRACT FROM AUTHOR]

The article discusses a prospective randomised control trial which investigated the need for more radiotherapy and the intensity of chemotherapy in advanced stage Hodgkin's lymphoma patients. Patients were randomly given different cycles of BEACOPP. It notes that positron emission tomography (PET)-guided radiotherapy following six cycles of BEACOPP therapy was less toxic and more effective with regards to avoidance of treatment failure.

Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of 2-3/100.000/year in developed countries. With modern multi-agent chemotherapy protocols optionally combined with radiotherapy (RT), 80% to 90% of HL patients achieve long-term remission and can be considered cured. However, current standard approaches bear a considerable risk for the development of treatment-related late effects. Thus, one major focus of current clinical research in HL is reducing the incidence of these late effects that include heart failure, infertility, chronic fatigue and therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML). In previous analyses, t-MDS/t-AML after treatment for HL was associated with a poor prognosis. Nearly all patients died rapidly after diagnosis. However, more recent analyses indicated an improved outcome among patients with t-MDS/t-AML who are eligible for modern anti-leukemic treatment and allogeneic stem cell transplantation (aSCT). This article gives an overview of recent reports on the incidence and the treatment of t-MDS/t-AML after HL therapy and describes the efforts currently made to reduce the risk to develop this severe late effect. [ABSTRACT FROM AUTHOR]

Meta-analyses have followed some of the most important advances in the treatment of early-stage Hodgkin lymphoma (HL). In this review, details on all meta-analyses of patients with early-stage HL are discussed. In 1990, the first meta-analysis addressing patients with early-stage HL compared radiotherapy alone to combined-modality treatment (CMT). It was followed in 1998 by an individual-patient meta-analysis examining the role of radiotherapy with and without chemotherapy. In 2006, a comprehensive meta-analysis focusing on the risk of secondary malignancies, including most of the treatment regimens analyzed in clinical trials, was issued. The final analysis was published 2010 and provides important information for the ongoing discussion concerning the role of CMT compared to chemotherapy alone and is therefore discussed in more detail. In addition, the methodology and reporting of meta-analyses have improved over time. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

After the global financial crisis, systemic risk regulation has taken centre stage. Many consider hedge funds a potential threat to financial stability. Regulating hedge funds, however, is necessarily a transnational challenge because no national government alone can effectively control the systemic risks affecting its economy. This article takes the example of hedge funds for a case study of emerging transnational regulation. After an introduction to hedge funds and the reasons for regulating them, it considers the possible elements of a transnational regulatory regime for hedge funds: transnational industry self-regulation, including such induced by the government, regulatory competition between government regulators, and harmonisation of government regulation. The main conclusions are: self-regulation cannot substitute fully for government regulation in controlling systemic risks caused by hedge funds. Equally, regulatory competition tends to undercut systemic risk regulation. Effective transnational regulation can only be accomplished through harmonisation of government regulation. Such harmonisation is likely to arise if regulation is needed to control systemic risk in global financial markets. [ABSTRACT FROM AUTHOR]

Background: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels. Methods: We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment. Results: The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1). Conclusions: In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.) N Engl J Med 2010;363:640-52. [ABSTRACT FROM AUTHOR]

When Council Regulation (EC) No 2157/2001 on the Statute for a European Company (Societas Europaea - SE) became effective on 8 October 2004, it offered existing publicly traded companies, for the first time, a choice between competing company laws, namely the national law of the company's home state and the law of the supranational SE. Using an event study methodology, we analyse a unique dataset of publicly traded firms that have announced to re-incorporate under the SE Regulation. [ABSTRACT FROM AUTHOR]

The article discusses adaptability as an essential characteristic of a legal system for economic development. It cites the use of legal origin as substitutes for adaptability by the Legal Origins Theory as measuring adaptability directly remains impossible. It indicates that the reliance on the courts as a proxy for adaptability fails to link the differences in substantive law responsible for the competitive advantage of common law jurisdictions. It suggests that the adaptability hypothesis cannot conclusively explain the superiority of the common law.

