In Memory of Professor Derek Pheby.

Abstract: Professor Derek Pheby's passing in November 2022 marked a profound loss for the scientific community. Professor Derek Pheby, a stalwart figure in the fields of autoimmune diseases and bioethics, was known for his dedication to scientific research and patients' support, particularly for those affected by paraneoplastic autoimmune syndromes. Professor Pheby made significant contributions to research, especially about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). His leadership of the ME Biobank and scientific coordination of EUROMENE demonstrated his commitment to pushing boundaries and fostering international collaborations. Professor Pheby's scientific work addressed various aspects of ME/CFS, from physician education to patient needs, the development of a post-mortem tissue bank, and effective treatments. Beyond his medical career, Professor Pheby was a crucial member of the Independent Ethics Committee of MAGI, he was a poet, humanitarian, and advocate for child protection. His generosity and boundless spirit left an enduring legacy, fostering innovative research in the pursuit of combating autoimmune diseases.

[Castleman's disease in the rheumatological practice]. / Morbus Castleman in der rheumatologischen Praxis.

The term Castleman's disease encompasses a group of rare lymphoproliferative diseases that show histopathological similarities in lymph node biopsy. Diagnostic criteria and a specific ICD-10 code have been available for a few years. Case studies listed at the beginning illustrate that close cooperation between clinicians and pathologists is required to enable a reliable diagnosis. For an optimal histopathological assessment, the pathologist is also dependent on the removal of a complete lymph node. Before distinguishing a potentially fatal multicentric idiopathic Castleman's disease from the resectable unicentric form, which is important in terms of prognosis and treatment, early diagnosis presupposes that Castleman's disease is considered in the differential diagnosis. Various immune phenomena and overlaps with autoimmune diseases can increase the probability of misdiagnosis or undetected cases in the clinical routine of rheumatologists. The intention of the present overview is therefore to point out the similarities with autoimmune diseases that are relevant for differential diagnoses and to point out situations that justify a review of the previous diagnosis.

Prognostic factors for survival after allogeneic transplantation in acute lymphoblastic leukemia.

Allogeneic stem cell transplantation (allo-SCT) offers a curative option in adult patients with acute lymphoblastic leukemia (ALL). Prognostic factors for survival after allo-SCT have not been sufficiently defined: pheno-/genotype, patients´ age, conditioning regimens and remission at allo-SCT are under discussion. We analyzed the outcome of 180 consecutive adult ALL-patients undergoing allo-SCT at our center between 1995 and 2018 to identify specific prognostic factors. In our cohort 19% were older than 55 years, 28% had Philadelphia-positive B-ALL, 24% T-ALL. 54% were transplanted in first complete remission (CR1), 13% in CR2 after salvage therapy, 31% reached no remission (8% within first-line, 23% within salvage therapy). In 66% conditioning contained total body irradiation (TBI). With a median follow-up of 10 years, we observed an overall survival of 33% at 10 years, and a progression free survival of 31%. The cumulative incidence of relapse was 41% at 10 years, the cumulative incidence of non-relapse mortality 28%. Acute graft-versus-host disease (GvHD) II°-IV° occurred in 31%, moderate/severe chronic GvHD in 27%. Survival was better in patients reaching CR before allo-SCT and in those receiving TBI. No difference between patients younger/older than 55 years and between different phenotypes was observed. Survival after allo-SCT improved considerably over the last decades.

First-line treatment with R-CHOP or rituximab-bendamustine in patients with follicular lymphoma grade 3A-results of a retrospective analysis.

Based on centroblast frequency, follicular lymphoma (FL) is subdivided into grades 1-2, 3A, and 3B. Grade FL3A frequently coexists with FL1-2 (FL1-2-3A). Based on clinical trials, FL1-2 is treated with rituximab (R) or obinutuzumab plus bendamustine (B) or CHOP, while FL3B is treated with R-CHOP. In contrast, there are little data guiding therapy in FL3A. We present a retrospective, multicenter analysis of 95 FL3A or FL1-2-3A and 203 FL1-2 patients treated with R-CHOP or R-B first-line. R-CHOP facilitated a higher response rate (95% versus 76%) and longer overall survival (OS) (3-year OS 89% versus 73%, P = 0.008) in FL3A or FL1-2-3A, whereas the difference in progression-free survival (PFS) did not reach statistical significance. While transformation rates into aggressive lymphoma were similar between both groups, there were more additional malignancies after R-B compared with R-CHOP (6 versus 2 cases). In FL1-2, R-B achieved a higher 3-year PFS (79% versus 47%, P < 0.01), while there was no significant difference regarding OS or transformation. With the limitations of a retrospective analysis, these results suggest a benefit for R-CHOP over R-B in FL3A or FL1-2-3A. Confirmatory data from prospective clinical trials are needed.

Diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI protocol for hepatocellular carcinoma screening.

