Unusual clinical presentation of a patient with multiple endocrine neoplasia type 2A.

The present report describes an unusual presentation of a female with MEN-2A. During 14 years she only had moderate symptoms. Occasionally she had slightly elevated basal calcitonin levels and abnormal pentagastrin tests, whereas thyroid scanning and echography were normal. At the age of 70 she developed bilateral pheochromocytoma. DNA-analysis demonstrated a germline Cys 611 Tyr mutation in the RET proto-oncogen on chromosome 10q11.2. One year after bilateral adrenalectomy again she developed overt symptoms of pheochromocytoma. The differential diagnosis and the importance of routine screening for RET mutations are discussed.

Thrombosis prophylaxis in hospitalised medical patients: does prophylaxis in all patients make sense?

BACKGROUND: Most studies on thrombosis prophylaxis focus on postoperative venous thrombosis. In medical wards thrombosis prophylaxis is generally restricted to patients who are immobilised. Our primary aim was to investigate the incidence of venous thrombosis in a general internal ward, to assess whether more rigorous prophylaxis would be feasible. METHODS: We investigated the incidence of venous thrombosis in patients hospitalised from 1992 to 1996 and related our findings to literature reports. RESULTS: The incidence of symptomatic venous thrombosis in internal patients during hospitalisation was 39/6332 (0.6%). Among these 39 patients, 24 had a malignancy, whereas 876 out of all 6332 patients had a known malignancy. So, the incidence in this group with cancer was 2.7% compared with 0.3% (15/5456) in the non-cancer group (relative risk for venous thrombosis due to malignancy was 10.0 (95%C.I. 5.3-18.9). CONCLUSION: The incidence of venous thrombosis during hospitalisation in a department of general internal medicine is low and does not justify prophylaxis in all internal patients. Cancer is a strong risk factor for hospital-acquired thrombosis in the medical ward. Further studies may answer the question as to whether thrombosis prophylaxis in this subgroup is feasible.

[Rat bite fever after a bite from a tame pet rat]. / Rattenbeetziekte na een beet van een tamme huisrat.

A 43-year-old woman presented with a generalized febrile illness, an exanthema with mixed maculopapulous and pustulous eruptions on the lower halves of the extremities, elbows, knees, palms and soles. There was also severe arthralgia and asymmetric arthritis. The diagnosis was rat bite fever. The disease became manifest eight days after she was bitten by a pet rat. Rat bite fever can easily be missed, even after adequate anamnesis and physical examination, while the differential diagnostic considerations are numerous. Our patient was cured completely after intravenous administration of penicillin G. Antimicrobial therapy was completed by an oral course of doxycycline.

Aortic graft infection by Lactobacillus casei: a case report.

A 65-year-old man with an abdominal aortic endoprosthesis presented with fever without other symptoms. Investigations revealed Lactobacillus casei bacteraemia. The Lactobacillus graft infection was at first successfully treated by antibiotic therapy. However, during follow-up a relapse occurred, and after surgical replacement of the graft the patient was cured. At surgery an aortoenteric fistula was found as source of the infection.

Granulocyte macrophage colony stimulating factor pretreatment induces an increase of rat Kupffer cells with enhanced cytotoxicity in vitro and prevention of tumor outgrowth in vivo.

Male Wag rats were pretreated for 7 days with 1000 U/ml recombinant murine granulocyte macrophage colony stimulating factor (rmGM-CSF). Rat Kupffer cells (KC) were isolated by a enzymatic method. We injected decreasing numbers of CC531 tumor cells in the portal system. Mean KC yield increased from 1.5 +/- 0.2 to 2.2 +/- 0.2 (p < 0.05). Mean percentage of KC-mediated cytotoxicity against CC531 increased from 20.0 +/- 0.5 to 42 +/- 1.0 after rmGM-CSF (p < 0.05). At 1 x 10(5) CC531 tumor cells we demonstrated prevention of formation of small foci of CC52+ tumor cells. We demonstrate increased isolated KC with enhanced cytotoxic capacity after rmGM-CSF. rmGM-CSF induced prevention of minimal residual disease in the rat liver.

Effect of intraperitoneal administration of granulocyte/macrophage-colony-stimulating factor in rats on omental milky-spot composition and tumoricidal activity in vivo and in vitro.

