Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis.

We have investigated the expression of cyclin D1 in adenocarcinoma of the pancreas and the relevance of cyclin D1 expression to clinical outcome. In comparison to normal pancreas, Southern blot analyses revealed amplification of the cyclin D1 coding gene in 25% of the cases, whereas with reverse transcription-PCR, overexpression of mRNA was observed in 82% of the examined tissues. Immunohistochemically, we could demonstrate nuclear overexpression in tumor cells in 68.4%, and this protein accumulation correlated significantly with poor prognosis [median survival, 18.1 versus 10.5 months; P < 0.01 (chi2 test)].

A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant syndrome in which eyelid malformation is associated with (type I BPES) or without premature ovarian failure (type II BPES). Mutations of a putative winged helix/forkhead transcription factor FOXL2 account for both types of BPES. We report on a 16-year-old adolescent girl with blepharophimosis and ptosis. Subsequently she developed oligomenorrhea, secondary amenorrhea for 6 months, and an extremely large cyst of one ovary. The cyst contained 8 l of cyst fluid and histopathology displayed a large corpus luteum cyst. Following laparotomy, gonadotropin levels were elevated (LH 17.2 U/l, FSH 29.4 U/l) and estradiol levels decreased (67 pmol/l). Because of clinical aspects of BPES and abnormal ovarian function we suspected a mutation of her FOXL2 gene and found a new in-frame mutation (904_939dup36) on one allele, leading to a 12 alanine expansion within the polyalanine domain. We conclude that the FOXL2 mutation 904_939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst. In contrast to known FOXL2 mutations with polyalanine expansions and association with BPES type II, clinical aspects of our girl may indicate some degree of ovarian dysfunction that might finally lead to BPES type I with premature ovarian failure.

Portal vein thrombosis: etiology, diagnostic strategy, therapy and management.

Myeloproliferative disorder, liver cirrhosis with portal hypertension, deficiency of natural anticoagulant proteins, gene mutation and hepatocellular carcinoma are the most frequent causes of portal vein thrombosis (PVT). Higher accuracy of the diagnostic methods is the reason why today the cause of PVT can be found more frequently. With imaging methods, PVT with or without cavernous transformation can be diagnosed. Fresh thrombus can be undetected in sonography due to the low echogenity but can be recognized in color Doppler sonography, especially with contrast-enhancing agent. Contrast-enhanced 3D MR angiography allows a comparable accuracy in the detection of PVT as digital subtraction angiography. Therapeutical options of PVT consist of mechanical recanalization of the portal vein, local fibrinolysis with or without placement of transjugular intrahepatic portosystemic stent shunt (TIPS), combination of mechanical recanalization and local fibrinolysis, systemic thrombolytic therapy, anticoagulation alone and surgical thrombectomy. Once PVT is found in sonography, Doppler sonography may be performed in order to distinguish benign from malignant thrombus. If further information is needed, MR angiography or contrast enhanced CT is the next step. If these tests are unsatisfactory, digital subtraction angiography should be performed. Until the early nineties, shunt surgery was recommended in patients with PVT who bled despite endoscopic treatment. Today, in symptomatic noncavernomatous PVT, recanalization with local methods is recommended. Additional implantation of TIPS should be performed when the patient is cirrhotic. In recent PVT in non-cirrhotic patients anticoagulation alone is recommended. It is expected that in old PVT anticoagulation can prevent further extension of the thrombus.

[Automated speech recognition for the generation of medical records in computed tomography]. / Digitale Spracherkennung bei der Erfassung computertomographischer Befundtexte.

PURPOSE: A study was performed to compare the performance of automatic speech recognition (ASR) with conventional transcription. MATERIALS AND METHODS: 100 CT reports were generated by using ASR and 100 CT reports were dictated and written by medical transcriptionists. The time for dictation and correction of errors by the radiologist was assessed and the type of mistakes was analysed. The text recognition rate was calculated in both groups and the average time between completion of the imaging study by the technologist and generation of the written report was assessed. A commercially available speech recognition technology (ASKA Software, IBM ViaVoice) running on a personal computer was used. RESULTS: The time for the dictation using digital voice recognition was 9.4 +/- 2.3 min compared to 4.5 +/- 3.6 min with an ordinary Dictaphone. The text recognition rate was 97% with digital voice recognition and 99% with medical transcriptionists. The average time from imaging completion to written report finalization was reduced from 47.3 hours with medical transcriptionists to 12.7 hours with ASR. The analysis of misspellings demonstrated (ASR vs. medical transcriptionists): 3 vs. 4 for syntax errors, 0 vs. 37 orthographic mistakes, 16 vs. 22 mistakes in substance and 47 vs. erroneously applied terms. CONCLUSIONS: The use of digital voice recognition as a replacement for medical transcription is recommendable when an immediate availability of written reports is necessary.

