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.

Heterophilic antibodies may be a cause of falsely low total IGF1 levels.

BACKGROUND: A low serum total IGF1 is considered as a diagnostic indicator of GH deficiency (GHD) in the presence of hypopituitarism. Introduction of IRMA and chemiluminescent immunometric assay (CLIA) IGF1 immunoassays has introduced endogenous antibodies as a new source of interference. In general, this goes unnoticed and might lead to unnecessary diagnostic and therapeutic interventions. CASE: A 56-year-old man was referred with a decline in physical performance, unexplained osteopenia, and weight loss of 3 kg over the past 8 months. Although clinical signs and symptoms were unremarkable, laboratory results pointed to secondary hypothyroidism and secondary hypogonadism. In addition, the serum total IGF1 level (CLIA; Siemens Medical Solutions Diagnostics) was in the low normal range. Two GH stimulation tests were performed, but these tests did not support the diagnosis GHD. Moreover, IGF1 bioactivity measured by the kinase receptor activation assay was normal. Interference of heterophilic antibodies was considered. After pretreatment with specific heterophilic blocking tubes that contain blocking reagents to eliminate heterophilic antibodies, serum-free thyroxine, testosterone, and IGF1 levels turned out to be normal. CONCLUSION: To the best of our knowledge, we here describe the first case in the literature of a patient with low serum total IGF1 levels due to interference from heterophilic antibodies in the used IGF1 immunoassay. When confronted with low-IGF1 levels that do not fit the clinical picture, interference of heterophilic antibodies should be considered in the differential diagnosis.

Monoarthritis of the elbow due to metastatic colon carcinoma: diagnosis based on the presence of adenocarcinoma cells in synovial fluid.

There are many diseases that can cause monoarthritis, malignancy being one of the more rare causes. We present such a case and discuss the relationship between malignancy and arthritis. Typically a large joint is involved, most frequently the knee and very rarely the elbow. The value of cytological examination of synovial fluid is stressed. Synovial fluid in malignant joint disease is usually sanguineous and not consistent with an inflammatory process. Synovial fluid analysis can avoid a biopsy of bone or synovium and lead to an early diagnosis and palliative treatment.

[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.

Paraneoplastic hypertrichosis lanuginosa acquisita: uncommon or overlooked?

Acquired hypertrichosis lanugo-type or hypertrichosis lanuginosa acquisita (HLA) is often associated with metabolic and endocrine disorders and use of certain drugs. The occurrence of HLA with malignancy was first noted in 1865, and it has since been described in 56 patients as a paraneoplastic syndrome both in women and in men. Sometimes HLA occurs concurrent with acanthosis nigricans, papillary hypertrophy of the tongue, and glossitis. The predominance of female cases is striking. Malignancy-associated HLA seems to occur especially in the age group 40-70 years. In women with HLA the most frequent malignancy is colorectal cancer, followed in order by lung cancer and breast cancer; in men lung cancer is the malignancy most frequently associated with HLA, followed by colorectal cancer. In 3 years we saw 10 patients with HLA, in whom the malignancy was usually metastasized. Only one patient had local disease; after removal of the primary tumour it took 2 years before the lanugo hair recurred. The aetiology of the syndrome is not clear: no specific hormonal or biochemical abnormalities have been identified as yet. The difference between hirsutism and lanugo-type hypertrichosis is discussed. It is stressed that the appearance of lanugo-type hypertrichosis in body areas previously perceived by patients as 'hairless' is highly indicative of internal malignancy.

[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.

Randomised Phase III study of biweekly 24-h infusion of high-dose 5FU with folinic acid and oxaliplatin versus monthly plus 5-FU/folinic acid in first-line treatment of advanced colorectal cancer.

BACKGROUND: A phase III study was started to compare oxaliplatin/5FU/LV in the first-line with bolus FU/LV in metastatic colorectal cancer. PATIENTS AND METHODS: 302 patients were randomised and received bolus 5-FU 425 mg/m(2) day 1-5, FA 20 mg/m(2) day 1-5, q 4 wk or oxaliplatin 85 mg/m(2), 2 h-infusion, FA 200 mg/m(2), 1-h infusion. 5-FU 2600 mg/m(2), 24-h infusion day 1, q 2 wk. The primary endpoint was response rate (RR). RESULTS: The median follow-up is 31.8 months, 90.4% of the patients have died. Confirmed RR, progression free survival (PFS; months) and median overall survival (OS; months) in 5FU/LV versus 5FU/LV/oxaliplatin were respectively 18.5% versus (vs) 33.8% (P = 0.004), 5.6 vs 6.7 (P = 0.016) and 13.3 vs 13.8 (P = 0.619). In the 5FU/LV/oxaliplatin arm less grade (3/4) toxicity was measured for diarrhoea, stomatitis, an increase in idiosyncratic side effects and neurosensory events compared with 5FU/LV. The quality of life (QOL) was equal in both arms. Second line treatment was given in 62% of the patients, crossover of 5FU/LV to 5FU/LV/oxaliplatin occurred in 14%. CONCLUSIONS: Oxaliplatin in the first-line resulted in an increased RR and PFS with less grade 3/4 mucositis/diarrhoea compared with 5FU/LV alone. Idiosyncratic side effects deserve attention with oxaliplatin. Despite a low treatment cross over rate, OS in both groups was comparable.

