Continuous complete hematological and cytogenetic remission with molecular minimal residual disease 9 years after discontinuation of interferon-alpha in a patient with Philadelphia chromosome-positive chronic myeloid leukemia.

Interferon-alpha has been used as standard therapy for patients with Philadelphia-positive chronic myeloid leukemia (CML) for more than 20 years. Recently randomized trials have shown a superiority of the tyrosine kinase inhibitor imatinib in respect to its efficacy to induce complete hematological and cytogenetic remissions and more importantly in overall survival. Although follow-up is much shorter for imatinib than for interferon-alpha, this data changed the treatment algorithms in this disease. At the end of the era of interferon-alpha as a single-drug first-line treatment for most patients we present a case report which exemplifies a rare but exciting property of interferon-alpha in CML: the induction of complete hematological and cytogenetic remissions which can persist over years after discontinuation of the drug. Hence, the enrollment of CML patients in clinical trials which explore a combination treatment of imatinib and interferon-alpha is warranted.

[Endoscopic removal of an intraluminal duodenal diverticulum in an adult with upper abdominal pain]. / Endoskopische Spaltung eines intraluminalen Duodenaldivertikels beim Erwachsenen wegen Oberbauchbeschwerden.

We report here on a 44-year-old previously healthy patient with a two-year history of intermittent upper abdominal pain. In the outpatient gastroduodenoscopy and X- ray examinations of the small intestine an intraluminal duodenal diverticulum was suspected. Clinical examination and laboratory tests did not show any abnormal findings. In order to exclude other causes for the patient's complaints coloscopy, ERP and MRCP were performed. The latter was done because the bile duct could not be intubated in the ERCP due to the altered anatomy. By use of endoscopic ultrasound a mucosal duplication was demonstrated and thus the diagnosis confirmed. Subsequently, the diverticulum sac was sliced by argon plasma coagulation. The postinterventional course was without complications and the patient was without symptoms afterwards. The intraluminal duodenal diverticulum is a rare differential diagnosis of pain in the upper abdomen. The diverticulum should be endoscopically removed if other causes for abdominal pain have been ruled out and possibly associated malformations have been excluded.

[Posthepatic icterus caused by a solitary granular cell tumor of the common bile duct]. / Posthepatischer Ikterus durch einen solitären Granularzelltumor des Ductus choledochus.

We report a case of a 26-year-old female patient who was referred to our hospital with a painless jaundice. By means of an ERCP we found a nearly complete occlusion of the common bile duct caused by a tumor. After stenting and normalization of the cholestasis parameters, additional investigations such as endosonography, cholangioscopy and MR angiography no longer showed any manifestation of the tumor. The histological and cytological specimens did not confirm a malignant process. As there was apparently only a solitary tumor a resection according to Whipple was performed. The histological examination showed a granular cell tumor. This case report demonstrates that a posthepatic icterus may rarely be caused by a granular cell tumor. Furthermore, it clearly shows the difficulty to correctly diagnose a tumor in the extrahepatic common bile duct as one may often have to rely solely on imaging procedures.

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

[Toxic liver damage caused by HMG-CoA reductase inhibitor]. / Toxischer Leberschaden durch HMG-CoA-Reduktase-Hemmer.

CASE REPORTS: We report on 4 patients who were referred to the clinic with suspected acute hepatitis and to investigate high transaminase values. After exclusion of specific hepatitis, unspecific virus hepatitis, autoimmune hepatitis, a metabolic disorder damaging the liver and extrahepatic cholestasis, a toxic liver damage remained as the probable cause and was histologically verified. Since other drugs and alcoholics could be eliminated as possible causes of the damage, the toxicity had to be attributed to statin ingestion. CLINICAL COURSE: After discontinuation of the medication with continuation of all other therapeutic agents of the general practitioners, the transaminase values normalized within a few weeks. Renewed administration of statin was not prescribed for ethical reasons. CONCLUSION: Therefore, when prescribing a HMG-CoA-reductase inhibitor, the possibility of liver damage should be mentioned and regular checks of the transaminase values should be performed.

Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary?

Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P = .00004), the German AMLCG requestioned the effect of maintenance randomly compared with sequential high-dose cytosine arabinoside (Ara-C) and mitoxantrone in patients who received intensified induction treatment. The results show an advantage for maintenance treatment (RFS rate of 32%) versus the sequential Ara-C and mitoxantrone treatment (RFS rate of 25%) (P = .021). We conclude that maintenance treatment continues to substantially contribute to the management of adult patients with AML, even as part of recent strategies using intensified induction treatment, and thus appears necessary in these settings.

[Granulomatous hepatitis and myelitis: an unusual manifestation of extrapulmonary sarcoidosis]. / Granulomatöse Hepatitis und Myelitis: Ungewöhnliche Manifestation einer extrapulmonalen Sarkoidose.