AIM: To evaluate the diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI (AMRI) in cirrhotic and chronic hepatitis B (CHB) patients for hepatocellular carcinoma (HCC) screening. MATERIALS AND METHODS: Seventy-nine consecutive patients at risk for HCC due to cirrhosis and/or CHB were included in this retrospective study. For each patient, the first gadoxetate disodium-enhanced MRI between 2008 through 2014 was analysed. Two independent readers read an anonymised abbreviated image set comprising axial T1-weighted (W) images with fat saturation in the hepatobiliary phase, 20 minutes or more after gadoxetate injection, and axial T2W single-shot fast spin echo images. Each observation >10 mm was scored as negative or suspicious for HCC. Inter-reader agreement was assessed. A composite reference standard was used to determine the per-lesion diagnostic performance for each reader. RESULTS: Inter-reader agreement was substantial (κ = 0.75). The final reference standard showed 27 HCCs in 13 patients (median 21 mm, range 11-100 mm). The two readers each correctly scored 23 as suspicious for HCC (sensitivity = 85.2%), scored a total of 27 and 32 observations as suspicious for HCC (positive predictive value [PPV] = 85.2% and 71.9%), and scored 83 and 78 observations or complete examinations as negative for HCC (negative predictive value [NPV] = 95.2% and 94.9%). CONCLUSIONS: The AMRI protocol provides higher per-lesion sensitivity and NPV than reported values for ultrasound, the current recommended technique for screening, and similar per-lesion sensitivity and PPV to reported values for complete dynamic contrast-enhanced MRI.

Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRß fusions and may benefit from targeted therapy. PATIENT AND METHODS: We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. RESULTS: The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. CONCLUSIONS: In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation.

The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non-relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey.

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft.

UNLABELLED: DNA-hypomethylating agents are a viable treatment option for AML/myelodysplastic syndrome (MDS) relapse after allograft by upregulating Ags on blasts before DLI. Seventy-two patients with relapsed AML (n=62), MDS (n=8) and other myeloid neoplasms (n=2) after allograft were treated with low-dose 5-azacytidine and, if feasible, DLI. PATIENT CHARACTERISTICS: median age 62 years (range 20-75), 42% with adverse cytogenetics, 82% not in remission at transplant and 83% received fludarabine-based reduced-toxicity conditioning. Median duration from transplant to 5-azacytidine was 289 days (range 59-2133). Response criteria: CR, temporary disease control or treatment failure. A median of 2.7 courses (range 1-10) were administered; 65 out of 72 patients also received DLI (41 already before 5-azacytidine). Ten patients developed acute GVHD and two succumbed to treatment-related sepsis. CR rate was 9.7% (in two patients lasting >5 years), 44% had temporary disease control (median duration 71 days, range 31-380). Median survival from 5-azacytidine was 108 days, 21 patients proceeded to subsequent transplant. In multivariate analysis, peripheral blood blasts <1% were predictive of longer OS (P=0.03). Taken together, long-term remissions can be induced by this well-tolerated outpatient treatment, particularly in patients without peripheral blood blasts.

Impact of prior treatment on outcome of transformed follicular lymphoma and relapsed de novo diffuse large B cell lymphoma: a retrospective multicentre analysis.

Transformation of follicular lymphoma (FL) into aggressive disease and relapse of de novo diffuse large B cell lymphoma (DLBCL) are considered highly unfavourable events. However, most published data were acquired when rituximab was not routinely used. We retrospectively analysed 50 patients with transformed FL (tFL) in a multicenter study and compared them to 50 individuals with relapsed DLBCL (rDLBCL) who all obtained rituximab for the treatment of their disease. Our goal was to identify factors that predict a more favourable prognosis. After a median follow-up of 5.4 years from diagnosis, there was no significant difference in median overall survival (OS) from the date of transformation (tFL) or date of the first relapse (rDLBCL) (1.9 versus 3.9 years, P = .542). Of note, 5-year OS of patients with tFL was 46 %. Follicular lymphoma patients, treatment naïve prior to transformation, fared significantly better than pretreated patients (median not reached versus 1.4 years, P = .014). Regarding rDLBCL, female gender (13.9 versus 1.8 years, P = .019) and absence of rituximab prior to the first relapse (14.0 versus 1.8 years, P = .035) were favourable prognostic factors in a uni- and multivariate analysis. Only a proportion of patients received high-dose chemotherapy with autologous stem cell transplantation (HDT-ASCT), i.e. 38 and 52 % of patients with tFL and rDLBCL, respectively. Our data indicate that a favourable prognosis is conferred by treatment naivety in tFL and by rituximab naivety in rDLBCL. In contrast, we did not find a prognostic impact of HDT-ASCT in our series.

Wnt signaling pathway pharmacogenetics in non-small cell lung cancer.

