Collaborative study for the establishment of Ph. Eur. Human immunoglobulin for electrophoresis BRP batch 4.

Due to the diminished stocks of the third batch of the European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human immunoglobulin for electrophoresis, in 2020 the European Directorate for the Quality of Medicines & HealthCare (EDQM) initiated an international collaborative study for the establishment of a replacement batch. The study was run under the aegis of the Biological Standardisation Programme (BSP). Nineteen laboratories participated in the collaborative study to verify the suitability of the candidate reference preparations according to the Ph. Eur. monographs Human normal immunoglobulin for intravenous administration (0918), Human normal immunoglobulin for intramuscular administration (0338) and Human normal immunoglobulin for subcutaneous administration (2788) using the zone electrophoresis method with cellulose acetate and/or agarose as the testing medium. Capillary zone electrophoresis (CZE), a technique not yet included in monographs 0338, 0918 and 2788, was also used by some laboratories. The assignment of a value for immunoglobulin as a percentage of the total protein content could only be made for agarose electrophoresis and for CZE. The candidate preparation was found suitable for the intended purpose and was subsequently adopted by correspondence in May 2021 by the Ph. Eur. Commission as Human immunoglobulin for electrophoresis BRP batch 4 with an assigned range for immunoglobulin of 82.5 % to 87.8 % of the total protein content.

[Minimally invasive percutaneous ablation of malignant hepatic tumors]. / Perkutane minimalinvasive Entfernung von Lebertumoren.

Three minimally invasive techniques for the treatment of primary and secondary malignant hepatic tumors - percutaneous ethanol injection, laser-induced thermotherapy and percutaneous radiofrequency thermotherapy--are reviewed and discussed. The initial clinical results suggest that these technics are safe and potentially effective in selected patients with inoperable liver tumors.

[Ultrasonically controlled percutaneous high frequency thermotherapy of liver tumors with perfused needle electrodes]. / Sonographisch gesteuerte perkutane Hochfrequenzthermotherapie von Lebertumoren mit perfundierten Nadelelektroden.

Percutaneous radiofrequency ablation (HFTT) is a new therapeutic technique for the treatment of inoperable primary and secondary liver tumors. We report our initial experience using a newly developed perfusion electrode. Twelve liver tumors (11 metastases of colorectal tumors, 1 hepatocellular carcinoma) were treated in 5 inoperable patients. The patients had 1 to 3 liver tumors. All lesions were cytologically confirmed and measured 12-47 mm. The technique was approved by the institutional review board and informed consent was obtained from all patients. A 12-mm-needle electrode with a 15-mm-active tip was introduced into the liver tumors under ultrasound guidance and tumors were coagulated with radiofrequency energy of 350 kHz. The needle electrodes were perfused with 0.9% saline during coagulation to increase the volume of coagulation necrosis without tissue vaporization. The serial changes in tumor size after therapy were evaluated with spiral CT imaging. Dynamic CT showed that unenhanced areas indicative of coagulation necrosis developed in all tumors. In 8 of 12 tumors no signs of recurrence appeared during the observation period of 7 (5-12) months. No major complications were observed. Our preliminary experience suggests that percutaneous radiofrequency coagulation can be a simple, safe and potentially effective treatment for selected patients with inoperable liver tumors. The results justify further studies to investigate the possible role in clinical practice.

Serum interleukin-6 is related to disease activity but not disease specificity in inflammatory bowel disease.

Interleukin-6 (IL-6) has a major function in the regulation of the inflammatory process. We aimed to define its role as a parameter of disease activity and extent in inflammatory bowel disease. Serum concentrations of IL-6 were measured in 28 patients with Crohn's disease (CD) and in 15 with ulcerative colitis (UC) before starting corticosteroid treatment. Disease activity was measured by standard activity indexes. Serum IL-6 levels were increased in patients with CD (36 +/- 8 pg/ml; p < 0.001) and UC (10 +/- 4 pg/ml; p < 0.05) as compared with 25 control patients. A significant correlation between serum IL-6 concentrations and disease activity was found in patients with CD as well as in patients with UC (active CD: 73 +/- 14 pg/ml, inactive disease: < 10 pg/ml, p = 0.003; active UC: 26 +/- 10 pg/ml, inactive disease: < 10 pg/ml, p = 0.004). IL-6 serum levels were related to the acute-phase reactant c-reactive protein (r = 0.51, p < 0.01) in CD patients. The serum IL-6 concentrations were more pronounced in CD of the colon than in disease limited to the small bowel (p < 0.05). In patients with CD as well as in patients with UC, IL-6 serum concentrations showed a higher sensitivity for disease activity (94 and 83%) than serum c-reactive protein levels. In patients without corticosteroid treatment, the IL-6 serum concentration is related to disease activity in CD as well as UC. Serum IL-6 levels show a higher correlation with disease activity than c-reactive protein levels.

