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.

Resistance of tumour cells to chemotherapy: importance of host defence factors.

The arguments favouring the hypothesis that chemotherapeutic agents might act in cooperation with host defence mechanisms are reviewed briefly. In patients with far advanced solid tumours plasma factors blocking in vitro immune reactions have been identified and successfully removed by immune adsorption or plasma exchange. By plasmapheresis performed in patients with metastatic malignancies resistant to chemotherapy it was possible to induce tumour regressions. In 25/28 patients responding to the combined plasmapheresis/chemotherapy procedure a positive correlation was found to clinical results and patterns of plasma-blocking factor activities.

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.

Mastectomy stimulates prolactin release in breast cancer patients.

Hyperprolactinaemia has been described to occur after mastectomy in breast cancer patients, but whether it may be the result of surgery or breast cancer is particularly unknown. Plasma prolactin levels were measured in 51 patients one day before, and 1, 7, 30, and 180 days after mastectomy (23 primary breast cancer patients), tumourectomy (10 patients with benign or malignant breast lesions), and cholecystectomy (18 patients with cholelithiasis). Elevated prolactin levels were found on the 7th and 30th postoperative day in mastectomized and laparotomized patients, but not in patients who underwent tumourectomy of benign or malignant breast lesions (p less than 0.01). The prolactin levels were in the normal range one day before and again 180 days after surgery in all patients. We conclude, therefore, that postoperative hyperprolactinaemia in breast cancer patients is a result of surgery rather than the disease.

[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.

[Metergoline in hyperprolactinemic breast cancer: a phase II study]. / Metergolin beim hyperprolaktinämischen Mammakarzinom: Eine Phase-II-Studie.

The prolactin release inhibiting action of the dopamine receptor agonist metergoline was investigated in 16 patients with metastatic breast cancer associated with hyperprolactinemia. At a daily dose of 12 mg p.o. for 30 days, the drug was highly effective in lowering prolactin levels (day 0: 1076 +/- 171, day 29: 249 +/- 46 mU/l) in these patients. Starting treatment with 4 mg/day, the side effects of the treatment were mild, including dizziness and nausea.

[Bromocriptine in chemotherapy-resistant, metastatic breast cancer. Results of the GO-MC-BROMO 2/82 AIO Study]. / Mammakarzinom. Ergebnisse der aio-studie go-mc-bromo 2/82.

In a case report a patient with metastatic breast cancer, who had chemotherapy resistance and hyperprolactinemia, showed a tumor remission following suppression of elevated prolactin levels with bromocriptine. Based on this observation, 18 patients with progressive metastatic breast cancer, chemotherapy resistance and hyperprolactinemia were treated with 10 mg bromocriptine/day in a prospective study. This treatment was in addition to chemotherapy, which was continued for 8 weeks in spite of progressive disease. In all patients, elevated prolactin levels (arithmetic mean 1388 +/- 201 mU/l before treatment) were suppressed to values under 100 mU/l. A partial remission was observed in one single patient which was not clearly attributed to suppression of plasma prolactin levels, but to delayed tumor remission. Side effects, mainly gastrointestinal disorders, were observed in all patients during therapy. In 6/18 patients treatment had to be stopped before end of study due to intolerable nausea and vomiting. It is concluded that suppression of elevated prolactin levels in progressive metastatic breast cancer patients is not effective in restoring tumor sensitivity to chemotherapy.

[Stimulation of prolactin secretion with thyroliberin (TRH). In vivo and in vitro studies of metastatic breast cancer]. / Stimulation der Prolaktinsekretion mit Thyreoliberin (TRH). In-vivo- und In-vitro-Untersuchungen beim metastasierten Mammakarzinom.

In 120 Patients with metastatic breast cancer prolactin stimulation tests with 200 mcg TRH i.v. were done. The mechanism of the TRH-induced prolactin release was characterized in vitro. Basal prolactin levels were stimulated in all patients with an average increase of 400% (means basal level 441 mU/l, after stimulation 1753 mU/l). Hyperprolactinemic patients showed the highest absolute prolactin levels following stimulation. Patients with basal prolactin levels under 500 mU/l showed the highest relative increase of prolactin levels (delta = 550%). The prolactin stimulation tests with TRH had no diagnostic advantage compared to the basal prolactin levels in predicting the activity of the disease (basal values: sensitivity 12%, specificity 100%, stimulated values: sensitivity 10%, specificity 99%). During inhibition of plasmaprolactin with bromocriptine, an 330% increase of plasmaprolactin following TRH was observed in vivo. The same was shown in vitro: Pituitary cells cultured in vitro with 10(-6) M dopamine showed an increase of prolactin secretion after coincubation with 10(-7) M TRH. There was a linear increase of the prolactin concentration during the incubation period in dopamine-free cell cultures. The increase of prolactin concentration in vitro was constant during the whole incubation period (5 h), not influenced by the basal prolactin concentration and was seen as early as 30 min in incubation. The in vivo and in vitro results are in agreement with the hypothesis of a rapid, dopamine-independent effect of TRH on the secretion of stored prolactin in the pituitary.

[Gaucher disease and pregnancy]. / Morbus Gaucher und Schwangerschaft.