After a slow start, the European Company (Societas Europaea - SE) has become increasingly popular. Besides documenting the growth of this new company type, we examine whether firms choose to incorporate in the SE corporate form because they engage in 'legal arbitrage' by exploiting differences in legal rules between jurisdictions. We specify a number of hypotheses on particular legal arbitrage motives. To validate our hypotheses, we use a broad telephone survey among SE users in Germany as well as a simple country-level regression model based on a unique, hand-collected dataset on SE incorporations. We find strong evidence that firms use the SE to mitigate the effect of mandatory codetermination rules. Establishing a one-tier board structure (in jurisdictions that impose a two-tier structure on their national public companies) and taking advantage of the SE's mobility for tax purposes also seem to be driving SE formations. By contrast, our analysis fails to support the suggestion that firms use the SE to shop for the most favourable national company law to fill the gaps in the SE Regulation. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the feasibility and efficacy of the intensified induction chemotherapy regimen ACOMED for patients with aggressive non-Hodgkin's lymphoma (NHL). Untreated adult patients with aggressive NHL, presenting with Ann Arbour stage II–IV disease or stage I with bulky disease, and with at least one of the following risk factors: age > 60 years, advanced disease, elevated serum lactate dehydrogenase level, Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, presence of extranodal sites of disease and bulky disease, were treated with the ACOMED regimen consisting of 4–6 cycles of adriamycin 25 mg/m 2 i.v. on days 4–5, cyclophosphamide 250 mg/m 2 i.v. on days 1–5, vincristine 2 mg i.v. absolute on day 1, methotrexate 500 mg/m 2 i.v. on day 1 with leucovorin-rescue after 24 h 30 mg/m 2 i.v. and 3 × 15 mg p.o., etoposide 100 mg/m 2 i.v. on days 3–5, dexamethasone 10 mg/m 2 p.o. on days 1–5 and granulocyte colony-stimualting factor support, repeated on day 21. Twenty-two patients were treated within this study at a single center. After 4–6 cycles of ACOMED followed by additional involved field radiotherapy in 18 patients, the complete and overall response rates were 86% (19 of 22 patients) and 95% (21 of 22 patients), respectively. After a median observation time of 10 years and 2 months, 16/22 (73%) patients are alive in continuous complete reponse without evidence of any late toxicities. ACOMED followed by involved field radiation presents a highly effective regimen for remission induction and long-term survival in patients with aggressive NHL, and merits further investigation. [ABSTRACT FROM AUTHOR]

The article discusses research on consolidation treatment for patients with relapsed or refractory Hodgkin's lymphoma. Topics discussed include a study on the use of brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA), event-free survival in Hodgkin patients, and dose intensity of chemotherapy in patients with relapsed Hodgkin's lymphoma.

In this issue of Blood, Fanale and colleagues report promising treatment results for patients with newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (see figure). [ABSTRACT FROM AUTHOR]

No abstract available [ABSTRACT FROM AUTHOR]

What is it that we actually see when looking at PET (positron emission tomography)-positive signals in Hodgkin lymphoma (HL)? Thus, the question of how to manage PET-positive lesions at the end of frontline therapy in HL is indeed crucial, because undertreating a disease that can be cured with firstline treatment in 80-90% of cases must definitely be avoided. As a result the authors concluded that it may not always be decisive to perform a biopsy for PET-positive residual mediastinal tissue after frontline therapy and that it was safe and appropriate to first closely observe asymptomatic patients instead of directly intensifying treatment. In the GHSG HD15 trial Engert et al. assessed whether administering RT only to patients with persistent PET-positive residues after chemotherapy was justifiable compared to earlier trials where irradiation was given to all initial bulky findings and all residual disease. [Extracted from the article]

The article offers information on the study on the effect of chemotherapy alone on the treatment of early stage Hodgkin lymphoma against chemotherapy with radiotherapy. It mentions that because most of the patients are young, the long-term harms of radiotherapy must be considered chemotherapy was added. It says that the various chemotherapy used in the study include adriamycin, bleomycin, vinblastine, and davarbazine (ABVD), cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP), and epirubicin, bleomycin, vinblastine, prednisone (EBVP). It argues that six cycles of chemotherapy with radiotherapy is much better than six cycle of chemotherapy alone. It adds that the control of tumor and relapse are better in combination treatment.