Fludarabine single-agent therapy for relapsed low-grade non-Hodgkin's lymphomas: a phase II study of the German Low-Grade Non-Hodgkin's Lymphoma Study Group.

In a phase II study, 45 patients with advanced low-grade non-Hodgkin's lymphomas (NHLs) who had failed on or had relapsed after first-line chemotherapy were treated with a 5-day regimen of fludarabine, 25 mg/m2/d, by a 30-minute infusion. All patients were pretreated and had received one to 11 preceding regimens (median, three regimens). Histologic subtypes included 17 centrocytic/centroblastic NHLs, three centrocytic NHLs, 23 lymphoplasmocytoid immunocytomas, and one case each of peripheral T-cell and lymphocytic lymphoma. From 38 presently evaluable patients, 12 (31%) cases responded (five [13%] complete and seven [18%] partial remissions). Treatment-associated toxicity was mild to moderate, with myelosuppression comprising the major side effect. From the 12 complete and partial response patients, seven are currently in unmaintained remission for more than 12 months. These data indicate a high activity of fludarabine in heavily pretreated patients with low-grade NHL. Further investigations are warranted to assess the most appropriate usage for this highly promising agent at earlier stages of low-grade NHL therapy.

Zinc supplementation stimulates tetanus antibody formation and soluble interleukin-2 receptor levels in chronic hemodialysis patients.

Immunodepression in end-stage renal disease has been associated with zinc deficiency. In a controlled study serum zinc levels, serum concentrations of soluble interleukin-2 receptor (sIL-2R), and tetanus IgG antibody titers were measured in 65 hemodialysis patients before and after intravenous zinc supplementation for 2 months. The hemodialysis patients had significantly lower predialysis serum zinc concentrations compared to healthy controls (63 +/- 1.65 versus 126 +/- 4.6 micrograms/dl, P < 0.001). Serum zinc concentrations increased to the normal range in the zinc-treated patients. After zinc substitution tetanus antibody titers rose significantly (0.81 +/- 0.12 versus 1.22 +/- 0.12 U/ml, P < 0.01). Pretreatment sIL-2R levels were elevated in 95% of examined patients. A further increase in sIL-2R was observed after zinc supplementation (234 +/- 14 versus 285 +/- 21 U/ml, P < 0.05). The results suggest that zinc induces the activation of T lymphocytes and T-cell dependent B lymphocytes in chronic uremic patients in vivo.

Combination therapy with interferon alpha-2b plus low-dose interferon gamma in pretreated patients with Ph-positive chronic myelogenous leukaemia.

Between March 1988 and July 1990, 28 adults with chronic myelogenous leukaemia (CML) were treated with a combination of recombinant human interferon (IFN) alpha-2b s.c. (initial dose 4 x 10(6) U/m2) and recombinant human IFN gamma s.c. (50 micrograms totally) daily. All patients were in chronic phase disease and had been treated previously with chemotherapy or bone marrow transplantation. A complete haematologic remission was achieved in three patients (11%), a haematologic remission in 12 patients (43%), and a partial haematologic remission in seven patients (25%). Six patients did not respond to this schedule. Acute side-effects were flu-like symptoms, fever and chills. During long-term treatment six patients developed polyarthralgia. Haematotoxicity WHO grade III occurred in three patients, and WHO grade IV in two patients. One patient developed psychosis, and in another patient an exacerbation of a pre-existing sarcoidosis was observed. We conclude that this combination is tolerable and effective in inducing haematological remissions in pretreated CML patients.

[Effect of zinc substitution on lymphocyte subsets and cellular immune function in hemodialysis patients]. / Einfluss einer Zinksubstitution auf Lymphozytensubsets und zelluläre Immunfunktionen bei Hämodialysepatienten.

