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Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML. [ABSTRACT FROM AUTHOR]

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from ever-pregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR]=0.91, 95% confidence interval [CI]: 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR=1.81, 95% CI: 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.

Background and Objectives: Donor characteristics have been implicated in transfusion-related adverse events. Uncertainty remains about whether sex, and specifically pregnancy history of the blood donor, could affect patient outcomes. Whether storage duration of the blood product could be important for patient outcomes has also been investigated, and a small detrimental effect of fresh products remains a possibility. Here, we hypothesize that fresh red blood cell products donated by ever-pregnant donors are associated with mortality in male patients., Materials and Methods: We used data from a cohort study of adult patients receiving a first transfusion between 2005 and 2015 in the Netherlands. The risk of death after receiving a transfusion from one of five exposure categories (female never-pregnant stored ≤10 days, female never-pregnant stored >10 days, female ever-pregnant stored ≤10 days, female ever-pregnant stored >10 days and male stored for ≤10 days), compared to receiving a unit donated by a male donor, which was stored for >10 days (reference), was calculated using a Cox proportional hazards model., Results: The study included 42,456 patients who contributed 88,538 person-years in total, of whom 13,948 died during the follow-up of the study (33%). Fresh units (stored for ≤10 days) from ever-pregnant donors were associated with mortality in male patients, but the association was not statistically significant (hazard ratio 1.39, 95% confidence interval 0.97-1.99). Sensitivity analyses did not corroborate this finding., Conclusion: These findings do not consistently support the notion that the observed association between ever-pregnant donor units and mortality is mediated by blood product storage., (© 2023 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Purpose: Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi)., Methods: MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks., Results: Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in JAK2 V617F-mutant allele fraction, which was associated with SVR35 response ( P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks., Conclusion: The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.

Occult lymph node (LN)-metastases are frequently found after upfront radical cystectomy (uRC) for bladder cancer (BC). We evaluated whether the implementation of 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG PET/CT) influenced nodal staging at uRC. All consecutive BC patients who underwent uRC with bilateral pelvic lymph node dissection (PLND) were identified and divided into two cohorts: cohort A consisted of patients staged with FDG PET/CT and contrast-enhanced CT (CE-CT) (2016-2021); cohort B consisted of patients staged with CE-CT only (2006-2011). The diagnostic performance of FDG PET/CT was assessed and compared with that of CE-CT. Thereafter, we calculated the occult LN metastases proportions for both cohorts. In total, 523 patients were identified (cohort A n = 237, and cohort B n = 286). Sensitivity, specificity, PPV and NPV of FDG PET/CT for detecting LN metastases were 23%, 92%, 42%, and 83%, respectively, versus 15%, 93%, 33%, 81%, respectively, for CE-CT. Occult LN metastases were found in 17% of cohort A (95% confidence interval (CI) 12.2-22.8) and 22% of cohort B (95% CI 16.9-27.1). The median size of LN metastases was 4 mm in cohort A versus 13 mm in cohort B. After introduction of FDG PET/CT, fewer and smaller occult LN metastases were present after uRC. Nevertheless, up to one-fifth of occult (micro-)metastases were still missed.

Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([ 15 O]water, [ 18 F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [ 15 O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [ 18 F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [ 15 O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [ 18 F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.

Objectives: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis., Methods: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation., Results: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001)., Conclusions: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence., Clinical Trial Registration: ClinicalTrials.gov registration no. NCT00893555., Competing Interests: Competing interests R.J. Bruggeman has received fees for consulting from Gilead, F2G and Amplyx and has received research grants and given lectures for Gilead, Pfizer, Merck and Astellas. All contracts were with Radboudumc and all payments were with Radboudumc. B.J. Biemond has received research support of Sanquin, Global Blood Therapeutics and Novartis. B.J.A. Rijnders reports grants from Gilead Sciences and personal fees from F2G, outside the submitted work. J.J. Swen reports personal fees from Roche, outside the submitted work. P.E. Verweij reports grants from MSD, Gilead Sciences, F2G and Pfizer and non-financial support from IMMY, outside the submitted work. J.W.C. Alffenaar reports other financial support from Pfizer, MSD and Gilead and grants from MSD, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).

