Wta van der Graaf

99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein.

99mTc-sestamibi (99mTc-MIBI) is a substrate for the P-glycoprotein (P-gp) pump but it is not known whether it is a substrate for the multidrug resistance-associated protein (MRP) pump. Therefore, 99mTc-MIBI was evaluated in the GLC4 cell line and its doxorubicin-resistant MRP-, but not P-gp-, overexpressing GLC4/ADR sublines as well as in the S1 cell line and its MRP-transfected subline S1-MRP. 99mTc-MIBI concentration decreased in the GLC4/ADR sublines with increasing MRP overexpression and was lower in S1-MRP than in S1. 99mTc-MIBI plus vincristine increased 99mTc-MIBI concentration in GLC4 lines compared with 99mTc-MIBI alone. 99mTc-MIBI efflux raised with increasing MRP expression in the GLC4 lines. Glutathione depletion elevated 99mTc-MIBI concentration in GLC4/ADR150x. Cross resistance for 99Tc-MIBI, used to test cytotoxicity of the Tc compound, was observed in GLC4/ADR150x vs GLC4. 99Tc-MIBI induced a synergistic effect on vincristine cytotoxicity in GLC4/ADR150x. These results show that 99mTc-MIBI is involved in MRP-mediated efflux. The fact that 99mTc-MIBI efflux is influenced by MDR1 and MRP expression must be taken into account when this gamma-rays-emitting complex is tested for tumour efflux measurements.

Susceptibility to Buruli ulcer is associated with the SLC11A1 (NRAMP1) D543N polymorphism

Similar to other mycobacterial diseases, susceptibility to Buruli ulcer (Mycobacterium ulcerans infection) may be determined by host genetic factors. We investigated the role of SLC11A1 (NRAMP1) in Buruli ulcer because of its associations with both tuberculosis and leprosy. We enrolled 182 Buruli ulcer patients (102 with positive laboratory confirmation) and 191 healthy neighbourhood-matched controls in Ghana, and studied three polymorphisms in the SLC11A1 gene: 3′ UTR TGTG ins/del, D543N G/A, and INT4 G/C. Finger prick blood samples from study subjects were dried on filter papers (FTA) and processed. D543N was significantly associated with Buruli ulcer: the odds ratio (adjusted for gender, age, and region of the participant) of the GA genotype versus the GG genotype was 2.89 (95% confidence intervals (CI): 1.41–5.91). We conclude that a genetic polymorphism in the SLC11A1 gene plays a role in susceptibility to develop Buruli ulcer, with an estimated 13% population attributable risk.

The changing distribution of stage in nonseminomatous testicular germ cell tumours, from 1977 to 1996

To determine the changes between 1977 and 1996 in the distribution of stages of testicular cancer (TC).

Colorectal cancer and the CHEK2 1100delC mutation

The CHEK2 1100delC mutation was recently identified as a low‐penetrance breast cancer susceptibility allele. The mutation occurred more frequently in families with clustering of breast and colorectal cancers (CRCs) than in families with clustering of breast cancer only. Hence, the 1100delC mutation could also be a low‐penetrance CRC susceptibility allele. To test this hypothesis, we examined the mutation in 629 unselected CRC cases, 230 controls, and 105 selected CRCs diagnosed in patients before age 50. The mutation was observed in 1.6% of unselected patients and in 0.3% of controls (Not significant (NS)). After stratifying unselected patients according to defined genetic risk (on the basis of age at diagnosis and family history of colorectal and endometrial cancer), the highest frequency was observed in high‐risk patients (12.5%), followed by moderate‐risk patients (3.3%), and was lowest in low‐risk patients (1.0%, Ptrend 0.014). In selected patients, 1.6% carried the mutation (NS). Subgroup analyses for tumor localization, gender, and age at diagnosis did not reveal an association with the 1100delC genotype. In addition, a pooled analysis, combining data of one published study in unselected CRC cases and our study, also did not reveal an association. In conclusion, the frequency of the 1100delC genotype was neither significantly increased in unselected CRC patients nor in selected CRC patients diagnosed before age 50. However, after stratifying unselected CRC patients according to defined genetic risk, a significant trend of increasing frequency was observed. Together, the results are consistent with a low‐penetrance effect (OR 1.5–2.0) of the CHEK2 1100delC on CRC risk. Large case–control studies are required to clarify the exact role of the CHEK2 1100delC mutation in CRC.

Testicular carcinoma and HLA Class II genes

The association with histocompatibility antigens (HLA), in particular Class II genes (DQB1, DRB1), has recently been suggested to be one of the genetic factors involved in testicular germ cell tumor (TGCT) development. The current study, which uses genotyping of microsatellite markers, was designed to replicate previous associations.

