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Supplementary Figure 3 from A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

Supplementary Table 2 from A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

We here describe a novel xenograft model of chronic lymphocytic leukemia (CLL) generated by infusion of human primary CLL cells into immunodeficient nonobese/severe combined immunodeficient (NOD/SCID) mice. Combined i.v. and i.p. injection of peripheral blood mononuclear cells (PBMC) from 39 patients with CLL resulted in highly reproducible splenic (37 of 39) and peritoneal (35 of 39) engraftment, which remained stable over a time span of 4 to 8 weeks. By comparison, recovery of leukemic cells from bone marrow (21 of 39) or peripheral blood (8 of 22) was substantially lower. The engraftment pattern of CLL PBMC 4 weeks posttransplant was correlated with clinical disease activity: infusion of PBMC from donors with Binet stage A, lymphocyte doubling time of >12 months, and normal lactate dehydrogenase (LDH) serum levels led to marked engraftment of T cells whereas comparably few tumor cells could be detected. In contrast, NOD/SCID mice receiving PBMC from donors with advanced stage Binet C, lymphocyte doubling time of

Supplementary Figure 2 from A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

Supplementary Figure Legends 1-3 from A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

Supplementary Table 1 from A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

Supplementary Figure 1 from A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

Background Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. Methods Data from 56 centres were analysed for adverse events (AE), progression-free survival (PFS), overall survival (OS). Results 126 patients actually received at least 1 cycle durvalumab. Compared to the PACIFIC trial, the EAP population had more advanced stage and included “oligometastatic” stage IV patients and patients with autoimmune disease. PFS (20.1 months) and OS (not reached) were similar in the EAP and the PACIFIC trial. 42.9 % completed 12 months of durvalumab without deaths during FU. Stage IV patients (n = 7) had encouraging OS (not reached at 27 months). Autoimmune disease did not affect survival. PFS and OS were similar in PD-L1-negative patients (n = 32) and PD-L1-positive patients (n = 79). Conclusions Survival in the EAP was comparable to the PACIFIC trial. Selected stage IV patients and patients with autoimmune disease may benefit from durvalumab consolidation and should be included in future immuno-oncological trials. PD-L1 did not predict survival challenging the exclusion of PD-L1-negative patients from durvalumab consolidation. In summary, durvalumab consolidation is safe and effective in a European real-world setting.

Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. 211 patients were registered by 90 German centres. Data were collected retrospectively by questionnaire and queries. 56 centres reported data on 126 patients who actually received at least one cycle of durvalumab. In contrast to the PACIFIC-trial population, some patients with oligometastatic disease and a history of autoimmune disease are included in the EAP population. Information on PD-L1 status was obtained for 111 patients. Baseline data include age, gender, ECOG, stage (IASLC 8th ed.), and smoking history. Treatment data include mode of chemoradiotherapy, used chemotherapy agent, and duration of durvalumab therapy. Adverse evants were documented according to CTAEC 5.0. Data were analysed for progression-free survival (PFS), overall survival (OS), and adverse events (AE). The results were published in Lung Cancer [1].

We retrospectively studied 73 consecutive patients who underwent surgery 2015–2020 for removal of cerebellar metastases (CM). Median overall survival (medOS) varied widely between patients and compared favorably with the more recent literature (9.2, 25–75% IQR: 3.2–21.7 months vs. 5–8 months). Prognostic factors included clinical (but not radiological) hydrocephalus (medOS 11.3 vs. 5.2 months, p = 0.0374). Of note, a third of the patients with a KPI &lt, 70% or multiple metastases survived &gt, 12 months. Chemotherapy played a prominent prognostic role (medOS 15.5 vs. 2.3, p &lt, 0.0001) possibly reflecting advances in treating systemic vis-à-vis controlled CNS disease. Major neurological (≥30 days), surgical and medical complications (CTCAE III–V) were observed in 8.2%, 13.7%, and 9.6%, respectively. The occurrence of a major complication markedly reduced survival (10.7 vs. 2.5 months, p = 0.020). The presence of extracerebral metastases did not significantly influence OS. Postponing staging was not associated with more complications or shorter survival. Together these data argue for individualized decision making which includes offering surgery in selected cases with a presumably adverse prognosis and also occasional urgent operations in cases without a preoperative oncological work-up. Complication avoidance is of utmost importance.

