Analysis of the impact of adherence to guidelines and expert advice in patients with myelodysplastic syndromes.

The European Leukemia Net (ELN) guidelines for treatment of myelodysplastic syndromes (MDS) connect heterogeneous MDS subgroups with a number of therapeutic options ranging from best supportive care to allogeneic stem cell transplantation (alloSCT). However, it is currently unknown whether adherence to guideline recommendations translates into improved survival. The sizeable database of the Duesseldorf MDS Registry allowed us to address this question. We first performed a retrospective analysis including 1698 patients (cohort 1) to whom we retrospectively applied the ELN guidelines. We compared patients treated according to the guidelines with patients who deviated from it, either because they received a certain treatment though it was not recommended or because they did not receive that treatment despite being eligible. We also performed a prospective study with 381 patients (cohort 2) who were seen in our department and received guideline-based expert advice. Again, we compared the impact of subsequent guideline-adherent versus non-adherent treatment. For the majority of treatment options (best supportive care, lenalidomide, hypomethylating agents, low-dose chemotherapy, and intensive chemotherapy), we found that adherence to the ELN guidelines did not improve survival in cohort 1. The same was true when patient management was prospectively enhanced through guideline-based treatment advice given by MDS experts (cohort 2). The only exceptions were alloSCT and iron chelation (ICT). Patients receiving ICT and alloSCT as recommended fared significantly better than those who were eligible but received other treatment. Our analysis underscores the limited survival impact of most MDS therapies and suggests to pursue alloSCT in all suitable candidates. Graphical abstract.

CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients.

BACKGROUND: Blood-based biomarkers may be particularly useful for patient selection and prediction of treatment response for angiogenesis inhibitors. Circulating endothelial cells (CECs) and haematopoietic progenitor cells (HPCs) might have a role in tumour angiogenesis and in tumour growth. Measurement of CECs and HPCs in the blood of patients could be a simple, non-invasive way to monitor or predict responses to treatment. METHODS: (VEGFR2(+)) CECs(,) (CD133(+)) HPCs, plasma vascular endothelial growth factor (VEGF) and erythropoietin were measured in blood from 25 non-small cell lung cancer (NSCLC) patients before and during treatment with sorafenib plus erlotinib (SO/ER). In order to assess the drug specificity of changes in CECs and HPCs, 18 patients treated with bevacizumab plus erlotinib (BV/ER) and 10 patients with erlotinib (ER) monotherapy were studied. Response was measured in all patient groups by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: At day 7, SO/ER-treated patients showed a three-fold increase in CECs (P<0.0001) comparable to BV/ER-treated patients (P<0.01), and the CECs did not change with erlotinib treatment (P=0.8). At day 7, CD133(+)/HPCs decreased with SO/ER treatment (P<0.0001). HPC numbers did not change with either BV/ER or erlotinib. In SO/ER-treated patients pre-treatment CD133(+)/HPCs were significantly lower in responders (P=0.01) and pre-treatment CD133(+)/HPC numbers lower than the median correlated with a longer time-to-progression (TTP) (P=0.037). CONCLUSION: Pre-treatment CD133(+)/HPCs are a promising candidate biomarker to further explore for use in selecting NSCLC patients who might benefit from SO/ER treatment.

Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia.

The fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) can be found in about one quarter of patients with acute myeloid leukemia (AML) [Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematology. Educ. Program 2006;178-84 [Review]]. Patients who carry this mutation have a high risk of relapse even after allogeneic stem cell transplantation [Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J 2003;4:41-6; Meshinchi S, Arceci RJ, Sanders JE, Smith FO, Woods WB, Radich JP, et al. Role of allogeneic stem cell transplantation in FLT3/ITD-positive AML. Blood 2006;108(1):400-1]. Recent reports show that Sorafenib, a multikinase inhibitor has significant activity against FLT3-ITD(+) blasts in vitro [Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y, et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007;21(3):439-45]. We here report the first clinical case of molecular remission induced by Sorafenib in a patient with FLT3-ITD(+) AML and extramedullary disease after allogenic stem cell transplantation.

Bringing unresectable liver disease to resection with curative intent.

