[Tumor vaccines-therapeutic vaccination against cancer]. / Tumorvakzinierung ­ therapeutische Vakzinierung gegen Krebs.

Tumor cells always exhibit differences to normal cells. These differences can be recognized by the immune system, enabling the destruction of tumor cells by T cells, as was impressively demonstrated by the success of immune checkpoint inhibition, e.g., in malignant melanoma. Many cancers, however, do not respond to this kind of therapy. In these cases, vaccination against tumor antigens could be very helpful. Nevertheless, all of the efforts made in this respect during the past 30 years have been virtually futile. With current knowledge and technology there is new hope.

Caudal vena cava progesterone and LH release patterns on Day 14 of gestation in primiparous sows.

The aim of the present study was to explore the relationship between systemic and local progesterone secretion and LH pulsatility during implantation in the pig. Differences in progesterone concentrations measured locally in the caudal vena cava and systemically in the jugular vein were studied in eight primiparous sows on Day 14 of pregnancy. LH pulsatility was analysed for its effects on the local progesterone-releasing pattern. Mean (±s.d.) progesterone concentrations in the vena cava (65.5±19.8ngmL-1) were approximately double basal concentrations (33.6±13.1ngmL-1). Basal concentrations of progesterone and LH were calculated as the average of the lowest six values. Basal caudal vena cava and mean jugular (27.6±1.5ngmL-1) progesterone concentrations did not differ significantly. Pre- and postprandial jugular progesterone concentrations were significantly different in the morning and afternoon (P=0.025 and 0.023). Mean LH ranged from 0.24 to 0.43ngmL-1 and was approximately double as high as basal LH in individual sows. In 60.8% of cases, LH pulses were followed by a progesterone pulse within 1h. In conclusion, the present study showed that corpus luteum function appears to respond to LH pulsatility on Day 14 of pregnancy. However, the response varies at the level of individual sows. In addition, systemic postprandial decreases in progesterone were confirmed on Day 14 of pregnancy.

Neonatal Marfan syndrome: unusually large deletion of exons 24-26 of FBN1 associated with poor prognosis.

Neonatal Marfan syndrome is a very rare subset of the classical Marfan syndrome with pronounced phenotypic expression especially of the cardiovascular manifestations. It is associated with a very poor prognosis, with approximately 50% of affected infants dying from cardiac failure during the first year of life. We present a newborn with the classical phenotype of neonatal Marfan syndrome. Within few hours after birth, progressive and refractory heart failure developed. Postmortal molecular study revealed an unusually large deletion of exons 24-26 within the so-called neonatal region of the gene FBN1, which might explain the unfavourable course of the disease in our patient.

Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute and chronic graft-vs.-host disease (aGvHD and cGvHD) are major complications after allogeneic hematopoietic cell transplantation (HCT) leading to substantial morbidity and mortality. This retrospective single-center study analyzes incidence, therapy, and outcome of GvHD in n = 721 patients ≥18 years having received allogeneic HCT 2004-2013 with a special focus on steroid refractory GvHD. Acute (n = 355/49.2%) and chronic (n = 269/37.3%) GvHD were mainly treated by steroids in first-line therapy. The proportion of steroid refractory aGvHD and cGvHD was 35.7% and 31.4%, respectively. As there is no standard therapy for steroid refractory GvHD, a range of different agents was used. In aGvHD, the overall response rate (ORR) of steroid refractory GvHD to second-line treatment was 27.4%. Mycophenolate mofetil (MMF) and mTOR inhibitors led to superior response rates (ORR 50.0% and 53.3%, respectively). In steroid refractory cGvHD therapy, ORR was 44.4%. Use of calcineurin inhibitors (CNI; n = 11/45.5%), MMF (n = 18/50.0%), mTOR inhibitors (n = 10/60.0%), and extracorporeal photophoresis (ECP; n = 16/56.3%) showed ORR above average. Targeted therapies lead to responses in 7.7% (n = 13). This data may help to improve the design of future prospective clinical studies in GvHD.

An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia.

