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BACKGROUND: Little is known about the longitudinal course of health-related quality of life (HRQoL) in patients with Hodgkin's lymphoma during their post-treatment follow-up and re-adaptation to normal life. We report on the HRQoL of patients treated in the randomised H8 trial of the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and the Groupe d'Etudes des Lymphomes de l'Adulte (GELA). We aimed to assess HRQoL and fatigue following treatment, to analyse relations with treatment, and to identify factors that predict persistent fatigue. METHODS: Patients received HRQoL questionnaires at the end of primary therapy and during follow-up. The EORTC QLQ-C30 was used to assess HRQoL, and the Multidimensional Fatigue Inventory (MFI-20) was used to assess fatigue. Changes of mean HRQoL scores over time were analysed with mixed models. Multiple polytomic nominal logistic regression was done to identify independent baseline predictors of fatigue within MFI-20 dimensions. Analyses were done on an intention-to-treat basis. This study is registered with www.ClinicalTrials.gov, number NCT00379041. FINDINGS: 2666 assessments from 935 patients were analysed. Mean follow-up was 90 months (range 52-118). Age affected all functioning and symptom scores except emotional functioning, with younger age associated with higher functioning and lower severity of symptoms; improvement with time showed similar patterns between age groups. Women reported lower HRQoL and higher symptom scores than did men. Overall, 3.2% (14/439 for role functioning) to 9.7% (43/442 for social functioning) and 5.8% (29/498 for reduced motivation) to 9.9% (49/498 for general fatigue) of patients reported impairments of 10 points or more (on a 0-100 scale) in QLQ-C30 and MFI-20 scores, respectively, independent of age and sex. Emotional domains were more affected than physical ones. There was no relation between HRQoL outcome and type of treatment. Fatigue (MFI-20 scores) at the end of treatment was the only predictive variable for persistent fatigue, with odds ratios varying from 2.58 (95% CI 1.00-6.67) to 41.51 (12.02-143.33; p

Purpose: The outcome of older patients with mantle cell lymphoma (MCL) has improved by the introduction of immunochemotherapy, followed by rituximab (R)-maintenance. Assessment of minimal residual disease (MRD) represents a promising tool for individualized treatment decisions and was a prospectively planned part of the European MCL Elderly trial. We investigated how MRD status influenced the efficacy of R-maintenance and how MRD can enable tailored consolidation strategies., Patients and Methods: Previously untreated patients with MCL age 60 years or older have been randomly assigned to R versus interferon-alpha maintenance after response to rituximab, fludarabine, cyclophosphamide (R-FC) versus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). MRD monitoring was performed by real-time quantitative polymerase chain reaction (qPCR) following EuroMRD guidelines., Results: A qPCR assay with a median sensitivity of 1 × 10 -5 could be generated in 80% of 288 patients in an international, multicenter, multilaboratory setting. More extensive tumor dissemination facilitated the identification of a molecular marker. The efficacy of R-maintenance in clinical remission was confirmed for MRD-negative patients at the end of induction in terms of progression-free survival (PFS; hazard ratio [HR], 0.38 [95% CI, 0.21 to 0.63]) and overall survival (OS; HR, 0.37 [95% CI, 0.20 to 0.68]), particularly in R-CHOP-treated patients (PFS-HR, 0.23 [95% CI, 0.10 to 0.52]; OS-HR, 0.19 [95% CI, 0.07 to 0.52]). R-maintenance appeared less effective in MRD-positive patients (PFS-HR, 0.51 [95% CI, 0.26 to 1.02]) overall and after R-CHOP induction (PFS-HR, 0.59 [95% CI, 0.28 to 1.26]). R-FC achieved more frequent and faster MRD clearance compared with R-CHOP. MRD positivity in clinical remission after induction was associated with a short median time to clinical progression of approximately 1-1.7 years., Conclusion: The results confirm the strong efficacy of R-maintenance in patients who are MRD-negative after induction. Treatment de-escalation for MRD-negative patients is discouraged by our results. More effective consolidation strategies should be explored in MRD-positive patients to improve their long-term prognosis.