Milky spots in the greater omentum are small accumulations of leucocytes that consist mainly of macrophages and have recently shown to be a selective dissemination site of intraperitoneal (i.p.) inoculated tumour cells. However, milky-spot macrophages show tumoricidal activity and may, therefore, be an excellent source of effector cells suited for local immunotherapy. In the present study we first examined whether granulocyte/macrophage-colony-stimulating factor (GM-CSF) treatment of isolated milky-spot macrophages affects the cytotoxicity against syngeneic colon carcinoma cells (CC531) in vitro. Secondly, we studied the influence of intraperitoneal GM-CSF administration on the number and antitumour activity of milky-spot and peritoneal macrophages. All studies were performed in Wag/Rij rats in which a syngeneic colon carcinoma cell line (CC531) is available. The results of the in vitro study showed that GM-CSF treatment of the omental macrophages led to an increased cytotoxicity against the tumour cell line. Intraperitoneal administration of 1000 U GM-CSF daily for 7 consecutive days demonstrated both an enhanced antitumour activity of the milky-spot macrophages and an increase in the milky-spot macrophage population. An increase in the proliferative capacity, according to bromodeoxyuridine incorporation, was shown in the milky-spot macrophages. Taking into account both the enhanced macrophage number and their enhanced activity upon i.p. GM-CSF treatment, the milky-spot macrophages may provide a rationale for local intraperitoneal immunotherapy in the prevention of intra-abdominal tumour growth.

The combination 5-fluorouracil/levamisole induces enhanced rat Kupffer cell-mediated cytotoxicity in vitro against the syngeneic colon adenocarcinoma cell line CC531.

The mode of action of the combination treatment 5-fluorouracil (5-FU) and levamisole in colorectal cancer patients is unknown. It is postulated that the beneficial effect may be explained by an immunomodulatory effect on Kupffer cell (KC) cytotoxicity. We evaluated the effect of levamisole (200 micrograms/ml) and 5-FU (10 microM) on rat KC cytotoxicity against syngeneic CC531 tumor cells. Viability of KCs was unaffected by 5-FU and/or levamisole. The combination did not enhance growth inhibition of CC531 compared to 5-FU alone. A significant increase in KC cytotoxicity was observed after 24-hr incubation with 5-FU/levamisole especially at an effector/target ratio of 10 (P < 0.05). 5-FU alone had no effect on KC cytotoxicity, while levamisole induced only a slight increase. Our in vitro data suggest that the additive effect of the combination 5-FU/levamisole on KC cytotoxicity may attribute to the beneficial effect of the adjuvant treatment in colorectal cancer patients.

Enhanced human Kupffer cell-mediated cytotoxicity after activation of the effector cells and modulation of the target cells by interferon-gamma: a mechanistic study at the cellular level.

In this study we demonstrate enhanced Kupffer cell (KC) cytotoxicity against several colorectal cell lines by activation of KC and by modulation of the targets (SW948, WiDR, HT29, and SW620) with IFN-gamma. We demonstrated that soluble TNF-alpha had no effect on these tumor cells, while cytotoxicity against SW948 and WiDR was blocked by anti-TNF-alpha. Experiments using a transwell system stressed the importance of close intercellular contact for this process. Anti-IL-1 did not inhibit cytotoxicity against SW948. Modulation of HT29, WiDR, and SW948 by IFN-gamma (500 U/ml) induced a significant increase in cytotoxicity. We conclude that cell-associated TNF-alpha may be responsible for KC cytotoxicity against SW948, a process requiring close intercellular contact. WiDR is only partly lysed by a TNF-alpha-dependent mechanism, whereas HT29 is not. Furthermore, IFN-gamma is involved in the regulation of tumor susceptibility.

Fresh colorectal tumor cells isolated from individual patients differ in their susceptibility to monocyte mediated cytotoxicity.

Studies on monocyte/macrophage mediated cytotoxicity usually pertain to the use of cell lines that are liable to antigenic and structural changes. Therefore we compared monocyte mediated cytotoxicity against colorectal tumor cell lines (WiDR, HT29, SW620, and SW948) with fresh colorectal tumor cells from patients. Fresh tumor cells were isolated from surgical specimens by a short enzymatic treatment (Collagenase/DNAse). Monocytes were obtained from one healthy donor. Cytotoxicity was determined using the MTT-assay. Fresh colorectal tumor cells displayed a similar differential susceptibility to cytotoxic monocytes as cell lines. Cytotoxicity against fresh tumor cells ranged from 4.9% to 50.4% at E/T ratio 5 (n = 9). Activation of monocytes with Interferon-gamma (100 U/ml) induced an increase of 6.2% +/- 1.6 (n = 4, P = 0.06). In this study we demonstrate monocyte mediated cytotoxicity against colorectal tumor cells isolated from individual patients. This may be important in view of the development of adoptive immunotherapy and cell-directed immunotherapy.