TPS8585 Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer death worldwide highlighting the importance of improving current therapeutic options. In particular, elderly and frail patients are not only underrepresented in clinical trials, but also frequently do not receive standard treatment regimens due to comorbidities. For example, patients with unresectable stage III NSCLC who are unfit for chemotherapy (CHT) do not benefit from the recent seminal therapy algorithm change for this disease, i.e. consolidation therapy with the immune checkpoint inhibitor (ICI) durvalumab after combined radiochemotherapy (RChT). Instead, these patients are treated with radiotherapy only, raising the serious concern of undertreatment. This issue is addressed by the TRADE-hypo clinical trial that investigates a novel therapy option for NSCLC stage III patients not capable of receiving CHT. To this end, thoracic radiotherapy (TRT) is administered together with durvalumab, employing the synergism created by the combination of restoring anti-tumor immune response by the ICI with the induction of immunogenicity by irradiation. The latter effect has been suggested to be further boosted by hypofractionated radiotherapy, which could also be more practicable for the patient. Taken these considerations into account, the TRADE-hypo trial addresses safety and efficacy of durvalumab therapy combined with either conventional or hypofractionated TRT. Methods: The TRADE-hypo trial is a prospective, randomized, open-label, multicentric phase II trial. Eligible patients are diagnosed with unresectable stage III NSCLC and not capable of receiving sequential RChT due to high vulnerability as reflected by a poor performance status (ECOG 2 or ECOG1 and CCI≥ 1) and/or high age (≥ 70)]. Two treatment groups are evaluated: Both receive durvalumab (1,5000 mg, Q4W) for up to 12 months. In the CON-group this is combined with conventionally fractionated TRT (30 x 2 Gy), while in the HYPO-group patients are treated with hypofractionated TRT (20 x 2.75 Gy). In the HYPO-arm, a safety stop-and-go lead-in phase precedes full enrollment. Here, patients are closely monitored with regard to toxicity (i.e., pneumonitis grade ≥ 3 within 8 weeks after TRT) in small cohorts of 6. The primary objective of the trial is safety and tolerability. As a primary efficacy endpoint, the objective response rate after 3 months will be evaluated. Further endpoints are additional parameters of safety and efficacy, as well as the comprehensive collection of biomaterials to be analyzed regarding treatment-induced changes and potential novel biomarkers. As of February 10, 2021, 9 patients of planned 88 patients have been enrolled in the TRADE-hypo trial. Clinical trial information: NCT04351256.

The t(11;14) translocation that juxtaposes the Cyclin D1 (CCND1) gene to the immunoglobulin heavy chain gene is considered a hallmark of mantel cell lymphoma (MCL).1 Immunohistochemical (IHC) analysis of CCND1 expression in formalin-fixed paraffin-embedded (FFPE) tissue sections of material from patients with suspected MCL is therefore the most obvious and effective diagnostic tool.2 We identified two cases of MCL based on morphology, expression of CD20, CD5 and SOX11 and absence of CD23 expression. Notably, both cases were negative for nuclear CCND1 staining by IHC (Figure 1G,J), despite being positive for the t(11;14)(q13;q32) translocation using fluorescence in situ hybridization (FISH, Figure 1H,L). Patient A was a 81-year-old female presenting with Ann Arbor stage IIIA. After six cycles of R-CHOP (rituximab, clorambucil, vincristine, prednisolone) and two additional cycles of rituximab, she achieved complete remission until last follow up 15 months after initial diagnosis. Patient B was an 87-year-old female with lymphadenopathy on both sides of the diaphragm, but staging remained incomplete. Due to comorbidities and patients' refusal of chemotherapy, rituximab mono-therapy was initiated until last follow up after two months. Surgical excision biopsies of an inguinal (patient A) and cervical (patient B) lymph node were submitted for consultation. In order to investigate if the lack of CCND1 immunostaining was due to low CCND1 expression, we performed quantitative PCR analysis of CCND1 expression in total RNA from patient A and patient B compared to CCND1 expression observed in two classical CCND1-positive MCL cases and two normal lymph nodes. The expression of CCND2 was also investigate as it is known that CCND2 can compensate for CCND1 in some cases.3 As shown in Figure 2A, both patients have CCND1 expression levels similar or higher to that observed in classical MCL samples and much higher than the expression observed in normal lymph nodes. These data are in line with the presence of a t(11;14) translocation in biopsies of the two patients and suggest that the lack of CCND1 immunostaining in patient A and patient B is not due to a defect in mRNA expression.

