Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy.

An increased dose-intensity can be achieved by either higher dose of chemotherapy per cycle (dose-escalation) or by shortening the interval between cycles (dose-dense). This multicenter randomized phase II study assessed the efficacy and safety of two different approaches: epirubicin 110 mg/m(2) combined with paclitaxel 200 mg/m(2) every 21 days and epirubicin 75 mg/m(2) combined with paclitaxel 175 mg/m(2) every 10 days, both supported with G-CSF. Patients with advanced breast cancer and without prior palliative chemotherapy were scheduled for 6 cycles. Evaluable for response were 101 patients and for toxicity 106 patients. Grade ≥ 3 toxicities occurred in 39% of patients in the dose-escalated arm and in 29% of the dose-dense arm, mainly febrile neutropenia, thrombocytopenia, neurotoxicity and (asymptomatic) cardiotoxicity. The median delivered cumulative doses for epirubicin/paclitaxel were 656/1194 and 448/1045 mg/m(2), treatment durations were 126 and 61 days, and delivered dose intensities were 36/67 and 51/120 mg/m(2)/week for the dose-escalated and dose-dense arm, respectively. Response rates were 75 and 70%, the progression-free survival 6 and 7 months, respectively. Dose-dense chemotherapy with a lower cumulative dose, a halved treatment time, but a higher dose-intensity may be as effective and safe as dose-escalated chemotherapy. The value of dose-densification over standard scheduled chemotherapy regimes yet needs to be determined.

[Diagnostic image (349). A woman with flushes]. / Diagnose in beeld (349). Een vrouw met opvliegers. Carcinoïd van het ovarium.

A 57-year-old woman suffered from frequent flushes due to an ovarian carcinoid tumour.

[Sustained weight loss 2 years after laparoscopic adjustable gastric banding for morbid obesity]. / Duurzaam gewichtsverlies 2 jaar na laparoscopische maagbandplaatsing wegens morbide obesitas.

OBJECTIVE: To analyse the results of the laparoscopic adjustable gastric banding (LAGB) procedure for morbid obesity. DESIGN. Retrospective, descriptive. METHOD: From November 1, 1995 to May 31, 2005, laparoscopic adjustable banding surgery was performed in St. Antonius Hospital, Nieuwegein, the Netherlands, in 411 patients. Inclusion criteria were BMI > or = 40 kg/ m(2) or BMI > 35 kg/m(2) and severe comorbidity with > 3 attempts at weight loss in the past. Selection, inclusion and follow-up were performed in a specialised, multidisciplinary setting. Height, weight, and complications were prospectively recorded. In 1995-2000 the perigastric surgical procedure was used and in 2000-2005 the pars-flaccida method. RESULTS: The study group consisted of 350 (85%) women and 61 (I5%) men with a median age of 38 years (range 17-60). Out of these 411 patients, the median weight was 133.4 kg, the median overweight, 69.6 kg and the median BMI 46.3 kg/m2. Two years after surgery, data was known for 267 patients where 206 (77%) had a weight loss > 30%, and 7 patients (3%) a weight gain. The median BMI difference was then -10.2 kg/m2 (range +4.7--26.4). The median loss of overweight was 46.3% (+10.00--97.8). The weight loss remained stable in the following years. The most commonly seen complications were fundus slippage (13%) and port-a-cath related complications (7%). These occurred more often in patients who had had the perigastric method surgery than in the parsflaccida surgical method. CONCLUSION: Three quarters of the patients with morbid obesity who received laparoscopic gastric banding surgery had achieved and sustained weight loss at 2 years following surgery. The pars-flaccida method resulted in fewer complications than the perigastric surgical method.

[Diagnostic image (303). A deeply tanned woman]. / Diagnose in beeld (303). Een sterk gebruinde vrouw.

A 50-year-old woman complained of nausea, diarrhoea, tiredness and dizziness five weeks after a visit to Egypt. She was deeply tanned with hyperpigmentation on the metacarpophalangeal joints, palm of hand creases and buccal mucosa, due to Addison's disease.

Inhibition of breast cancer tissue aromatase activity and estrogen concentrations by the third-generation aromatase inhibitor vorozole.