The majority of patients with colorectal liver metastases presents with unresectable disease. Without resection, the prognosis for these patients is extremely poor. The technical inability to completely remove all metastases while leaving at least 30% of remnant normal functioning liver parenchyma is nowadays regarded as the only absolute contraindication to resection. Chemotherapy regimens containing combinations of 5-fluorouracil, leucovorin, oxaliplatin and/or irinotecan can provide significant downstaging of liver disease enabling curative rescue resection and resulting in improved long-term survival. The addition of cetuximab and bevacizumab may result in higher resectability rates that may offer curative surgery in a larger amount of patients. In addition, different surgical techniques like portal vein embolization, two-stage hepatectomy and local ablation are available to achieve a resectable situation. Due to vascular exclusion and reconstruction techniques, tumoral involvement of the hepatic veins and inferior vena cava no longer limits the indication of resection. Overall, surgery should be performed as soon as liver metastases become resectable. Collaboration between oncologists and surgeons is essential to optimize individual therapeutic strategies.

[Better treatment for patients with colorectal liver metastases]. / Betere behandelingsmogelijkheden voor patiënten met colorectale levermetastasen.

Three patients, 61, 58 and 63 years old, presented with non-resectable liver metastases from colorectal cancer. The first patient, a man, who had a solitary lesion in the liver and severe cardiovascular morbidity, was successfully treated with laser-induced interstitial thermotherapy. The second patient, a woman, had large multiple liver metastases and two concomitant isolated pulmonary metastases. Following chemotherapy with fluorouracil, leucovorin and oxaliplatin, all lesions were downsized and a hemihepatectomy and pulmonary wedge resections were able to be performed in two stages. At the last follow-up, both patients were disease-free after 12 and 24 months respectively. The third patient, a man, presenting with multiple synchronous liver metastases, showed a significant decrease of hepatic tumour involvement after six courses of capecitabine. At present he is in a good condition and his disease is stable. Surgical resection ofcolorectal liver metastases leads to a 5-year survival rate of up to 45% in selected patients. Unfortunately, only 10 to 20% of patients are amenable to surgical resection. In the remaining group, a combination of new treatment options using local tumour ablative therapies and novel chemotherapeutic regimens provide alternative strategies with the potential of long-term survival.

[Supratentorial primitive neuroectodermal tumor: a single center experience and comparison with the literature]. / Supratentorieller primitiver neuroektodermaler Tumor: Erfahrungen in einem Zentrum im Vergleich zur Literatur.

Supratentorial primitive neuroectodermal tumors (stPNETs) are malignant tumors. We saw within three years six children with stPNETs. In four of the six children radical resection could be achieved. All had craniospinal irradiation and chemotherapy according to the HIT-91 protocol. The two children with incomplete resection died due to tumor progression after 7 and 10 months. Two of the 4 children with complete tumor resection had local relapses 8 months after diagnosis and died after 14 and 18 months. One child had a diffuse meningeal relapse 12 months after diagnosis. Despite (high-dose) systemic chemotherapy and intraventricular mafosfamide, he died 21 months after diagnosis due to tumor although remission could be achieved. Only one child is still in remission 86 months after diagnosis.

Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a disease mostly confined to the thoracic cavity. Untreated, the median survival is <1 year. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy is used to kill residual tumor cells on the surface of the thoracic cavity while having limited systemic side effects. METHODS: From August 1998 to August 2001, 22 patients with stage I MPM were included in this study. Two patients were irresectable at operation because of extrathoracic tumor growth. Twenty procedures were performed. After cytoreduction, a perfusion was performed with cisplatin and doxorubicin at 40 degrees C to 41 degrees C for 90 minutes. Adjuvant radiotherapy was given to surgical scars and drainage tracts. RESULTS: There was no perioperative mortality, but significant morbidity was seen in 13 patients (65%), including bronchopleural fistula, diaphragm rupture, wound dehiscence, persistent air leakage, and chylous effusion. No hair loss or leucopenia was noticed. The median follow-up was 14 months. The median survival (Kaplan-Meier) was 11 months, with a 1-year survival of 42%. A favorable pharmacokinetic ratio was observed for both cisplatin and doxorubicin. CONCLUSIONS: Cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy for stage I MPM is feasible. However, this treatment is accompanied by considerable morbidity. Survival data were less encouraging.

Sequential deletion of C-terminal amino acids of the E(1)alpha component of the pyruvate dehydrogenase (PDH) complex leads to reduced steady-state levels of functional E(1)alpha(2)beta(2) tetramers: implications for patients with PDH deficiency.

