Bifunctional NHS-BAT ester for antibody conjugation and stable technetium-99m labeling: conjugation chemistry, immunoreactivity and kit formulation.

UNLABELLED: Conjugation chemistry and kit formulated binding of the NHS ester of 6-(4'-(4"-carboxyphenoxy)butyl)-2, 10-dimercapto-2,10-dimethyl-4,8-diazaundecane (NHS-BAT ester) to monoclonal antibodies (MAbs) was investigated. The functionalities of the resulting BAT conjugated and 99mTc-labeled MAbs BW 431/26, MAb 425 and bispecific MDX210 (fragment construct) were tested by immunoreactivity and immunoscintigraphy. METHODS: The kinetics and chemistry of the conjugation reaction were monitored by high-performance liquid chromatography, size-exclusion chromatography and positive fast-atom-bombardment mass spectra (FAB-MS). The 99mTc BAT-MAbs were tested with various immunoreactivity assays. The biodistribution of 99mTc-BAT-BW 431/26 in rats was compared with directly labeled BW 431/26. RESULTS: At pH 8.5 and 25 degrees C, the reactivity of the NHS-BAT ester was high with 90% completion after 30 min. The conjugation yield of 19 microM MAb and 228 microM NHS-BAT ester amounted to 30%. Higher NHS-BAT ester concentrations afforded higher BAT-to-MAb ratios. According to FAB-MS, the conjugation competing hydrolysis surprisingly occurred at the NHS ring. Almost quantitative 99mTc labeling was achieved after 5 min at 25 degrees C. Immunoreactivity of the 99mTc-BAT antibodies showed > 90% recovery and proved to be insensitive to BAT-to-MAb ratios of up to 10. The 99mTc-BAT-BW 431/26 showed similar organ distribution but revealed less urinary excretion compared with the directly labeled BW 431/26. Immunoscintigraphy with 99mTc-labeled and BAT-BW 431/26 and BAT-MAb 425 showed the respective biological function in vivo. CONCLUSION: According to straightforward conjugation chemistry, the ease of 99mTc labeling and the application of a simple ultrafiltration technique, the NHS-BAT ester represents a nondestructive, universally applicable biofunctional ligand to introduce stable 99mTc protein binding sites. Kit formulated conjugation/labeling can be performed with little time requirements and laboratory experience.

[Mucoepidermoid carcinoma of the submandibular gland after high-dose radioiodine therapy: case report and review of the literature]. / Mukoepidermoid-Karzinom der Glandula Submandibularis nach hochdosierter Radioiodtherapie: Fallpräsentation und Literaturübersicht.

Case report of a 42 year old female, who received 14th-20th year of life six radioiodine therapies with altogether 19.2 GBq131I because of a papillary thyroid carcinoma. 17 years after the last therapy, she developed a histologically proven chronic radiogenic sialadenitis of the left submandibular gland. Further four years later, the right submandibular gland has been extirpated because of a mucoepidermoid carcinoma with infiltration of a regionary lymphatic node. Review of the previous published secondary-malignancies of the salivary glands after high-dose radioiodine therapies.

[Methodical evaluation of immunoluminometric determination of thyroid peroxidase in serum]. / Methodische Untersuchung zur immunoluminometrischen Bestimmung von Thyreoperoxidase im Serum.

With the identification of thyroid peroxidase (TPO) as the specific autoantigen in autoimmune diseases of the thyroid, the development of a commercial assay for detection of TPO in human serum became possible. The diagnostic value of this TPO assay was evaluated in 194 patients with various thyroidal diseases. The assay appeared to be easily affected by specific and/or unspecific interferences such as TPO-auto-antibodies in the patient's blood samples. To analyze these effectors every sample was checked in a parallel recovery test. In most of the cases with elevated anti-TPO levels an exact determination of TPO could not be estimated correctly. Whenever a correct measurement of TPO was possible, to none of the different examined groups of thyroid diseases a correlation of TPO-levels could be demonstrated. Moreover, the value of TPO determination as a tool in the follow-up of differentiated thyroid carcinoma was not provable. For the time being our studies do not suggest TPO measurements being helpful in thyroidal diagnosis.

[Impact of pretreatment variables on the outcome of standardized 131I therapy with 150 Gray in Graves' disease]. / Einfluss prätherapeutischer Variablen auf die Wirkung einer standardisierten 131J-Therapie mit 150 Gray beim Morbus Basedow.