We here describe a novel xenograft model of chronic lymphocytic leukemia (CLL) generated by infusion of human primary CLL cells into immunodeficient nonobese/severe combined immunodeficient (NOD/SCID) mice. Combined i.v. and i.p. injection of peripheral blood mononuclear cells (PBMC) from 39 patients with CLL resulted in highly reproducible splenic (37 of 39) and peritoneal (35 of 39) engraftment, which remained stable over a time span of 4 to 8 weeks. By comparison, recovery of leukemic cells from bone marrow (21 of 39) or peripheral blood (8 of 22) was substantially lower. The engraftment pattern of CLL PBMC 4 weeks posttransplant was correlated with clinical disease activity: infusion of PBMC from donors with Binet stage A, lymphocyte doubling time of >12 months, and normal lactate dehydrogenase (LDH) serum levels led to marked engraftment of T cells whereas comparably few tumor cells could be detected. In contrast, NOD/SCID mice receiving PBMC from donors with advanced stage Binet C, lymphocyte doubling time of

High-dose chemotherapy (HD-CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high-grade non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD-CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD-CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5-yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event-free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment-related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of > or = 2 and resistant disease to first-line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.

Received 18 May 2005; returned 12 August 2005; revised 7 October 2005; accepted 14 October 2005Background: Caspofungin has shown efficacy in empirical antifungal therapy in neutropenic patients,refractory invasive Aspergillus infections and invasive candidiasis. Here we report the currently largestseries of patients treated with caspofungin outside clinical trials.Methods:CentresinGermanythatwereknowntotreatpatientswithinvasivefungalinfectionswereaskedtofilloutdetailedquestionnairesforallpatientstreatedwithcaspofungin.Noeffortwasmadetoinfluencethe decision to use caspofungin.Results:Atotalof118patientswereevaluable(medianage48years,interquartilerange38–58),outofwhich41(35%)sufferedfromacuteleukaemia,31(26%)hadallogeneicstemcelltransplants,16(14%)lymphomaor myeloma, 8 (7%) autologous stem cell transplants and 22 (19%) other causes for immunosuppression.Onehundredandsixpatientswereevaluableforefficacyoutofwhich68(64%)patientsachievedacompleteor partial remission. A total of 81out of 115 (70%) patients were alive 30 days after the end of caspofungintherapy. Response ratesweresimilar inproven (20/32,63%) andprobable (27/46,59%) infections, inneut-ropenic patients (41/55, 75%) and in patients who were (44/70, 63%) or were not (24/36, 67%) refractoryto antifungal pre-treatment. The response rate in mechanically ventilated patients was 29% (7/24).Caspofungin was well tolerated, even in 14 patients, who were concomitantly treated with ciclosporin A,no drug-related elevations of bilirubin, alanine aminotransferase or creatinine were found.Conclusions: This open case study of severely ill patients with invasive fungal infections demonstratesboth excellent efficacy and very low toxicity of caspofungin.Keywords: fungal infections, candidiasis, aspergillosis, safety