Human pyruvate dehydrogenase (PDH) complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. We have characterized novel mutations that affect the C-terminal portion of the PDH-E(1)alpha-coding sequence. Although the molecular defects underlying these mutations are different, both effectively produce a stop codon prematurely three amino acids from the C-terminus. The clinical and biochemical consequences of these mutations are unusual in that the affected individuals are very long-term survivors with PDH complex deficiency despite having low (<20%) activity in skin fibroblasts. These findings prompted us to investigate the C-terminus of E(1)alpha in greater detail. We constructed and expressed a series of PDH-E(1)alpha deletion mutants in a cell line with zero PDH complex activity due to a null E(1)alpha allele. Sequential deletion of the C-terminus by one, two, three and four amino acids resulted in PDH complex activities of 100, 60, 36 and 14%, respectively, compared with wild-type E(1)alpha expressed in PDH complex-deficient cells. The immunodetectable protein was decreased by the same amount as the activity, suggesting that the stability and/or assembly of the E(1)alpha(2)beta(2)heterotetramer might depend on the intactness of the PDH-E(1)alpha C-terminus. In addition, we compared the somatic and the testis-specific isoforms of E(1)alphaand concluded that they are biochemically equivalent.

Ceftazidime in combination with glycopeptide antibiotic is an effective first-line therapy for patients undergoing high-dose therapy with autologous peripheral blood stem cell support.

It was the objective of this study to evaluate the efficacy and toxicity of an empirical antibiotic therapy consisting in ceftazidime and a glycopeptide antibiotic. All patients enrolled in the study had hematological malignancies and underwent high-dose therapy with peripheral blood stem cell (PBSC) support. In this retrospective study, 183 of 207 patients who had received a PBSC-supported high-dose therapy were evaluable. Any patients who had fever higher than 38.5 degrees C received ceftazidime in combination with vancomycin (105 patients) or teicoplanin (69 patients). In 80 of 174 patients with fever (45%) the fever resolved within 72 h as a result of the treatment with ceftazidime and the glycopeptide antibiotic. In nonresponding patients, the changes included the replacement of ceftazidime by imipenem/cilastin (94 patients) and the addition of erythromycin (12 patients) or metronidazole (3 patients). Amphotericin B was administered in 29 patients. Following hematological reconstitution, the fever and clinical signs, including radiographic findings, resolved in 20 primarily nonresponding patients. In blood cultures, a significantly higher incidence of gram-positive than of gram-negative bacteria was observed (26 vs 7). The toxicity of the first-line antibiotic therapy was limited to allergic skin reactions in 12 patients. Ceftazidime in combination with a glycopeptide antibiotic provides an effective and safe first-line therapy for patients with neutropenic fever following PBSC-supported high-dose therapy.

Endocrine function and bone metabolism 5 years after autologous bone marrow/blood-derived progenitor cell transplantation.

BACKGROUND: High dose chemotherapy with or without total body irradiation supported by autologous transplantation of hematopoietic progenitor cells is increasingly being used for hematologic and solid tumors. However, there is only limited information available on late toxicity. METHODS: The authors investigated endocrine function and bone metabolism in 29 patients with a median interval of 5 years after autografting. RESULTS: In accordance with an earlier report on this patient cohort, ovarian failure was observed to be unchanged, except for one woman with recovered ovarian function who gave birth to two healthy children. In two-thirds of the men, follicle-stimulating hormone levels were elevated, suggesting germinal aplasia. Determination of bone mineral density did not reveal osteopenia, despite several risk factors: prolonged immobilization, high dose corticosteroid treatment, and, in women, transient estrogen insufficiency. Frequent impairment of thyroid function has been reported in patients receiving single dose total body irradiation. Overt or subclinical hypothyroidism was not detected, most likely because the total body irradiation was hyperfractionated. CONCLUSIONS: With the exception of gonadal failure, no significant late effects on endocrine function or bone metabolism were observed in this patient cohort.

Granulocytes harvested following G-CSF-enhanced leukocyte recovery retain their functional capacity during in vitro culture for 72 hours.