Background: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome., Methods: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation., Findings: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27-43), whilst it was 7.1% (95% CI: 6.0-8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0-4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28-39) for the PREF group, 57% (95% CI 54-61) in patients with PR, 51% (95% CI 43-58) in the SD group after first-line therapy and 63% (95% CI: 66-72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12-31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31-44]) (p-value = 0.001)., Interpretation: Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Randomized controlled trials have studied different dose-intensity and dose-interval regimens of R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL). This study was undertaken to confirm these results in a population-based setting, with special emphasis on the value of 6xR-CHOP21 among patients aged 18-64 years. Two thousand three hundred and thirty-eight stage II-IV DLBCL patients, ≥18 years, we confirmed the similar efficacy of six versus eight cycles of R-CHOP and of R-CHOP21 versus R-CHOP14 regimens across all age groups on overall survival (median follow-up 36.4 (1.3-167.6) months). Nevertheless, overall survival decreased with older age. Interestingly, in patients 18-64 years, the adjusted risk of mortality among recipients of 6xR-CHOP21 compared to other R-CHOP regimens seems to be similar (HR 0.62; 95%CI: 0.38-1.02; p = .059). Although this finding might suggest that 6xR-CHOP21 could be considered as first-line regimen for all stage II-IV DLBCL patients, it should be confirmed in forthcoming population-based studies with larger patient numbers and longitudinal follow-up.

Background: Decision making regarding future fertility can be very difficult for female cancer patients. To support patients in decision making, fertility preservation decision aids (DAs) are being developed. However, to make a well-informed decision, patients need personalized information tailored to their cancer type and treatment. Tailored cancer-specific DAs are not available yet., Methods: Our DA was systematically developed by a multidisciplinary steering group (n = 21) in an iterative process of draft development, three rounds of alpha testing, and revisions. The drafts were based on current guidelines, literature, and patients' and professionals' needs., Results: In total, 24 cancer-specific DAs were developed. In alpha testing, cancer survivors and professionals considered the DA very helpful in decision making, and scored an 8.5 (scale 1-10). In particular, the cancer-specific information and the tool for recognizing personal values were of great value. Revisions were made to increase readability, personalization, usability, and be more careful in giving any false hope., Conclusions: A fertility preservation DA containing cancer-specific information is important in the daily care of female cancer patients and should be broadly available. Our final Dutch version is highly appraised, valid, and usable in decision making. After evaluating its effectiveness with newly diagnosed patients, the DA can be translated and adjusted according to (inter)national guidelines., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A 65-year-old female complained of diffuse and rapidly progressive gingival enlargement. Gingival overgrowth can be caused by medication, infections or systemic diseases. In case of generalized, quickly progressive gingival enlargement, acute myeloid leukemia should be considered. Blood results showed an acute myelomonocytic leukemia. Treating the leukemia resolved the symptoms.

After a registered drug is available on the market and used in everyday circumstances, hitherto unknown adverse drug reactions (ADRs) may occur. Furthermore, the patient can experience a previously unknown course of a known ADR. Voluntary reports by patients play an important role in gaining knowledge about ADRs in daily practice. The Netherlands Pharmacovigilance Centre Lareb received a report from a 55-year-old female-to-male transgender patient who experiences secondary polycythemia while using lifelong testosterone therapy. The onset age of the symptoms was 38 years. The symptoms appeared gradually and after approximately 1 year it was clear that the patient's hemoglobin and hematocrit had started to increase. A Naranjo assessment score of 6 was obtained, indicating a probable relationship between the patient's polycythemia and use of the suspect drug. Polycythemia is a known ADR in testosterone treatment, but little attention has been paid to the possible severity and complications of these symptoms as well as the impact on the patient's well-being.

Purpose: [ 18 F]-fluorothymidine ([ 18 F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution., Methods: 18 F-FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived., Results: SUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment., Conclusion: Simultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images., Advances in Knowledge: For [ 18 F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment., Implications for Patient Care: In [ 18 F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [ 18 F]-FLT PET images., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Bone disease in multiple myeloma is characterized by reduced bone formation. The gold standard of bone formation is the mineral apposition rate (MAR), an invasive technique reflecting bone formation at a single site. We compared (18)F-fluoride-PET with the MAR in myeloma patients., Methods: Bone formation was measured before and after bortezomib treatment by determination of the MAR in iliac bone marrow biopsies and the measurement of (18)F-uptake., Results: The inter- and intra-individual variations in (18)F-uptake (SUVA50%) were pronounced as 33.50 (range 4.42 to 37.92) and 27.18 (range 4.00 to 31.18), respectively. A significant correlation between the MAR and (18)F-uptake was found (r = 0.80, p = 0.017). There was a heterogeneous response after treatment varying from -2.20 to 4.53., Conclusions: Iliac (18)F-uptake was associated with the local MAR in myeloma patients. Furthermore, (18)F-fluoride-PET demonstrated the heterogeneity of in vivo bone formation, enabling monitoring during treatment.