Sarcoidosis is a chronic multisystem disorder of unknown cause characterized by the presence of noncaseating epitheloid granulomas and derangement of the normal skin architecture. Though an array of organs may be affected by the disease the most common site of affection is the lung. An extrathoratic manifestation is rare. We describe a 66-year-old patient who was admitted to our hospital because of weight loss and hepatomegaly. A thorough examination revealed the diagnosis of a granulomatous hepatitis characterized by a markedly elevated alkaline phosphatase concentration of 1,490 U/I. A drug-induced hepatitis could be excluded and no evidence was found for the existence of a bacterial or viral infection or an autoimmune disorder. An ERCP revealed a normal common bile duct and normally branching small intrahepatic ducts. The patient was discharged with the diagnosis of a biliary cirrhosis. Half a year later the patient was readmitted to the hospital because of severe intestinal bleeding due to pancytopenia. A bone marrow biopsy showed infiltration of the marrow by granulomas. A histiocytosis X could be ruled out. The diagnosis of an extrathoracic sarcoidosis was assumed and a therapy with prednisone was started. Within six weeks the blood count normalized. After 18 months the serum alkaline phospatase concentration also normalized and no granulomas were found in the bone marrow. The case demonstrates that pancytopenia in sarcoidosis is not due to bone marrow failure.

[Transesophageal endosonographically-guided fine needle aspiration biopsy of mediastinal space-occupying lesions of uncertain importance]. / Die transösophageale endosonographisch gesteuerte Feinnadelaspirationsbiopsie mediastinaler Raumforderungen unklarer Dignität.

BACKGROUND AND OBJECTIVE: Endoscope-guided fine-needle biopsy of mediastinal space-occupying lesions is a recently introduced method of low invasiveness. This is a report of the authors' experience. PATIENTS AND METHODS: Between Nov. 1996 and April 1999 endoscope-guided mediastinal biopsies (Pentax FG 32 UA) were performed in 31 patients (eight women, 23 men; aged 27-80 years). The space-occupying lesion had to be less than 1 cm from the oesophagus and not more easily approachable in other ways. RESULTS: The method was successful in 23 of the 31 patients (74%). In ten of the 31 patients (32%) a malignant lesion was histologically proven. In six patients (19%) sarcoidosis was revealed. Of the eight patients with inadequate biopsy material a malignancy was ultimately diagnosed in three, sarcoidosis in one (in three by mediastinoscopy, in one by laparoscopy). Thus the sensitivity of diagnosing a malignancy was 77%, with a specificity of 100%. Follow-up examinations in the remaining four patients excluded a malignancy. CONCLUSION: Endoscope-guided fine-needle biopsy of mediastinal space-occupying lesions is a technically simple method causing little stress to the patient that can frequently elucidate the lesion's benignity or malignancy. Invasive procedures, such as mediastinoscopy, may thus be avoided in some patients.

The clonal relationship between nodular sclerosis Hodgkin's disease with a clonal Reed-Sternberg cell population and a subsequent B-cell small noncleaved cell lymphoma.

We evaluated the clonal relationship between a case of nodular sclerosis Hodgkin's disease (NSHD) and a small noncleaved cell (SNC) lymphoma that subsequently developed. Single Hodgkin and Reed-Sternberg (H-RS) cells were isolated from immunostained sections of the NSHD by micromanipulation, and the immunoglobulin heavy chain gene (IgH) complementarity determining region (CDR) III of the cells was amplified by the polymerase chain reaction (PCR). A clonal population of H-RS cells was found in the NSHD tumor. The nucleotide sequence of the clonal H-RS cells was compared with the clonal IgH CDRIII sequence from the SNC lymphoma. The two sequences were found to be unrelated. In addition, clone-specific primers and probes were designed from the two clonal IgH CDRIII sequences and used to investigate the presence of the respective clonal population in the NSHD tumor. The latter studies confirmed the presence of a major clonal H-RS cell population, as detected by the single cell assay, but cells corresponding to the SNC clone were not demonstrable by this highly sensitive technique. These findings suggest that the SNC arising in this case represents the development of the second neoplasm clonally unrelated to the preceding NSHD. They also support the recent findings that the H-RS cells in classical HD consist of a clonal population of B cells.

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.

[DNA ploidy and dysplasia in ulcerative colitis--interim analysis of a prospective study]. / DNA-Ploidie und Dysplasie bei Colitis ulcerosa--Interimsanalyse einer prospektiven Studie.

DNA ploidy and cell cycle phases were evaluated by flow cytometry in colonic biopsy specimens from 107 patients with ulcerative colitis in order to analyse the prevalence of DNA aneuploidy as an indicator of numerical chromosomal aberrations and the cell proliferation in all forms of ulcerative colitis. Whereas G2/M-phase fractions in ulcerative colitis and in controls were comparable (2.7 +/- 1.1% vs. 2.8 +/- 1.1%), S-phase fractions in ulcerative colitis exceeded those of controls (7.5 +/- 3.2% vs. 6.5 +/- 2.3%; p < 0.01). In 28 control patients, only diploid DNA histograms existed. Single or multiple aneuploid stem lines were detected in 10 patients with ulcerative colitis (9.3%). Aneuploidy was nearly exclusively associated with pancolitis. Dysplasia was present in 13 patients (indefinite: 8; low-grade: 5), of whom 5 patients also showed DNA aneuploidy. 5 patients with non-dysplastic mucosa exhibited DNA aneuploidy. Because dysplasia and DNA aneuploidy can be discordant and might therefore identify different subgroups at risk, flow cytometry might play a role as a valuable complement to histological examination in surveillance programs of ulcerative colitis.