[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.

Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-refractory prostate cancer.

Satraplatin is a novel oral platinum (IV) complex that shows activity against hormone-refractory prostate cancer (HRPC) in cisplatin-resistant human tumor lines in phase I and phase II trials. A randomized multicenter phase III trial with a target sample size of 380 patients was initiated in men with HRPC. After 50 randomized patients, the trial was closed to further accrual by the sponsoring company. An ad hoc analysis of all available data is reported here. Eligibility criteria included pathological proof of prostate cancer, documented progression despite prior hormonal manipulation, WHO PS 0-2, and no daily intake of narcotic analgesics. Patients were randomized between satraplatin 100 mg/m(2) for 5 days plus prednisone 10 mg orally BID or prednisone alone. Compliance was excellent. 48/50 patients have progressed and 42 have died, mostly due to prostate cancer. Median overall survival was 14.9 months (95% CI: 13.7-28.4) on the satraplatin plus prednisone arm and 11.9 months (95% CI: 8.4-23.1) on prednisone alone (hazard ratio, HR = 0.84, 95% CI: 0.46-1.55). A >50% decrease in prostrate specific antigen (PSA) was seen in 9/27 (33.3%) in the satraplatin plus prednisone arm vs. 2/23 (8.7%) on the prednisone alone arm. Progression-free survival was 5.2 months (95% CI: 2.8-13.7) on the satraplatin plus prednisone arm as compared to 2.5 months (95% CI: 2.1- 4.7) on the prednisone alone arm (HR = 0.50, 95% CI: 0.28-0.92). This difference is statistically significant (p = 0.023). Toxicity was generally minimal in both arms. This randomized comparison of a combination of satraplatin and prednisone versus prednisone alone supports the antitumor activity of the combination. Its role in the treatment of HPRC remains to be elucidated in an appropriate phase III setting.

[Clinical reasoning and decision making in practice. A depressive foreign woman with symptoms of malaise]. / Klinisch denken en beslissen in de praktijk. Een depressieve buitenlandse vrouw met klachten van malaise.

A 27-year-old woman was admitted to the hospital with a depression, anaemia and fatigue. She had come from Angola to the Netherlands as a refugee 2 years before this evaluation. As an explanation for her symptoms tropical infectious diseases of parasitic origin were considered, but no clues were found in this direction. The test for trypanosomiasis was considered to be suggestive for an infection in the past (persistent titre 1:200). She was discharged but readmitted 6 months later because of a deterioration of her clinical condition. Magnetic resonance imaging showed bilateral signal abnormalities within the white matter of the brain. On examination no neurological signs or abnormalities were found. Again, no definite diagnosis could be made and the patient was discharged. Because of a further deterioration of her clinical condition she was readmitted a short time later for the third time. On the MRI the white matter lesions had increased. The serum protein electrophoresis was markedly abnormal with an elevated IgM Level. Finally, at a repeated lumbar puncture mobile trypanosomes were found. The diagnosis of 'West African sleeping sickness' was made and the patient was treated with eflornithine. She recovered completely during the next 18 months.

[High dose chemotherapy and stem cell transplant in patients with operable breast cancer and a poor prognosis; not indicated for the time being]. / Hooggedoseerde chemotherapie en stamceltransplantatie bij patiënten met operabel mammacarcinoom en slechte prognose: voorlopig niet geïndiceerd.

Early breast cancer with multiple tumour-positive axillary lymph glands is still characterised by a considerable mortality despite improvements in surgery, radiotherapy, chemotherapy and endocrine treatment. High-dose chemotherapy and bone-marrow support instead of the usual chemotherapy seemed to be a very promising approach back in the 1980s. Several phase-II studies supported this view and therefore phase-III studies were carried out. In a Cochrane review published at the start of 2003, a meta-analysis of several phase-III studies revealed that the results after high-dose chemotherapy were not significantly better than those after the usual treatment. Two large multicentre studies, one performed in the Netherlands and one in the USA, have recently been published. Neither of the two studies revealed survival differences, although one study demonstrated a significant benefit in actuarial 5-year relapse-free survival. Therefore, the routine clinical application of high-dose chemotherapy cannot be advocated yet.

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.

[Metabolic disregulation after starting feeding: "refeeding" syndrome: the central role of phosphate]. / Metabole ontregeling na opnieuw beginnen met voeding: 'refeeding'-syndroom; de centrale rol van fosfaat.

A 47-year-old man was admitted due to serious weight loss after several months in which he had not eaten and had drunk almost solely beer. Shortly after the start of enteral tube feeding, the patient developed serious heart failure. This was associated with severely disrupted electrolyte levels and in particular hypophosphataemia and hypomagnesaemia. This condition is termed refeeding syndrome. The circulating volume increases due to the hyperinsulinaemia which occurs during the feeding phase. Furthermore a shortage of ATP occurs and the heart may fail. In efforts to establish feeding, a weight increase of not more than 1 kg per week should be attempted; if the weight increases by more than this, then fluid retention is the probable cause.