Enhanced killing capacity of human Kupffer cells after activation with human granulocyte/macrophage-colony-stimulating factor and interferon gamma.

In this study we investigated the effect of the cytokines human granulocyte/macrophage-colony-stimulating Factor (hGM-CSF) and interferon gamma (IFN gamma) on human Kupffer-cell-mediated cytotoxicity against the SW948 colon carcinoma cell line. Kupffer cells were isolated from small liver wedge biopsies, taken from 14 patients who had had abdominal surgery for colon carcinoma or partial hepatectomy. The cells were incubated with hGM-CSF (100 ng/ml), or with IFN gamma (100 U/ml) or with their combination and the percentage cytotoxicity was determined using a recently described modified assay. Additional experiments were performed with tumour-necrosis-factor-alpha (TNF alpha)-sensitive U937 cells as target. The TNF alpha secretion of Kupffer cells was measured and we evaluated the effect of TNF alpha on colon tumour targets. We performed human-Kupffer-cell-mediated cytotoxicity blocking experiments with anti-TNF alpha and used paraformaldehyde-fixed Kupffer cells to demonstrate lysis of TNF alpha-sensitive WEHI-164 cells and of SW948 cells. The overall cytotoxicity against SW948 caused by unactivated Kupffer cells (n = 14), and by Kupffer cells activated with hGM-CSF (n = 14), IFN gamma (n = 6) or their combination (n = 6) was respectively: 19.5 +/- 2.6%, 25.3 +/- 2.9%, 41 +/- 9.4% and 45.6 +/- 8% at E/T = 1 and 28.2 +/- 2.9%, 35.6 +/- 3.2%, 55.6 +/- 9.7% and 62.8% at E/T = 5. All differences were statistically significant (P < 0.05). No growth-promoting activity by hGM-CSF on the SW948 tumour cells was observed. U937 cells were highly susceptible to Kupffer-cell-mediated cytotoxicity. The TNF alpha secretion by human Kupffer cells increased in parallel to their cytotoxicity after incubation with these cytokines. Soluble TNF alpha had only a slight anti-proliferative effect on SW948 cells, while specific anti-TNF alpha blocked Kupffer cell cytotoxicity by up to 80%. Finally, paraformaldehyde-fixed Kupffer cells were able to lyse WEHI-164 and SW948 cells. This indicates that expression of cell-associated TNF alpha is the main cytolytic mechanism of human-Kupffer-cell-mediated cytotoxicity. The implications for the use of hGM-CSF and IFN gamma in vivo are discussed.

Surgical treatment of pulmonary metastases from soft tissue sarcomas: a retrospective study in The Netherlands.

Sixty-seven of 87 patients with soft tissue sarcoma underwent complete resection of the metastases in the lung. In this retrospective study, follow-up was for a median of 24 months. The 5-year overall, crude and disease-free survival was 38%, 45%, and 41%, respectively. Twenty-seven (40%) patients developed a recurrence in the lung. Of the six prognostic variables, the only factor significantly related to disease-free survival was grade. It is concluded that surgery for lung metastases of soft tissue sarcoma should be considered as standard therapy when preoperative evaluation predicts a complete resection. By adding chemotherapy to surgery, an improvement of prognosis probably can be achieved.

[Increasing frequency of soft tissue sarcomas in The Netherlands]. / Stijgende frequentie van weke-delensarcomen in Nederland.

Recent data from literature show an increase in incidence and mortality due to soft tissue sarcoma (STS). In the Netherlands age-standardised mortality rates of soft tissue sarcoma (STS) over the period 1950-1988 show a more than fivefold increase. Males predominate over females by a factor of 1.17. Age-adjusted hospital admission rates in 1980-1988 show an increase by a factor of 1.36. The mean estimated incidence is 4.74 per 100,000 person years over a three-year period (1988-1990). The most prevalent histological types in that period were leiomyosarcoma (20.1%), malignant fibrous histiocytoma (16.2%), Kaposi's sarcoma (13.9%) and liposarcoma (13.8%). The distribution of the different histological types changes in time. The increasing incidence of Kaposi's sarcoma is due to the increasing prevalence of AIDS. Hospital admission rates for STS increased from 0.67% of admission rates for all malignant neoplasms in 1970, to 0.96% in 1988. Further epidemiological studies are needed to elucidate the increase of STS throughout the world.