[Fluorouracil as monotherapy or combined with folinic acid in the treatment of metastasizing colorectal carcinoma]. / Fluorouracil als Monotherapie oder in Kombination mit Folinsäure in der Behandlung des metastasierten kolorektalen Karzinoms.

In a prospective randomized multicentre trial 139 patients with metastatic colorectal carcinoma (70 men, 69 women; age 35-81 years) were given palliative treatment with fluorouracil (400 mg/m2 daily for 5 days) alone or combined with folic acid (100 mg/m2 before each dose of fluorouracil). Both groups were comparable in respect of age, sex, Karnofsky index and number of localisations of metastases. The criterion for starting the treatment was progression of the malignancy or clinical symptoms caused by the tumour. Resulting remission rates (fluorouracil monotherapy vs combination with folic acid) were: complete or partial remission, 9 vs 16%; arrest of tumour growth, 20 vs 60%; progression 71 vs 24%. Peripheral side effects, such as stomatitis and diarrhoea, were similarly frequent with the two treatment regimens and reasonably tolerable. Median survival time for the fluorouracil monotherapy was 7.24 months from onset of treatment, and 9.1 months from the time that any metastases were diagnosed. The combination treatment with folic acid achieved a significantly longer median survival time (P less than 0.0001), 14.98 months from treatment onset and 16.3 months from metastasis diagnosis. The higher rate of response and the significantly prolonged survival time signify an improvement of the therapeutic profile of fluorouracil by addition of folic acid in the palliative therapy of colorectal carcinomas.

[Acquired protein C deficiency in ulcerative colitis. The cause of thromboembolic complications]. / Erworbener Protein-C-Mangel bei Colitis ulcerosa. Ursache thromboembolischer Komplikationen.

Three patients with an acute exacerbation of ulcerative colitis (a 40-year-old and a 31-year-old man and a 30-year-old woman) developed a protein C deficiency (serum protein C activity between 32 and 48%). In the two men the protein C deficiency was diagnosed only after the onset of severe thromboembolic complications (cavernous sinus thrombosis; pulmonary embolism) during heparin treatment. But in the woman protein C activity was measured immediately after hospital admission (in the knowledge of the first two cases) even before heparin administration was started. All three patients received treatment with sulphasalazine (3 g daily) and fluocortolone (60 mg daily), as well as full heparinization (22,500-36,000 IU daily). Protein C activity returned to normal on remission of the ulcerative colitis (in one case only after subtotal colectomy). These case reports show that acquired protein C deficiency can be reversed by rigorous treatment of the underlying disease.

[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.

[Hypoglycemia in type II diabetic patients]. / Hypoglykämie bei Typ-II-Diabetikern.

The incidence of hypoglycemia was determined in 138 type-2 diabetics treated with insulin (40%) or sulfonylureas (60%). Within one year, ten patients (7%) experienced one severe hypoglycemic episode characterized by a loss of consciousness and the necessity of parenteral glucose administration. Insulin treatment and advanced age increased the risk of hypoglycemia. The knowledge about hypoglycemia was poor. Only 45% of the patients could give a correct definition, 18% knew more than two symptoms, and 15% knew at least one cause of hypoglycemia. 66% would treat hypoglycemia with oral carbohydrates. The risk of hypoglycemia should be considered in the planning of adopted teaching and treatment programs for patients with type-2 diabetes.

[Disorders of intestinal absorption in patients treated with cytostatic chemotherapy]. / Störungen der intestinalen Resorption bei Patienten unter zytostatischer Chemotherapie.

We have investigated the acute and chronic side effects of cancer chemotherapy on the intestinal absorption of adult patients with neoplastic diseases. D-xylose absorption was reduced by 35% in 34 of 50 patients within 48 hours after one course (p less than 0.001), while the vitamin B12 absorption was diminished by 41% in 27 of 38 patients (p less than 0.001). The serum digoxin level fell in 7 of 8 patients by 43% at the first day (p less than 0.01) and normalized after one week. Electron microscopy of the jejunal biopsy specimens revealed damages of the microvilli and defects in the glycocalix. Chronic effects, which were measured after several courses and a pause of four weeks, showed a diminished D-xylose absorption of 36% in 16 of 19 cases (p less than 0.01). Vitamin B12 absorption was reduced by 37% in 11 of 13 patients (p less than 0.01). Microscopical investigations of the jejunum revealed a shortening of the villi and a destruction of microvilli. Acute and chronic malabsorption after cancer chemotherapy should be considered in patients, who are treated with enteral medication and nutrition.