Antibody-dependent cellular cytotoxicity (ADCC) of natural killer (NK) cells largely contributes to the success of monoclonal antibody (mAb) treatment in cancer. As no antibodies are clinically available for immunotherapy of myeloid leukemias (MLs), we aimed to develop an Fc-optimized CD133 mAb for induction of NK ADCC against MLs. When comparing different available CD133 mAbs, no difference was observed with regard to binding to primary chronic myeloid leukemia cells. However, clone 293C3 recognized acute myeloid leukemia (AML) cells in a substantially higher percentage of patient cases and was thus chosen to generate chimeric mAbs with either wild-type Fc part (293C3-WT) or a variant containing amino-acid exchanges (S239D/I332E) to enhance affinity to CD16 on NK cells (293C3-SDIE). In vitro, treatment with 293C3-SDIE significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by allogeneic and autologous NK cells as compared with its wild-type counterpart. In line with the observed lower expression levels of CD133 on healthy cells compared with malignant hematopoietic cells, 293C3-SDIE caused no relevant toxicity towards committed hematopoietic progenitor cells. In a NOD.Cg-PrkdcscidIL2rgtmWjl/Sz xenotransplantation model, 293C3-SDIE facilitated elimination of patient AML cells by human NK cells. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for elimination of minimal residual disease in the context of allogeneic stem cell transplantation in AML.

[Pulmonary infection in neutropenia]. / Pulmonale Infektion bei Neutropenie - Fall 1/2015.

UNLABELLED: MEDICAL HISTORY AND CLINICAL COURSE: A 42-year-old patient with hairy cell leukemia had been treated for 3 years by a hematologist in private practice. Initially the patient received 1 course of cladribine upon which the disease went into complete remission. 6 weeks ago a relapse was diagnosed and combination therapy with cladibrin and rituximab was initiated. Now the patient presented to the emergency room with shortness of breath and pain when breathing. INVESTIGATIONS, TREATMENT AND COURSE: In the chest x-ray, patchy infiltrates and pleural effusions were found on both sides. The subsequently performed computed tomography showed bilateral compactions with an Halo suspicious for fungal infiltrates. Upon admission to the hospital, an empirical antibiotic therapy with clarithromycin and piperacillin/tazobactam was initiated, which was later escalated to meropenem and linezolid. Additionally, an antifungal therapy with voriconazole was started and later switched to liposomal amphotericin B. At his admission, a positive aspergillus antigen could be detected in the microbiological laboratory. Under antimycotic treatment the aspergillus antigen was repeatedly negative. The patient presented with pronounced cytopenias and after a switch of therapy to vemurafenib and filgrastim, the hematopoiesis could only be stimulated insufficiently. The patient was transferred to the intensive care unit three days after admission with severe respiratory failure. He died on day 8 after admission. AUTOPSY AND DIAGNOSIS: Diagnosis was consistent with relapse of hairy cell leukemia with positive BRAF mutation and a bone marrow infiltration > 80 %. Autopsy revealed a significant hepato-splenomegaly, a lack of erythro-, granulo- and thrombopoiesis. Clots interspersed with fungal hyphae were found in both lungs and an infarction of the spleen with evidence of fungal hyphae was detected. The cultural findings post mortem on yeast or mold were negative. CONCLUSION: Patients with refractory hairy cell leukemia and prolonged neutropenia are at increased risk for systemic fungal infections. Therefore, prohylactic antimycotic therapy should be considered early in this group of patients. The therapeutic approach of vemurafenib in treatment-refractory hairy cell leukemia is promising and offers an additional treatment option. In the present case, the patient could unfortunately not be stabilized due to the septic complications.

Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules and impairment of the glomerular filtration rate.

This study has confirmed impairment of the glomerular filtration rate (GFR) (increase of the serum creatinine concentration) by fibrosing processes in the renal cortical interstitium. In addition statistically significant correlations were found between the decrease of the total area of the proximal tubules and of the area of the epithelial cells and both the extent of the renal cortical interstitial fibrosis and the serum creatinine concentration. Further statistically significant positive correlations were observed between the age of the patients and both the grade of interstitial fibrosis and the serum creatinine concentration. No correlation could be established between the age of the patients and the total area of the epithelial cells of the proximal tubules. Pathogenetically it is conceivable that with progressive interstitial fibrosis the tubules become atrophic as a result of malnutrition. The function of these atrophied tubules may be disturbed, the reabsorptive capacity for NaCl impaired and consequently the GFR reduced not only by slowing of the glomerular blood flow secondary to interstitial fibrosis, but also by the tubular-glomerular feedback-mechanism.

The consequences for renal function of widening of the interstitium and changes in the tubular epithelium of the renal cortex and outer medulla in various renal diseases.

