Bente Lund

Nitrogen cycling in the Barents Sea—I. Uptake of nitrogen in the water column

Abstract Uptake of ammonium, nitrate and urea by phytoplankton in the Barents Sea was measured in May–June and in August 1984 by a 15 N-technique. Ammonium was the most important nitrogen source for the phytoplankton. Nitrate was an important nitrogen source in water with large phytoplankton biomass but was of no importance in water with small phytoplankton biomass (after the spring bloom). Nitrate uptake was inhibited by ammonium concentrations > 0.8 μ g-at. N 1 −1 . Urea uptake was variable and highest in phytoplankton and nutrient-poor water. Urea uptake in the dark was 30–50% of light-saturated uptake. The concentrations of urea were ⩽1.7 μ g-at. N 1 −1 . Only 27% of the concentrations were > 0.5 μ g-at. N 1 −1 , and kinetic experiments indicated that some of these values were overestimated. No signs of severe nitrogen limitation of the phytoplankton growth were found.

Combined high-dose carboplatin and cisplatin, and ifosfamide in previously untreated ovarian cancer patients with residual disease.

Carboplatin 200 mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3, ifosfamide 1,500 mg/m2 days 1 to 3, and mesna 900 mg/m2 days 1 to 3 every 4 weeks for six cycles were given to 37 previously untreated ovarian cancer patients with residual disease after the primary laparotomy. The median observation time was 17+ months (range, 9+ to 24+ months). Of all the patients, 81% had primary residual disease larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 36 assessable patients was 58%, PCR was 42%. Of the PCR patients, 53% had primary residual tumor larger than 5 cm. The substantial hematologic toxicity was manageable, but also the main reason for dose modifications. During treatment, 92% and 100% of the patients developed WBC and platelet nadir values corresponding to World Health Organization (WHO) grades 3 to 4. Dose-limiting encephalopathy, nephro- and neurotoxicity each occurred in 6% of the patients. The high PCR rate warrants further investigations of combined high-dose platinum and ifosfamide.

Mutual interference of ammonium, nitrate, and urea on uptake of 15N sources by the marine diatom Skeletonema costatum (Grev.) Cleve

Abstract 14 N- and 15 N-labelled ammonium, urea, and nitrate were used to determine mutual influence effects on uptake in Skeletonema costatum (Grev.) Cleve. The following combinations of N sources showed mutual interference on uptake rates: ammonium on nitrate, ammonium + urea on nitrate, urea on ammonium, nitrate + urea on ammonium, nitrate on urea, ammonium on urea, and ammonium + nitrate on urea, whereas there was no mutual interference of nitrate on ammonium and of urea on nitrate. In all cases, but one, the uptake rates were constant throughout the incubation period. The uptake rate of nitrate, with the simultaneous addition of ammonium + urea, decreased in a hyperbolic manner with time. The summed uptake rates for an oxidized (nitrate) and a reduced N source (urea, ammonium) greatly exceeded the uptake rate necessary to maintain the preconditioned growth rate, whereas the summed uptake rate of two reduced N sources exceeded this maintenance rate to a lesser degree. The experiments were begun immediately before the preconditioned cells had used the available nitrate. A model is described whereby the uptake of 15 N can be calculated in uptake experiments, where the initial amount of cellular N is known instead of the final, and where there is a simultaneous uptake of other (unlabelled) N sources.

Urea turnover in a coastal marine sediment measured by a 14C-urea short-term incubation

Abstract A method is described for the determination of urea turnover in marine sediments. 14 C-urea was injected into sediment cores and 14 CO 2 and the total 14 C content were measured in a time-course incubation (29, 72, 109 and 141 min). he method is a true-tracer technique as the addition of urea does not significantly alter the ambient concentration. Urea was not bound or adsorbed to the sediment, within the time span of the incubation, indicating that it was a free porewater pool of urea that was turned over. The turnover rate of urea was calculated by means of three different isotope-dilution models. Model I described nonsteady-state conditions and was the valid model for this study. Models II and III were both steady-state models and were invalid. The urea pool was assumed to change linearly with time in Model I and to remain constant in Models II and III. The 14 C-urea pool was predicted to decrease exponentially in Models I and II and to decrease linearly in Model III within a short time span in the beginning of the incubation. The turnover rate was slightly overestimated, 21%, on an areal basis, when Model II was applied and severely overestimated, 33%, when Model III was applied. We suggest macrofauna to be responsible directly and/or indirectly for a major part of the urea production and urea to be the main source for NH 4 + mineralization, in the study area.