Long-term haematological recovery following high-dose chemotherapy with autologous bone marrow transplantation or peripheral stem cell transplantation in patients with solid tumours

Long-term peripheral blood counts and factors influencing long-term trilineage haematological recovery of consecutive patients in a single institution treated with high-dose chemotherapy (HDC) and ABMT or PSCT for solid tumours were examined. Patients with a relapse-free survival of <1 year were included in the analysis (n = 131). Peripheral blood counts were examined 6 months and yearly following transplantation. Median follow-up was 4.1 years (range 1–10+ years). Three years after transplantation 91% of patients had normal white blood counts (WBC), 94% normal haemoglobin (Hb) and 75% normal platelets. Trilineage recovery was complete in 70% (n = 83) at 3 years and 85% (n = 50) at 5 years. Recovery of Hb occurred before WBC and platelet recovery. Approximately 25% of patients displayed an elevated MCV throughout the follow-up period. These long-term results were independent of age, high-dose regimen, number of reinfused stem cells and stem cell source. Double (n = 12) vs single (n = 119) transplantations showed significantly slower trilineage recovery and higher MCV. No secondary graft failure, myelodysplasia or leukaemia was encountered. In conclusion, complete trilineage recovery after HDC followed by ABMT or PSCT occurs slowly. PSCT and ABMT are capable of maintaining long-term haematopoiesis. Slower recovery is seen after double transplantations. The results suggest lasting implications for bone marrow function after autologous transplantation. Bone Marrow Transplantation (2001) 27, 959–966.

A 20-year-old male with thoracic pain and a lower thoracic mass

A 20-yr-old Caucasian male construction worker had a previous history of a road traffic accident 3 yrs before presentation. A computed tomography (CT) scan of the thoracic spine was carried out to exclude vertebral damage. No evidence of vertebral bone damage or other lesions was seen, and the patient recovered without sequelae. A week before presentation, he noticed a stabbing pain in his right hemithorax, without dyspnoea. The pain persisted, and the patient was referred, by his general practitioner, for a chest radiograph (fig. 1⇓). Based on these results, the patient was referred to a general hospital for further diagnostic tests. A CT scan of thorax and abdomen (not shown) revealed a large mass, which was interpreted to arise in the right upper abdomen, probably originating from the liver. A malignant tumour, or a metastatic lesion, was suspected and the patient was referred to University Medical Center Groningen (Groningen, The Netherlands). Fig. 1— a) Postero-anterior and b) lateral chest radiographs at presentation. The patient did not suffer from dyspnoea, cough or haemoptysis and there was no history of fever, weight loss, fatigue or excessive sweating. There were no neurological or gastro-intestinal complaints. The patient was a nonsmoker, and did not use any medication. On physical examination, a healthy appearing, haemodynamically stable young male, of normal posture was seen. On percussion, a dull sound was found in the right lower zone of the chest. Auscultation revealed normal cardiac sounds without murmurs, and normal breathing sounds on the left side and upper right side of the chest. Abdominal examination revealed no palpable masses or other abnormalities. No palpable lymph nodes were present. Additional physical examination revealed no other abnormalities. Laboratory tests only showed a slightly elevated serum alkaline phosphatase of 174 U·L−1 (normal value: 13–120 U·L−1). Serum lactate dehydrogenase, α-fetoprotein and β-human chorionic gonadotropin values …

The 16p11 breakpoint in myxoid liposarcomas might affect the expression of the LRP gene on 16p11.2 encoding the multidrug resistance associated major vault protein.

Chromosome breakage could influence the expression of genes. This has been noticed in specific cases of acute myeloid leukaemia, where the 16p13 breakpoint affects the expression of the multidrug resistance related protein (MRP). Myxoid liposarcomas (LPS) are characterized by the t(12; 16)(q13; p11), which leads to the formation of a FUS‐CHOP fusion transcript. This study investigates the relationship between the cytogenetically detected breakpoint 16p11 in myxoid LPS, the presence of the FUS‐CHOP fusion transcript in nonmyxoid LPS and the expression of the lung resistance major vault protein (LRP) gene on 16p11.2.