The authors analyzes the role of bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen in the treatment of relapsed Hodgkin lymphoma (HL). It is stated that, although BEACOPP has been found to improve treatment results in patients with early unfavorable HL, the risk to exceed the maximal cumulative anthracycline dose is one of the reasons on the basis of which arguments against the use of the regimen are given.

A letter to the editor is presented in response to the article "Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer Associated Anemia" by C. L. Bennett, S. M. Silver and B. Djulbegovic in a previous issue.

With defined chemotherapy and radiotherapy (RT) and risk-adapted treatment, early-stage classical Hodgkin lymphoma (HL) has become curable in a majority of patients. Hence, a major current goal is to reduce treatment-related toxicity while maintaining long-term disease control. Patients with early-stage favorable disease (ie, limited stage without risk factors [RFs]) are frequently treated with 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (2xABVD) followed by 20-Gy involved-field or involved-site RT (IF/ISRT). In patients with early-stage unfavorable disease (ie, limited stage with RFs), 4 cycles of chemotherapy are usually consolidated with 30-Gy IF/ISRT. Compared with 4xABVD, 2 cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (2xBEACOPPescalated) followed by 2xABVD improved 5-year progression-free survival (PFS), with similar 5-year overall survival. Recently, treatment strategies based on [18F]fluorodeoxyglucose positron emission tomography (PET) response were evaluated. In early-stage unfavorable HL, a majority of patients achieved a negative interim PET after 2xABVD and an excellent outcome after 4xABVD, whereas in those with a positive interim PET, 2xBEACOPPescalated improved 5-year PFS. Furthermore, a PET-guided RT approach was evaluated to decrease long-term toxicity. Although both the RAPID and H10 trials reported poorer disease control without RT, PET-guided omission of RT can constitute a valid therapeutic option in patients with an increased risk of RT-associated toxicity (eg, because of sex, age, or disease localization). Implementation of drugs such as the anti-CD30 antibody-drug conjugate brentuximab vedotin or the anti--programmed death 1 antibodies nivolumab or pembrolizumab might allow further reduction of overall mortality and improve quality of life in affected patients. [ABSTRACT FROM AUTHOR]

Summary: B‐cell content in the tumour microenvironment (TME) of classic Hodgkin lymphoma (HL) is known to be associated with prognosis. Here we demonstrate that whole slide image analysis using routinely available slides predicts outcomes in patients treated with ABVD in a prospective trial with a high B‐cell content being associated with a favourable prognosis. B cells in the TME did not correlate with B cells in peripheral blood. In the TME maturation, stages of B cells (naive and memory) were consistent. However, we detected down‐regulation of CD73 in HL with low B cells suggestive of an antibody‐independent function of B cells in the TME of HL. [ABSTRACT FROM AUTHOR]

The article reviews the book "Neoplastic Diseases of The Blood," edited by P.H. Wiernik, J.M. Goldman, J. Dutcher and R.A. Kyle.

Objectives: Patients with classical Hodgkin lymphoma (cHL) relapsing after second‐line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising (pre‐)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL). Methods: Patients ≥18 years with histologically confirmed r/r cHL who failed second‐line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28‐day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT‐based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression‐free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2‐stage phase 2 design (Simon 1989). Results: Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1‐year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported. Conclusion: Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1. [ABSTRACT FROM AUTHOR]