Improved classification of epithelial ovarian cancer: results of 3 danish cohorts

Objective An increasing body of evidence has suggested that epithelial ovarian cancer (EOC) patients can broadly be divided into 2 groups on the basis of histopathologic parameters and molecular profiles. Type 1 tumors are slow-growing tumors with inherent mutations such as KRAS or BRAF mutations, whereas type 2 tumors are more rapidly growing tumors of which many contain TP53 mutations. In the present study, we performed a comprehensive study in a large Danish material to evaluate the clinical importance. Materials and Methods A total of 512 tissue samples were included (430 EOCs, 34 borderline, 28 benign tumors, and 20 normal ovaries). KRAS mutations (codon 12/13) and BRAF codon 600 mutations were analyzed from formalin-fixed paraffin-embedded tissue by ARMS qPCR. p53 expression was examined by immunohistochemistry. Results Of the EOC patients, 25% had histopathologically classified type 1 tumors, and of these, 44% were either KRAS or BRAF mutated. Of patients with histopathologic type 2 tumors, 66% showed p53 protein overexpression, whereas 4 (1.5%) patients contained a KRAS mutation. In a univariate survival analysis, a large difference in survival was seen between patients with type 1 and type 2 tumors. Patients with type histologic 2 tumors had significantly worse survival compared with patients with type 1 tumors (P < 10−5). International Federation of Gynecology and Obstetrics (FIGO) stage, tumor grade, residual tumor, and KRAS/BRAF mutation were independent predictors of overall survival in the multivariate analysis. Patients with KRAS/BRAF mutated carcinomas showed independent decreased overall survival with a hazard ratio of 2.01 (95% confidence interval, 1.13–3.57; P = 0.018). Conclusions KRAS/BRAF mutations are with very few exceptions constrained to patients with histopathologic type 1 tumors, whereas p53 overexpression is very frequent in type 2 tumors. KRAS/BRAF mutations had independent prognostic importance. The classification presented here should have a major therapeutic implication and serve as a hallmark of future clinical trials.

Multicenter phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer

Gemcitabine has activity in advanced ovarian cancer, with responses in platinum-resistant disease. This study assessed the activity of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. All patients had histologically verified invasive epithelial ovarian cancer, International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease and no prior chemotherapy. Patients received gemcitabine 1250 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Radiological response was assessed after two cycles. Between December 1992 and October 1995, 35 patients were enrolled. Of 33 evaluable patients, there was one complete response and five partial responses, for an overall response rate of 18% (95% confidence interval 7-36%). Forty-two percent of patients had a greater than 50% decrease in their CA-125 levels. Of the 25 patients who received platinum-based chemotherapy following treatment with gemcitabine, 12 achieved an overall response rate of 48%. Toxicity was mild, with two episodes of WHO grade 4 neutropenia (not associated with fever) and two episodes of grade 4 thrombocytopenia (not associated with bleeding). Gemcitabine has single-agent activity for poor-prognosis patients with advanced ovarian cancer. Similar results with subsequent platinum-based therapy indicate a lack of cross-resistance. This, combined with gemcitabines favorable toxicity profile, warrants testing in comparative trials.

Health-related quality of life in recurrent platinum-sensitive ovarian cancer—results from the CALYPSO trial

BACKGROUND In the CALYPSO trial, carboplatin-pegylated liposomal doxorubicin (CD) demonstrated superior therapeutic index versus carboplatin-paclitaxel (CP) in patients with recurrent ovarian cancer. This paper reports the health-related quality of life (HRQoL) findings. MATERIALS AND METHODS HRQoL was measured with the EORTC QoL-QC30 questionnaire and OV28 ovarian cancer module. Mean change scores from baseline in HRQoL subscales (five functional scales and global health status) in each arm and the proportion of patients improved or worsened were calculated every 3 months until 12 months. RESULTS Compliance was 90% at baseline and 76%, 64%, 57% at 3, 6, and 9 months, respectively. Baseline HRQoL showed already impaired global scores (mean 62/100) and considerable symptom burden (90% of patients reporting nonzero scores). Global QoL and abdominal symptom scores improved over time in both arms; at 6 months, 36% of patients met criteria for improved symptoms. Treatment with CD resulted in less peripheral neuropathy (9.8 versus 24.2), fewer other chemotherapy side-effects (9.5 versus 16.2), and less impact on body image (3.8 versus 10.4) versus CP (all P<0.02) at 6 months. CONCLUSIONS These patient-reported outcomes confirm the overall lower toxicity of CD versus CP. The improved disease-related outcomes achieved with CD were not at the expense of QoL.