The following parameters were measured in 63 renal biopsy specimens, most of which exhibited mesangioproliferative glomerulonephritis: the relative area of the interstitium and the area of the capillaries in the cortex and outer stripe of the outer medulla, and the area of the epithelium of the proximal tubules and of the ascending limbs of Henle's loop. The percentage of hyalinized glomeruli was also determined. Investigation of correlations between these values and parameters of renal function revealed the following: 1) The serum creatinine concentration increases and the endogenous creatinine clearance decreases significantly as the interstitium of both the cortex and the outer stripe of the outer medulla increases in width. 2) The urine osmolality decreases significantly as the epithelial areas of the proximal tubules and ascending limbs of Henle's loop decrease, and as the serum creatinine concentration rises and the areas of the interstitium increase. 3) No significant correlation exists between the percentage of hyalinized glomeruli and the urine osmolality. 4) The total area of the intertubular capillaries in the cortex decreases significantly as the interstitium in this area increases in width and as the serum creatinine concentration increases. 5) Compensatory hypertrophy of individual nephrons, as proposed by Bricker's hypothesis, was found only where more than 90% of the glomeruli were hyalinized.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure and function of the kidney in diabetic glomerulosclerosis. Correlations between morphological and functional parameters.

Histological and clinical findings in 103 middle-aged patients suffering from diabetic glomerulosclerosis (gs) (biopsy material) are reported. In diabetic gs (as in other inflammatory and non-inflammatory glomerular disease) a statistically highly significant positive correlation exists between the grade of fibrosis of the renal cortical interstitium and the serum creatinine concentration at the time of biopsy. Rank correlations exist between vessel index and relative cortical interstitial volume on the one hand as well as serum creatinine concentration on the other. Significant differences are also shown to exist between the mean values of the cortical interstitium as well as the serum creatinine concentration and the vessel index in the four grades of diabetic gs. Severe glomerular lesions may be accompanied by a normal serum creatinine concentration, only if the interstitium shows no fibrotic changes. Mild glomerular lesions, when accompanied by an interstitial fibrosis, always have elevated serum creatinine concentrations. The incidence of hypertension, proteinuria, the nephrotic syndrome and hematuria in diabetic gs appears to vary greatly. From the highly significant correlation between the cortical interstitium and the serum creatinine concentration we presume the following: Alterations of the postglomerular vessels by interstitial fibrotic changes result in an increased resistance to renal cortical blood flow with a subsequent reduction of glomerular perfusion. This reduction of the glomerular perfusion may result in a rise of the serum creatinine concentration, independently of the severity of the glomerulosclerosis. It is also conceivable that glomerular function is affected by the malfunctioning atrophic tubules in areas of interstitial fibrosis.

Creatinine clearance and renal interstitium in diffuse endocapillary proliferative glomerulonephritis.

Morphometric investigations of the renal cortex on biopsies obtained from patients with diffuse proliferative endocapillary glomerulonephritis (EPGN) were compared to biopsies without pathological changes, both groups having a normal serum creatinine concentration at the time of biopsy. Our findings are as follows: In both groups a statistically significant correlation exists between the decrease of the endogenous creatinine clearance and the broadening of the interstitium. The mean endogenous creatinine clearance value in EPGN is 107.6 +/- 40.6 ml/min/1.73 qm, the mean endogenous creatinine clearance in normal kidneys is 108.2 +/- 28.5 ml/min/1.73 qm; the mean interstitial volume in EPGN is 14.5 +/- 2.9 vol.%, that in normal kidneys 9.5 +/- 2.9 vol.%, the difference is statistically significant. Comparing the run of the two curves (relationship between endogenous creatinine clearance and interstitial volume) of the investigated groups, one finds that they run a nearly parallel course, the curve of the EPGN being shifted statistically significant to the right. The mean values of number, single- and total area of the peri- and intertubular capillaries are identical in the cases of EPGN and in those biopsies without pathological findings. Furthermore no correlations could be established between the above mentioned measuring values and the endogenous creatinine clearance in the both investigated groups. Consequently in these cases with normal serum creatinine concentration the reduction of the glomerular filtration rate (gfr) accompanied by interstitial broadening cannot be explained by an impairment of the postglomerular blood flow. Perhaps a tubular functional disturbance, the cause or the consequence of the interstitial broadening impairs glomerular function by the tubular-glomerular feedback-mechanism and/or by an elevation of the intratubular hydrostatic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term prognosis of AA and AL renal amyloidosis and the pathogenesis of chronic renal failure in renal amyloidosis.