Summary: Different studies have characterized the microenvironment and its prognostic impact in classic Hodgkin lymphoma whereas such analyses are pending for nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL). We thus investigated characteristics of tumour cells and microenvironment in NLPHL and evaluated possible correlations with the clinical presentation. Lymph node samples from 152 NLPHL patients who had first‐line treatment within the randomized German Hodgkin Study Group HD16–HD18 trials were available and analysed with regard to IgD status and nuclear size of the tumour cells as well as presence of PD1‐positive follicular T helper cells and CD163‐positive macrophages in the microenvironment. While large tumour cell nuclei and high numbers of PD1‐positive follicular T helper cells in the microenvironment were more common in patients presenting with early/intermediate stages than in patients with advanced‐stage disease (p < 0.0001, unpaired t‐test; p = 0.0022, Mann–Whitney test), no differences between risk groups were observed in terms of the IgD status of the tumour cells and the content of CD163‐positive macrophages in the microenvironment. PD1‐positive follicular T helper cells were present in both cases with typical and variant growth patterns and rosetting around the tumour cells was observed in 96% of patients, indicating an important role of PD1‐positive follicular T helper cells in NLPHL. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) has become a highly curable malignancy even in advanced stages when treated adequately. However, relapsed or refractory disease and treatment-related toxicity constitute a significant clinical challenge. Innovative approaches are thus needed to improve treatment of these mainly young patients. In HL lesions, very few malignant Hodgkin and Reed-Sternberg (HRS) cells are embedded in an immunosuppressive microenvironment of reactive cells. Novel approaches such as bispecific antibodies, antibody-drug conjugates, immune-checkpoint inhibitors or adoptive cellular therapies are currently being investigated with promising results in relapsed or refractory patients. Encouraging response rates and a favorable toxicity profile have recently been reported in early phase clinical trials with antibodies blocking the programed-death receptor 1 (PD1). This review will summarize the current clinical knowledge on mechanism, safety and efficacy of the different agents and discuss potential future strategies, which are partly already investigated within clinical trials. [ABSTRACT FROM AUTHOR]

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A–C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2–28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life. [ABSTRACT FROM AUTHOR]

Background: 18F -fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the staging and response assessment of lymphoma patients. Our aim was to explore the predictive relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with early stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD16 trial.Methods: 18F-FDG PET/CT images were available for MTV and TLG analysis in 107 cases from the HD16 trial. We calculated MTV and TLG using three different threshold methods (SUV4.0, SUV41% and SUV140%L), and then performed receiver-operating-characteristic analysis to assess the predictive impact of these parameters in predicting an adequate therapy response with PET negativity after 2 cycles of chemotherapy.Results: All three threshold methods analyzed for MTV and TLG calculation showed a positive correlation with the PET response after 2 cycles chemotherapy. The largest area under the curve (AUC) was observed using the fixed threshold of SUV4.0 for MTV- calculation (AUC 0.69 [95% CI 0.55-0.83]) and for TLG-calculation (AUC 0.69 [0.55-0.82]). The calculations for MTV and TLG with a relative threshold showed a lower AUC: using SUV140%L AUCs of 0.66 [0.53-0.80] for MTV and 0.67 for TLG [0.54-0.81]) were observed, while with SUV41% an AUC of 0.61 [0.45-0.76] for MTV, and an AUC 0.64 [0.49-0.80]) for TLG were seen.Conclusions: MTV and TLG do have a predictive value after two cycles ABVD in early stage Hodgkin lymphoma, particularly when using the fixed threshold of SUV4.0 for MTV and TLG calculation.Trial Registration: ClinicalTrials.gov NCT00736320 . [ABSTRACT FROM AUTHOR]

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18. Keywords: bone marrow involvement; Hodgkin lymphoma; intensive chemotherapy; positron emission tomography; prognosis EN bone marrow involvement Hodgkin lymphoma intensive chemotherapy positron emission tomography prognosis e5 e8 4 03/30/22 20220401 NES 220401 Newly diagnosed advanced-stage Hodgkin lymphoma (HL) has become a curable malignancy in the vast majority of patients.1,2 With response-adapted treatment comprising four or six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in escalated dose (eBEACOPP), outstanding cure rates are achieved through a comparatively short and safe treatment approach.3,4 Around 5 to 15% of HL patients present with bone marrow (BM) involvement, as assessed by conventional biopsy.5-7 According to the Ann Arbor classification, BM involvement reflects a high tumour burden and therefore defines stage IV disease.8 Positron emission tomography (PET) using SP 18 sp F-fluoro-2-deoxy-d-glucose (FDG) has demonstrated superior sensitivity compared to BM biopsy.9-11 In paediatric advanced HL, only individuals showing three or more BM lesions were assumed to be at higher risk for progression or relapse.12 Yet, there are insufficient data available to establish whether this also holds true for adult patients receiving intensive first-line treatment. PET imaging was shown to identify BM lesions at a higher sensitivity than biopsy of the iliac bone and has become part of diagnostic work-up in most countries.15 Current study protocols no longer recommend BM biopsy in PET-negative individuals. [Extracted from the article]