Objective: In line with screening guidelines, cancer survivors were consecutively screened on depressive symptoms (as part of standard care), with those reporting elevated levels of symptoms offered psychological care as part of a trial. Because of the low uptake, no conclusions could be drawn about the interventions' efficacy. Given the trial set-up (following screening guidelines and strict methodological quality criteria), we believe that this observational study reporting the flow of participation, reasons for and characteristics associated with nonparticipation, adds to the debate about the feasibility and efficiency of screening guidelines., Methods: Two thousand six hundred eight medium- to long-term cancer survivors were consecutively screened on depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9). Those with moderate depressive symptoms (PHQ-9 ≥ 10) were contacted and informed about the trial. Patient flow and reasons for nonparticipation were carefully monitored., Results: One thousand thirty seven survivors (74.3%) returned the questionnaire, with 147 (7.6%) reporting moderate depressive symptoms. Of this group, 49 survivors (33.3%) were ineligible, including 26 survivors (17.7%) already receiving treatment and another 44 survivors (30.0%) reporting no need for treatment. Only 25 survivors (1.0%) participated in the trial., Conclusion: Of the approached survivors for screening, only 1% was eligible and interested in receiving psychological care as part of our trial. Four reasons for nonparticipation were: nonresponse to screening, low levels of depressive symptoms, no need, or already receiving care. Our findings question whether to spend the limited resources in psycho-oncological care on following screening guidelines and the efficiency of using consecutive screening for trial recruitment in cancer survivors., (© 2019 The Authors. Psycho-Oncology Published by John Wiley & Sons Ltd.)

The current first line treatment of a patient with mantle cell lymphoma (MCL) is often considered as too toxic for elderly patients. The elderly, however, comprise the majority of the patients with MCL. The results of several recent studies have shown that the outcome of this patient group is not as dismal as in the past. Indeed, if patients are not considered frail, and can tolerate rituximab and moderate intensive chemotherapy such as R-CHOP followed by rituximab maintenance or R-bendamustine, a 4-year overall survival of >80% can be achieved. In this chapter the developments of the regimens, resulting in the standard treatment options for these patients, are discussed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Presently, no validated data exist on symptom severity and disease-specific quality-of-life (QoL) for patients with mastocytosis. Simultaneously, clinical trials and drug application processes increasingly mandate reporting patients' perspectives on symptoms and QoL. We report on the development and validation of the mastocytosis quality-of-life questionnaire (MQLQ) and the mastocytosis symptom assessment form (MSAF)., Methods: Both outcome measures were developed in a standardized stepwise method, starting with the identification of items in focus groups (n = 12), item reduction and subsequent cross-sectional validation in a 63% female cohort of 164 adult patients with indolent systemic mastocytosis., Results: The MSAF reveals that fatigue is the severest mastocytosis symptom while the MQLQ indicates that fear of anaphylaxis mostly impacts QoL. Cross-sectional validity was assessed by correlating both individual domains and the total scores of the MQLQ and MSAF with independent measures of mastocytosis. The total scores of both the MQLQ (P < 0.001; Spearman's r: 0.568) and the MSAF (P < 0.001; Spearman's r: 0.559) correlated significantly with the consensus on physician-scored mediator symptoms. The MQLQ domains displayed a high internal consistency (Cronbach's alpha: 0.841-0.958) and the domains 'bones', 'skin symptoms' and 'anaphylaxis' differed significantly between patients with and without osteoporosis, urticaria pigmentosa or anaphylaxis, respectively (P < 0.001)., Conclusions: The MQLQ is the first disease-specific QoL questionnaire for mastocytosis and is complemented by the MSAF, a short and convenient symptom scoring form. Both patient-reported outcome measures are valid, reliable and discriminate between patients with different disease characteristics, making them useful instruments for clinical research., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI., Patients and Methods: Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort., Results: The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b., Conclusion: Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine., (© 2016 by American Society of Clinical Oncology.)