Mandatory for the diagnosis of myelodysplastic syndromes (MDS) is the presence of dysplasia in >10% of cells within one or more cell lineages or presence of >15% ring sideroblasts or presence of MDS-associated cytogenetic (CG) abnormalities. Discrimination between neo-plastic and non-neoplastic causes of cytopenias can be challenging when dysplastic features by cytomorphology (CM) are minimal and CG abnormalities are absent or non-discriminating from other myeloid neoplastic disorders. This study evaluated a standard diagnostic approach in 379 patients with unexplained cytopenias and highlights the additional value of flow cytometry (FC) in patients with indeterminate CM and CG. CM reached no clear-cut diagnosis in 44% of the patients. Here, CG was able to identify two additional patients with MDS; other CG results did not reveal abnormalities or were not contributory. Based on the FC results, patients without a diagnosis by CM and CG were categorized 'no MDS-related features' (65%), 'limited number of MDS-related changes' (24%), and 'consistent with MDS' (11%). Patients were followed over time in an attempt to establish or confirm a diagnosis (median follow-up 391 d, range 20-1764). The specificity (true negative) of MDS-FC analysis calculated after follow-up was 95%. FC can aid as a valuable tool to exclude MDS when CM and additional CG are not conclusive in patients with cytopenia., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML., (© The Author(s), 2014.)

Unlabelled: Considering the different treatment strategy for transformed follicular lymphoma (TF) as opposed to follicular lymphoma (FL), diagnosing transformation early in the disease course is important. There is evidence that (18)F-FDG has utility as a biomarker of transformation. However, quantitative thresholds may require inclusion of homogeneous non-Hodgkin lymphoma subtypes to account for differences in tracer uptake per subtype. Moreover, because proliferation is a hallmark of transformation, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) might be superior to (18)F-FDG in this setting. To define the best tracer for detection of TF, we performed a prospective a head-to-head comparison of (18)F-FDG and (18)F-FLT in patients with FL and TF., Methods: (18)F-FDG and (18)F-FLT PET scans were obtained in 17 patients with FL and 9 patients with TF. We measured the highest maximum standardized uptake value (SUVmax), defined as the lymph node with the highest uptake per patient, and SUVrange, defined as the difference between the SUVmax of the lymph node with the highest and lowest uptake per patient. To reduce partial-volume effects, only lymph nodes larger than 3 cm(3) (A50 isocontour) were analyzed. Scans were acquired 1 h after injection of 185 MBq of (18)F-FDG or (18)F-FLT. To determine the discriminative ability of SUVmax and SUVrange of both tracers for TF, receiver-operating-characteristic curve analysis was performed., Results: The highest SUVmax was significantly higher for TF than FL for both (18)F-FDG and (18)F-FLT (P < 0.001). SUVrange was significantly higher for TF than FL for (18)F-FDG (P = 0.029) but not for (18)F-FLT (P = 0.075). The ability of (18)F-FDG to discriminate between FL and TF was superior to that of (18)F-FLT for both the highest SUVmax (P = 0.039) and the SUVrange (P = 0.012). The cutoff value for the highest SUVmax of (18)F-FDG aiming at 100% sensitivity with a maximum specificity was found to be 14.5 (corresponding specificity, 82%). For (18)F-FLT, these values were 5.1 and 18%, respectively. When the same method was applied to SUVrange, the cutoff values were 5.8 for (18)F-FDG (specificity, 71%) and 1.5 for (18)F-FLT (specificity, 36%)., Conclusion: Our data suggest that (18)F-FDG PET is a better biomarker for TF than (18)F-FLT PET. The proposed thresholds of highest SUVmax and SUVrange should be prospectively validated., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Transformation from indolent non-Hodgkin lymphoma (NHL) to diffuse large B cell lymphoma (DLBCL) has historically been associated with a poor prognosis. A small series of autologous stem cell transplantation (ASCT) studies using conventional conditioning regimens has demonstrated durable progression-free survival (PFS) rates ranging from 25% to 47%, but data in the rituximab era are lacking. Here we report the results of a multicenter retrospective trial evaluating ASCT in patients with transformed lymphoma using the Z-BEAM conditioning regimen, which combines yttrium-90-labeled ibritumomab tiuxetan (Zevalin) with high-dose BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy. Sixty-three patients from 4 institutions were treated between 2003 and 2011. Histological confirmation of transformation was required and defined as a diagnosis of DLBCL in patients with either a prior history or concomitant diagnosis of low-grade B cell NHL. Median patient age at ASCT was 59.5 years, median number of prior regimens was 2, and all patients were exposed to rituximab. Disease status at ASCT was as follows: first complete remission (CR) (n = 30), first partial remission (n = 11), first relapse (n = 14), and at least second CR (n = 8). The median time from diagnosis of histological transformation to ASCT was 7.5 months (range, 2.8 to 116). Two-year nonrelapse mortality was 0%. Median follow-up for living patients was 28 months (range, 5 to 103). Two-year PFS was 68% (95% confidence interval, 58% to 75%), and overall survival was 90% (95% confidence interval, 80% to 95%). In conclusion, the Z-BEAM conditioning regimen for ASCT is well tolerated by patients with transformed lymphoma and demonstrates encouraging clinical outcomes., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We studied the outcome of allo-SCT after reduced-intensity conditioning in relapsed or refractory indolent and aggressive lymphoid malignancies. All 54 patients (diagnosis: B-CLL n=13, indolent lymphoma n=12, aggressive lymphoma n=13, transformed lymphoma n=16) received conditioning with fludarabine and CY between July 2001 and November 2010. They underwent allo-SCT because of relapse after auto-SCT or because no other therapy could lead to a meaningful remission. Patients received an unmanipulated peripheral blood stem-cell graft. Median follow-up was 67 months. Thirty-two patients had received rituximab. Immediately after transplantation, remission status had improved in 21 patients, all without DLI. During the follow-up six additional patients achieved CR without further therapy. Four-year OS (EFS) was 46% (46%) for B-CLL, 83% (75%) for indolent lymphoma, 69% (55%) for aggressive lymphoma and 74% (67%) for transformed lymphoma (P=0.28 (P=0.54)). Forty two percent developed acute GVHD, 68% chronic GVHD (16% limited, 52% extensive). Previous auto-SCT did not influence OS, while acute GVHD did. Two-year non-relapse mortality was 16%. In conclusion, reduced-intensity conditioning with fludarabine-CY is feasible and effective for both indolent and aggressive lymphoid malignancies, even after previous auto-SCT. Because of the excellent anti-B-cell/lymphoma activity fludarabine-CY decreases tumor load, gaining time for the development of a graft versus lymphoma effect.