Eine Heilung von Tumorpatienten ist haufig nur mit risikoreichen Therapiestrategien moglich. Hierbei konnen lebensbedrohliche Nebenwirkungen auftreten, die eine intensivmedizinische Behandlung erforderlich machen. Das Ziel dieser Arbeit war es, die Prognose von Patienten mit einer malignen Tumorerkrankung, die intensivmedizinisch behandelt werden mussten, zu bestimmen und prognostische Faktoren zu ermitteln. Retrospektiv wurden die Krankenakten von 94 Patienten mit einer malignen Tumorerkrankung ausgewertet, die in einem Zeitraum von 5 Jahren intensivmedizinisch behandelt werden mussten. Von 94 Tumorpatienten hatten 64 eine hamatologische und 30 eine solide Tumorerkrankung. 92 Patien- ten (98%) waren chemotherapeutisch vorbehandelt. Die Grunde fur die intensivmedizinische Behandlung waren respiratorische Insuffizienz (49%), Sepsis (21%), Blutungen (7.4%) und kardiale Dekompensation (6,4%). Eine Intubation mit maschineller Beatmung war bei 68% der Patienten erforderlich und 66% der Patienten benotigten kreislaufunterstutzende Medikamente (Noradrenalin, Dopamin). Die Letalitat wahrend des intensivmedizinischen Aufenthaltes und wahrend des gesamten Krankenhausaufenthaltes betrug 55 bzw. 67%. In der multivariaten Regressionsanalyse waren respiratorisches Versagen mit der Notwendigkeit der maschinellen Beatmung, eine erhohte Konzentration der Laktatdehydrogenase im Serum und multiples Organversagen gemessen mit dem SOFA-Score unabhangige ungunstige prognostische Faktoren fur die Letalitat auf der Intensivstation. Respiratorisches Versagen mit der Notwendigkeit der maschinellen Beatmung, multiples Organversagen gemessen mit dem SOFA-Score und der Remissionsstatus der zugrunde liegenden Tumorerkrankung waren prognostisch signifikant fur das Gesamtuberleben. Respiratorisches Versagen und multiples Organversagen sind die bedeutsamsten unabhangigen prognostischen Faktoren fur die Letalitat wahrend des Aufenthaltes auf der Intensivstation, wahrend der Remissionsstatus der zugrunde liegenden Tumorerkrankung die Langzeitprognose beeinflusst.

A pulmonary nodule is defined as a round opacity, at least moderately well marginated, which has a longest diameter of 3 cm or less, surrounded by ventilated lung parenchyma, and not associated with pulmonary obstruction or pleural effusion. Solitary pulmonary nodules are frequently detected on radiograms or computed tomograms (CT) of the chest conducted for other medical reasons. The differentiation between benign and malignant lesions is of clinical significance. The chest CT can provide radiomorphological features in relation to the likelihood of malignancy. Additional criteria, which have to be taken into account, include medical history, clinical context, comparison with previous scans, smoking history, patient's age, and the anatomical localisation of the nodule. The workup algorithm for solitary pulmonary nodules is based on whether the dignity of these nodules is considered to be malignant, benign, or intermediate. A pulmonary nodule is considered benign when no progression is observed within 2 years. For these nodules no further evaluation is required. Criteria of malignancy comprise progression in size or a nodule diameter of more than 3 cm. For such lesions resection and histological evaluation is mandatory. For pulmonary nodules, which can not be allocated to either of these groups, further diagnostic workup such as biopsy with histological evaluation, follow-up CT-scans and/or PET/CT is indicated.

Introduction This randomized phase II study investigated pemetrexed in combination with the epidermal growth factor receptor (EGFR)-targeting monoclonal antibody matuzumab compared with pemetrexed alone as second-line therapy for patients with advanced non-small cell lung cancer. Methods Patients received pemetrexed 500 mg/m 2 every 3 weeks either alone ( n = 50) or in combination with matuzumab at either 800 mg weekly ( n = 51) or 1600 mg every 3 weeks ( n = 47). The primary end point was objective response, as assessed by an independent review committee. Results Tumor EGFR expression was detected in 87% of randomized patients. The objective response rate for the pooled matuzumab-treated arms was 11% compared with 5% for pemetrexed alone ( p = 0.332). Apart from one patient in the pemetrexed alone group, all responses occurred in patients whose tumors expressed EGFR. The objective response rate for patients receiving weekly matuzumab was 16% compared with 2% for those receiving matuzumab every 3 weeks. There was also a trend for improved overall survival in patients receiving matuzumab weekly versus every 3 weeks (12.4 months versus 5.9 months, respectively, versus 7.9 months for pemetrexed alone). The combination of pemetrexed and matuzumab demonstrated an acceptable safety profile, with the most common grade 3/4 adverse event being neutropenia. Conclusion Although the analysis on the pooled matuzumab-treated arms did not demonstrate a statistically significant improvement in objective response for the addition of matuzumab to pemetrexed compared with pemetrexed alone, the trends for improvement in objective response and overall survival for pemetrexed plus weekly matuzumab compared with pemetrexed alone warrant confirmation in additional clinical trials.