Functional characterization of a heterozygous GLI2 missense mutation in patients with multiple pituitary hormone deficiency.

CONTEXT: The GLI2 transcription factor is a major effector protein of the sonic hedgehog pathway and suggested to play a key role in pituitary development. Genomic GLI2 aberrations that mainly result in truncated proteins have been reported to cause holoprosencephaly or holoprosencephaly-like features, sometimes associated with hypopituitarism. OBJECTIVE: Our objective was to determine the frequency of GLI2 mutations in patients with multiple pituitary hormone deficiency (MPHD). DESIGN: Patients were selected from participants in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) program. Patients with mutations within established candidate genes were excluded. PATIENTS: A total of 165 patients with MPHD defined as GH deficiency and at least 1 additional pituitary hormone deficiency were studied regardless of the presence of extrapituitary clinical manifestations. MAIN OUTCOME MEASURES: Prevalence of GLI2 variations in MPHD patients was assessed and detailed phenotypic characterization is given. Transcriptional activity of identified GLI2 variants was evaluated by functional reporter assays. RESULTS: In 5 subjects, 4 heterozygous missense variants were identified, of which 2 are unpublished so far. One variant, p.R516P, results in vitro in a complete loss of protein function. In addition to GH deficiency, the carrier of the mutation demonstrates deficiency of thyrotrope and gonadotrope function, a maldescended posterior pituitary lobe, and polydactyly, but no midline defects. CONCLUSIONS: For the first time, we show that heterozygous amino acid substitutions within GLI2 may lead to MPHD with mild extrapituitary findings. The phenotype of GLI2 mutations is variable, and penetrance is incomplete. GLI2 mutations are associated with anterior pituitary hypoplasia, and frequently, ectopy of the posterior lobe occurs.

Imaging and radiological interventions of portal vein thrombosis.

Portal vein thrombosis (PVT) is diagnosed by imaging methods. Once diagnosed by means of ultrasound, Doppler ultrasound can be performed to distinguish between a benign and malignant thrombus. If further information is required, magnetic resonance angiography or contrast-enhanced computed tomography is the next step, and if these tests are unsatisfactory, digital subtraction angiography should be performed. Many papers have been published dealing with alternative methods of treating PVT, but the material is fairly heterogeneous. In symptomatic non-cavernomatous PVT, recanalization using local methods is recommended by many authors. Implantation of transjugular intrahepatic portosystemic shunt is helpful in cirrhotic patients with non-cavernomatous PVT in reducing portal pressure and in diminishing the risk of re-thrombosis. In noncirrhotic patients with recent PVT, some authors recommend anticoagulation alone. In chronic thrombotic occlusion of the portal vein, local measures may be implemented if refractory symptoms of portal hypertension are evident.

[Alcohol and hematopoiesis]. / Alkohol und Hämatopoese.

In a survey of quantitative and qualitative changes of blood and blood-forming cell systems by big consumption of alcohol is informed about the frequency of such lesions and the importance of additional substances of alcohol, particularly of the fusel oils with their cancerogenic, mutagenic, hepato- and haemototoxic effects. The alcohol-conditioned lesions of the erythrocytopoiesis with disturbances of maturation by deficiency of folic acid under formation of a megaloblastosis, the alcoholinduced disturbances of the iron metabolism with increase of the sideroblasts as well as the formation of vacuoles in the cytoplasm of the proerythroblasts are discussed. In this connection the symptomatic anaemias, caused by alcoholic liver lesion and its sequelae as well as by ulcerous haemorrhage, particularly also of Zieve's syndrome, are discussed. Functional disturbances of the granulocytes and granulocytopenias are to be brought into connection with the particular susceptibility to infections of patients suffering from alcoholism. Functional disturbances of the thrombocytes and thrombocytopenias, to be sure, rarely lead to a haemorrhagic diathesis, deserve, however, more consideration as possible causing factors in apoplexias under big consumption of alcohol. On principle the direct alcohol-toxic (at least ethanol-toxic) defects of haemotopoiesis are reversible for a short time.