Summary: Reinduction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second‐line standard of care for transplant‐eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high‐dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant‐eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase‐I‐part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end‐point of computed tomography (CT)‐based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT‐based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end‐point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy. [ABSTRACT FROM AUTHOR]

Summary: High programmed cell death 1 ligand 1 (PD‐L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin‐ and Reed–Sternberg cells (HRSC) have been shown to be associated with favourable response to anti‐PD‐1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD‐L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti‐PD‐1‐based first‐line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced‐stage or r/r cHL. All but two cases (97%) showed PD‐L1 expression by the tumour cells in variable amounts. While MHC‐I was rarely expressed in >50% of HRSC, MHC‐II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD‐L1 and MHC‐I/II expression on early response to the highly effective anti‐PD‐1‐based NIVAHL first‐line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti‐PD‐1 first‐line cHL treatment. [ABSTRACT FROM AUTHOR]

Summary: We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET‐2) tended to be more common (P = 0·1078). Five‐year progression‐free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET‐2‐guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET‐2‐guided escalated BEACOPP. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of 2-3/100 000/year in Europe and North America. The disease generally occurs in all age groups, but young adults are most often affected. Thus, adolescents aged 15 or 16 to 21 represent a relevant portion of patients. The optimum treatment for this age group is undefined. Both pediatric protocols such as OEPA (vincristine, etoposide, prednisone, adriamycin) or ABVE-PC (adriamycin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) and adult regimens such as ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) or BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) have been shown to be safe and active, resulting in long-term survival rates of 80% and more. However, a prospective comparison of pediatric and adult treatment strategies in terms of efficacy and other important questions such as treatment-related acute and long-term toxicity has not been undertaken so far. This review aims at shedding some light on potential treatment approaches for adolescents with HL and includes more recent analyses in this patient group. [ABSTRACT FROM AUTHOR]

The article focuses on quality of life (QL) of long-term survivors from Hodgkin's disease and the use of QL measurements to identify possible treatments for Hodgkin's patients. QL instruments are needed to address issues from the start of the therapy and to gather information from the patients themselves. An obstacle to designing QL modules specific for Hodgkin's disease is the difficulty of identifying specific disease- and treatment-related problems such as fatigue, sexuality, spirituality and gender issues.

Purpose: The role of radiotherapy (RT) after intensive chemotherapy in patients with advanced stage Hodgkin's lymphoma (HL) is still unclear. The German Hodgkin Study Group (GHSG) randomized HD12 trial was designed to test whether consolidative RT in the region of initial bulky disease and of residual disease is necessary after effective chemotherapy. A quality control program based on a multidisciplinary panel of radiation oncologists, radiologists, and medical oncologists who reviewed all patients' staging and restaging imaging was initiated. Methods and Materials: A total of 1661 patients aged 16 to 65 years with HL in Stage IIB (large mediastinal mass and/or E-lesions) or Stage III to IV were randomized from January 1999 to January 2003 according to a factorial design between: 8 esc.BEACOPP + RT (arm A), 8 esc.BEACOPP non-RT (arm B), 4+4BEACOPP + RT (arm C), 4+4BEACOPP non-RT (arm D). Results: In the fifth interim analysis, 1449 patients were eligible for the arm comparison with regard to RT. After a median observation time of 48 months the FFTF rate was 86% and the OS 92%. The FFTF was 95% in the RT arms A+C and 88% in the non-RT arms B+D: no sequential significant difference. One thousand and eighty four patients were evaluated by the panel. The panel defined initial bulky disease in 800 patients and residual disease in 600 patients. The panel recommended continuation of therapy according to the randomization for 934 of 1084 patients and additive RT independently from the randomization arm for 145 of 1084 patients. Conclusions: The study showed that RT can be reduced substantially after effective chemotherapy. However, because of the irradiation of 10% of patients in the non-RT arms, equivalent effectiveness of a non-RT strategy cannot be proved. A substantial limitation of consolidative RT according to expert panel recommendations appears to be possible without reducing effectiveness. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials (RCTs) are the best tool to evaluate the effectiveness of clinical interventions. The Consolidated Standards for Reporting Trials (CONSORT) statement was introduced in 1996 to improve reporting of RCTs. We aimed to determine the extent of ambiguity and reporting quality as assessed by adherence to the CONSORT statement in published reports of RCTs involving patients with Hodgkin lymphoma from 1966 through 2002. Methods: We analyzed 242 published full-text reports of RCTs in patients with Hodgkin lymphoma. Quality of reporting was assessed using a 14-item questionnaire based on the CONSORT checklist. Reporting was studied in two pre-CONSORT periods (1966–1988 and 1989–1995) and one post-CONSORT period (1996–2002). Results: Only six of the 14 items were addressed in 75% or more of the studies in all three time periods. Most items that are necessary to assess the methodologic quality of a study were reported by fewer than 20% of the studies. Improvements over time were seen for some items, including the description of statistics methods used, reporting of primary research outcomes, performance of power calculations, method of randomization and concealment allocation, and having performed intention-to-treat analysis. Conclusions: Despite recent improvements, reporting levels of CONSORT items in RCTs involving patients with Hodgkin lymphoma remain unsatisfactory. Further concerted action by journal editors, learned societies, and medical schools is necessary to make authors even more aware of the need to improve the reporting RCTs in medical journals to allow assessment of validity of published clinical research. [ABSTRACT FROM AUTHOR]

