Rupert Engelhardt

Hematologic and molecular spontaneous remission following sepsis in acute monoblastic leukemia with translocation (9;11): a case report and review of the literature

Abstract:  Spontaneous remission in patients with acute myeloid leukemia (AML) is a rarely reported phenomenon of usually short duration. The etiology remains unclear, but an association with preceding blood transfusions or bacterial infections has been reported. Triggered immune responses are suggested to play a potential role in the development of spontaneous remission. Acute monocytic leukemia was diagnosed in a 61‐yr‐old male patient. Cytogenetic analysis revealed a sole translocation (9;11) (q22;q23) and RT‐PCR the MLL/AF9 fusion gene. As a result of the patients reduced performance status and septic condition, cytostatic therapy was withheld. No microorganisms could be detected. Hematologic and molecular remission occurred after initiating antibiotic therapy without any cytostatic treatment; 29 months after the initial diagnosis, he is in complete remission, and excellent physical condition. Our report includes a review of the literature since 1985, reporting cases of patients with AML and spontaneous remission together with informative cytogenetics. Balanced translocations such as in core binding factor (CBF) leukemias appear somewhat overrepresented. We speculate that AML‐specific T cells might be relevant for induction of spontaneous remission and need to be further investigated.

Myelodysplastic syndrome in transformation to acute myeloid leukemia presenting with diabetes insipidus: due to pituitary infiltration association with abnormalities of chromosomes 3 and 7

Abstract: A 31‐yr‐old woman with myelodysplastic syndrome (MDS) in transformation to acute myeloid leukemia (AML) presented with initial symptoms of polyuria and polydipsia. Cytogenetics revealed monosomy 7 and translocation (3;3)(q21;q26). The initial symptoms, in conjunction with a low serum level of anti‐diuretic hormone (ADH) and magnetic resonance imaging (MRI) findings demonstrating loss of the ‘bright spot’ of the neurohypophysis, indicated diabetes insipidus (DI), e.g. caused by leukemic infiltration of the neurohypophysis. After induction chemotherapy the patients bone marrow revealed blast persistence, and following a second course of chemotherapy and normalisation of MRI, an allogeneic peripheral blood stem cell transplantation (PBSCT) from the patients HLA‐identical brother was performed, resulting in ongoing complete remission. Recently, Lavabre‐Bertrand et al. reported an association of AML with DI, elevated platelet counts, and monosomy 7 and chromosome 3 abnormalities in three patients (Eur. J. Haematol. 2001: 66: 66–69). Our report of an MDS with trilineage dysplasia and these karyotypic changes associated with DI indicates that this new entity may also include preleukemic cases.

Hereditary deficiency of glucosephosphate isomerase as a cause of nonspherocytic hemolytic anemia

SummaryThe molecular heterogeneity of GPI deficiency is demonstrated. All variants studied are different from each other. The clinical picture is characterized by nonspherocytic hemolytic anemia.ZusammenfassungDie molekulare Heterogenität des Glucosephosphat-Isomerase-Mangels wird beschrieben. Alle untersuchten Varianten sind voneinander verschieden. Das klinische Bild ist durch eine nichtsphärozytäre hämolytische Anämie gekennzeichnet.

Effects of cytostatic drugs and 40.5°C hyperthermia on human clonogenic tumor cells

Abstract A tumor colony-forming assay was used to investigate the effect of 40.5° C hyperthermia and drugs on the colony-forming ability of human clonogenic tumor cells. In order to be able to perform repeated incubations with identical tumor material, specimens were used that were augmented in the nude mouse system. Five tumor samples (two malignant melanomas, two squamous cell carcinomas of the lung and one small cell carcinoma of the lung) were incubated with seven drugs: doxorubicin, actinomycin-D, bleomycin, melphalan, vincristine, vinblastin and cisplatinum. One additional tumor specimen (chondrosarcoma) was incubated with doxorubicin immediately after resection. The incubation with drugs at 37° C revealed dose response curves typical for each tumor. Incubation at 40.5° C for 2 hr showed enhanced drug effects in five out of the six tumors tested. The drugs, with an enhanced effect and the pattern of enhancement were different in each individual tumor.