In about one-third of advanced breast cancers, estrogen deprivation causes tumor regression. Estrogen concentrations in tumor tissue seem to depend largely on local production. The aromatase enzyme complex is thought to be the key enzyme in this respect. In the present study, the effect of the new third-generation nonsteroidal aromatase inhibitor vorozole (Rivizor) on tumor tissue aromatase activity and estrogen concentrations was evaluated. During 7 days preceding mastectomy, 11 postmenopausal breast cancer patients were treated with 2.5 mg of vorozole once daily. Eight patients could be evaluated. Intratumoral aromatase activity and estrone and estradiol levels were measured and compared to the values of nine untreated postmenopausal breast cancer patients. In treated patients, median tissue aromatase activity was 89% lower than that in controls (P < 0.001). Similarly, median tissue estrone and estradiol concentrations were 64 and 80% lower, respectively, in treated patients (P = 0.001 and P < 0.05, respectively). These results support the hypothesis that depleting the tumor of estrogens, thus impairing estrogenic stimulation, is an important mechanism in the antitumor activity of aromatase inhibitors.

Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group.

PURPOSE: Time to progression (TTP), overall survival, and quality of life (QL) were compared in patients with hormone-resistant prostate cancer (HRPC) treated with prednisone (5 mg orally, four times a day) or flutamide (250 mg orally, three times a day). PATIENTS AND METHODS: Symptomatic patients were randomized to receive either prednisone (101 patients) or flutamide (100 patients). Subjective response was assessed based on performance status, the use of analgesics, and the need to apply alternative palliative treatment. Prostate-specific antigen (PSA)-based biochemical response (>or= 50% reduction of baseline PSA) was recorded. At baseline and at 6-week intervals during follow-up, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30. RESULTS: There was no difference between the groups in median TTP (prednisone, 3.4 months; flutamide, 2.3 months) or overall survival (prednisone, 10.6 months; flutamide, 11.2 months). In the prednisone group, 56% of the patients experienced a subjective response, compared with 45% in the flutamide group (P: = .18). The median response duration was 4.8 months for prednisone and 4.2 months for flutamide. A biochemical response was observed in 21% and 23% of the prednisone and flutamide groups, respectively. Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone. The QL assessment parameters favored the use of prednisone with statistically significant differences in pain, fatigue, role functioning, appetite loss, gastrointestinal distress, and overall QL. CONCLUSION: In symptomatic HRPC, treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response. The QL results favor the use of low-cost prednisone in patients with HRPC.

[Delayed recognition of falciparum malaria from a non-endemic region in the Dominican Republic]. / Laat herkende malaria tropica uit een niet-endemisch gebied in de Dominicaanse Republiek.

A 28-year-old patient had suffered from fever, headache, abdominal pains and vomiting for the past three weeks. She had visited a region in the Dominican Republic where the risk of malaria is considered to be low. The complaints were initially regarded as a viral infection. Later, however, she was found to have severe falciparum malaria. She recovered completely following antibiotic therapy. Since November 2004, 17 cases of falciparum malaria have been reported world-wide among travellers to non-endemic regions in the Dominican Republic. Physicians should always consider the possibility of malaria in travellers because a timely diagnosis of falciparum malaria can be of vital importance.

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

BACKGROUND: Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall-bladder emptying. AIM: To elucidate the effects of a new long-acting octreotide formulation (Sandostatin LAR) on gall-bladder emptying, cholecystokinin release and gallstone formation. METHODS: Postprandial gall-bladder and gastric emptying were determined by ultrasonography and cholecystokinin release was measured in seven patients on days 0, 14, 28, and 75 (Sandostatin LAR, 20 mg intramuscularly on days 1, 30, and 60). RESULTS: During treatment, fasting gall-bladder volumes increased from 26.5 +/- 3.2 mL to 61.4 +/- 7.5 mL, but postprandial cholecystokinin release and gall-bladder emptying (from 63.9 +/- 3.8% to 12.3 +/- 3.5%) were severely suppressed. Gallstones formed in six out of seven patients within 8 months of treatment. Gastric emptying did not change during the therapy. CONCLUSIONS: The risk of gallstone formation is greatly increased during Sandostatin LAR. This is probably related to profound suppression of cholecystokinin release and gall-bladder emptying.

Vasculitis due to gemcitabine.

We report the first occurrence of gemcitabine-induced vasculitis. It concerns a 45-year-old man diagnosed with non-small lung cancer since 2 months. After the first cycle of chemotherapy, consisting of gemcitabine and cisplatin, he developed myalgia and swelling of arms and legs with impairment of movement. This re-occurred during the second cycle of chemotherapy. Further anemia, elevated ESR and increased creatininephosphokinase. A surgical biopsy showed leucocytoclastic vasculitis and necrosis of muscle tissue. The chemotherapy was stopped and the complaints disappeared and did not return.