[Risk factor benzene (author's transl)]. / Risikofaktor Benzol.

Nearly one hundred years ago clinical and epidemiological studies have already assigned benzene as a markedly haematotoxic substance. Nowadays benzene is known as an important professional noxa, which is straight off directed against the haematopoietic system, essentially to a dose-time-effect. By this it can be taken as a model also for other noxious substances. Similar solvents often contain so-called "hidden benzene", that means not declared benzene, so that the consumer don't know what dangerous substance are available for his personal use. Impairment caused by benzene mostly are manifested earliest after months, years or for tens of years, and the point is, that these haematopoietic disorders are irreversible disturbances of the haematopoietic stem cell compartment. The consequence of this fact is a deep involvement of the proliferation of the erythro-, mono-, granulo- and thrombopoietic cell lines, mostly with the predominance of one of these myeloproliferative cell systems. In the further progression of the impairments due to benzene three different clinical pictures can be observed: the aplastic bone marrow syndrome (i.e. aplastic anemia), the haematopoietic dysplasia (i.e. preleukemia) and the acute leukemias (with the subtypes erythroleukosis, myeloblastic-promyelocytic or myelomonocytic from respectively). Also the transition from one clinical picture to another is possible.

[Cytogenesis and cytomorphology of the Hodgkin- and Sternberg-Reed cells]. / Zur Zytogenese und Zytomorphologie der Hodgkin- und Sternberg-Reed-Zellen.

As well the pathogenesis of the lymphogranulomatosis, the cytogenesis of the Hodgkin- and Sternberg-Reed-cells is still an unsolvable problem too. The priority in the discussion of this question have such hypothesis, in which a descend of these cells either from the lymphocytic or the monocyte-macrophage-system is important. The karyokinesis of the Hodgkin cells leads actually to the growth of the nucleus and the whole cell, but the formation of the Sternberg-Reed-cells in their property as gigantic cells means a "blind alley", connected with a blockade in their farther proliferation. The cytomorphology of the Hodgkin-cells and the causes for the formation of the Sternberg-Reed-cells with their multiform, partial bizarre nuclei will be discussed. In the consequence of anomalies of the mitosis, produced by so called disturbances of the spindle, several "partial nuclei" arise. These partial nuclei have the property to make partly a fusion together. In this connection the different shapes of the nuclei of the Sternberg-Reed-cells will be explained.

[Standard methods in a hematologic laboratory--a prerequisite for an optimal diagnosis]. / Standardisierte Methoden im hämatologischen Laboratorium--Voraussetzung einer optimalen Diagnostik

State of scientific knowledge and economic prerequisites determined the selection of the optimum methods for the necessary parameters in standardizing haematologic methods. Concerning the methods of counting, measuring and staining in the haematologic laboratory, we have to do above all with so-called conventional methods with an expenditure of work considerable in most cases. In the single steps necessary for obtaining a laboratory result the physician in a clinic or outpatient department essentially participates particularly in such cases when EDTA venous blood is applied. It is especially referred to the advantage of EDTA venous blood for taking blood samples for haematologic parameters compared with the taking of capillary blood which has a high rate of error. Apart from the common efforts of physicians in clinics or out-patient departments and laboratory physicians to obtain reliable results of the findings, the use of an improved technique (particle counters, dilutor, automatic picture analysis among others) as well as further proceedings of standardization (dye for panoptic staining and others) will achieve this aim.

[The number and kind of leukocytes in the saliva (salivary corpuscles) in healthy subjects and in patients]. / Ubersicht uber Zahl und Art der Leukozyten im Speichel ("Speichelkörperchen") bei Gesunden und Kranken.

In the form of a survey a report is given on the concept of the saliva corpuscle, its origin, composition, different degree of damage, its number and function. The quantitative behaviour enables a statement to be made about the actual unspecific cellular defence in parodontopathy (increased number of saliva corpuscles) and in various blood diseases (decreased number of saliva corpuscles. This has a particular diagnostic value.

[Nosology of myeloproliferative disorders]. / Zur Nosologie der myeloproliferativen Erkrankungen.

