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2026 Background: The prognostic impact of MD in PCNSL is still debated. Within the framework of a multicenter randomized trial (G-PCNSL-SG1) we evaluated patients for outcome according to the prese...

Ischemic stroke is a serious disease leading to significant morbidity and mortality. Multifocal and recurrent strokes are usually caused by embolic diseases, i.e. atrial fibrillation, but rare causes like cerebral vasculitis and clotting disorders are also well known. Here we report on two patients suffering from the very rare intravascular large B-cell lymphoma leading to multifocal and recurrent strokes in the brain and spinal cord as the prominent neurological symptom. The difficulties and the need for diagnostic brain biopsy in making an ‘in vivo’ diagnosis in this particular disease are outlined. Furthermore, the prerequisite for an interdisciplinary approach in these patients is strongly emphasized. Delayed diagnosis for several reasons was the most probable cause for cerebral relapse leading to death in one patient a few months after diagnosis. Conversely, early initiation of immunochemotherapy with a classical lymphoma schedule (R-CHOP) led to long-lasting remission of the disease in the other patient. With this report we like to improve alertness to intravascular large B-cell lymphoma as a cause for multifocal and recurrent strokes.

Large granular lymphocyte leukaemia (LGL) is a rare lymphoproliferative T-cell disorder characterised by abnormal CD3?CD8?CD57? lymphocyte infiltration of blood, bone marrow, spleen and liver [3]. It is associated with autoimmune diseases like rheumatoid arthritis (RA) and immune-mediated cytopenias. However, the clinical course is mostly indolent [4]. Treatment is indicated, if patients suffer from symptomatic anaemia, neutropenia or RA. Due to the rarity of the disease therapy remains nonstandardised. Mostly, immunosuppressants like low-dose methotrexate and cyclophosphamide are recommended [4]. Leptomeningeal or CNS involvement of LGL has never been reported in the literature so far. A 63-year-old man with LGL diagnosed 5 years ago suffered from progressive auditory loss until complete deafness since 2 years. Strong visual impairment of the right eye was also noticed at that time. He was intermittently treated for neutropenia with corticosteroids, cyclosporine and cyclophosphamide. On admission, he presented with progressive visual loss of the left eye. No symptoms or clinical signs of the spinal cord were present. Laboratory work-up disclosed anaemia (haemoglobin 83 g/l), but normal leucocytes and thrombocytes. The MRI of the brain showed predominant dural contrast enhancement with no further structural abnormalities (Fig. 1a, b). CSF examination including immunophenotyping revealed T-cell pleocytosis (204 cells/ll; 96 % lymphocytes with characteristic granulation). A clonal rearrangement of the T-cell receptor gamma of the cells derived from the CSF confirmed leptomeningeal LGL infiltration. In the absence of an established therapeutic option with regard to the CNS manifestation the patient underwent cerebral irradiation to a cumulative dose of 30 Gray in 10 fractions. Intrathecal chemotherapy was rejected as the CSF compartment of the optical nerve sheath was found to be less accessible by this treatment modality. Symptoms partially resolved after whole brain radiotherapy and the patient was prevented from becoming blind. After 1 year of follow-up the patient clinically relapsed but was successfully treated with intrathecal liposomal cytarabine for 9 months. Afterwards, treatment was stopped according to further neurological deterioration. 33 months after diagnosis of leptomeningeal manifestation of LGL the patient is still alive, but suffers from progressive neurological symptoms. He is currently treated with best supportive care. T. Hundsberger (&) Department of Neurology, Cantonal Hospital, Rorschacherstr. 95, 9007 St. Gallen, Switzerland e-mail: thomas.hundsberger@kssg.ch

Summary Background High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. Methods Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age ( vs ≥60 years) and institution (Berlin vs Tubingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m 2 ) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m 2 ) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. Findings 551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8–39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5–46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6–25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3–16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). Interpretation No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors. Funding German Cancer Aid.

We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in Pompe disease is moderately effective and a life-long therapy is warranted. Clinical investigations of temporary ERT interruption are lacking, but might be of clinical signifi cance (i.e. due to patient’s wish, adherence issues, holidays, or problems with drug supply). In Switzerland, ERT for Pompe disease was interrupted after the federal court judged that the treatment costs for adults were greatly out of proportion. Retreatment was initiated after therapy was fi nally licensed.