The aim of this study was to determine the prognostic significance of soluble human leukocyte antigen (HLA) class I (sHLA-I) and HLA-G molecules in lung cancer patients. A total of 23 small-cell lung cancer (SCLC) and 114 non-small-cell lung cancer (NSCLC) patients, including 55 adenocarcinoma, 46 squamous cell carcinoma (SCC), and 13 patients with undifferentiated carcinoma, were prospectively enrolled. Levels of sHLA-G and sHLA-I were analyzed by specific enzyme-linked immunosorbent assay. Median levels of sHLA-G and sHLA-I were significantly increased in patients compared with controls (34 ng/ml [3.6-160] vs 14 ng/ml [0-98], p < 0.0001; 2580 ng/ml [749-5770] vs 1370 ng/ml [274-2670], p < 0.0001, respectively). Regarding the different subgroups, patients with NSCLC or SCLC showed increased sHLA-I levels, whereas sHLA-G was exclusively elevated in NSCLC, especially in patients with SCC. Patients with sHLA-I

PURPOSE: To compare the depiction of brain metastases of bronchial carcinomas on susceptibility-weighted and contrast-enhanced images with 7 T and at 1.5 T MRI. MATERIALS AND METHODS: Twelve patients with brain metastases of bronchial carcinomas underwent 7 T and 1.5 T MRI. Minimum intensity projections (MinIP) of a 1.5 T SWI sequence (voxel size = 0.9 × 0.9 × 2.0 mm 3 ) were compared to 7 T SWI MinIPs (voxel size = 0.4 × 0.4 × 1.5 mm 3 ). A T 1-w 3D MPRAGE at 1.5 T (voxel size = 1 × 1 × 1 mm 3 after double-dose (DD) gadoterate meglumine, Gd-DOTA) was compared to a 7 T MPRAGE sequence (voxel size = 0.7 × 0.7 x × 0.7 mm 3 , single dose (SD) Gd-DOTA) in all patients, and to DD Gd-DOTA in 6 patients after a 10 minute delay. The number of intracranial microhemorrhages in SWI MinIPs and the number of contrast-enhancing metastases in MPRAGE images were compared in each patient grouped into three size ranges (≤ 2 mm, > 2 mm and < 6 mm, ≥ 6 mm) by two radiologists in consensus. RESULTS: In all 12 patients the 7 T SWI with spatially higher resolution allowed the identification of 87 versus 67 cerebral microhemorrhages at 1.5 T. 7 T T 1-w images after SD Gd-DOTA depicted 198 brain metastases versus 238 at 1.5 T after DD Gd-DOTA. After doubling the contrast dose in six patients, 4 additional brain metastases were identified at 7 T. CONCLUSION: Our preliminary results indicate that despite the higher spatial resolution the detection of brain metastases on 7 T MPRAGE images is almost equal to 1.5 T MPRAGE images. The 7 T SWI sequence with spatially higher resolution allowed the detection of 20 % more microhemorrhages in brain metastases compared to the 1.5 T SWI sequence.