Panitumumab and Pegylated Liposomal Doxorubicin in Platinum-Resistant Epithelial Ovarian Cancer With KRAS Wild-Type: The PaLiDo Study, a Phase II Nonrandomized Multicenter Study

Objective The increasing number of negative trials for ovarian cancer treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may improve survival. The aim of this study was to investigate the response rate in platinum-resistant, KRAS wild-type ovarian cancer patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. Patients and Methods Major eligibility criteria were relapsed ovarian/fallopian/peritoneal cancer patients with platinum-resistant disease, measurable disease by GCIG CA125 criteria and KRAS wild-type. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m2 day 1, every 4 weeks. Results Forty-six patients were enrolled by 6 study sites in this multi-institutional phase II trial. The response rate in the intention-to-treat population (n = 43) was 18.6%. Progression-free and overall survival in the intention-to-treat population was 2.7 months (2.5–3.2 months, 95% confidence interval) and 8.1 months (5.6–11.7 months, 95% confidence interval), respectively. The most common treatment-related grade 3 toxicities included skin toxicity (42%), fatigue (19%), and vomiting (12%). Conclusions The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients but the skin toxicity was considerable.

A phase II study of combination chemotherapy in early relapsed epithelial ovarian cancer using gemcitabine and pegylated liposomal doxorubicin

OBJECTIVE Treatment of epithelial ovarian cancer patients relapsing with a short treatment-free interval (TFI) after prior chemotherapy is unsatisfactory. This phase II trial evaluated the activity and feasibility of pegylated liposomal doxorubicin (PLD) plus gemcitabine in this setting. METHODS Patients who had received prior platinum and paclitaxel with a TFI 0-12 months received PLD 25 mg/m(2)day 1 plus gemcitabine 800 mg/m(2)day 1, 8 every 21 days. Gemcitabine was dose escalated to 1000 mg/m(2)day 1, 8 from course 2 in the absence of grade 3/4 toxicity. The primary endpoint was progression-free survival (PFS). Patients were stratified according to response to primary chemotherapy. RESULTS Seventy-nine patients (n=26 with CR on prior chemotherapy and TFI 6-12 months; n=20 with CR and TFI 0-6 months; n=33 with PR/SD and TFI 0-12 months) were enrolled. The median age was 59 years (range 31-77 years), and 33 patients had received ≥ 2 prior treatments. A median of five courses was delivered per patient (total 389 courses). Gemcitabine was dose escalated in 124 courses and reduced in 105 courses. No PLD dose reductions occurred. Grade 3/4 toxicities were febrile neutropenia (n=4), PPE (n=2), and mucositis (n=2). One toxic death occurred (pneumonitis/alveolitis). Responses were complete in 5.1%, partial in 27.9%, and stable disease in 55.7%. Median OS and PFS were 12.5 and 6.4 months, respectively. CONCLUSIONS The PLD-gemcitabine combination is an effective and well-tolerated salvage treatment for relapsed epithelial ovarian cancer and is a valid candidate for evaluation in a phase III trial.

RADIOBIOLOGICAL IMPACT OF REDUCED MARGINS AND TREATMENT TECHNIQUE FOR PROSTATE CANCER IN TERMS OF TUMOR CONTROL PROBABILITY (TCP) AND NORMAL TISSUE COMPLICATION PROBABILITY (NTCP)

Dose escalation in prostate radiotherapy is limited by normal tissue toxicities. The aim of this study was to assess the impact of margin size on tumor control and side effects for intensity-modulated radiation therapy (IMRT) and 3D conformal radiotherapy (3DCRT) treatment plans with increased dose. Eighteen patients with localized prostate cancer were enrolled. 3DCRT and IMRT plans were compared for a variety of margin sizes. A marker detectable on daily portal images was presupposed for narrow margins. Prescribed dose was 82 Gy within 41 fractions to the prostate clinical target volume (CTV). Tumor control probability (TCP) calculations based on the Poisson model including the linear quadratic approach were performed. Normal tissue complication probability (NTCP) was calculated for bladder, rectum and femoral heads according to the Lyman-Kutcher-Burman method. All plan types presented essentially identical TCP values and very low NTCP for bladder and femoral heads. Mean doses for these critical structures reached a minimum for IMRT with reduced margins. Two endpoints for rectal complications were analyzed. A marked decrease in NTCP for IMRT plans with narrow margins was seen for mild RTOG grade 2/3 as well as for proctitis/necrosis/stenosis/fistula, for which NTCP <7% was obtained. For equivalent TCP values, sparing of normal tissue was demonstrated with the narrow margin approach. The effect was more pronounced for IMRT than 3DCRT, with respect to NTCP for mild, as well as severe, rectal complications.