Purpose To evaluate toxicity and efficacy of the combination of lomustine, temozolomide (TMZ) and involved-field radiotherapy in patients with newly diagnosed glioblastoma (GBM). Patients and Methods Thirty-one adult patients (median Karnofsky performance score 90; median age, 51 years) accrued in two centers received involved-field radiotherapy (60 Gy in 2-Gy fractions) and chemotherapy with lomustine 100 mg/m2 (day 1) and TMZ 100 mg/m2/d (days 2 to 6) with individual dose adjustments according to hematologic toxicity. Results A median of five courses (range, one to six courses) were delivered. WHO grade 4 hematotoxicity was observed in five patients (16%) and one of these patients died as a result of septicemia. Nonhematologic toxicity included one patient with WHO grade 4 drug-induced hepatitis (leading to discontinuation of lomustine and TMZ) and one patient with WHO grade 2 lung fibrosis (leading to discontinuation of lomustine). The progression-free survival (PFS) rate at 6 months was 61.3%. The median PFS was 9 months (95% CI, 5.3 to 11.7 months), the median overall survival time (MST) was 22.6 months (95% CI, 12.5 to not assessable), the 2-year survival rate was 44.7%. O6-Methylguanine–DNA methyltransferase (MGMT) gene-promoter methylation in the tumor tissue was associated with longer PFS (P = .014, log-rank test) and MST (P = .037). Conclusion The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a major determinant of methylating anticancer drug resistance. Inactivation of MGMT by pseudosubstrate inhibitors, such as O(6)-benzylguanine (O(6)BG), sensitizes tumor cells to O(6)-alkylating agents. However, systemic administration of O(6)BG causes depletion of MGMT in all tissues of the body. Therefore, dose reduction of O(6)-alkylating drugs administered together with O(6)BG is required in order to avoid unwished toxic side effects. To attenuate the increased systemic toxicity caused by MGMT inhibitors, local MGMT inactivation would be desirable. Here, we report on intracerebral treatment with O(6)BG of a patient suffering from glioblastoma. O(6)BG was administered weekly in the tumor cavity by means of an Ommaya reservoir. This application was well tolerated. Concomitant treatment with temozolomide (Temodal) was associated with transient tumor stabilization without detectable side effects. Although evidence is still lacking that local O(6)BG administration caused MGMT to be depleted in the residual tumor, the trial shows that intracerebral treatment with O(6)BG is feasible. It might be a safe strategy for improving glioma therapy by treatment with temozolomide (and presumably also other O(6)-alkylating drugs) concomitant with O(6)BG without augmenting drug-induced systemic side effects.

Background There is only limited data on improvements of critical medical care is resulting in a better outcome of comatose survivors of cardiopulmonary resuscitation (CPR) with generalized myoclonus. There is also a paucity of data on the temporal dynamics of electroenephalographic (EEG) abnormalities in these patients. Methods Serial EEG examinations were done in 50 comatose survivors of CPR with generalized myoclonus seen over an 8 years period. Results Generalized myoclonus occurred within 24 hours after CPR. It was associated with burst-suppression EEG (n = 42), continuous generalized epileptiform discharges (n = 5), alpha-coma-EEG (n = 52), and low amplitude (10 μV Conclusion Generalized myoclonus in comatose survivors of CPR still implies a poor outcome despite advances in critical care medicine. Anticonvulsive drugs are usually ineffective. All postanoxic EEG-patterns are transient and followed by a variety of EEG sequences composed of different EEG patterns, each of which is recognized as an unfavourable sign. Different EEG-patterns in anoxic encephalopathy may reflect different forms of neocortical dysfunction, which occur at different stages of a dynamic process finally leading to severe neuronal loss.

8527 Background: The role of whole brain radiotherapy (WBRT) in first-line therapy of primary CNS lymphoma (PCNSL) has been increasingly questioned. This is the final report of the G-PCNSL-SG-1 tri...

Leptomeningeal carcinomatosis is a serious complication of advanced cancer. Various clinical manifestations may present, such as headache, nausea, seizures, cranial neuropathies. In this article, we report the case of a 65-year-old woman with metastatic breast cancer who was admitted to hospital suffering from facial palsy, which was suspected to be caused by leptomeningeal tumor infiltration. Magnetic resonance imaging (MRI) scans of the head and spine showed meningeal enhancement of the facial nerve, conus medullaris, and fibers of the cauda equina, which were radiologically interpreted as leptomeningeal carcinomatosis. Assessment of cerebrospinal fluid found no malignant cells but investigation for infectious diseases established the diagnosis of neuroborreliosis. Antibiotic treatment with doxycycline was performed. After completion of treatment, follow-up MRI scans found complete regression of meningeal enhancement. Several months later, the patient is still in good condition and without neurological symptoms. Hence, initial diagnosis of leptomeningeal carcinomatosis was rejected. This case report should alert oncologists to carefully rule out infectious diseases before leptomeningeal carcinomatosis is diagnosed. Cerebrospinal fluid analysis is strongly recommended due to low specificity of MRI images in this regard.

