A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib.

BACKGROUND: Conjunctival malignant melanoma (CMM) is a rare malignancy and in the advanced setting there is no effective treatment. In contrast, half of cutaneous melanomas have BRAF mutations and treatment with BRAF inhibitors is established for patients with disseminated disease. The most common form of ocular melanoma, uveal melanoma, lacks these mutations, however, their presence has been reported for CMM. CASE PRESENTATION: We used the BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from a BRAF(V600E) mutated metastatic CMM. The patient benefited from the treatment, a response was evident within a week and she experienced a progression free survival of four months. CONCLUSIONS: To our knowledge, this is the first described case of response to vemurafenib treatment in a patient with ocular melanoma.

The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy.

BACKGROUND: To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. PATIENTS AND METHODS: The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS). RESULTS: The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%. CONCLUSIONS: The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Prediction of irinotecan and 5-fluorouracil toxicity and response in patients with advanced colorectal cancer.

Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).

A temperature-dependent growth model for the three-spined stickleback Gasterosteus aculeatus.

Specific growth rates of individually reared juvenile three-spined sticklebacks Gasterosteus aculeatus were investigated under laboratory conditions to parameterize a complete temperature-dependent growth model for this species. To test the applicability of experimentally derived optima in growth response rates to natural conditions, the effects of commercial pellets and natural prey on growth rates were investigated. In addition, to test for seasonal effects on growth, laboratory trials were performed in both spring and winter. Growth took place from 5 to 29° C with a temperature for optimum growth reaching a sharp peak at 21° C. Modelled optimal temperature for maximum growth was estimated to be 21.7° C and lower and upper temperatures for growth were estimated to be 3.6 and 30.7° C, respectively. There were no significant differences in growth rates between fish reared on invertebrates or commercial pellets. Seasonal effects on growth were pronounced, with reduced growth rates in the winter despite similar laboratory conditions. On average, 60% higher growth rates were achieved at the optimum temperature in summer compared to the winter. The strong seasonality in the growth patterns of G. aculeatus indicated here reduces the applicability of the model derived in this study to spring and summer conditions.

A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer.

BACKGROUND: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design. PATIENTS AND METHODS: Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500 mg once daily for the remaining 28-day cycles. Progression was assessed on the basis of radiographic imaging, rise in carcinoembryonic antigen or lactate dehydrogenase (LDH) levels or by appearance of clinical symptoms. RESULTS: Twenty-eight patients received daily enzastaurin. The 6-month PFS rate was 28% [95% confidence interval (CI) 13%-45%] and median PFS was 1.9 months (95% CI 1.8-4.5 months). Twelve (43%) patients had stable disease with a median duration of 6.1 months. The survival rate at 20 months was 77% (95% CI 47%-92%). No grade 4 toxicity was reported and grade 3 toxic effects were observed in three patients with one patient showing probable drug-related elevation of liver transaminases. CONCLUSION: The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.

Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer.

BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer.

BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

No evidence of increased growth or mortality in fish exposed to oxazepam in semi-natural ecosystems.

An increasing number of short-term laboratory studies on fish reports behavioral effects from exposure to aquatic contaminants or raised carbon dioxide levels affecting the GABAA receptor. However, how such GABAergic behavioral modifications (GBMs) impact populations in more complex natural systems is not known. In this study, we induced GBMs in European perch (Perca fluviatilis) via exposure to a GABA agonist (oxazepam) and followed the effects on growth and survival over one summer (70days) in replicated pond ecosystems. We hypothesized that anticipated GBMs, expressed as anti-anxiety like behaviors (higher activity and boldness levels), that increase feeding rates in laboratory assays, would; i) increase growth and ii) increase mortality from predation. To test our hypotheses, 480 PIT tagged perch of known individual weights, and 12 predators (northern pike, Esox lucius) were evenly distributed in 12 ponds; six control (no oxazepam) and six spiked (15.5±4µgl-1 oxazepam [mean±1S.E.]) ponds. Contrary to our hypotheses, even though perch grew on average 16% more when exposed to oxazepam, we found no significant difference between exposed and control fish in growth (exposed: 3.9±1.2g, control: 2.9±1g [mean±1S.E.], respectively) or mortality (exposed: 26.5±1.8individuals pond-1, control: 24.5±2.6individuals pond-1, respectively). In addition, we show that reduced prey capture efficiency in exposed pike may explain the lack of significant differences in predation. Hence, our results suggest that GBMs, which in laboratory studies impact fish behavior, and subsequently also feeding rates, do not seem to generate strong effects on growth and predation-risk in more complex and resource limited natural environments.