A nosological description of the myeloproliferative diseases has to demonstrate the characterizing features of the various entities as well as their common characteristics and peculiarities. Here it becomes evident that one must differentiate between diseases with neoplastic proliferation of above all one series of cells (pure cell proliferation) and such one with two or more series of cells (mixed cell proliferation). Transitions from pure cell forms to mixed cell forms and change of the prevailing cell series in mixed cell proliferations, respectively, may be expected like certain terminal results (blastic transformation, myelofibrosis). The proposition of an improved classification demands a correct cytological, cytochemical and histological investigation of the bone marrow as well as repeated analyses of the course.

[Diagnosis of malignant lymphomas]. / Zur Diagnostik der malignen Lymphome.

In the diagnostics of the malignant lymphomas is to be differed between the proper diagnosing, i. e. the morphological confirmation of the disease and the enlarged diagnostics which, after ascertainment of the histologicopathological findings and prior to the beginning of a therapy is necessary for the statement of the size of the spreading of the disease (classification of stages) as well as for the inclusion in group A or B and for the registration of the most different signs of activity. Swellings of the lumph nodes in adults should be clarified morphologically after three weeks, since only on this way an early diagnostics is guaranteed. In an unclear fever an abdominal lymphogranulomatosis is to be excluded. The explorative laparotomy and splenectomy is - if possible - to be performed before the beginning of a treatment. When pronounced signs of activity are present, however, a cytostatic treatment should precede this operation in order to decrease the risik of the operation. The classification in stages with exclusively clinical examination methods at present comprises a vast number, which in all stages must always be performed as an interdisciplinary task in a haematologico-oncological centre under control of an internist. The classification after Kiel of the non-Hodgkin-lymphomas does not only demand the knowledge of the nomenclature, but also the evaluation by the internist in order to perform the optimum therapy in these patients.

[Rational hematologic diagnosis with reference to modern laboratory procedures]. / Rationale hämatologische Diagnostik unter Berücksichtigung moderner Laboratoriumsverfahren.

The spectre of methods for the diagnostics and differentiation of haemolytic anaemias, particularly for the establishment of congenital, autoimmune haemolytic, drug-conditioned and other anaemias is treated. The clear delimitation of an iron deficiency from a disturbance of the iron distribution is advantageously to be achieved by iron staining of the bone marrow and by a determination of serum ferritin. The value of the diagnostic methods in megaloblastic anaemia is classified according to newer knowledge, in which case the vitamin-B12-absorption test and the serum level determination of vitamin B12 by no means range in the first place. Long-term culture results of haematopoietic stem cells are particularly evident in the aplastic syndrome of the bone marrow and further haematological diseases concerning the establishment of the intensiveness of proliferation. The classification of the acute leukemias demands conventional as well as cytochemical staining methods; recently, it is essentially improved using monoclonal antibodies. In leukemias cytogenetic investigations are more and more attracted to the estimation of the prognoses. In lymphogranulomatosis among others functional disturbances of the cellular immunity, in the group of the non-Hodgkin-lymphomas haematological, protein-analytic and immunological laboratory investigations are methods supporting the diagnosis. Altogether is to be established that the haematological diagnostics has become more and more perfect, in which case apart from new techniques old approved methods are still further used.

[Methods and techniques of sampling and performing of cytologic lymph node smears (author's transl)]. / Methodisch-technisches Vorgehen bei der Gewinnung und Anfertigung zytologischer Präparate von Lymphknoten.

Within the diagnostics of lymphoma the indication for cytodiagnosis and the coice of gaining material and its preparation (punction and exstirpation of lymph nodes with making smears in a squeezing manner to effect simulated tissue pattern) are the basis of an appropriate and effective work of the cytologist. The good diagnostic efficiency of the cytodiagnosis of lymph nodes is in no proportion to the totally insufficient application of those methods by physicians of various medical disciplines in the hospitals and outpatient departments. The lack of an adequate teaching of students and postgraduates is a main reason for the described situation. In order that each physician may have the possibility to apply the cytodiagnosis of lymph nodes within his diagnostic programms, some special references are given for the gaining and preparation of lymph node material.

[Determination of capillary lesions during diagnosis by means of the tourniquet test of microangiopathies in diabetes mellitus]. / Zum Nachweis von Kapillarschäden im Rahmen der Mikroangiopathie-Diagnostik beim Diabetes mellitus mittels Stauversuchs.