Aromatase and COX-2 expression in human breast cancers.

We have investigated aromatase and the inducible cyclooxygenase COX-2 expression using immunocytochemistry in tumors of a series of patients with advanced breast cancer treated with aromatase inhibitors. Aromatase was expressed in 58/102 breast cancers. This is similar to the percentage previously reported for aromatase activity. Interestingly, aromatase was expressed in a variety of cell types, including tumor, stromal, adipose, and endothelial cells. Since prostaglandin E2 is known to regulate aromatase gene expression and is the product of COX-2, an enzyme frequently overexpressed in tumors, immunocytochemistry was performed on the tissue sections using a polyclonal antibody to COX-2. Aromatase was strongly correlated (P<0.001) with COX-2 expression. These results suggest that PGE2 produced by COX-2 in the tumor may be important in stimulating estrogen synthesis in the tumor and surrounding tissue. No correlation was observed between aromatase or COX-2 expression and the response of the patients to aromatase inhibitor treatment. However, only 13 patients responded. Nine of these patients were aromatase positive. Although similar to responses in other studies, this low response rate to second line treatment suggests that tumors of most patients were no longer sensitive to the effects of estrogen. Recent clinical studies suggest that greater responses occur when aromatase inhibitors are used as first line treatment. In the intratumoral aromatase mouse model, expression of aromatase in tumors is highly correlated with increased tumor growth. First line treatment with letrozole was effective in all animals treated and was more effective than tamoxifen in suppressing tumor growth. Letrozole was also effective in tumors failing to respond to tamoxifen, consistent with clinical findings. In addition, the duration of response was significantly longer with the aromatase inhibitor than with tamoxifen, suggesting that aromatase inhibitors may offer better control of tumor growth than this antiestrogen.

Serum elimination half-life of tamoxifen and its metabolites in patients with advanced breast cancer.

In breast cancer patients discontinuing chronic tamoxifen therapy, the serum elimination of metabolites X, Y and E paralleled that of tamoxifen, whereas that of metabolite Z did not. The serum elimination of tamoxifen and metabolites X and B was increased by amino-glutethimide treatment, whereas that of metabolites Z, Y, and E was not.

Serum and urine levels of tamoxifen and its metabolites in patients with advanced breast cancer after a loading dose and at steady-state levels.

PURPOSE: To compare serum and urine levels of tamoxifen and metabolites after a loading dose and at the steady state. METHODS: A loading dose of 160 mg of tamoxifen was given to 14 patients with advanced breast cancer. Thereafter a regular daily dose of 30 mg of tamoxifen was given. Serum and urine levels of tamoxifen and metabolites were measured by high-performance liquid chromatography and compared with levels determined in 31 patients with advanced breast cancer at the steady state at a daily dose of 30 mg of tamoxifen. RESULTS: Serum and urine levels (24-h values) of tamoxifen and metabolites were lower (P < 0.05) after a loading dose than at the steady state. The difference was most pronounced for the metabolites, whereas the tamoxifen loading-dose level was near the steady state. CONCLUSION: Tamoxifen steady state can be reached in 1-2 days by the administration of a loading dose of 160 mg of tamoxifen for 2 days. Tamoxifen metabolite steady-state levels are reached regularly after 4 or more weeks during application of a loading dose. Very little tamoxifen or metabolites are excreted into the urine.

Pharmacokinetics of the cytostatic drugs used in the CMF-regimen.

Forty-one clinical patients were studied on the first day of the first course of the CMF-regimen; administered by a fixed dosage scheme depending solely on body surface area of the patient in question. Parmacokinetic parameters were calculated for each drug: the data were analysed in conformity with the usual pharmacokinetic models. The results indicate a large pharmacokinetic variability, especially for cyclophosphamide (C). The large variability in plasma concentrations of C is presumed to be substantially attributable to the drug formula used.

Induction of chromosomal alterations as an assay for cytostatic drug activity in plasma.

Information about the extent and persistence of cytostatic activity in blood plasma after administration of a cytostatic drug into the body is needed for a better evaluation of the inter-individual variations in drug metabolism and disposition. As an assay for cytotoxic activity, a test system was chosen in which Chinese hamster ovary cells (CHO) were incubated with plasma containing active metabolites of cyclophosphamide (from human patients or rats), after which the frequencies of induced sister-chromatid exchanges per cell were determined. The treatment with plasma increased the frequencies of SCEs very effectively at concentrations of metabolites that were negative in the Salmonella typhimurium back-mutation test with strain TA100. The results obtained indicate that the SCE test system offers the possibility to follow the cytotoxic activity of plasma at various time intervals after administration of cyclophosphamide.