Bioaccumulation of five pharmaceuticals at multiple trophic levels in an aquatic food web - Insights from a field experiment.

Pharmaceuticals derived from manufacturing and human consumption contaminate surface waters worldwide. To what extent such pharmaceutical contamination accumulates and disperses over time in different compartments of aquatic food webs is not well known. In this study we assess to what extent five pharmaceuticals (diphenhydramine, oxazepam, trimethoprim, diclofenac, and hydroxyzine) are taken up by fish (European perch) and four aquatic invertebrate taxa (damselfly larvae, mayfly larvae, waterlouse, and ramshorn snail), by tracing their bioconcentrations over several months in a semi-natural large-scale (pond) system. The results suggest both significant differences among drugs in their capacity to bioaccumulate and differences among species in uptake. While no support for in situ uptake of diclofenac and trimethoprim was found, oxazepam, diphenhydramine, and hydroxyzine were detected in all analyzed species. Here, the highest bioaccumulation factor (tissue:water ratio) was found for hydroxyzine. In the food web, the highest concentrations were found in the benthic species ramshorn snail and waterlouse, indicating that bottom-living organism at lower trophic positions are the prime receivers of the pharmaceuticals. In general, concentrations in the biota decreased over time in response to decreasing water concentrations. However, two interesting exceptions to this trend were noted. First, mayfly larvae (primarily grazers) showed peak concentrations (a fourfold increase) of oxazepam, diphenhydramine, and hydroxyzine about 30days after initial addition of pharmaceuticals. Second, perch (top-predator) showed an increase in concentrations of oxazepam throughout the study period. Our results show that drugs can remain bioavailable for aquatic organism for long time periods (weeks to months) and even re-enter the food web at a later time. As such, for an understanding of accumulation and dispersion of pharmaceuticals in aquatic food webs, detailed ecological knowledge is required.

Phase I study of UFT plus leucovorin with radiotherapy in patients with inextirpable non-rectal gastrointestinal cancer.

BACKGROUND AND PURPOSE: Chemoradiotherapy is increasingly used in the primary management of patients with loco-regionally advanced gastrointestinal (GI) cancer. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may represent a convenient way of delivering protracted infusion of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with radiation and determine the maximum-tolerated dose (MTD) and a recommended dose for further testing. PATIENTS AND METHODS: Patients with inextirpable GI cancer received escalating doses of UFT (starting at 300 mg/m(2)/d with 50 mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). UFT and LV were given 5 days per week concurrently with radiation to 50 Gy (2 Gy/fraction). RESULTS: Twenty-five patients were treated, and 22 received the planned treatment. Three patients were withdrawn from treatment, two due to disease-progression and one due to toxicity. The MTD of UFT with radiation was 400 mg/m(2)/d with 90 mg/d of LV. Diarrhoea was the main dose limiting toxicity (DLT). Since some toxicity (3/12 DLTs) was seen in the expanded cohort at the level below, but none (0/9 DLT) at the starting level, the recommended dose chosen for further testing is 300-350 mg/m(2)/d depending upon the size of the target volume. CONCLUSION: Concomitant chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated since tumour responses were frequently seen.

Size-dependent foraging efficiency, cannibalism and zooplankton community structure.