Decreased capillary resistance is documented by a pathologic tourniquet test (Rumpel-Leede), which demonstrates the existance of microangiopathy in diabetics. Thanks to its simple and rapid execution the tourniquet test is suitable for early diagnostic assessment of the situation in the microcirculation. The longer the patients have had diabetes, the more frequently is the tourniquet test pathological. There is also a direct correlation between the type of therapy (as an index of the severity of the disease) and the accumulation of pathologic results in measurement of capillary resistance. In diabetics with hypertension, capillary resistance is always decreased to a pathologic degree.

[Bone marrow capacity and reaction]. / Knochenmarkkapazität und -reaktion.

The formation of the blood cells leads via proliferation, differentiation and maturation processes, in which cases the bone marrow capacity expresses the functional capacity of this comprehensive system of cell renovation. Nowadays clues to the quantitative behaviour of proliferation of the various compartments (stem cell compartment, indicator cell compartment and morphologically characterizable cell compartment) are already existing also for man, in which cases various proliferation-kinetic tests give adequate informations. Via a quantitative determination of the granulocytes of the bone marrow an estimation of the postmitotic bone marrow storage of the granulocytopoiesis is at present possible. The responsiveness of the neutrophil granulocytes after stimulation (glucocorticoids, endotoxin) may be used in the clinic as bone marrow functional test with restricted statement. The diagnostic possibilities of the agar-colony-technique for the judgment of the bone marrow capacity are represented on the basis of an instance.

[Diagnosis and therapy of iron overload with desferrioxamine]. / Einige Aspekte zur Diagnostik und Therapie der Eisenüberladung mit Desferrioxamin.

In polytransfused patients the diagnostics of the iron overload belongs to the strategic programme of the treatment. It is particularly referred to the value of the desferal test. In the therapy of the transfusion haemosiderosis desferrioxamine is the remedy of choice. Its at present most favourable form of application is the subcutaneous infusion by means of the infusion group. A success of the treatment is only to be guaranteed, when the therapy is consequently performed over years under balancing the iron supply and excretion.

[Cytogenetic findings in acute myelogenous leukemias (FAB M 1 to M 6)]. / Zytogenetische Befunde bei akuten myeloischen Leukämien (FAB M 1 bis M 6).

The results published in the period from 1973 to 1983 entitled "Cytogenetic findings in acute myeloic leukemias" (M 1 to M 6 of FAB classification) were compiled. In 50-60 per cent of those patients affected with acute myeloic leukemia a deviating karyotype could be detected. With a markedly higher frequency chromosomes 8 and 21 will take part in aberrations, with translocations (8; 21) having the main share with about 30-40 per cent. More than half the male bearers of translocation exhibits a loss of the Y-chromosome, a third of female patients a loss of the X-chromosome. Trisomy 8 and 9 as well as monosomy 7 appear in about 20 per cent. These aberrations can also be found in all other leukemic and preleukemic processes. Patients with karyotypic abnormalities in all their cells will have the slightest average survival time and the worst appeal to therapy. The sole appearance of monosomy 7 or Ph1-chromosome respectively seems to be an unfavourable sign from a prognostic point of view. Children with acute myeloic leukemia will possess an aberrant karyotype more frequently than adults, but they have a longer average life, boys are more frequently affected by this. Acute promyelocytic leukemia can be characterized cytogenetically in 94 per cent of the cases by translocation (15; 17). However, distinct geographical differences can be observed here, the causes of which have not been elucidated. About 40 per cent of the patients with acute myelo-monocytic leukemia developed aberrations. Further investigations will have to show whether the chromosome 11 really took part in it somewhat more frequently than merely at random. Chromosome anomalies have not a visible influence on the course of the disease. In 30-40 per cent of patients with a rarely occurring acute monocytic leukemia, an abnormal karyotype could be found. There was an incidence of 47 per cent for a specific translocation (9; 11) or a similar variant respectively. Erythroleukemia is characterized by a high instability of chromosomes and karyotypical variability, particularly in erythrocyte precursors and by an average survival time of one months. Megakaryoblastic and eosinophilic leukemia are very rare kinds of acute leukemias. The small number of publications allows no general statement to be made concerning karyotypical changes.