To analyse the transcription pattern of the five tcdA-E genes of the pathogenicity locus (PaLoc) of Clostridium difficile a protocol was established to purify RNA from strain VPI10463. Transcription analysis of the five tcdA-E genes showed that they were all transcribed. In the early exponential phase, a high level of tcdC and low levels of tcdA,B,D,E transcripts were detectable; this was inverted in the stationary phase, suggesting that TcdC might have a negative influence on transcription of the other genes. Three transcription initiation sites, one for tcdA and two for tcdB were determined by primer extension analysis. Readthrough transcripts from outside the locus were not obtainable, so that parts of the transcription of tcdD, tcdB, tcdA and tcdC must occur by monocistronic transcription. Within the locus all possible intergenic readthrough transcripts were detectable except that between tcdC and tcdA, a stretch of DNA interrupted by a functional transcription terminator. Thus we found mono- and polycistronic transcription of tcdA and tcdB to occur which should lead to production of a surplus of tcdA over tcdB transcripts. This would explain the surplus of TcdA over TcdB expression observed in vitro. Due to its basic nature and similarity to BcnA of Clostridium perfringens and to Orf-22 of Clostridium botulinum, TcdD is most probably a regulatory protein with DNA-binding properties. On the basis of the presented study we discuss a model for the growth-phase-related, coordinate regulation of toxin expression wherein tcdC has a negative and tcdD a positive regulatory function on transcription of the tcdD,B,E and tcdA genes.

We determined the nucleotide sequence 3.8 kb upstream and 5.2 kb downstream of the toxin genes A and B of Clostridium difficile. Nine ORFs were discovered. Based on PCR-directed approaches, two were attributed to the pathogenicity locus (PaLoc). The other seven were found in every C. difficile isolate obtained from the human gastrointestinal tract, respectless of their toxinogenicity. The ORFs cdu1 and cdu2/2' upstream of the PaLoc displayed similarity to repressors of Gram-positive bacteria (cdu1), and to an Na+/H+ antiporter described for Enterococcus hirae (cdu2/2'). Downstream of the locus a putative ABC transporter (cdd2-4) was identified. With a set of three paired primers used in polymerase chain reactions we succeeded in delineating the PaLoc. Sequencing of the appropriate stretch of DNA in C. difficile VPI10463 and four additional toxinogenic strains proved a high conservation of the borders of the PaLoc in all these strains. Our data define the locus as a distinct genetic element. Comparing the sequences of five toxinogenic and five non-toxinogenic strains the integration site of the PaLoc was defined. This showed that a stretch of 115 bp found in non-toxinogenic strains is replaced by the 19-kb locus in toxinogenic strains. Analysis of the boundary sequences showed that the locus is obviously not a mobile genetic element by itself. Instead we propose that it is the independent pathogenic part of a more extended genetic element associated with virulence. The 115 bp of non-toxinogenic strains replaced by the locus in toxinogenic strains carry the putative transcription terminator of the cdu1, a predicted repressor protein. A possible polar effect of the loss of this terminator on transcription of the TcdABCDE genes is discussed. Such an effect would explain the unidirectional insertion of the PaLoc at a single site of the C. difficile genome and might give a rationale for the development of the disease which is induced after antibiotical treatment.

Mit der Einfuhrung von Makrolid-Antibiotika wie Clindamycin traten vermehrt schwere Darmerkrankungen auf [4, 5], die sich zunachst in Form von Durchfallen und im weiteren Verlauf als mitunter todliche pseudomembranose Kolitis (PMC) auserten. Der scheinbare Zusammenhang gab der Erkrankung zunachst den Namen „Clindamycin-assoziierter Durchfall“, heute weis man, das neben Zytostatikatherapie [1] und grosen bauchchirurgischen Eingriffen [52] nahezu alle in der Klinik eingesetzten Antibiotika das Krankheitsbild auslosen konnen [31]. Ende der 70er Jahre wurde im Stuhl erkrankter Patienten eine zytotoxische Aktivitat entdeckt [4], von der man zunachst annahm, es handle sich um ein Virus, das auf Zellen aufgebracht zu dem zu beobachtenden zytopathischen Effekt fuhre. Erst als Antiseren gegen clostridiale Toxine eingesetzt wurden, entdeckte man die Ursache, die im Stuhl enthaltenen Toxine [43, 59]. Scit 1979 ist bekannt, das toxinbildende C. difficile Isolate die Erkrankung auslosen [6,32].