Investigation of the long-term prognosis and pathogenesis of chronic renal failure in 225 cases of AA and AL renal amyloidosis (perireticular and perireticular + pericollagenous amyloidosis) yielded the following results: 1) The prognosis of both AA and AL amyloidosis is poor, and is worse than all other types of glomerulopathy with the exception of rapidly progressive glomerulonephritis. 2) The probability of maintaining renal function in AL amyloidosis is no lower than that in AA amyloidosis. 3) The prognosis of both AA and AL amyloidosis is significantly worse in cases in which the renal cortical interstitium exhibits fibrosis at the time of the biopsy than in those in which it is normal. 4) In AA and AL amyloidosis, as in various types of inflammatory glomerulopathy, the relative area of the renal cortical interstitium shows a significant positive correlation with the serum creatinine concentration and a significant negative correlation with the creatinine clearance. However, the extent of interstitial amyloid deposition does not correlate with the serum creatinine concentration. Deposition of amyloid in the renal cortical interstitium has no effect on renal excretory function. 5) The long-term prognosis of renal amyloidosis is related to the severity of the glomerular amyloidosis in as much as it is generally worse in Grades III to V than in Grades I and II. However, it must be borne in mind that the incidence of interstitial fibrosis, which is decisive for the long-term prognosis, increases with the severity of glomerular changes. 6) The long-term prognosis of renal amyloidosis is worse if acute renal failure or interstitial fibrosis is present at the time of the biopsy. Patients with both acute renal failure and interstitial fibrosis have the worst prognosis. 7) Isolated glomerular amyloidosis, even if there is severe vascular amyloidosis (vas afferns), does not lead to renal insufficiency or even to a rise in serum creatinine concentration. 8) The number of T lymphocytes in the tubular epithelium in AA and AL amyloidosis is significantly greater than normal, and the number of T lymphocytes, macrophages/monocytes, and fibroblasts/fibrocytes per unit area of interstitium is also significantly increased. 9) As far as the pathogenesis of renal cortical interstitial fibrosis in renal amyloidosis is concerned, it is proposed that, in some cases, this develops from the interstitial edema that is seen in biopsy specimens of patients with renal amyloidosis and acute renal failure.(ABSTRACT TRUNCATED AT 400 WORDS)

The consequences of tubulo-interstitial changes for renal function in glomerulopathies. A morphometric and cytological analysis.

Morphometric investigation of the structures of the cortex in kidneys exhibiting various types of glomerulopathy revealed the following: 1. In various types of glomerulonephritis, diabetic glomerulosclerosis, and glomerular amyloidosis there are significant correlations between the severity of fibrosis of the renal cortical interstitium and tubular atrophy resulting from chronic interstitial inflammation, and the serum creatinine concentration, creatinine clearance, inulin clearance and PAH clearance. 2. As illustrated with the example of membranoproliferative glomerulonephritis type I, if glomerulopathy alone is present, there is no elevation of the serum creatinine concentration, even if the glomerular inflammatory changes are severe; neither are severe renal amyloidosis that is confined to the glomeruli and severe isolated diabetic glomerulosclerosis associated with elevation of the serum creatinine concentration. 3. There is a significant negative correlation between the severity of interstitial fibrosis resulting from chronic inflammation and the total number and cross-sectional area of the intertubular capillaries; i.e., the total cross-sectional area and number of capillaries per unit area decrease as the fibrosis of the cortical interstitium increases. 4. Cases of glomerulonephritis in which there is accompanying fibrosis of the renal cortical interstitium have a significantly worse long-term prognosis than those in which there is only severe glomerulitis. 5. Obliteration of the post-glomerular capillaries leads to an increase in the cross-sectional area of the glomerular capillary convolution, the morphological equivalent of an increase in intraglomerular pressure. 6. The cause of the disease of the renal cortical interstitium that may accompany the various types of glomerulonephritis is not known. It is considered possible, as a working hypothesis, that this inflammation represents a T-cell stimulated autoimmune process in which fibroblast proliferation occurs, leading to an increase in numbers of fibrocytes in the renal cortical interstitium and thus to increased production of collagen.

Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia.

