J.H.J.M. van Krieken

Comparison of inflammatory cell counts in asthma: induced sputum vs bronchoalveolar lavage and bronchial biopsies

Background Induced sputum potentially allows monitoring of airway inflammation in patients with asthma in a non‐invasive way. However, the relationship between the cellular content in sputum and airway tissue has not been fully clarified.

Chemotherapy for operable gastric cancer: results of the Dutch randomised FAMTX trial

The aim of this trial was to investigate whether pre-operative chemotherapy leads to a 15% higher curative resectability rate in patients with operable gastric cancer. In this randomised trial, patients were allocated to receive either four courses of chemotherapy using 5-fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery only. Patients younger than 75 years of age with a good physical and mental condition and a histologically proven adenocarcinoma of the stomach without clinical or radiographic (computed tomography scan) evidence of distant metastases were eligible for this trial. Early gastric cancer or cardia carcinoma were excluded. The response to chemotherapy was evaluated after two and four courses. In case of progressive disease (PD) after two courses, patients were operated upon as soon as possible. Otherwise complete response (CR) partial response (PR) or stable disease (SD), two more courses were scheduled. The standard surgical procedure was a limited lymphadenectomy (D1) with staging biopsy of the para-aortic lymph nodes. Between September 1993 and February 1996, 56 eligible and evaluable patients were entered: 27 were randomised to receive FAMTX before surgery and 29 to undergo surgery only. In the FAMTX + surgery treatment group, 15/27 (56%) had curative resections versus 18/29 (62%) in the surgery only arm. There was no difference in the frequency of TNM stages I + II in both treatment arms: 15/27 versus 15/29. Due to PD and/or toxicity, 12 patients (44%) could not complete the planned four courses of FAMTX. Response evaluation after chemotherapy was possible in 25 patients: 2 CR, 6 PR, 8 SD and 9 PD. The difference in curative resectability rate was 6.5% (95% confidence interval -32 to +19%) in favour of surgery only. Downstaging for stages I + II did not occur. PD was more often the reason for not completing the planned four courses than toxicity. More active regimens than FAMTX are required for future randomised trials.

Splenic marginal zone lymphocytes and related cells in the lymph node: A morphologic and immunohistochemical study

The marginal zone of the spleen contains a well-defined population of lymphocytes with an unknown function. The question is whether this cell population is unique to the spleen or is it also present in the lymph node. These cells have medium-sized nuclei and a moderate amount of cytoplasm. Immunohistochemistry and enzyme histochemistry revealed a marker pattern by which these cells could be distinguished from the lymphocytes of the mantle zone of the spleen: IgD-, CD23-, KiB3-, and alkaline phosphatase+. In the lymph node, the outer side of the follicular mantle contains a subpopulation of B lymphocytes with a similar morphology and the same marker pattern. This subpopulation differs from the marginal zone cells in the spleen in that it does not form a distinct zone. These cells are especially prominent in lymph nodes with fatty atrophy. Their relationship to other subpopulations of B lymphocytes and to malignant lymphomas is evaluated but remains questionable.

Effective treatment of experimental lupus nephritis by combined administration of anti-CD11a and anti-CD54 antibodies

Mice with chronic graft‐versus‐host disease (GVHD), induced by injection of DBA/2 lymphocytes in (C57BL10*DBA/2) F1 hybrids, develop a syndrome resembling systemic lupus erythematosus (SLE) with immune complex glomerulonephritis. In this model we evaluated the role of interactions between CD11a (LFA‐1α) and CD54 (intercellular adhesion molecule‐1 (ICAM‐1)) molecules on leucocytes in the development of renal disease in systemic autoimmunity. Two weeks after induction of GVHD, when anti‐nuclear autoantibodies were detected in the circulation and immune complexes had formed in the glomeruli, mice were injected twice per week with rat anti‐CD11a and anti‐CD54 MoAbs, or with their vehicle PBS, or with control rat IgG. MoAb treatment significantly lowered albuminuria and increased survival compared with control mice with GVHD. In the glomeruli of MoAb‐treated mice there was markedly less binding of immunoglobulin and C3, while anti‐renal tubular epithelium autoantibodies, but not anti‐glomerular basement membrane autoantibodies, were significantly lowered in the circulation 4 weeks after disease induction. In addition, MoAb treatment inhibited the glomerular influx of CD11a+ cells and decreased development of histological abnormalities in the kidneys. Both rat IgG‐ and MoAb‐treated mice developed anti‐rat immunoglobulin antibodies. Furthermore, a marked splenomegaly with an increase of the T cell compartment was observed in MoAb‐treated mice with GVHD. These results show that CD11a/CD54 interactions are crucial for the full‐blown development of lupus nephritis in this model. Treatment aimed at blocking the activity of these molecules profoundly attenuated the development of renal disease in chronic GVHD even if started when first symptoms of SLE (i.e. anti‐nuclear autoantibodies in sera and glomerular binding of immunoglobulins) were already detectable.