Background: Currently, measurement of serum tryptase level is the most commonly used test to estimate the need for bone marrow biopsy in patients suspected to have indolent systemic mastocytosis (ISM). Yet tryptase levels do not solely reflect the mast cell load and can be elevated by overweight, older age, and impaired renal function. The influence of these factors on urinary methylhistamine (MH) and methylimidazole acetic acid (MIMA) is still unknown., Objective: We investigated the impact of age, body mass index (BMI), and kidney function on the diagnostic accuracy of tryptase, MH, and MIMA to select the most optimal test indicating the necessity of a bone marrow biopsy in ISM-suspected patients., Methods: Retrospective data analysis of all adults in whom bone marrow investigations were performed because of high clinical suspicion and/or elevated tryptase, MH, or MIMA., Results: 194 subjects were included. ISM was present in 112 and absent in 82 subjects (non-ISM). Tryptase was elevated by age and body weight in non-ISM subjects and by BMI in ISM subjects; however, these factors did not influence MH or MIMA. In the total study population, the diagnostic accuracy of tryptase, MH, and MIMA were comparable (area under the curve 0.80, 0.80, and 0.83). In subjects >50 years with a BMI >25 kg/m(2), the diagnostic accuracy of MIMA was higher compared with that of tryptase (area under the curve 0.93 vs 0.74; P = .011)., Conclusion: In ISM-suspected patients >50 years with a BMI of >25 kg/m(2), MIMA has a greater value compared with tryptase in estimating the need for bone marrow biopsy., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Bleeding disorders have been recognized as important etiologic or contributory factors in women with heavy menstrual bleeding. Fibrinolysis in the endometrium plays a role in heavy menstrual bleeding. It is unknown whether increased systemic fibrinolysis might also increase the risk of heavy menstrual bleeding., Objective: To investigate fibrinolytic parameters, including clot lysis time, in women with heavy menstrual bleeding., Methods: We included 102 patients referred for heavy menstrual bleeding (Pictorial Bleeding Assessment Chart score of > 100) in our cohort. Patients and controls (28 healthy volunteers without heavy menstrual bleeding) underwent hemostatic testing in the first week after menstruation. For 79 patients and all controls, fibrinolytic parameters (thrombin-activatable fibrinolysis inhibitor activity, and plasminogen activator inhibitor-1, tissue-type plasminogen activator and plasmin inhibitor levels) and clot lysis time were available., Results: Fibrinolytic parameters were similar between patients and controls, except for thrombin-activatable fibrinolysis inhibitor (89.4% vs. 82.5%) and plasmin inhibitor (106% vs. 96%), the levels of which which were significantly higher in patients. In women with menorrhagia without gynecologic abnormalities, we found lower thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 levels than in women with gynecologic abnormalities (thrombin-activatable fibrinolysis inhibitor, 85.4% vs. 94.8%; plasminogen activator inhibitor-1, 16.0 μg L(-1) vs. 24.5 μg L(-1) )., Conclusion: Systemic fibrinolytic capacity is not increased in women with heavy menstrual bleeding. Overall, levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor were even higher in patients than in controls. However, in a subgroup of women without gynecologic abnormalities, relatively lower levels of inhibitors may contribute to the heavy menstrual bleeding., (© 2014 International Society on Thrombosis and Haemostasis.)

CD30 is a transmembrane receptor, normally not expressed by mast cells, which regulates proliferation/apoptosis and antibody responses. Aberrant expression of CD30 by mastocytosis mast cells and interaction with its ligand CD30L (CD153) appears to play an important role in the pathogenesis and clinical presentation of systemic mastocytosis. This article highlights the expression profile and role of CD30 and CD30L in physiologic and pathologic conditions, the applicability of CD30 as a marker for systemic mastocytosis, the consequences of mast cell-expressed CD30, and the possibility of future anti-CD30 based cytoreductive therapies., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Study Question: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors?, Summary Answer: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood., What Is Known Already: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before., Study Design, Size, Duration: This is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors., Participants/materials, Setting, Methods: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36)., Main Results and the Role of Chance: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen., Limitations, Reasons for Caution: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed., Study Funding/competing Interests: Lance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.