Two pregnancies in a patient with Gaucher's disease type I are reported. Anemia and thrombocytopenia were augmented during pregnancy, but no effect on the spleen and liver was observed. The first delivery was associated with a severe post partum haemorrhagia (platelet count 56,000/mcl, hemoglobin before delivery 10.2 g/100 ml, postpartum 5.5 g/100ml). At the end of the second pregnancy the platelet count was 33,000/mcl. Platelet transfusions were given after induction of preterm labor and no bleeding complications were observed. The obstetric aspects of Gaucher's disease are reviewed. Post partum haemorrhagia is associated with thrombopenia and is observed in patients with platelet counts under 100,000/mcl. Platelet infusions are recommended before delivery in these patients. Thrombocytopenic patients should be carefully monitored during labor with crossmatched blood on standby.

[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.

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.

[Plasma-prolactin concentrations in breast cancer at various stages, in mastopathy and other malignant tumors]. / Plasma-Prolactin-Konzentrationen bei Mammakarzinomen in verschiedenen Stadien, bei Mastopathie und anderen malignen Tumoren.

7% of 204 patients with metastatic breast cancer had hyperprolactinemia (greater than 1000 mIU/1 = 30.8 ng/ml) in the measurements of morning plasma prolactin basal levels. The incidence of hyperprolactinemia was significantly higher in patients with metastatic breast cancer than in 173 patients with non-metastatic breast cancer (p less than 0.001), in 151 patients with mastopathy (p = 0.01), in 63 patients with local (p = 0.001) and 56 patients with advanced solid tumors of different histology without prolactin stimulating medication (p = 0.001). After 5 measurements with a median interval of 2 months, elevated prolactin levels over 1000 mIU/l were found at least once in 35% of the patients with metastatic breast cancer. 93% of the women with hyperprolactinemic breast cancer were in progression at the time of the measurements, and none in remission; on the other hand, all patients with advanced breast cancer in remission had normal prolactin levels.

[Comparative studies of prolactin, estrogen, progesterone and androgen receptor levels in human breast cancers]. / Vergleichende Untersuchungen zum Prolaktin-, Ostrogen-, Gestagen- und Androgenrezeptorgehalt menschlicher Mammakarzinome.

A receptor for lactogenic hormones (prolactin of several species and human growth hormone) was characterized in crude plasma membrane preparations of adult female rat liver. The binding of 125J-labeled prolactin to receptors was specific, saturable, reversible, and of high affinity (Kd = 0.23 x 10(-10)M). The maximum amount of prolactin specifically bound to liver of untreated female rats was 45 fmol/mg protein, whereas no specific prolactin binding was detected in plasma membrane preparations of adult male or immature rats. With this assay, a specific and reversible binding of ovine prolactin was detected in plasma membrane preparations of 25 human breast cancers, ranging from 2-29% of total activity. The estrogen-, progesterone- and androgen receptor content was determined in the breast cancer specimens using the dextran-coated charcoal method. Specimens with the highest specific prolactin binding showed the lowest steroid receptor concentrations, but no significant correlation between estrogen-, progesterone-, androgen-, and prolactin receptor content and other prognostic factors was observed in our series. We conclude, that steroid and prolactin receptors are expressed independently in human breast cancer.

Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer.

In a long-term follow-up study, prolactin levels were measured in 149 patients with advanced metastatic breast cancer. Control groups included 221 patients with primary operable breast cancer and 150 women with benign breast disease. Hyperprolactinemia (greater than 1,000 mIU/I; HYPRL) occurs in 44% of patients with metastatic breast cancer in the course of the disease (p less than 0.001 compared to patients with non-metastatic disease). HYPRL is associated with progressive breast cancer in 88% of cases. In patients experiencing several episodes of disease remission and relapse, incidence of HYPRL increases with each relapse. Prolactin blood levels return to normal if hyperprolactinemic patients experience remission after chemotherapy. Patients expressing HYPRL have a shorter survival time after mastectomy when compared to patients who never developed HYPRL (154/89 months, p = 0.01). It is concluded that HYPRL is of prognostic significance and a reliable indicator of progressive disease in advanced metastatic breast cancer.

[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.

[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.

[Pathophysiology of hyperprolactinemia in breast cancer]. / Pathophysiologie der Hyperprolaktinämie beim Mammakarzinom.

To characterize the prolactin secretion in human breast cancer, plasma prolactin levels were measured in 514 patients with breast cancer in long term follow-up studies. In hyperprolactinemic patients suppression and stimulation tests were performed and the 24-h secretion profile was recorded. Tissue extracts and sera of hyperprolactinemic breast cancer patients were incubated with cultured pituitary cells in vitro to detect a prolactin releasing activity in these specimens. 44% of breast cancer patients developed hyperprolactinemia in the course of the disease. In 35% of measurements hyperprolactinemia was induced by non tumor related causes, e.g. prolactin-stimulating drugs, surgery, uremia, prolactinoma. Excluding such influences on the prolactin level, hyperprolactinemia over 1,000 mU/l was almost only found in patients with progressive metastatic disease. In these patients hyperprolactinemia was associated with tumor load, but not correlated to BSR, CEA or prognostic factors. Hyperprolactinemia in breast cancer was not of paraneoplastic origin. No prolactin-releasing activity was detected in tumor tissue and sera of hyperprolactinemic breast cancer patients.