AIM: We examined the impact of several pretreatment variables on thyroid size and function in 61 patients with Graves' disease one year after a standardized [131]I treatment with 150 Gray. METHODS: FT3, FT4, and TSH serum concentrations were determined before and 1.5, 3, 6, and 12 months after therapy. Thyroid size was measured by ultrasound and scintigraphy before and one year after therapy. RESULTS: One year after therapy, 30% of the patients had latent or manifest hyperthyroidism, 24% were euthyroid, and 46% had developed latent or manifest hypothyroidism. Age and initial thyroid volume were major predictors of post-therapeutical thyroid function. Thus, persistent hyperthyroidism was observed in 70% of the patients age 50 years and older with a thyroid size of more than 50 ml. With few exception, thyroid size markedly decreased after therapy. Initial thyroid size and age were also major predictors of posttherapeutical thyroid volume. Thyroid size normalized in all patients younger than 50 years of age, independent from initial thyroid size. CONCLUSION: Radioiodine treatment with 150 Gray causes a considerable decrease in thyroid size in most patients with Graves' disease. Age and initial thyroid volume are important determinants of thyroid function and size after therapy and should be considered in dose calculation.

[Semiquantitative 99mTc-HMPAO SPECT in dementia of the Alzheimer type: influence of the selection of reconstruction filter and reference region]. / Semiquantitative 99mTc-HMPAO-SPECT bei Demenz vom Alzheimer-Typ: Auswirkungen der Wahl von Rekonstruktions-filter und Referenzregion.

AIM: The aim of the study was to clarify, whether the selection of the reference-region and/or the reconstruction-filter influences the result of the semiquantitative analysis of a 99mTc-HMPAO-SPECT that was conducted to diagnose the dementia of the Alzheimer type (DAT). METHODS: A group of 19 DAT-patients according to the criteria of NINCDS-ADRDA and DSM-III-R was examined together with a comparison group (n = 14) with normal cerebral perfusion. Three reference-regions (cerebellum, whole slice, occipital cortex) and four reconstruction-filters (Hanning fc = 0.7 and 1.0 Nyquist; Butterworth (n = 8); fc = 0.5 and 0.9 Nyquist) were applied to twelve standardized regions of interest (per patient) respectively. The data was evaluated through a ROC-analysis. RESULTS: It has been showed, that the bilateral parieto-temporal perfusion reduction as a characteristic of DAT depends on the filters and reference-regions used. The most secure separation of both groups of patients was obtained through a Butterworth-filter (n = 8; fc = 0.5) in combination with the cerebellum as reference-region. CONCLUSION: The selection of the reference-region and the reconstruction-filter has an important influence on the results of a semiquantitative analysis. Therefore standardisation in dependency on the actual questioning is necessary.

[99m-Tc-MIBI for recurrent and metastatic differentiated thyroid carcinoma]. / 99mTc-MIBI zur Rezidiv- und Metastasensuche bei differenzierten Schilddrüsenkarzinomen.

AIM: The aim of the study has been the examination of the diagnostic value of 99mTc-MIBI scintigraphy for the detection of local tumor or metastases following total thyroidectomy and 131I ablation therapy in differentiated thyroid carcinoma. METHODS: MIBI-scintigraphy has been indicated in 85 patients because of ascending thyroglobulin values or suspected local recurrencies by ultrasonography. The results have been compared to cytology or histology or ultrasonography, computed tomography, X-ray and radioiodine scanning. RESULTS: MIBI scintigraphy was found positive in 32 of 40 metastases. Only 18 metastases have been seen by radioiodine. MIBI scintigraphy was most effective in detecting local tumor recurrencies and lymph node metastases (94%). The specificity of MIBI and radioiodine was similar (100%). In inflammatory enlarged lymph nodes no MIBI uptake was found, so it is possible to differentiate reactive lymph node enlargement from metastatic disease. CONCLUSION: In conclusion scintigraphy with 99mTc-MIBI is advisable in suspected local recurrencies and negative radioiodine scan. It is favourable that withdrawing TSH-suppressive hormone medication is not necessary.

Chylothorax in a twin pregnancy of 34 weeks--sonographically diagnosed.

In a twin pregnancy of 34 gestational weeks sonographic follow-up revealed a rapidly spreading hydrothorax in one twin and slight ascites in the other. Analysis of aspirated fluid by intrauterine needle puncture suggested a chylothorax. Pathogenesis of chylothorax is discussed. Differential diagnosis of hydrothorax is presented. Intrauterine puncture is the only method of achieving prenatal diagnosis and therapy.