Background: Increased basal serum tryptase (bsT) levels are a well-described risk factor for Hymenoptera venom-induced anaphylaxis (HVAn) in patients allergic to Hymenoptera venom. Increased bsT levels might also indicate the presence of mastocytosis. In this study we evaluated whether the risk of HVAn increases with increasing mast cell load in patients with mastocytosis., Methods: Consecutive patients with different subtypes of mastocytosis (n = 329) admitted to the University Medical Center Groningen were retrospectively assessed. As markers for mast cell load, levels of both bsT and the urinary histamine metabolites methylhistamine and methylimidazole acetic acid (MIMA) were used., Results: In the entire patient group, irrespective of disease subtype and Hymenoptera venom exposure, HVAn prevalence gradually increased with increasing marker levels to a maximum of 36% to 47% at a bsT level of 28.0 μg/L, a methylhistamine level of 231.0 μmol/mol creatinine, and a MIMA level of 2.7 mmol/mol creatinine but decreased thereafter with a further increase in these levels. In patients with indolent systemic mastocytosis with a history of Hymenoptera venom exposure after age 15 years or greater (n = 152), MIMA and age at the most recent Hymenoptera sting were independent predictors for HVAn (odds ratios of 0.723 [P = .001] and 1.062 [P < .001], respectively)., Conclusions: In patients with mastocytosis, HVAn prevalence does not increase constantly with increasing levels of mast cell load parameters: after a gradual increase to a maximum of near 50%, it decreases with a further increase in these levels. In the indolent systemic mastocytosis population, all mast cell load markers were independent negative predictors of HVAn. These findings suggest a complex pathophysiologic association between mast cell load and HVAn risk in patients with mastocytosis., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

To complement the existing treatment guidelines for all tumour types, ESMO organizes consensus conferences to focus on specific issues in each type of tumour. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, next to the 11th International Conference on Malignant Lymphoma. The conference convened ∼30 experts from all around Europe, and selected six lymphoma entities to be addressed; for each of them, three to five open questions were to be addressed by the experts. For each question, a recommendation should be given by the panel, referring to the strength of the recommendation based on the level of evidence. This consensus report focuses on the three less common lymphoproliferative malignancies: marginal zone lymphoma, mantle cell lymphoma, and peripheral T-cell lymphomas. A first report had focused on diffuse large B-cell lymphoma, follicular lymphoma, and chronic lymphocytic leukaemia.

Background: Risk indicators of indolent systemic mastocytosis (ISM) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa (UP)] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid (MIMA) and methylhistamine (MH) to select patients for bone marrow investigations to diagnose ISM., Methods: Retrospective data analysis of all adults, in whom bone marrow investigations were performed to diagnose ISM, was carried out., Results: In total, 142 patients were included. SM was absent in all 44 patients with tryptase <10 μg/l, in 45 of 98 (46%) patients with tryptase ≥10 μg/l and in 18 of 52 patients (35%) with tryptase >20 μg/l. Above 43 μg/l, all patients had ISM (n = 11). Male gender, insect venom anaphylaxis as presenting symptom, tryptase, MIMA, and MH were independent ISM predictors. If tryptase was ≥10 μg/l, the diagnostic accuracy of MIMA and MH was high (areas under the ROC curve 0.92)., Conclusions: In suspected patients without UP, the ISM risk is very low (if present at all) if tryptase is <10 μg/l. If tryptase is ≥10 μg/l, this risk depends on MIMA and MH, being low if these are normal, but high if these are elevated. Male gender and insect venom anaphylaxis are additional risk indicators. We recommend refraining from bone marrow examinations in suspected patients without UP if tryptase is <10 μg/l. Our results question the reliability of the minor diagnostic World Health Organization criterion of tryptase >20 μg/l., (© 2012 John Wiley & Sons A/S.)