Purpose: To determine biophysical parameters from the complication probability data during and after radiotherapy of Hodgkin’s lymphoma (HL), based on the number of gastrointestinal side effects that were found in the multicenter HD8 trial of the German Hodgkin Lymphoma Study Group. Methods and Materials: Between 1993 and 1998, 1204 patients with newly diagnosed, histology-proven HL in clinical Stages I/IIA/IIB with defined risk factors and stage IIIA without risk factors were enrolled into the multicenter HD8 study. Patients were randomized to receive two cycles of COPP (cyclophosphamide, vincristine, procarbazine, prednisone) alternating with two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) followed by radiotherapy (RT) of 30 Gy extended field plus 10 Gy to bulky disease (Arm A) or 30 Gy involved field plus 10 Gy to bulky disease (Arm B). For 910 patients, the rates of acute gastrointestinal side effects during and after RT could be determined. Comparison showed differences between Arms A and B (Grade 1–2: 16.6 vs. 3.9; Grade 3–4: 0.9 vs. 0.2; p < 0.001). From the dose–volume histograms for a “standard patient” (volume intestine 2300 cm3), we determined the normal tissue complication probability (NTCP) (V, D, m, n, TD50 ), the biophysical parameter TD50 , and n (volume dependent) in such a manner that the observed NTCP in Arm A in cases of supradiaphragmatic involvement only and in cases of infradiaphragmatic involvement correlated with the calculated values. Results: Of 1,204 patients randomized, 1,064 patients were informative for the comparison of study arms. The median observation time was 54 months. The overall survival for all eligible patients was 91%, and freedom from treatment failure was 83%. Survival rates at 5 years after start of RT revealed no differences in terms of freedom from treatment failure (85.8% in Arm A, 84.2% in Arm B) and overall survival (90.8% and 92.4%). There were also no differences between the two arms in terms of complete remission, progressive disease, relapse, death, and secondary neoplasias. In contrast, acute side effects, including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity, were more frequent in the extended field arm. Concerning gastrointestinal toxicity, the different radiation treatment volumes resulted in different NTCPs. On the basis of these findings, values of n = 0.09 and TD50 = 32 Gy were derived. However, this biophysical model is sensitive to variations of the parameters. A deviation of 1% of TD50 results in a deviation of 10% of the NTCP. Conclusion Radiotherapy volume reduction from extended field to involved field after two cycles of COPP/ABVD chemotherapy gives similar results and less toxicity in patients with early-stage, unfavorable HL. Biophysical parameters could be determined from the complication probability data after RT of HL. Because of the exponential dependence, this biophysical model is unstable. It represents a “start model” until further data can be incorporated. [Copyright &y& Elsevier]