Hypopituitarism following complicated child birth (Sheehan's syndrome).

We describe two patients with hypopituitarism and a history of severe bleeding or hypotensive shock at the time of child birth. Both patients had a decrease of all or some endocrine functions of the anterior pituitary. Although the frequency of Sheehan's syndrome is low in developed countries, it should still be considered in the differential diagnosis of hypopituitarism. An interval of many years between delivery and time of diagnosis does not exclude the diagnosis.

The choriocarcinoma syndrome: an emergency.

A 36-year-old male patient is described who presented with gynaecomastia, pulmonary nodules and a retroperitoneal mass in combination with a markedly elevated HCG level. A diagnosis of "choriocarcinoma syndrome" was made. Despite a clear response from the tumour to chemotherapy the patient died, at least partially due to delay in treatment. Prompt treatment even without cytological or histological proof is therefore stressed.

A patient with diabetes insipidus and periorbital swellings; Erdheim-Chester disease.

Erdheim-Chester disease is a rare multisystem disease in which a progressive xanthogranulomatous infiltration of several tissues can be seen. We describe a woman, known to have diabetes insipidus for ten years, with periorbital, retroperitoneal, mediastinal, axillar and inguinal involvement. On histological examination a granulomatous infiltration of fatty tissue and striated muscle was seen, consisting of Touton giant cells, histiocytes with foamy cytoplasm and lymphocytes. Immunohistochemical staining with CD-1a and S-100 was negative and on electron microscopy no Langerhans granules were seen. These findings led to the diagnosis of Erdheim-Chester disease. She had a good response on steroids. Because of some similar clinical features of Langerhans cell histiocytosis and Erdheim-Chester disease, a histiocyte disorder seems the most probable cause.

Non-islet-cell tumour induced hypoglycaemia: a case report and review of literature.

A 54-year-old man presented with a poorly differentiated adenocarcinoma of the rectum with multiple metastases to the liver. During hospitalization the patient developed periods of hypoglycaemia due to production of "big" IGF-II by the tumour. Possible pathophysiological mechanisms of non-islet-cell tumour-induced hypoglycaemia are discussed.

A phase I dose-escalating study of docetaxel plus folinic acid and 5-fluorouracil in anthracycline-pretreated patients with metastatic breast cancer.

BACKGROUND: Since the need for nonanthracycline-containing chemotherapy regimens increases with the increased use of anthracyclines in earlier stages of breast cancer, we investigated the feasibility of the combination of docetaxel and 5-fluorouracil (5-FU) with folinic acid (FA). PATIENTS AND METHODS: Anthracycline-pretreated patients with metastatic breast cancer were eligible. Docetaxel was administered as a one-hour infusion every three weeks on day 1, FA 500 mg/m2 (fixed dose) as a two-hour infusion on days 1 and 15 and 5-FU as a 24-hour infusion on days 1 and 15. The dose levels tested were (docetaxel/5FU in mg/m2): 60/1800, 75/1800, 85/1800, 100/1800, and 100/2100. RESULTS: Altogether 28 patients were accrued and treated in this multicentre open-label study. Dose-limiting toxicities (DLTs) were not observed at dose level I, and in two patients in each of the higher dose levels. DLTs observed were grade III/IV infection (n=4), febrile neutropenia (n=2), diarrhoea (n=1) and erythema (n=1). Partial responses were observed in 10 out of 24 evaluable patients (42%, 95% confidence interval 22.1 to 63.4%). Dose escalation beyond the highest dose level (100/2100) was deemed inappropriate, because these dose levels correspond to recommended dose levels for each drug as a single agent. CONCLUSION: Combination of docetaxel (100 mg/m2, one-hour infusion q3 weeks on day 1), FA (500 mg/m2, two-hour infusion on days 1 and 15) and 5-FU (2100 mg/m2, 24-hour infusion on days 1 and 15) is a feasible regimen with encouraging activity in anthracycline-pretreated patients.

Strongyloides stercoralis infection: how to diagnose best?

Four patients are described with a Strongyloides stercoralis infection. Several techniques to diagnose this infection are discussed. The so-called Baermann method is emphasised. Especially in chronic infections the combination of serology and the Baermann method seems the best diagnostic approach. Treatment with albendazole or ivermectin are suggested treatments.