The therapeutic efficacy of humanized or chimeric second-generation antitumor antibodies is clearly established, but often limited. In recent years, defined modifications of the glycosylation pattern or the amino-acid sequence of the human immunoglobulin G1 Fc part have resulted in the development of third-generation antibodies with improved capability to recruit Fc receptor-bearing effector cells. The first antibodies of this kind, currently evaluated in early clinical trials, are directed against lymphoma-associated antigens. Fc-engineered antibodies targeting myeloid leukemia are not yet available. We here report on the generation and preclinical characterization of an Fc-optimized antibody directed to the FMS-related tyrosine kinase 3 (FLT3), an antigen expressed on the leukemic blasts of all investigated patients with acute myeloid leukemia (AML). This antibody, termed 4G8SDIEM, mediated markedly enhanced cellular cytotoxicity against FLT3-expressing cell lines as well as blasts of AML patients. FLT3 expression levels on AML cells varied between 300 and 4600 molecules/cell and, in most cases, were substantially higher than those detected on normal hematopoietic precursor cells and dendritic cells (approximately 300 molecules/cell). Antibody-mediated cytotoxicity against these normal cells was not detectable. 4G8SDIEM has been produced in pharmaceutical quality in a university-owned production unit and is currently used for the treatment of leukemia patients.

[Two autopsy cases with systemic amyloidosis--case 11/2010]. / Zwei Autopsiefälle mit systemischer Amyloidose--Fall 11/2010.

HISTORY AND ADMISSION FINDINGS: A 37-year old patient was admitted with upper abdominal pain, vomiting and diarrhea. A 38-year-old patient was admitted for liver failure. INVESTIGATIONS: Case 1 was diagnosed with an AL amyloidosis due to deposition of the immunoglobulin light chain kappa in all tissues analyzed. In the bone marrow plasma cells were increased to 20-30%. Case 2 suffered from AA amlyoidosis secondary to familial mediterranean fever and underwent dialysis treatment for years. He was positive for hepatitis B and C. DIAGNOSIS, TREATMENT AND COURSE: Patient 1 developed refractory nephrotic syndrome and low blood pressure. During hemodialysis circulatory failure occured and she died during resuscitation. In patient 2 a flare of chronic hepatitis B was found and treated with antiviral therapy. He was referred to ICU for rectal bleeding and developed pulmonary arrest. After resuscitation he died because of lactate acidosis and refractory circulatory failure. Both cases were subjected to autopsy. CONCLUSIONS: The vast majority (90%) of amyloidoses are due to acquired AA or AL amyloidosis. Prognosis remains poor, in particular when cardiac and vascular involvement occurs.

Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: a morphometric contribution.

This is an editorial review of investigations into the correlation of structure and function of the kidney in various inflammatory and noninflammatory glomerular diseases and in focal and diffuse interstitial nephritis. In detail these investigations produced the following results: (1) The excretory function of the glomeruli for substances usually eliminated with the urine is, in the case of inflammatory and noninflammatory glomerular diseases, detrimentally affected by tubulointerstitial changes, i.e. by processes accompanied by interstitial fibrosis and tubular atrophy. Likewise primary interstitial renal diseases when accompanied by interstitial fibrosis and tubular atrophy may lead to reduction in GFR. (2) Inflammatory and noninflammatory glomerular diseases, even when very severe, are not accompanied by a measurable reduction in GFR when the renal cortex interstitium shows no changes and the tubules exhibit no pathological findings. (3) The concentration ability of the kidney, too, depends primarily on tubulointerstitial changes and not primarily on a reduction of the glomerular filtration surface area. As interstitial fibrosis and tubular atrophy increase, the maximum concentration ability of the kidney decreases, even when the glomerular structure is preserved. (4) The decrease in GFR in the case of processes in the renal cortex accompanied by severe interstitial fibrosis is the result of the reduction of the number and of the area of the postglomerular vessels, i.e. the result of an impeded outflow from the glomeruli and of a concomitant slower circulation through the glomeruli. (5) In the case of inflammatory and noninflammatory glomerular and extraglomerular renal diseases accompanied by slight interstitial fibrosis and tubular atrophy, the GFR is detrimentally affected via a hormonally controlled self-regulating mechanism (Thurau-mechanism) in the form as modified by Baumbach and Skott and Leyssac. The glomerular function thereby adapts to an insufficient tubular function, without there necessarily being any structural changes in the glomeruli.