Mattle V, Behringer K, Engert A, Wildt L. Female fertility after cytotoxic therapy– protection of ovarian function during chemotherapy of malignant and non-malignant diseases.Eur J Haematol 2005: 75 (Suppl. 66): 77–82.© Blackwell Munksgaard 2005.Due to the dramatic improvements in cure and survival of young patients of reproductive age suffering from malignant or systemic disease, the preservation of fertility and ovarian function during cytostatic treatment has become of increased importance during the last decade. Pharmacological therapy with GnRH analogues and the cryopreservation of ovarian tissue are discussed in this context. The value of these treatment procedures and their potential clinical applications are critically reviewed in this article. [ABSTRACT FROM AUTHOR]

Gossmann A, Eich HT, Engert A, Josting A, Müller R-P, Diehl V, Lackner K-J. CT and MR imaging in Hodgkin's disease– present and future.Eur J Haematol 2005: 75 (Suppl. 66): 83–89.© Blackwell Munksgaard 2005.Initial staging of Hodgkin's disease is crucial to determine the location and extent of disease, and is the hallmark for the choice of treatment. At present, the established radiological technique for staging Hodgkin's disease is computed tomography (CT). Modern multidetector row CT scanners allow fast imaging from the scull base to the groins during a single breath hold with a spatial resolution of approximately 1 mm. Both, nodal and extranodal involvement of Hodgkin's disease can be diagnosed with CT. Magnetic resonance (MR) imaging is another useful cross-sectional imaging modality for staging Hodgkin's disease. The development of fast MR imaging techniques has considerably reduced imaging time without compromising the quality of MR images. As a consequence, MR imaging is now considered to be as diagnostic as CT for staging Hodgkin's disease. The excellent soft-tissue contrast and the lack of exposure to ionizing radiation are the main advantages of MR imaging. For the detection of extranodal Hodgkin's disease, MR imaging is superior to assess involvement of the brain, the spinal cord and bone marrow; while CT allows excellent evaluation of lung disease. Common major problems in staging Hodgkin's disease are still the detection of nodal involvement in normal sized lymph nodes and residual tumor masses after therapy. In the future, newly developed lymphotropic contrast agents for MR imaging might be helpful to answer these questions. [ABSTRACT FROM AUTHOR]

This article discusses a consumer network for haematological malignancies. Medical research requires participation of patients and related persons to ensure all relevant interests in medicine are considered. Therefore the objective of the Cochrane Collaboration is to involve so called "consumers." Overall the evaluations revealed general satisfaction with the workshops. Medical research requires participation of patients and other parties to ensure that all particular interests in medicine are considered.

Purpose: The HD16 trial of the German Hodgkin Study Group (NCT00736320) demonstrated that radiation therapy in early-stage Hodgkin lymphoma without risk factors cannot be safely omitted, and therefore combined modality therapy (CMT) remains the standard treatment. To demonstrate the local effect of consolidating involved-field radiation therapy (IF-RT), we performed an analysis of the recurrence pattern of positron emission tomography (PET)-negative HD16 patients.Methods and Materials: Between 2009 and 2015, 1150 patients with early-stage Hodgkin lymphoma without risk factors were randomly assigned to PET guided to 20 Gy IF-RT after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the HD16 study of the German Hodgkin Study Group. The study was designed as a prospective randomized controlled trial. We correlated the localization of recurrence with the panel-based IF-RT plan, which was drawn up for all patients prospectively, blinded to treatment allocation. Accordingly, we were able to identify recurrences that occurred at least in part inside or outside of the (potential) radiation field (in-field and out-field, respectively).Results: There were 328 and 300 PET-negative patients assigned to CMT and PET-guided treatment (ie, chemotherapy alone), respectively. Within a median 47-month follow-up, disease progression or recurrence was documented for 15 and 29 patients treated with and without IF-RT, respectively. Relapse localization was unknown in 1 CMT patient. Without IF-RT, 5-year incidence of in-field relapses was 10.5% (95% confidence interval, 6.5-14.6) compared with 2.4% (0.5-4.3) with CMT (P = .0008). There were no relevant differences in out-field recurrences (5-year incidence 4.1% [1.7-6.6] vs 6.6% [3.0-10.3], P = .54). There was no grade 4 toxicity observed during IF-RT, and incidence of second primary malignancies was similar in both groups.Conclusions: PET-negative patients of the HD16 study showed no significant toxicity after 20 Gy IF-RT, and we demonstrated that omission of IF-RT resulted in more, particularly local, recurrences. Therefore, consolidation IF-RT should still be considered as standard therapy in this setting. [ABSTRACT FROM AUTHOR]