Imaging in osteomyelitis in the growing skeleton.

In acute osteomyelitis of childhood a rapid diagnosis and initiation of antibiotic therapy is necessary in order to prevent late sequelae. Thus, diagnostic imaging plays a crucial role. If acute osteomyelitis is suspected in a child, imaging starts with conventional radiography in order to exclude other differential diagnoses. This is followed by sonography for the purpose of diagnosing a subperiosteal abscess or joint fluid from which the causative organism could be isolated. If the diagnosis is unclear, the next step should be either MRI or 99m Tc-MDP bone scan, depending on the possibility of clinical localization and the site of the suspected lesion. MRI is superior to bone scan in depicting the exact anatomy, which is extremely important in spinal osteomyelitis and preoperatively. The bone scan can show the whole skeleton in one examination and should be favored if there is no definite localization or in suspected multifocal osteomyelitis. Rarely scintigraphy with labeled white blood cells is indicated. The 67 Ga scan, however, should not be used in children because of the high level of radiation exposure. The different imaging modalities are described in detail and an imaging diagnostic workup is outlined.

[Purpose and usefulness of the present day risk catalog (author's transl)]. / Sinn und Nutzen des derzeitigen Risikokataloges.

Risk catalogs have proved to be an important instrument of preventive medicine for the identification of pregnancies at risk. Their purpose and usefulness is beyond all doubt. Nevertheless problems of principle are attached to them since they deflect the attention from the living reality of the individual case to statistically formed collectives. The importance of the problems for risk catalogs changes according to the social change and the constantly improved perinatal results. Age, parity and socioeconomic risks reflect such trends in development most clearly. Future tasks lie in the quantification of risks by differentiating the degrees of severity. A certain intrinsic dynamism of the present risk catalogs leads, e. g. to a constantly increasing incidence of sections. For this reason a constant feedback must exist between risk catalog and statistics.

[Unexpected risks during labour and delivery following a low risk pregnancy (author's transl)]. / Unvorhergesehene Geburtsrisiken nach risikofreier Schwangerschaft.

Of the maternity patient of the Munich perinatal study from 1975-1977 54.4% were considered to be low risk at the end of the pregnancy. Of these every third patient (17%) developed at least one risk during labour and delivery. These were considered to be consequence risks if they and been present at the onset of labour and delivery or progress risks if they developed during labour and delivery. The progress risks were defined as unpredictable and occurred in 4.7% of the total study. In this group the incidence of spontaneous delivery was only 36.0% compared with 88.5% in the compare group. The perinatal mortality of 6.9% was three times higher than for women who remained low risk during labour and delivery. The commonest unpredictable risks are anomalies of presentation. Acidosis and pyrexia during labour and delivery and emergency risks occur most often in women who start labour and delivery with existing risks. For these so-called progress risks with a high incidence of operative deliveries an operating room must be available at all times in the interest of mother and fetus. The monitoring of the fetus must also be available. Even following a low risk pregnancy monitoring and operation may become necessary.

[Ultrasound diagnoses and cardiotocography in case of full-time carried intraligamentous gravidity (author's transl)]. / Ultraschalldiagnostik und Kardiotokographie bei einer ausgetragenen intraligamentären Schwangerschaft

Description of the course of disease concerning an intraligamentous pregnancy carried to full term, but diagnosed only during operation. Subsequent evaluation of the ultrasonic and cardiotocologic graphs. Constantly rectilinear pressure curves without uterine activities are interpreted as characteristic tocographic criteria of an advanced ectopic gravidity.

[Ultrasound in the differential diagnosis of Wilms tumors (author's transl)]. / Ultraschall in der Differentialdiagnose des Wilms-Tumors

The usefulness of ultrasound for distinguishing between Wilms tumor and hydronephrosis is shown in a case where radiographic signs were not clear. Ultrasound always permits differentiation between cystic and solid tumors.

[Pregnancy and birth after jejunoileostomy because of adiposity (author's transl)]. / Schwangerschaft und Geburt nach Jejunoileostomie wegen Adipositas.