The purpose of this study was to compare two different in vitro culture conditions for the preservation of human granulocytes. These cells could be used in patients with severe neutropenia following cytotoxic chemotherapy if the functional capacity was retained, and autologous transfusions of granulocytes would circumvent the risk of alloimmunization. Granulocytes were obtained from the peripheral blood of healthy donors and patients with hematologic malignancies who received cytotoxic chemotherapy supported by recombinant human granulocyte colony-stimulating factor (R-metHuG-CSF, 300 micrograms/day, s.c.). Granulocytes were either cultured for 72 h at 4 degrees C in the presence of 100 ng/ml G-CSF or cryopreserved at -196 degrees C. The viability, surface antigen expression, and function of the granulocytes were assessed. Since effective microbial killing involves the attachment of granulocytes to blood vessel walls, transmigration into tissues, chemotaxis, and phagocytosis, the surface expression of the adhesion molecules LFA-1 (CD11a/CD18) and gp 150,95 (CD11c/CD18) was measured. In addition, the IgG receptors Fc gamma RI (CD64), Fc gamma RII (CD32), and Fc gamma RIII (CD16), as well as the complement receptor CR3 (CD11b/CD18), were assessed. Dynamic superoxide anion release served as a measure of the metabolic pathway of the oxidative burst after f-Met-Leu-Phe (fMLP) and phorbol-12-myristate-13-acetate (PMA) stimulation. Substantial differences in the preservation of granulocyte integrity and function were observed between the two storage conditions. Cryopreservation abolished reactivity to extracellular stimuli and severely affected the cell phenotype. On the other hand, functional activity could be maintained for up to 72 h when in vivo primed granulocytes of patients were incubated at 4 degrees C in the presence of G-CSF. This storage modality may permit the use of granulocyte autotransfusion to reduce the risk of neutropenic fever.

Glycoinositol phospholipid anchor and protein C-terminus of bovine erythrocyte acetylcholinesterase: analysis by mass spectrometry and by protein and DNA sequencing.

Purified bovine erythrocyte acetylcholinesterase (AChE) was radiomethylated on its amine groups and incubated with bacterial phosphatidylinositol-specific phospholipase C to remove the lipid portion of the AChE glycoinositol phospholipid (GPI) anchor, and a C-terminal tryptic fragment that contained the residual GPI glycan was isolated by HPLC. Analysis by electrospray-ionization mass spectrometry revealed a parent ion of m/z 3798. The fragmentation patterns produced by collision-induced dissociation mass spectrometry of the +4 and +5 states of the parent ion indicated a 23-amino acid peptide in amide linkage to ethanolamine-P04-Hex-Hex-Hex(PO4-ethanolamine)(HexNAc)-Hex N(Me)2-inositol phosphate. The glycan structure is completely consistent with that obtained previously for the GPI anchor of human erythrocyte AChE except for the addition of the HexNAc substituent. A nearly complete peptide sequence was deduced from the fragmentation patterns, although four assignments were based only on single fragments of very low abundance. To resolve this uncertainty, a segment of bovine genomic DNA corresponding to the C-terminal AChE sequence was amplified by PCR. DNA sequencing established the 23-amino acid peptide sequence to be FLPKLLSATASEAPCTCSGPAHG, in agreement with the MS data and consistent with results from Edman protein sequencing. Dimerization of AChE polypeptides is mediated by intersubunit disulphide bonding in this C-terminal segment, but the bovine AChE contained two cysteine residues in a ...CTC... motif, in contrast with human AChE which contains only a single cysteine in this segment. Although bovine AChE contained no free thiol groups reactive with iodo[14C]acetamide, partial reduction and alkylation with iodo[14C]acetamide revealed that conversion into monomers occurred with an overall incorporation of only one alkyl group per monomer. An identical level of alkylation was observed when dimeric human AChE was converted into monomers by partial reduction. The question of whether the bovine AChE contains one or two intersubunit disulphide linkages is considered.

Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions.

Propionic acidemia is a rare genetic disorder of amino acid metabolism caused by deficient activity of propionyl coenzyme A carboxylase. Neuropathologic changes previously reported in infants have been white-matter vacuolization or spongiosis. In children who survive beyond infancy, abnormalities have been found primarily in the basal ganglia. We report neuropathologic findings in two patients with propionic acidemia diagnosed in infancy who survived 35 months and 9 years, respectively. Examination of the brain of the 35-month-old boy showed vascular and parenchymal mineralization, focal pallor and spongy change, and foci of acute neuronal injury. These changes were similar to those previously described. The 9-year-old girl was in good metabolic control when she died, and presented a neuropathologic picture not previously described. She was found at autopsy to have acute hemorrhagic lesions in the caudate, putamen, and globus pallidus bilaterally and in the left ventral thalamus. There was focal neuronal loss, but no acute hypoxic/ischemic neuronal injury. Vascular proliferation and swollen endothelial cells were seen in the basal ganglia, thalamus, and substantia nigra, but not in other regions of the brain. Electron microscopy showed swelling of endothelial cells with viable adjacent brain parenchyma. The endothelial changes suggest a breakdown of the blood-brain barrier.