2004 Background: The purpose of this study was to establish prognostic factors in newly diagnosed primary central nervous system lymphoma (PCNSL) in immunocompetent patients. Methods: Four-hundred ...

2005 Background: Acute chemotherapy-associated toxicity is an important issue in PCNSL since these patients are usually of advanced age, in impaired clinical condition, and often suffer from comorb...

13018 Background: There is no established standard chemotherapy for recurrent glioblastoma (GBM). In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated GBM. After temozolomide has been established as the standard for primary therapy of GBM, nimustin and teniposide is now been used as a second or third line chemotherapy for recurrent GBM. However, there are no data on toxicity and efficacy of this regimen in recurrent GBM. Methods: In two neurooncological centers, all patients with recurrent glioblastoma who had received nimustine (90 mg/m2, day 1/42) and tenoposide (45–60 mg/m2, days 1–3/42) chemotherapy were analyzed retrospectively for progression-free survival, overall survival and toxicity. Results: Thirty-five patients, median age 51 years (range 25–71), all of them pretreated with temozolomide were identified. The rate of progression-free patients at 6 months after initiation of therapy was 29%. The median overall survival after initiation ...

1566 Background: Primary chemotherapy with single agent temozolomide or nitrosourea-based chemotherapy in addition to radiotherapy prolongs survival in patients with glioblastoma. Previous studies ...

To the Editor: Vertebral artery (VA) dissection is a well-known cause of vertebrobasilar ischemia in young people and may be due to preceding chiropractic maneuvers, cystic medial necrosis, mucopolysaccharidosis and reticular fiber diseases, vasculitis,1 2 or a yet-unknown arteriopathy.3 Common findings in VA dissection are unilateral or bilateral neck pain associated with cerebellar and brain stem (usually medullary) infarctions,2 3 which are rarely associated with clinical signs of spinal cord lesions.4 5 6 Recently, 1 patient each was described with bilateral spinal cord infarction7 and Brown-Sequard’s syndrome8 as the sole manifestation of spontaneous unilateral VA dissection. We add another patient with spontaneous bilateral VA dissection causing MRI-documented bilateral cervical cord infarction without clinical, electrophysiological, or radiological signs …

Zusammenfassung Hintergrund Der Morbus Pompe ist eine lysosomale Multisystemerkrankung mit prädominanter Myopathie, für die eine Enzymersatztherapie (EET) mit rekombinanter α-Glucosidase verfügbar ist. Diese muss aktuell zweiwöchentlich lebenslang erfolgen. Um die Belastung durch diese Behandlungsform gering zu halten, besteht bei vielen Betroffenen der Wunsch, die EET zu Hause als sog. Heiminfusionstherapie durchzuführen. Ziele und Methoden Im Rahmen zweier Deutsch-Österreichisch-Schweizerischer Konsensus-Expertentreffen in den Jahren 2019 und 2020 wurde diskutiert, welche Voraussetzungen gegeben sein müssen, damit eine Heiminfusionstherapie medizinisch vertretbar erfolgen kann, wie diese sachgemäß durchzuführen ist und wie die Rechtslage für delegierende Ärzte aussieht. Ergebnisse und Diskussion Prinzipiell ist bei Patienten mit Morbus Pompe eine Heiminfusionstherapie möglich, wenn bestimmte Voraussetzungen erfüllt sind. Die Entscheidung muss für jeden Patienten individuell getroffen werden. Der behandelnde Arzt delegiert die Durchführung der Heiminfusionstherapie ad personam an eine Pflegekraft. Die Endverantwortung für die korrekte Durchführung der EET verbleibt aber beim Arzt. Die Heiminfusionstherapie muss durch speziell geschultes Pflegepersonal erfolgen. Hauptrisiko ist das Auftreten allergischer Reaktionen. Deren adäquate Erstbehandlung muss ebenso sichergestellt sein wie die Verfügbarkeit einer notfallmedizinischen Versorgung. Um die psychosoziale Belastung von Patienten mit Morbus Pompe in deutschsprachigen Ländern zu minimieren und delegierenden Ärzten größere Rechtssicherheit zu geben, sind klarere Regelungen für die Durchführung einer Heiminfusionstherapie wünschenswert.