Five pregnancies in two patients after jejunoileal bypass because of adiposity are reported. One pregnancy ended with a spontaneous abortion of two dystrophic children one died postpartum after a pregnancy complicated by cholecystectomy, cholangitis and pancreatitis. The extent of postoperative weight loss acquires a certain importance in assessing the risk of dystrophy to the child.

[The reticuloendothelial system. An overview of function, pathology and recent methods of measurement]. / Das retikuloendotheliale System. Eine Ubersicht über Funktion, Pathologie und neuere Messmethoden.

The Reticuloendothelial System (RES) consists of cells descending from the monocytes which are able to perform phagocytosis of foreign materials and particles. 90% of the RES are located in the liver. The most important function of the RES ist phagocytosis, but it also takes part in cytotoxicity against tumor cells and has a function in the regulation of the immune system. The importance of the RES is obvious in diseases of the bile ducts. An obstruction can lead to a decrease in the function of the RES. Beside a mathematical model there are also a few experimental methods to measure the phagocytic capacity and thus the efficiency of the RES. They are based on a clearance study of the amount of particles absorbed by the RES. This study can e.g. be done with Nanocoll which has been marked with 99mTc. But instead of the bloody clearance, a scintigraphic study using a gamma camera can be performed. With that, the increase time, the liver extraction fraction and the steepness of increase can be determined. Such a test could be of clinical relevance as a parameter for the prognosis of patients with trauma, sepsis or shock. The function of the RES in the pathogenesis of the biliary pancreatitis could also be examined closer with the help of such a test. The requirements a test of the RES should meet are reproducibility, repeatability and practicability.

[Osteomyelitis during the growth period. Diagnostic imaging]. / Osteomyelitis im Wachstumsalter. Bildgebende Diagnostik.

In acute osteomyelitis of childhood a rapid diagnosis and initiation of antibiotic therapy is necessary in order to prevent late sequelae. Thus, diagnostic imaging plays a crucial role. If acute osteomyelitis is suspected in a child, imaging starts with conventional radiography in order to exclude other differential diagnoses. This is followed by sonography for the purpose of diagnosing a subperiosteal abscess or joint fluid from which the causative organism could be isolated. If the diagnosis is unclear, the next step should be either MRI or 99mTc-MDP bone scan, depending on the possibility of clinical localization and the site of the suspected lesion. MRI is superior to bone scan in depicting the exact anatomy, which is extremely important in spinal osteomyelitis and preoperatively. The bone scan can show the whole skeleton in one examination and should be favored if there is no definite localization or in suspected multifocal osteomyelitis. Rarely scintigraphy with labeled white blood cells is indicated. The 67Ga scan, however, should not be used in children because of the high level of radiation exposure. The different imaging modalities are described in detail and an imaging diagnostic workup is outlined.

[Partial hydatidiform mole with significantly increased serum HCG levels in the triploidy syndrome]. / Die partielle Blasenmole mit stark erhöhten Serum-HCG-Spiegeln beim Triploidie-Syndrom.

The authors report on a triploid pregnancy with foetal malformations and a sonographically diagnosed partial hydatit mole. The course of this pregnancy was characterised by pre-eclampsia. The fact that in this case, for example, HCG serum levels were very high and persisted post abortum, similar to the concentrations seen in complete hydatit mole, underlines the difficulties in assessing and diagnosing a partial hydatit mole.

[Time sequence of risks. a new approach to weighting perinatal perils (author's transl)]. / Das zeitliche Gefüge der Schwangerschafts- und Geburtsrisiken. Ein neuer Ansatz zur Gewichtung perinataler Gefährdung.

In the Munich area from 1975 to 1977 37.3% of 55089 women came to birth without any risk, 7.4% with anamnestic risks (i.e. existing before pregnancy), 12.1% with gestational risks acquired during pregnancy, 4,0% with anamnestic and gestational risks. In 17,0% risks were developed at first during delivery. 4.0% of the pregnant women had anamnestic and birth risks, 12.6% gestational and birth risks, and 5.5% anamnestic and gestational and birth risks. There were remarkable interrelationships between the combination of risks, obstetrical management and outcome (perinatal mortality and infant transferral rate as a crude measure of neonatal morbidity). Anamnestic risks are followed by gestational risks with a chance of 50%. If pregnancy began without risks the probability of gestational risks is approximately 33%. Some distinct anamnestic risks considerably contribute to cesarean section rate. Risks solely occurring during pregnancy have a rather low perinatal mortality (6%o compared to 2%o of riskfree pregnancies). The combination of gestational and birth risks increases perinatal mortality and neonatal morbidity by a factor of 10. This increase is due to some "mortgage-risks", i.e. impairments which are still present at birth. Among those risks conditions most often associated with threatening preterm delivery predominate. Pregnant women who develop such persisting risks should be transferred to a perinatal center.