To examine size-dependent food web interactions in systems with cannibalism, we compared the abundances of zooplankton and phytoplankton over 2 years in four lakes with cannibalistic perch (Perca fluviatilis) of which two also supported the top predator pike (Esox lucius). The abundance of perch 2 years and older was lower in lakes with pike than in lakes with only perch. In contrast, the abundance of small perch (young-of-the-year and 1-year old) was lower in lakes with only perch suggesting that intense cannibalism reduced these size classes to low levels in lakes lacking pike. Functional response experiments with differently sized perch and zooplankton showed that the attack rate of small perch susceptible to cannibalism was much higher than that of large cannibalising perch. The optimal body size of perch with respect to attack rate was also lower for small zooplankton prey than for large zooplankton. The zooplankton communities in lakes with only perch were dominated by the relatively small species Ceriodaphnia quadrangula and Bosmina spp. and total zooplankton biomass was higher in these lakes than in lakes with both pike and perch. In contrast, the mean size of cladoceran zooplankton was largest in lakes with both pike and perch owing to a dominance of the large zooplankton species Holopedium gibberum in these lakes. We relate these patterns to (1) the low foraging efficiency of large perch on small zooplankton and (2) the low abundance of small zooplanktivorous perch (due to cannibalism) in lakes with only perch. The differences in zooplankton community structure also resulted in different seasonal dynamics of phytoplankton between lakes. Cannibalism introduces a vertical heterogeneity to food webs that causes consumer-resource dynamics that are not predictable from linear food chain models.

Resource limitation during early ontogeny: constraints induced by growth capacity in larval and juvenile fish.

The presence of and mechanisms behind density-dependent growth and resource limitation in larval and juvenile stages of organisms with high mortality such as fish are much debated. We compare observed consumption and growth rates with maximum consumption and growth rates to study the extent of resource limitation in young-of-the-year (YOY) roach (Rutilus rutilus) and perch (Perca fluviatilis). Diet, habitat use, consumption rate and growth rate were measured under varying YOY fish densities over 2 years in four lakes. In the first year, YOY roach and perch were studied under allopatric conditions. Experimental addition of perch roe in the second year also allowed study of YOY of the two species under sympatric conditions in two of the lakes. The diet of YOY roach was dominated by cladoceran zooplankton and YOY roach habitat use was restricted to the shore region in both years. This restricted habitat use did not involve any cost in foraging gain in the first year as consumption and growth rates were very close to maximum rates. During the second year, when the two species coexisted, resources were limited in late season, more so in the littoral than in the pelagic habitat in one lake while the reverse was the case in the other lake. The diet of YOY perch was also dominated by zooplankton, and with increasing perch size the proportion of macroinvertebrate prey in the diet increased. After hatching, YOY perch first utilized the pelagic habitat restricting their habitat use to the shore after 1 to several weeks in the pelagic zone. During the larval period, perch were not resource limited whereas juvenile perch were resource limited in both years. The fact that YOY perch were more resource limited than YOY roach was related to the higher handling capacity and lower attack rate of perch relative to roach, rendering perch more prone to resource limitation. Estimates of resource limitation based on consumption rates and growth rates yielded similar results. This supports the adequacy of our approach to measure resource limitation and suggests that this method is useful for studying resource limitation in organisms with indeterminate growth. Our results support the view that density-dependent growth is rare in larval stages. We suggest that density-dependent growth was absent because larval perch and roach were feeding at maximum levels over a wide range of larvae densities.

Impacts of elevated terrestrial nutrient loads and temperature on pelagic food-web efficiency and fish production.

Both temperature and terrestrial organic matter have strong impacts on aquatic food-web dynamics and production. Temperature affects vital rates of all organisms, and terrestrial organic matter can act both as an energy source for lower trophic levels, while simultaneously reducing light availability for autotrophic production. As climate change predictions for the Baltic Sea and elsewhere suggest increases in both terrestrial matter runoff and increases in temperature, we studied the effects on pelagic food-web dynamics and food-web efficiency in a plausible future scenario with respect to these abiotic variables in a large-scale mesocosm experiment. Total basal (phytoplankton plus bacterial) production was slightly reduced when only increasing temperatures, but was otherwise similar across all other treatments. Separate increases in nutrient loads and temperature decreased the ratio of autotrophic:heterotrophic production, but the combined treatment of elevated temperature and terrestrial nutrient loads increased both fish production and food-web efficiency. CDOM: Chl a ratios strongly indicated that terrestrial and not autotrophic carbon was the main energy source in these food webs and our results also showed that zooplankton biomass was positively correlated with increased bacterial production. Concomitantly, biomass of the dominant calanoid copepod Acartia sp. increased as an effect of increased temperature. As the combined effects of increased temperature and terrestrial organic nutrient loads were required to increase zooplankton abundance and fish production, conclusions about effects of climate change on food-web dynamics and fish production must be based on realistic combinations of several abiotic factors. Moreover, our results question established notions on the net inefficiency of heterotrophic carbon transfer to the top of the food web.