Early-onset secondary malignancies after high-dose chemotherapy and autologous hematopoietic stem cell transplantation

Abstract We treated 500 patients with high-dose chemotherapy (HDC) and autologous bone marrow (ABMT) or autologous peripheral blood stem cell transplantation (PBSCT). Treated conditions included leukemia, lymphomas, breast cancer, lung cancer, germ-cell carcinomas, and other solid tumors. In order to assess relapse of primary malignancy or occurrence of new neoplasms, routine screening after ABMT or PBPCT was performed at regular and close intervals. With a total follow-up of 1358 person-years and a median follow-up of 34 months (range 9–91), 10/500 (2%) patients developed second malignancies after PBSCT or ABMT; i.e., one new cancer occurred every 136 person-years. All malignancies were detected at routine follow-up examinations; and 7/10 diagnoses were made in an asymptomatic phase; 6/10 neoplasms were amenable to complete surgical resection, five of which remain in CR at a median of 23+ months after autotransplantation. We conclude that regular and close follow-up examination of patients after autologous hematopoietic stem cell transplantation may be beneficial, since successful treatment of second malignancies is possible in selected cases after early detection.

Immune response as a possible mechanism of long-lasting disease control in spontaneous remission of MLL/AF9-positive acute myeloid leukemia

Spontaneous complete remission (CR) is a rare, poorly understood phenomenon in acute myeloid leukemia (AML). We describe the 10-year follow-up of a patient with MLL-AF9-positive AML (Müller et al. Eur J Haematol 73:62–66, 2004), including ex vivo antileukemic immune responses which may contribute to the long-lasting spontaneous CR (tantamount to cure). We could demonstrate strong in vitro cytotoxic activity mediated by the patient’s serum (cryopreserved at diagnosis 2001) against myeloid cell lines. We also addressed cellular cytotoxic activity against myeloid leukemia cells. When the patient’s natural killer (NK) cells (obtained in 2007) were tested against the K562 cell line, upregulation of CD107 occurred, implying that long-term CR in this patient could be due to NK cell-mediated disease control.

Gibt es die „Febrile Proteinurie“?

SummaryThe significance of proteinuria during febrile infectious diseases is widely underestimated, although the more marked proteinuria probably signalizes a parainfectious nephropathy rather than a functional disorder. This study shows that mild proteinuria of less than 0.65 g/24 h (normal range less than 0.3 g/24 h using the sensitive tannine-FeCl3-technique) might be caused by the elevated body temperature alone. 9 out of 18 volunteers without renal disease undergoing experimental hyperthermia of 40–41° C for 1–2 h did not develop a proteinuria according to quantitative and qualitative (SDS-PAGE) measurements. In 6/18 the amount and composition of urinary proteins changed giving a glomerular type of proteinuria, possibly caused by temperature related transient glomerular alterations. In 3/18 a mild glomerulopathy existed before hyperthermia, as deduced from a glomerular pattern despite a quantitatively physiological proteinuria, leading in all 3 to pathological proteinuria during hyperthermia. In all 18 volunteers alterations reversed to normal within 12 h.Therefore, the degree of proteinuria during febrile diseases should be considered. Proteinuria of less than 0.5–1 g/24 h in adults might be explained by an altered glomerular function alone. Proteinurias exceeding this value, with a slow regressing tendency will indicate glomerular or tubulo-interstitial diseases, caused possibly by immunologic or toxic products resulting from underlying infectious disease.The significance of proteinuria during febrile infectious diseases is widely underestimated, although the more marked proteinuria probably signalizes a parainfectious nephropathy rather than a functional disorder. This study shows that mild proteinuria of less than 0.65 g/24 h (normal range less than 0.3 g/24 h using the sensitive tannine-FeCl3-technique) might be caused by the elevated body temperature alone. 9 out of 18 volunteers without renal disease undergoing experimental hyperthermia of 40-41 degrees C for 1-2 h did not develop a proteinuria according to quantitative and qualitative (SDS-PAGE) measurements. In 6/18 the amount and composition of urinary proteins changed giving a glomerular type of proteinuria, possibly caused by temperature related transient glomerular alterations. In 3/18 a mild glomerulopathy existed before hyperthermia, as deduced from a glomerular pattern despite a quantitatively physiological proteinuria, leading in all 3 to pathological proteinuria during hyperthermia. In all 18 volunteers alterations reversed to normal within 12 h. Therefore, the degree of proteinuria during febrile diseases should be considered. Proteinuria of less than 0.5-1 g/24 h in adults might be explained by an altered glomerular function alone. Proteinurias exceeding this value, with a slow regressing tendency will indicate glomerular or tubulo-interstitial diseases, caused possibly by immunologic or toxic products resulting from underlying infectious disease.