Mast Cell Infiltration in Intestine Used for Bladder Augmentation in Interstitial Cystitis

Two patients with histologically confirmed interstitial cystitis underwent bladder augmentation procedures (clam cystoplasty and Mainz pouch cystoplasty) because of therapy resistant low abdominal pain and decreased functional bladder capacity. However, symptoms of low abdominal pain and urinary retention (1 patient) persisted, and cystectomy was performed in both patients after 14 and 20 months, respectively. Histological examination of the specimens showed changes in the intestinal areas of the augmented bladder, resembling interstitial cystitis. The etiology of this phenomenon and the possible role of intestinal interstitial cystitis in augmentation failures are discussed.

Bronchiolitis obliterans organizing pneumonia after adjuvant radiotherapy for breast carcinoma

External radiotherapy following surgery for breast carcinoma may induce radiation injury to the lungs in a number of patients. Two types of injury are recognized that are temporally related to radiotherapy; an acute pneumonitis-like illness and fibrosis, with abnormalities confined to the radiation port (1). However, the spectrum of radiotherapy-induced sequelae may be more diverse. Two patients developed a syndrome of idiopathic bronchiolitis obliterans organizing pneumonia (BOOP; synonym: cryptogenic organizing pneumonitis) after surgical intervention for breast carcinoma and treatment with external radiotherapy. As a distinctive feature, the syndrome was associated with migratory, recurrent infiltrates.

Using Kryofix as Alternative for Formalin Results in More Optimal and Standardized Immunostaining of Paraffin Sections

Although used for over one century formalin has several disadvantages which Kryofix, an alternative fixative for paraffin blocks used in Leiden for 6 years, does not have. In this study the effects of Kryofix on tissue regarding immunohistochemistry are compared with those of buffered formalin. All markers studied showed enhanced staining in the Kryofix blocks after 4 hours of fixation, whilst in some cases the immunostaining of the formalin blocks was even negative. For all markers, the sera could be further diluted for the Kryofix sections, for some with as much as a factor 20, enhancing the cost-effectiveness of the method. We established that for formalin, the fixation time strongly influenced the results. For Kryofix there was no time factor: the immunostaining results of 1 hour fixation were identical to those after 3 months of fixation. This study shows that by this method of fixation, in which there is no cross-linking of proteins, immunostaining of paraffin sections is optimized and standardized.

Urogenital Malacoplakia Treated with Fluoroquinolones

We report 2 cases of urogenital malacoplakia and discuss the problems associated with diagnosing and treating this rare disease. In 1 case extensive pelvic disease was successfully controlled with ciprofloxacin. In the other case the malacoplakia was localized in the distal ureter and was initially mistaken for urothelial carcinoma. Nephrectomy was performed due to persistent ureteral obstruction and renal dysfunction. In the management of urogenital malacoplakia it seems essential that urinary tract infections be effectively treated. The new fluoroquinolones appear to be potentially successful in managing this disorder due to their high uptake of macrophages.

Severe hepatitis and pure red cell aplasia in adult Still's disease: Good response to immunosuppressive therapy

Adult-onset Stills disease is a systemic inflammatory disorder with a highly variable clinical course. Mild hepatitis and anemia are common manifestations. We describe a patient with adult Stills disease who developed a severe hepatitis and a life-threatening pure red cell aplasia. The hepatitis developed after treatment with NSAIDs was started. The patient was successfully treated with a combination of prednisone, cyclosporin, and methotrexate. Physicians should be aware that severe hepatitis and pure red cell aplasia can occur in adult Stills disease. We recommend a careful monitoring of liver functions in patients with adult Stills disease who are being treated with NSAIDs.

The molecular biology of B-cell lymphoma: Clinicopathologic implications

SummaryNonrandom chromosomal translocations like the t(14;18), t(8;14), and t(11;14) are found in distinct types of B-cell malignancies. Recent molecular studies concerning their structure and origin showed that many translocations occur in early precursor B cells and may be interpreted as aberrant immunoglobulin gene rearrangements. The available data from in vitro experiments, transgenic mice, and normal human individuals indicate that these translocations are essential but insufficient for full tumorigenesis. The consequent “multi-hit” concept might have important implications for the detection of minimal residual disease using the polymerase chain reaction for these translocations. The strong associations with specific types of lymphomas underline their differences in histogenetic origin. Thus, based on differences inbcl-1 andbcl-2 rearrangements, molecular analysis may help to distinguish follicular lymphoma from diffuse centrocytic lymphoma and chronic lymphocytic leukemia. Furthermore, based on differences inbcl-2 and c-myc rearrangements, subtypes of de novo centroblastic lymphoma can be distinguished that have striking differences in biological behavior, especially nodal versus extranodal presentation. Therefore, future studies will show an increasing clinical relevance of molecular analysis in B-cell neoplasia.