Ziele: Ziel der Studie ist die Darstellung von Hirnmetastasen von Bronchialkarzinomen mittels suszeptibilitatsgewichteter und Kontrastmittel-verstarkter Magnetresonanztomographie (MRT) bei 1.5 Tesla (T) bzw. 7T. Methode: 12 Patienten mit bekannten Hirnmetastasen von histologisch gesicherten Bronchialkarzinomen wurden mittels 1.5T MRT (Magnetom Espree, Siemens Healthcare, Erlangen) in Kombination mit einer 12-Kanal-Empfangsspule (Siemens, Erlangen) und 7T MRT (Magnetom 7T, Siemens Healthcare, Erlangen) in Kombination mit einer 8-Kanal-Sende-und Empfangsspule (Rapid, Wurzburg) untersucht. Die Anzahl der nachweisbaren Metastasen wurde anhand von Minimumintensitatsprojektionen axialer SWI-Sequenzen (1,5T: TR/TE=49/40ms, Flipwinkel=15°, Voxelgrose=0,9×0,9×2mm3; 7T: TR/TE=27/15ms, Flipwinkel=15°, Voxelgrose=0,4×0,4×1,5mm3, n=12 Patienten) und anhand von Kontrastmittel-verstarkten T1w-Sequenzen (MPRAGE, 1,5T: TR/TE=1910/3,07ms, Flipwinkel=10°, Voxelgrose=1×1x1mm3, Doppeldosis Gd-DTPA; 7T: TR/TE=2500/1,54ms, Flipwinkel=6°, Voxelgrose=0,7×0,7×0,7mm3, Doppeldosis Gd-DTPA, n=6 Patienten) verglichen. Ergebnis: Durch die hoher aufgeloste 7T SWI-Sequenz konnten 23% mehr Mikrohamorrhagien bzw. Hamosiderinablagerungen in Hirnmetastasen gegenuber der 1.5T SWI-Sequenz nachgewiesen werden. Die 0,7mm isotrope MPRAGE-Sequenz in Kombination mit einer Doppeldosis Gd-DTPA konnte 10% mehr Hirnmetastasen darstellen als durch 1mm isotrope 1,5T MPRAGE. Schlussfolgerung: Die vorlaufigen Ergebnisse belegen, dass die erhohte Sensitivitat fur Suszeptibilitatskontraste und die hohere Auflosung der 7T SWI-Sequenz die Nachweisbarkeit eingebluteter Hirnmetastasen gegenuber der 1.5T SWI-Sequenz verbessern. Ferner konnen durch die raumlich hoher aufgeloste, KM-verstarkte 7T MPRAGE gegenuber der 1,5T MPRAGE mehr Hirnmetastasen nachgewiesen werden. Korrespondierender Autor: Monninghoff C Universitatsklinikum Essen, Institut fur diagnostische und interventionelle Radiologie und Neuroradiologie, Hufelandstrase 55, 45147 Essen E-Mail: christoph.moenninghoff@uk-essen.de

Anthracyline-based chemotherapy is the treatment of choice for patients with aggressive B-cell non-Hodgkin’s lymphoma (NHL). However, anthracyclines have been associated with long-term cardiac toxicity. We conducted a study using a sequential combination chemotherapy with a reduced cumulative dose of anthracyclines in younger patients with good-prognosis aggressive NHL. Chemotherapy consisted of one cycle of vincristine, ifosfamide, etoposide, and dexamethasone, followed by three cycles of epirubicin, cyclophosphamide, vincristine, and dexamethasone, and a fifth cycle containing carboplatin, etoposide, and dexamethasone. 86 patients were treated, 65 without and 21 with additional rituximab. Consolidating involved-field irradiation was applied in patients with stage I/II, bulky disease, or localized residual lymphoma. Complete and partial remissions were achieved in 67 and 27% of patients, respectively, and the 3-year event-free and overall survival estimates were 75 and 87%. The survival estimates were substantially better in patients who received rituximab. Main toxicity was grade 3/4 leukocytopenia in 89% patients with neutropenic fever in 30%. Two patients died of septic shock. The treatment appears to be effective in this group of patients. The hematological toxicities, particularly after the first and fifth cycle, require the use of G-CSF and/or a dose reduction in selected patients.