Background/objectives: The traditional view that patients with hemophilia are protected against cardiovascular disease is under debate. The aim of the present study was to evaluate the presence and extent of atherosclerosis by coronary artery calcification score (CACS) and carotid intima media thickness (IMT) in patients with hemophilia, and to evaluate their cardiovascular risk profile., Methods: Sixty-nine patients (51 with hemophilia A; 18 with hemophilia B) were studied [median age: 52 years (interquartile range [IQR] 43–64)]. Cardiovascular risk factors and prior major adverse cardiovascular events (MACEs) were recorded. CACS was derived from electron-beam or dual-source computed tomography, and carotid IMT was assessed by ultrasound measurements and compared with age-specific reference values., Results: The median CACS in all patients was 35 (IQR 0–110) and the geometric mean IMT was 0.80 mm (95% confidence interval [CI] 0.76–0.84); neither was different from the reference values. Patients with a previous MACE (n = 9) had significantly higher CACS and IMT than patients without a previous MACE:CACS median 1013 (IQR 530–1306) vs. 0 (IQR 0–67), and IMT geometric mean 1.09 mm (95% CI 0.95–1.26) vs. 0.76 mm (95% CI 0.73–0.79), both P < 0.001. A higher calculated 10-year cardiovascular risk was related to higher IMT and CACS., Conclusion: Patients with hemophilia are not protected against the development of atherosclerosis as measured by CACS and IMT. The extent of atherosclerosis is related to the traditional cardiovascular risk factors. This suggests that traditional cardiovascular risk factors should be monitored and treated in patients with hemophilia.

Reproductive choices, pregnancy and childbirth are influenced by culture and traditions. This probably also plays a role in carriers of haemophilia. The aim of the study is to evaluate the reproductive choices and obstetrical experiences in the current generation of carriers of haemophilia in our Haemophilia Centre in the north of the Netherlands, a largely secular country with liberal abortion laws and a unique tradition of home births. Retrospective survey among haemophilia carriers. We sent a questionnaire to 74 carriers, 65 were available, 75% responded. Median age was 41 (range 20-83) years. Of the 49 women, 46 had 120 pregnancies: 25 resulted in foetal loss, two in pregnancy termination (one for haemophilia) and 93 in live births. No woman had chosen not to start a family. Mean number of children was 2.0, 2.4 vs. 1.8 in women with and without sons with haemophilia (P = 0.008), respectively. Twenty women (20 of 46) were unaware of their carriership during 1st pregnancy; they were younger at 1st pregnancy than known carriers (25 vs. 29 years, P = 0.03). Twenty-three percentage reported bleeding complications during the first delivery. Overall, 10% vs. 3% of deliveries was complicated by a primary and secondary postpartum haemorrhage (PPH), respectively. In our Haemophilia Centre, carrier state has not influenced reproductive choices in the past, other than older age at first pregnancy. Carriers of haemophilia have an increased risk of primary PPH., (© 2010 Blackwell Publishing Ltd.)

Background: Lack of survival improvement in adolescents and young adults (AYA) with cancer has led to increased awareness of this young population., Design: We carried out a population-based study of incidence and survival of primary tumours and second primary tumours in patients aged 12-24 in north Netherlands. Age-specific incidence rates per 100,000 and 3-year moving means were calculated. Factors associated with incidence and survival were assessed using a Poisson model, log-rank test and multivariate Cox proportional hazards analysis., Results: From 1989 to 2003 a total of 1118 patients were diagnosed. The total age-specific incidence rates per 100,000 were as follows: males: 13.4 (12-15 years), 26.9 (16-19 years) and 27.5 (20-24 years) and females: 13.9, 20.7 and 20.7. Male : female ratio was 1.32. The overall estimated annual percentage change (EAPC) in incidence was 2.15% (P < 0.01). Five-year survival was 80.8% and did not improve during the study period. With median follow-up of 5.5 years (range 0.0-16.0) in our cohort the standardized incidence ratio (SIR) of second primary tumours was 30.55 (95% confidence interval = 19.96-44.76, P < 0.05)., Conclusions: The total incidence of cancer in AYA increased (EAPC = 2.15%). Survival was unchanged. The SIR of a second primary tumour in this young cohort increased 31-fold. Further research is needed to study this increasing incidence and optimise treatment outcome in these young patients.