Wingless-type protein (Wnt)/ß-catenin pathway alterations in non-small cell lung cancer (NSCLC) are associated with poor prognosis and resistance. In 598 stage III-IV NSCLC patients receiving platinum-based chemotherapy at the MD Anderson Cancer Center (MDACC), we correlated survival with 441 host single-nucleotide polymorphisms (SNPs) in 50 Wnt pathway genes. We then assessed the most significant SNPs in 240 Mayo Clinic patients receiving platinum-based chemotherapy for advanced NSCLC, 127 MDACC patients receiving platinum-based adjuvant chemotherapy and 340 early stage MDACC patients undergoing surgery alone (cohorts 2-4). In multivariate analysis, survival correlates with SNPs for AXIN2 (rs11868547 and rs4541111, of which rs11868547 was assessed in cohorts 2-4), Wnt-5B (rs12819505), CXXC4 (rs4413407) and WIF-1 (rs10878232). Median survival was 19.7, 15.6 and 10.7 months for patients with 1, 2 and 3-5 unfavorable genotypes, respectively (P=3.8 × 10(-9)). Survival tree analysis classified patients into two groups (median survival time 11.3 vs 17.3 months, P=4.7 × 10(-8)). None of the SNPs achieved significance in cohorts 2-4; however, there was a trend in the same direction as cohort 1 for 3 of the SNPs. Using online databases, we found rs10878232 displayed expression quantitative trait loci correlation with the expression of LEMD3, a neighboring gene previously associated with NSCLC survival. In conclusion, results from cohort 1 provide further evidence for an important role for Wnt in NSCLC. Investigation of Wnt inhibitors in advanced NSCLC would be reasonable. Lack of an SNP association with outcome in cohorts 2-4 could be due to low statistical power, impact of patient heterogeneity or false-positive observations in cohort 1.

Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation.

Propylene Glycol-Free melphalan HCL for Injection (PGF-Mel) is a new formulation that incorporates Captisol, a specially modified cyclodextrin, to improve melphalan stability. In this phase IIa, open-label, randomized, cross-over design bioequivalence study, the pharmacokinetics of PGF-Mel were compared with the marketed formulation of melphalan, or Alkeran. Patients received half of the total dose of melphalan in the form of Alkeran and the other half in the form of PGF-Mel in an alternating manner. The pharmacokinetic measures were determined using WinNonlin 6.2 and bioequivalence was assessed using log-transformed systemic exposure parameters. Twenty-four patients, 11 females and 13 males, were enrolled between 4 February 2010 and 16 May 2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. The median age of enrolled subjects was 58 years (range: 48-65). All patients achieved myeloablation 3 days post autologous graft followed by successful neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis showed that PGF-Mel was bioequivalent with Alkeran and also revealed that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher (~10%) after PGF-Mel administration. In conclusion, PGF-Mel is considered bioequivalent to Alkeran while also demonstrating a marginally higher systemic drug exposure.

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML.

A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m(2) and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients ≥ 65 years old who relapsed >12 months after the first allograft (n=20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse.

Identification of risk factors for bronchiolitis obliterans syndrome after reduced toxicity conditioning before hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) of older or patients with comorbidities has become possible due to new regimens for reduced-intensity conditioning. The use of fludarabine, carmustine and melphalan as the preparative regimen (FBM) reduces toxicity while providing substantial anti-leukemic activity. Chronic GVHD (cGVHD) of the lung or bronchiolitis obliterans syndrome (BOS) remains a serious non-infectious complication contributing to treatment-related morbidity. We conducted a retrospective analysis of 259 patients (median age: 61.5, range: 24-76 years) transplanted after FBM conditioning to identify and characterize clinical risk factors for developing BOS. The cumulative incidence rate of BOS was 4.2% (95% confidence interval (CI): 2.4-7.6%) at 1 year and 8.5% (95% CI: 5.6-12.9%) at 5 years after allo-HCT with a median follow-up of 36.5 (range: 3-136) months. In multivariate analysis, age <55 years at allo-HCT (who received 25% higher carmustin-dose in preparative regimen), pulmonary complications after allo-HCT and GVHD prophylaxis without in-vivo T-cell depletion (cyclosporine-A/ATG or cyclosporine-A/alemtuzumab) were associated with BOS. We observed no significant differences in clinical variables such as smoking or lung diseases before allo-HCT. In contrast to cGVHD affecting other organs, BOS showed no impact on overall survival. In conclusion, we identified risk factors associated with developing BOS after conditioning with a reduced toxicity protocol.

[Current diagnostics and therapy of B cell Non Hodgkin Lymphoma]. / Aktuelle Diagnostik und Therapie bei B-Zell Non Hodgkin Lymphomen.

New diagnostic tools and therapeutic options for Non Hodgkin Lymphoma (NHL) contributed to several improvements in the understanding and treatment of this hematological malignancies. In diffuse large cell lymphoma (DLBCL) gene expression profiling and molecular analyses of myc and bcl-2 gene rearrangements resulted in the description of new DLBCL entities with significant differences in outcome. Combination immunochemotherapy according to the R-CHOP protocol remains the mainstay for treatment of DLBCL in younger and older patients. Mantle cell lymphoma is characterised by the overexpression of cyclin D1. While older patients should be treated with R-CHOP with rituximab maintenance therapy, first line treatment of younger patients should also include AraC containing regimens and autologous stem cell transplantation. Cases with follicular lymphoma very often show the t(14; 18) translocation resulting in overexpression of BCL2 and diminished apoptosis. Compared to R-CHOP treatment new combinations with R-Bendamustin have shown high efficacy with reduced toxicity and should therefore be regarded as standard in patients in need for therapy.