Dynamic liver scintigraphy: a new way of measuring the function of the reticuloendothelial system of the liver.

The phagocytic function and biokinetics of the hepatic reticuloendothelial system (RES) were evaluated using a 25-nm diameter colloid (Nanocoll) and a scintillation camera technique in opossums with obstruction of the pancreatic duct (group I) and additional obstruction of the common bile duct (group II). The liver net uptake curve was analysed using natural log regression. The regression curves proved to fit very well (r > 0.93) and a parameter R was calculated to describe the curves. In group I there was a slight but significant decrease in the RES function and no morphological change in the pancreas. In group II, RES function was significantly more suppressed than in group I. The opossums developed severe haemorrhagic pancreatitis. The results show that the regression parameter R is well suited to described liver RES function, and suggest that a suppressed liver RES after biliary obstruction could be an important factor in the pathogenesis of biliary pancreatitis.

Reticuloendothelial system blockade promotes progression from mild to severe acute pancreatitis in the opossum.

OBJECTIVE: To examine the relation between hepatic reticuloendothelial system (RES) dysfunction and the development of acute biliary pancreatitis. In an opossum model, the authors tested the hypothesis that RES blockade can turn the mild pancreatitis seen after pancreatic duct obstruction (PDO) into the severe form. SUMMARY BACKGROUND DATA: Biliary obstruction is considered the decisive event in gallstone pancreatitis. Suppression of the RES occurs during biliary obstruction. METHODS: Eighteen opossums were placed into three groups of six animals each: group A, RES blockade with lambda-carrageenan; group B, PDO; and group C, PDO and RES blockade with carrageenan. The severity of pancreatitis was evaluated by enzyme serum levels and percentage of pancreatic tissue necrosis. RES capacity was measured by dynamic liver scintigraphy, and hepatic blood flow was documented using the hydrogen clearance technique. RESULTS: No changes in hepatic blood flow occurred in groups A to C. RES capacity was suppressed in groups A and C; in group B, RES function remained unchanged. In group A, amylase and lipase levels remained normal, 3 +/- 1.9% of pancreatic tissue were necrotic. The animals in group B developed mild edematous pancreatitis with an increase in amylase and lipase levels and 15 +/- 10% of pancreatic necrosis. In group C, amylase and lipase increased significantly and histology revealed severe necrotizing pancreatitis, with 72 +/- 11% of necrotic areas. CONCLUSIONS: Artificial RES blockade can promote the progression from mild pancreatitis as observed after PDO to the severe necrotizing form of the disease. Thus, RES dysfunction resulting from biliary obstruction might be an important cofactor in the pathogenesis of bile-induced pancreatitis.

[Influence of hormonal contraceptives upon carbohydrate metabolism in women with abnormal glucose assimilation during previous pregnancy (author's transl)]. / Einfluss hormonaler Kontrazeptiva auf den Kohlenhydratstoffwechsel bei Frauen mit abnormer Glukoseassimilation in vorausgegangener Schwangerschaft

Carbohydrate metabolism was examined--by means of the 100-gm-glucose standard tolerance test--in 23 patients showing a decrease in glucose tolerance during pregnancy; the examinations were carried out postpartum and after a three months' intake of a hormonal contraceptive (compound preparation: mestranol 0.1 mg, lynestrenol 1.0 mg). The peak values and the two-hour-values, being statistically significant, showed a normalization after delivery, and furthermore again a deterioration of glucose tolerance during the intake of the preparation. A remarkable increase in weight, as a possible cause for the dysbolism during contraception, was not observed.

PIP: Carbohydrate metabolism was examined (100-gm-glucose standard tolerance test) in 23 patients showing a decrease in glucose tolerance during pregnancy; the examinations were carried out postpartum and after a 3 months' intake of a hormonal contraceptive (compound preparation; mestranol .1 mg, lynestrenol 1.0 mg). The peak values and the 2-hour values, being statistically significant, showed a normalization after delivery, and then a deterioration of glucose tolerance during the intake of the preparation. A remarkable increase in weight, as a possible cause for the dysbolism during contraception, was not observed.