An explorative study on the clinical utility of baseline and serial serum tumour marker measurements in advanced upper gastrointestinal cancer.

The value of early tumour marker changes during palliative chemotherapy in patients with upper gastrointestinal adenocarcinoma (UGIA) is unclear. Seventy-three patients with advanced UGIA were randomised to receive 45 mg/m2 docetaxel or 180 mg/m2 irinotecan with 5-FU/leucovorin. After every 2nd course the patients were crossed over to the other regimen. Serum was sampled before start of chemotherapy and every 2nd week during 8 weeks for CEA, TPA, TPS, CA72-4, CA19-9 and CA242 measurements. Eighteen patients (25%) had partial response (PR) and 21 patients had stable disease for at least 4 months (SD4). All baseline marker levels, except CA72-4, correlated with time to progression and survival. Patients with normal levels, except CA72-4, also had more clinical responses (PR+SD4) than patients with elevated values. Tumour marker changes early during treatment provided modest predictive information for tumour response and survival. A model combining baseline level, the change and the interaction between them gave the best prediction of outcome, however, insignificantly better than baseline level for all markers except CA242. Baseline tumour marker levels provide prognostic information for patients with UGIA on palliative chemotherapy. Early changes generally failed to provide accurate information for tumour response and survival.

Clinical signs and physical function in neck and upper extremities among elderly female computer users: the NEW study.

The aim of the study was to present the prevalence of clinical signs and symptoms among female computer users above 45 years, both in a group with self-reported neck/shoulder trouble (NS cases) and in a group without such trouble (NS controls). The hypothesis was that computer users with self-reported neck/shoulder trouble have more clinical findings than those not reporting trouble, and that a corresponding pattern holds true for physical function. In total 42 and 61 questionnaire-defined NS cases and NS controls participated and went through a clinical examination of the neck and upper extremities and five physical function tests: maximal voluntary contraction (MVC) of shoulder elevation, abduction, and handgrip, as well as endurance at 30% MVC shoulder elevation and a physical performance test. Based on clinical signs and symptoms, trapezius myalgia (38%), tension neck syndrome (17%) and cervicalgia (17%) were the most frequent diagnoses among NS cases, and were significantly more frequent among NS cases than NS controls. A total of 60% of the subjects with reported trouble had one or several of the diagnoses located in the neck/shoulder. Physical function of the shoulder was lower in subjects with self-reported trouble as well as in the subgroup of NS cases with clinical diagnoses. In conclusion, the present clinical diagnoses and physical function tests differed between NS cases and NS controls, and are therefore recommended to be included as quantitative objective measures in assessing musculoskeletal health. Physical function tests should be further developed in order to be able to detect pre-stages of work-related disorders for preventive strategies.

Correlation between basic fibroblast growth factor immunostaining of stromal cells and stromelysin-3 mRNA expression in human breast carcinoma.

We examined the localization of basic fibroblast growth factor (bFGF) in a series of human breast carcinomas using immunohistochemistry. Staining was observed in tumour cells in 15 out of 54 (28%) tumours and in the adjacent stroma in 34 out of 54 (63%) tumours examined. No correlation was observed between positive staining of these two compartments. The relationship between bFGF staining and expression of the metalloprotease stromelysin-3, and between bFGF and microvessel density, was examined. A statistically significant correlation (P < 0.003) was observed between bFGF staining of the stromal compartment and high expression of stromelysin-3 (ST-3; MMP-11) metalloprotease mRNA by stromal cells. In contrast, no correlation was observed between bFGF and intratumour microvessel density (IMD). These results raise the possibility that bFGF may be involved in the induction of stromelysin-3 mRNA expression in breast cancer stroma.