A young female with an endodermal sinus tumor in a pericardial localized cyst

Mediastinal germ cell tumors are extremely rare. We describe a 27-year-old female who presented with an endodermal sinus tumor in a previously diagnosed pericardial cyst. In retrospect, the first CT scan of the chest showed a calcification in the cyst, suggesting teratoma. The diagnosis of endodermal sinus tumor could have been made earlier by measuring the serum level of alpha-fetoprotein. Case report. A 27-year-old female psychologist was referred to our center after a recent thoracotomy in another hospital. A month earlier, she presented with sudden onset pain in the right axilla. The past medical history revealed suspected right-sided pericardial cyst at a routine chest radiograph, which was taken after a medical examination for an appointment 18 months earlier (Fig. 1). The patient had no complaints and the mediastinal mass on the CT scan of the chest was also interpreted as a pericardial cyst (Fig. 2). Ultrasonography showed a thin-walled cyst with a small partition. The patient remained asymptomatic and came for regular visits to a pulmonologist every 6 months. During followup, chest radiographs did not show any changes from the first x-ray. When the patient presented with the axillary pain, physical examination revealed increased dullness to percussion at the right side of the chest. Laboratory data showed normal blood counts, a normal lactate dehydrogenase serum level and normal renal and hepatic function. The posteroanterior chest radiograph revealed an increase in the size of the supposed pericardial cyst with a small amount of pleural effusion (Fig. 3a and b). Because leakage from the pericardial cyst was suspected, a thoracoscopic marsupialization of the cyst was planned. Unexpectedly, not a cyst but a solid tumor was found. A thoracotomy was performed, during which a huge necrotic tumor fixed to the pericardium and mediastinum was removed with difficulty. In retrospect, on the first CT scan a calcification in the supposed cyst was observed and on the preoperative chest x-ray a coin lesion projecting through the heart shadow was visible. Additional blood chemistry was performed; the serum level of beta human chorionic gonadotropin was less than 0.6 mg/l and of alpha-fetoprotein (AFP) was 9900 mg/l. The diagnosis of mediastinal endodermal sinus tumor was made. Histological examination revealed necrotic and cystic masses and tumor tissue compatible with a diagnosis of endodermal sinus tumor. Gynaecological examination and CT of the abdomen ruled out the possibility of a primary gonadal germ cell tumor. Postoperative CT of the chest showed residual tumor in a mediastinal cavity and multiple lung metastases. The patient was treated with four courses of chemotherapy consisting of cisplatin, etoposide and bleomycin. Unfortunately, she did not reach a biochemical complete remission and had progressive disease with a rise of the serum AFP level and reappearance of lung metastases within a month after completion of the chemotherapy. Palliative treatment was started but the patient died 6 months later. Discussion. Pericardial cysts are not rare, and are often found incidentally on a routine chest radiograph (1). The most frequently reported localization (70–80%) is the right anterior cardiophrenic angle. Pericardial cysts seldom produce symptoms, which renders routine operative removal of the cyst unjustified. Although the diagnosis is often made on a chest roentgenogram alone, two dimensional echo and MRI might be useful to differentiate solid from cystic masses, to better define the relationship with anatomical surroundings and to provide better insight in the nature of these cysts. Mediastinal endodermal sinus tumor, also called yolk sac tumor, is an extremely rare extragonadal germ cell tumor (2–4). Within the subset of germ cell tumors, mediastinal germ cell neoplasms account for 1–3% of all germinal tumors (5). In general, the tumor is associated with a poor prognosis, which is due to its highly malignant potential but also to the advanced stage at which the disease is commonly diagnosed. Extragonadal germ cell tumors are usually located in the anterior mediastinum (6) and usually occur in the first three decades of life. Most of these tumors are mature cystic teratomas, which are discovered incidentally on routine rontgenograms of the chest. The male–female ratio is approximately equal as far as mature teratomas are

Effects of peripheral stem cell or bone marrow reinfusion on peripheral serotonin metabolism

Reinfusion of autologous hematopoietic peripheral blood stem cells (PBSC) or bone marrow is often accompanied by flushing, dyspnea, abdominal cramping, nausea and diarrhea. These symptoms and the observation that they can be prevented by ondansetron, a selective 5-HT3 receptor antagonist, led to the assumption that these side-effects are due to infusion of free serotonin during the reinfusion of PBSC or bone marrow. Twenty-five patients with solid tumors received, after myeloblative chemotherapy, a total of 30 reinfusions of PBSC and/or bone marrow. In 17 patients, serotonin levels in the bags containing the PBSC were measured. In all patients, platelet serotonin levels were determined before and 1 h post-reinfusion. In addition, before and 24 h after reinfusion urine was collected for determination of 5-hydroxyindole acetic acid (5-HIAA) and serotonin concentrations. Mean (± s.d.) total serotonin concentration in the bags was 2404 ± 1555 nmol/l. Mean total volume reinfused was 471 ± 185 ml. After reinfusion, the mean (± s.d.) levels of serotonin in platelets in patients increased from 3.2 ± 1.4 nm/109 at baseline to 3.8 ± 2.0 nm/109 (P = 0.02). Neither 24 h urinary 5-HIAA nor serotonin levels were affected. These results indicate that reinfusion of PBSC or bone marrow is accompanied by substantial infusion of free serotonin, which might explain the observed side-effects and justify the use of 5-HT3 receptor antagonists as pre- medication for this procedure.