Background: We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the 'excess' uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL)., Methods: We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, 18 F-FLT-PET had been performed., Results: 18 F-FLT uptake was lower in FL than in DLBCL (median SUVmax 5.7 vs. 8.9, p = 0,004), but the ratio of 18 F-FLT-SUVmax to percentage of MIB-1 positive cells was significantly higher in FL compared with DLBCL (p = 0.001). The median percentage of MIB-1 positive cells was 10% (range, 10% to 20%) in FL and 70% (40% to 80%) in DLBCL. In contrast, the median percentages of PCNA, TK-1 and RPA1 positive cells were 90% (range, 80 to 100), 90% (80 to 100) and 100% (80 to 100) in FL versus 90% (60 to 100), 90% (60 to 100) and 100% (80 to 100) in DLBCL, respectively., Conclusions: This is the first demonstration of a striking discordance between 18 F-FLT uptake in FL and tumour cell proliferation. High expression of DNA replication and repair markers compared with the pure proliferation marker MIB-1 in FL suggests that this discordance might be due to error-prone DNA repair. While DNA repair-related 18 F-FLT uptake considerably contributes to 18 F-FLT uptake in FL, its contribution to 18 F-FLT uptake in highly proliferative DLBCL is small. This apparently high contribution of DNA repair to the 18 F-FLT signal in FL may hamper studies where 18 F-FLT is used to assess response to cytostatic therapy or to distinguish between FL and transformed lymphoma.

A 53-year-old woman with respiratory discomfort came to the Emergency Department. The blood smear, made because of a new thrombocytopenia, showed leukocytes with butterfly-shaped nuclei and fine cytoplasmic granulation. The diagnosis 'microgranular variant of acute promyelocytic leukemia' was made.

Spontaneous remission of acute myeloid leukaemia (AML) is extremely rare and usually of short duration. We report two patients with documented AML who developed spontaneous remission of their leukaemia shortly after an episode of severe sepsis and respiratory failure requiring mechanical ventilation. The underlying mechanisms of spontaneous remission remain unclear but an association with preceding blood transfusions and severe systemic infections has been reported. An overwhelming immune response due to sepsis and leading to raised levels of TNF-alpha, INF-gamma, IL -2 and an increased activity of NK cells, cytotoxic T-cells and macrophages are thought to play an important role. Better insights into the mechanisms of spontaneous remission of AML after recovery from sepsis could help in developing new therapies for AML.

We report a patient with Legionella pneumophila pneumonia after infliximab therapy for rheumatoid arthritis. Arguments are discussed for an emerging incidence of infections with intracellular microorganisms, granulomatous and non-granulomatous, in patients having received anti-TNFalpha therapy. These discussions consist of clinical and epidemiological data, experimental data in animals, theoretical evidence, and we provide a possible pathogenetic mechanism.