Patients with neutropenia, especially neutropenia following aggressive myeloablative therapy, are at high risk for developing infectious complications caused by bacteria and opportunistic fungi. Infections remain one of the leading causes of treatment failure in patients with cancer. Thus, new and innovative therapeutic strategies are needed for management of neutropenic patients with infection. Because neutrophils represent the first line of host defense, granulocyte transfusion therapy should be a logical therapeutic approach. Although such therapy has been employed sporadically for several decades, clinical benefit has been compromised by technical problems and low granulocyte yields resulting from inadequate donor stimulation. The discovery of granulocyte colony-stimulatng factor (G-CSF) as a means to elevate blood neutrophil counts when administered to normal donors has rekindled interest in granulocyte transfusion therapy. Extensive experience has been gained worldwide with G-CSF in clinical practice, and adverse events have been minimal when G-CSF has been administered to patients or healthy persons in human trials. This review focuses on the use of G-CSF in granulocyte transfusion therapy, including technical considerations of granulocyte leukapheresis and storage, donor selection and stimulation, as well as treatment results and associated risks. [ABSTRACT FROM AUTHOR]

Many haematology/oncology departments still provide a germ-free diet for neutropenic patients (neutropenic diet, ND) to minimise pathogen exposure, even though evidence on benefits is missing. We analysed the effects of a standard diet (SD) in neutropenic high-risk patients with cancer while focussing on infection-related outcomes. Based on the Cologne Cohort of Neutropenic Patients, we conducted a propensity score–matched case-control study in haematological/oncological patients with a period of neutropenia longer than five days treated at our department between January 2004 and December 2012 (implementation of SD in January 2008). We assessed the association between an SD and selected infection-related end-points in an adjusted multivariable regression model and time-to-event analysis. In total, 2086 neutropenic episodes (1043 per diet group) were included into analysis. The median days of neutropenia were 9 (interquartile range 7–16). The adjusted multivariable model revealed no association between the SD and severity and persistence of fever, death within 28 days, antibiotic treatment and weight loss >3 kg and a non-significant adjusted association between SD and duration of antibiotic treatment and blood stream infections. There was a significant association between SD and incidence of diarrhoea (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.45–0.68; P < 0.001), nausea (OR, 0.53; 95% CI, 0.43–0.66; P < 0.001) and weight loss >1 kg (OR, 0.93; 95% CI, 0.89–0.98; P = 0.002) with fewer events in SD than in the ND group. The hazard ratios of SD for the analysed end-points were non-significant. In our study, the implementation of an SD for high-risk neutropenic patients with cancer was safe regarding infection-related end-points. • The benefits of a germ-free diet for neutropenic patients with cancer are scarce. • Food restrictions may increase malnutrition and gastrointestinal side-effects. • Standard diets do not increase infectious complications in neutropenic patients. • Incidence of diarrhoea and nausea can be reduced by standard diets. • Implementation of standard diets for neutropenic patients with cancer is safe. [ABSTRACT FROM AUTHOR]

Summary: Data on non‐Hodgkin lymphoma (NHL) after classical Hodgkin lymphoma (cHL) are scarce. We therefore performed a retrospective analysis comprising 11·841 cHL patients who had first‐line treatment within the randomized German Hodgkin Study Group (GHSG) HD7–HD15 studies. After a median follow‐up of 106 months, 175 patients (1·5%) had developed NHL. The median time to NHL was 44 months, the median age at NHL diagnosis was 54 years. The five‐year event‐free survival and overall survival estimates from the diagnosis of NHL were 36·9% and 44·2%, respectively. Thus, NHL after cHL is a rare event primarily affecting older individuals and often resulting in the patient´s death. [ABSTRACT FROM AUTHOR]