Infection is a major cause of morbidity and mortality in patients undergoing hemodialysis for end stage renal disease. Low plasma zinc levels have been associated with immunodepression in these patients. In a randomized, placebo controlled double-blind cross over study, plasma zinc levels, delayed hypersensivity to 7 Antigens (Merieux-Multitest), absolute lymphocyte counts, T- and B-lymphocytes, suppressor-T and helper T-cells and natural killer cells were studied in 25 hemodialysis patients before, during and after intravenous zinc supplementation for 8 weeks. The hemodialysis patients had significantly lower predialysis plasma zinc concentrations compared to 76 healthy controls (74 +/- 12 vs. 126 +/- 28 mcg/dl, p less than 0.001). The plasma zinc concentrations increased to the normal range during the treatment period. Lymphocyte subtype analysis showed a significant decrease of suppressor-T cells and an increase of the helper-T/suppressor-T ratio (2.09 +/- 0.26 vs. 3.18 +/- 0.48, p less than 0.05) after zinc supplementation. Delayed hypersensivity to intradermal antigens increased significantly only after zinc treatment (2.0 +/- 0.7 vs. 5.8 +/- 1.7, p less than 0.05), not after placebo. The changes were reversible after finishing the zinc treatment. It is concluded, that plasma zinc levels are reduced in hemodialysis patients and that the substitution of zinc restores some of the depressed immune functions in these patients.

[Decreased plasma zinc levels in metastatic breast cancer]. / Erniedrigte Plasmazinkspiegel beim metastasierten Mammakarzinom.

Zinc is an essential component of many metalloenzymes for DNA and proteinsynthesis including RNA and DNA polymerases. It has been shown by several investigators that zinc is accumulated in breast cancer tissues. To investigate a possible relation between plasma zinc levels and tumor load, plasma zinc levels were evaluated in 76 patients with non metastatic breast cancer (no evidence for disease after mastectomy) and in 66 patients with metastatic breast cancer. Zinc concentrations were measured in plasma using an atomic absorption spectrophotometer (normal range 80-150 mcg/dl). In patients with metastatic disease plasma zinc concentrations were in the lower region of the normal range or depressed (arithmetic mean: 84.9 SD 21.6 mcg/dl), whereas patients with non metastatic breast cancer had normal zinc levels (arithmetic mean: 126.0 SD 27.7 mcg/dl). The difference between the two groups was highly significant (p = 0.001, t = -9.742, 140 degrees of freedom). It is concluded, that plasma zinc in breast cancer patients is depressed according to the stage of the disease. Based on experimental data a substitution of zinc cannot be recommended.

[Ultrasonically guided fine-needle puncture. The limits of the method in the abdomen and retroperitoneal space]. / Ultraschallgesteuerte Feinnadelpunktion. Grenzen der Methode im Abdomen und Retroperitonealraum.

The sensitivity and specificity of ultrasound-directed fine-needle biopsy in the differentiation of malignancy or otherwise of structures in the abdomen or retroperitoneal space which look suspicious on ultrasound was evaluated from results in 558 patients (306 men, 252 women). Data from two different centres were used to characterize further the influence of different techniques of puncture, cytopathologists and groups of patients on the validity of the examination. Sensitivity (in the two centres) was 88 and 80%, respectively, specificity 100 and 99%. The validity of the examination was the same at both centres. In both centres the sensitivity was worst for pancreatic tissue, at only 72 and 61% respectively, compared with other organs (e.g. liver, lymph nodes, kidney) (P less than 0.05). Fine-needle biopsy of abdominal and retroperitoneal organs will thus be subject to a not insignificant number of false-negative results of cytological examination.

[Clinical model concept of the evolution of malignant tumors: implication for hormone therapy of breast cancer]. / Klinische Modellvorstellung der Evolution maligner Tumoren: Implikationen für die Hormontherapie des Mammakarzinoms.

An analysis is made of current concepts about heterogeneity, instability and autonomy of tumor cells which accounts for the clinical course of incurable, late-stage malignant disease which as such is characterized by a growing independence from growth control mechanisms of the host, by progressive metastatic spread and by unpredictable malignancy associated events. Increasing heterogeneity, instability and autonomy are best demonstrated by the development of resistance phenomena and are potentially reversible processes. This reversibility can be exploited using biological response modifiers. Understanding this triad also helps explain certain clinical phenomena such as qualitative differences in remissions and mixed responses, early vs. late stage disease, and the potential therapeutical hazards which can lead to further tumor heterogeneity. On the breast cancer example further clinical implications are illustrated, namely receptor heterogeneity, autocrine autonomy, and combination therapy with hormones. The concepts discussed are the basis for the development of non-toxic tumor therapies which are aimed less at tumor cell kill than at stabilization.