Because of the variable clinical course of multiple myeloma, the identification of prognostic parameters is of clinical interest. Therefore, we analyzed the clinical significance of serum levels of soluble human leukocyte antigen class I molecules (sHLA-I), carboxy-terminal telopeptide of type-I collagen (ICTP), and receptor activator of nuclear factor kappa B ligand (RANKL). Compared with controls, sHLA-I were threefold (p < 0.001) elevated in multiple myeloma. Increased levels of ICTP and RANKL were demonstrated in 50 and 43% of patients, respectively. sHLA-I correlated significantly with stage of disease. Serial determination of sHLA-I in 11 patients revealed significantly higher sHLA-I levels (median [range] mug/l) during active disease than during remission (700 [250-2090] versus 380 [130-920]). ICTP demonstrated an association with stages of disease and the presence of osteolytic lesions, whereas there were no differences with respect to active/remittent disease. Importantly, levels of sHLA-I > or = 1000 microg/l and ICTP > or = 5 microg/l were significantly associated with a poor overall survival. For RANKL, no significant associations were observed with disease stages, disease status, osteolytic lesions, and survival. In conclusion, sHLA-I and ICTP serum levels seem to be of prognostic significance in multiple myeloma and might be helpful to identify patients of poor prognosis.

Aims and Background To improve the survival of patients with aggressive non-Hodgkin's lymphoma, we evaluated a risk-adapted therapeutic approach using high-dose (HD) or conventional-dose (CD) chemotherapy (CT) for poor-risk and good-risk patients, respectively. Methods Twenty patients were treated in each group. In both groups, the first chemotherapy cycle consisted of dexamethasone, vincristine, ifosfamide, and etoposide. Thereafter, the CD or HD patients received 3 or 2 cycles of dexamethasone, vincristine, epirubicin, and cyclophosphamide, respectively, followed by 1 cycle of dexamethasone, carboplatin, and etoposide. In the HD group cyclophosphamide, epirubicin, carboplatin, and etoposide were dose-escalated by a factor of 6, 3, 3, and 3, respectively, as compared to the CD group, and autologous peripheral blood stem cells were administered after each HD-CT cycle. Results Grade III-IV toxicities were neutropenia and thrombocytopenia (100%), anemia (55%), and stomatitis (30%) in patients with HD-CT, and neutropenia (90%) in patients with CD-CT. One toxic death occurred in a patient with HD-CT. The overall response rate was 100% in HD-CT patients, including 70% complete remissions, and 80% in CD-CT patients, including 60% complete remissions. The 10-year overall survival was 55% for patients with HD-CT and 80% for patients with CD-CT. Conclusions The risk-adapted treatment approach showed tolerable toxicities and was associated with encouraging results.

Major histocompatibility complex class I-related chain A (MICA) molecules are frequently expressed in lymphoproliferative malignancies including multiple myeloma (MM). MICA activates NK cells and co-stimulates T cells by interaction with its immunoreceptor NKG2D. In contrast, soluble MICA (sMICA) molecules impair the functions of NKG2D(+) T and NK cells, which may facilitate tumor cell escape from immunosurveillance. Here, we analyzed the clinical relevance of sMICA in 97 MM patients. sMICA (mean+/-SEM pg/ml) was significantly increased (p305 pg/ml are associated with a poor overall (p=0.004) and progression-free survival (p=0.002). Multivariate analysis revealed sMICA as an independent predictive factor for overall (p=0.007) and progression-free survival (p=0.002). Thus, our results suggest sMICA as a potent prognostic marker in MM, which may be useful to identify risk patients.

The present study evaluated cellular and humoral immune parameters in myeloma patients, focusing on the effect of treatment and the risk of opportunistic infections. Peripheral blood lymphocyte subsets and serum levels of nonmyeloma immunoglobulins (Ig) were analysed in 480 blood samples from 77 myeloma patients. Untreated myeloma patients exhibited significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells, as well as nonmyeloma IgA, IgG and IgM. Conventional-dose chemotherapy resulted in significantly reduced CD4+ and even further decline of CD4+/CD45RO+ and CD19+ cells, most notably in relapsed patients. Additional thalidomide treatment had no significant effects on these parameters. Following high-dose chemotherapy (HD-CTX), prolonged immunosuppression was observed. Although CD8+, NK, CD19+ and CD+/CD45RO+ cells recovered to normal values within 60, 90, 360 and 720 days, respectively, CD4+ counts remained reduced even thereafter. Nine opportunistic infections were observed, including five cytomegalovirus (CMV) diseases, one Pneumocystis carinii pneumonia (PCP) and three varicella zoster virus infections with CMV diseases and PCP occurring exclusively after HD-CTX. Opportunistic infections were correlated with severely reduced CD4+, as well as CD4+/CD45RO+ and CD19+ counts. Thus, myeloma patients display cellular and humoral immunodeficiencies, which increase following conventional as well as HD-CTX, and constitute an important predisposing factor for opportunistic infections.