Cytostatic drug effects on human clonogenic tumor cells and human bone marrow progenitor cells (CFU-C) in vitro

SummaryHuman tumor cells from a squamous cell carcinoma of the lung and from a malignant melanoma and human bone marrow progenitor cells were cultured in a methylcellulose monolayer system. To obtain tumor material for repeated experiments with human tumor specimens, human xenografts grown in the nude mouse system were used. The cultures were incubated continuously with adriamycin, actinomycin-D, bleomycin, cisplatinum, and melphalan. Dose response curves for bone marrow and tumor cell colonies were established. A comparison of bone marrow and tumor cell colony dose response curves might be useful for the assessment of the drug sensitivity of tumor cells independent of in vivo pharmacologic data and duration of drug exposure.

[Changes in clinical and immunological laboratory parameters of healthy adults after exposure to a one-hour 40 degree C-whole-body hyperthermia (author's transl)].

There are no signs of organ lesions in healthy subjects exposed to an 1-hour 40 degree C whole-body hyperthermia, induced by radiofrequency or infrared light. As to the immunological in vitro parameters, only a slight decrease of the relative T-cell count is seen, T-cell functions however being normal. A leukocytosis appearing during infrared-induced hyperthermia is probably related to the erythema caused by skin heating. About possible indications and clinical values of this treatment, nothing can however be said so far.SummaryThere are no signs of organ lesions in healthy subjects exposed to an 1-hour 40° C whole-body hyperthermia, induced by radiofrequency or infrared light.As to the immunological in vitro parameters, only a slight decrease of the relative T-cell count is seen, T-cell functions however being normal.A leukocytosis appearing during infrared-induced hyperthermia is probably related to the erythema caused by skin heating.About possible indications and clinical values of this treatment, nothing can however be said so far.ZusammenfassungNach einer einstündigen, durch Dezimeterwellen oder Infrarotlicht induzierten Ganzkörperhyperthermie von 40° C, treten bei Gesunden keine Anzeichen für Organschäden auf.Unter den immunologischen in vitro Parametern findet sich lediglich ein leichter Abfall der relativen T-Zell-Konzentration, jedoch ohne Beeinträchtigung der T-Zellfunktionen.Eine Leukozytose die während der Infrarot-induzierten Hyperthermie auftritt, wird auf das Hitze-Erythem zurückgeführt.Über Indikation oder Nutzen einer solchen Behandlungs-Maßnahme kann jedoch noch nichts ausgesagt werden.

Treatment of human clonogenic tumor cells and bone marrow progenitor cells with bleomycin and peplomycin under 40.5°C hyperthermia in vitro

Tumor cells derived from 13 different individual human tumors were plated in a colony forming monolayer assay. The effect of bleomycin and peplomycin on colony formation was assessed in normothermic conditions and after a hyperthermic treatment at 40.5 degrees C for 2 h at the beginning of the culture. In three out of the 13 tumor samples (two colon carcinomas, one malignant melanoma), hyperthermic incubation resulted in a thermal enhancement of the effects of bleomycin and peplomycin. In addition, human bone marrow progenitor cells (CFU-C) were subjected to the same procedure. Peplomycin proved to be less toxic to CFU-C than bleomycin. In samples from eight different donors, homogeneous dose-response curves were observed. There was no difference between normo- and hyperthermic incubation.