Anti-inflammatory and wound healing activity of a growth substance in Aloe vera.

Aloe vera improves wound healing and inhibits inflammation. Since mannose-6-phosphate is the major sugar in the Aloe gel, the authors examined the possibility of its being an active growth substance. Mice receiving 300 mg/kg of mannose-6-phosphate had improved wound healing over saline controls. This dose also had anti-inflammatory activity. The function of mannose-6-phosphate in A. vera is discussed.

[Regional hyperthermia with systemic chemotherapy in children and adolescents: feasibility and clinical follow-up of 34 intensively pretreated patients with prognostically unfavorable tumor diseases]. / Regionale Hyperthermie mit systemischer Chemotherapie bei Kindern und Jugendlichen: Durchführbarkeit und klinische Verläufe bei 34 intensiv vorbehandelten Patienten mit prognostisch ungünstigen Tumorerkrankungen.

Temperature elevation for a few degrees (degrees C) increases significantly the cytotoxicity of several antineoplastic drugs under experimental conditions. An isolated elevation of the tumour temperature, which is possible since a few years, might be able to improve local tumour control without increasing the systemic toxicity. This study was performed to examine the feasibility of regional hyperthermia with systemic chemotherapy in pediatric patients. The special interests were the level of temperatures that could be achieved as well as the degree of toxicity and undesired side effects. Furthermore there was some hope to attain local tumour control in cases with very poor prognosis. 34 patients up to 18 years were treated in Munich and Essen until the end of 1992. 21 suffered of local relapse, in 11 cases it was the 2nd up to the 7th relapse. In another 11 cases the indication for the combined treatment was tumour progress or non-response to previous therapy. 33 patients were pretreated by aggressive chemotherapy, 20 patients had received radiotherapy before. In 28 cases the tumour was located in the pelvis. The heating device that we use is commercially available. It is based on external electromagnetic radiation which induces heat by absorption within the tissue. Since the temperature distribution inside the tumours is very heterogeneous thermometry is necessary which can only be performed invasively. For this sake we use closed tip catheters which are inserted into the tumour by puncture or surgically. The catheters remain in place for the whole treatment duration of several weeks. Chemotherapy was performed in treatment cycles (3.4/patient) mainly using etoposide, ifosfamide, and carboplatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Can the magnesium content of mononuclear blood cells be altered by oral magnesium supplementation?

A randomized, double-blind, placebo-controlled trial was performed on a rigorously defined group of normal subjects to see if magnesium (Mg) supplementation could affect serum Mg levels or Mg content of mononuclear blood cells. Forty-nine subjects were randomized to either placebo, tablets containing 90% United States recommended daily allowance (USRDA) of Mg, or tablets containing 180% USRDA of Mg. We were unable to demonstrate a statistically significant increase in Mg content of mononuclear blood cells.

Carnitine reduces fasting ketogenesis in patients with disorders of propionate metabolism.

Patients with disorders of propionate metabolism have low plasma levels of free carnitine and excrete higher than normal quantities of esterified carnitine. The response to a 19 h fast was assessed as a physiological index of carnitine deficiency. In patients with propionic acidaemia and methylmalonic acidaemia a substantial ketogenesis developed in response to fasting. Supplementation with L-carnitine significantly reduced this ketogenic response.

[Anti-thymocyte globulin therapy in severe aplastic anemia: an alternative to bone marrow transplantation]. / Anti-Thymozyten-Globulin Therapie bei schwerer aplastischer Anämie: eine Alternative zur Knochenmarkstransplantation.

Eight patients with severe aplastic anemia (SAA) and two patients with congenital hypoplastic anemia (CHA) were treated with absorbed samples of rabbit anti-thymocyte globulin (ATG) at a total dose of 50-75 mg/kg body weight intravenously over 5 days. Duration of the disease was 1-14 years. Median age of the ten patients was 11 (4-15) years. Four of the eight patients with SAA were responders and transfusion independent for a follow up of 11 to 50 months. In two cases thrombocytopenia of about 100 000/mm3 is present. Four patients were non-responders three of them died in the meantime by the underlining disease. Two patients with CHA did not respond to ATG treatment. The CFU-C level of all eight patients with SAA before treatment was severely decreased. In co-culture studies with normal bone marrow no growth inhibition of normal bone marrow could be demonstrated. Also 20% patients serum did not inhibit normal bone marrow growth. The results are compared with data from literature and discussed in respect to alternative therapies.