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1-7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m2 daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of beta2-microglobulin (beta2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R.

While vaccination with antigen-pulsed dendritic cells (DCs) represents a promising therapeutic strategy in multiple myeloma (MM), clinical benefit, so far, has been limited to individual patients. To identify potential problems with this approach, we have analyzed the influence of treatment parameters, in particular high-dose chemotherapy (HD-CTX) and thalidomide, on in vitro DC generation and peripheral blood lymphocyte subsets in MM patients. From a total of 25 MM patients, including 14 patients on thalidomide treatment and 11 after HD-CTX, in vitro DC generation from peripheral blood monocytes under serum-free condition was investigated. In addition, peripheral blood lymphocyte subsets were assessed in 17 patients including 10 patients on thalidomide treatment and 9 patients after HD-CTX. Efficient in vitro generation of DCs (median 7.1x10(6)/100 ml peripheral blood; range 0.1-42.5x10(6)/100 ml peripheral blood) expressing DC-typical surface markers was observed in 23 MM patients (92%), although reduced expression of CD1a, CD40, CD83, and HLA-DR was observed in patients treated with thalidomide. With respect to lymphocyte subsets, MM patients showed significantly (p

The present study aimed to evaluate the side-effects and efficacy of thalidomide in combination with an anthracycline-containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty-one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high-dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high-dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event-free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

Hemolytic uremic syndrome (HUS) has been described following the administration of multiple antineoplastic agents, most notably mitomycin C. More recently, several cases of gemcitabine-induced HUS have been observed with the overall incidence of gemcitabine-induced HUS estimated at 0.015-0.25%. We here report on four patients who developed HUS following gemcitabine therapy at our institution within the last year (incidence 1.4%). All these patients had advanced-stage disease, were heavily pretreated, and received prolonged gemcitabine application, suggesting that in this subgroup of patients HUS may be more frequently encountered than documented so far.

This study evaluates cellular and humoral immune parameters in myeloma patients focusing on the effect of treatment and the risk of opportunistic infections. Peripheral blood lymphocyte subsets and serum levels of nonmyeloma immunoglobulins (Ig) were analyzed in 480 blood samples from 77 myeloma patients. Untreated myeloma patients exhibited significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells as well as nonmyeloma IgA, IgG, and IgM. Conventional-dose chemotherapy (conv-CTX) resulted in significantly reduced CD4+ and even further decline of CD4+/CD45RO+ and CD19+ cells, most notably in relapsed patients. Patients treated with conv-CTX in combination with thalidomide showed significantly increased counts of monocytes as well as serum levels of nonmyeloma IgA and IgM as compared to patients on conv-CTX without additional thalidomide. Following high-dose chemotherapy (HD-CTX) prolonged immunosuppression was observed. While CD8+, NK, CD19+, and CD4+/CD45RO+ cells recovered to normal values within 60, 90, 360, and 720 days, respectively, CD4+ counts remaining reduced even thereafter. Nine opportunistic infections were observed including 5 cytomegalovirus (CMV) diseases, 1 pneumocystis carinii pneumonia (PCP), and 3 varicella zoster virus (VZV) infections with CMV diseases and PCP occurring exclusively after HD-CTX. Opportunistic infections were correlated with severely reduced CD4+ as well as CD4+/CD45RO+, and CD19+ counts. Thus, myeloma patients display cellular and humoral immunodeficiencies, which increase following conv- as well as HD-CTX and constitute an important predisposing factor for opportunistic infections.