Predictive factors for toxicity and survival of second-line sunitinib in advanced gastrointestinal stromal tumours (GIST).

Introduction: Sunitinib is a standard second-line treatment in advanced gastrointestinal stromal tumours (GIST). We aimed to search for predictive factors for grade 3 and 4 toxicity, progression-free survival (PFS) and overall survival (OS) in a GIST reference center patient population, outside clinical trials.Methods: A retrospective analysis was performed of patients treated in two European Comprehensive Cancer Centers between January 2005 and December 2015. Demographic and clinical features, tumour characteristics and biological parameters were investigated. Logistic regression models were used to find factors associated with grade 3 and 4 toxicity. To identify predictive factors for PFS and OS, variables that were statistically significant in univariate analysis were used in the multivariate Cox proportional hazards model.Results: Ninety-one patients were included in this analysis. Age >60 years (HR 5.0, p = .006) and body weight ≤70 kg (HR 4.7, p = .009) were predictive factors for grade 3 and 4 toxicity. When divided into two categories, non-haematological grade 3 and 4 toxicity was predicted by age >60 years (HR 3.8, p = .012) and body weight ≤70 kg (HR 3.3, p = .025) whereas haematological toxicity had no significantly associated predictive factors. The median PFS and OS with sunitinib were 8.8 months and 27.5 months, respectively. The use of imatinib less than six months compared to 6-12 months (HR 0.2, p = .013) and to >12 months (HR 0.3, p = .016) and liver and/or peritoneal metastases (HR 0.1, p < .001, HR 0.2, p = .003 and HR 0.2, p = .004) compared to locally advanced disease only were predictive for longer PFS. High neutrophil (HR 3.1, p = 0.04) and platelet count (HR 2.4, p = .046) predicted a shorter OS. Flexible sunitinib dosing was associated with superior OS (p = .021).Conclusion: In advanced GIST patients treated with sunitinib, older and low-weight patients are at risk for grade 3 and 4 toxicity. Clinical (prior imatinib use and metastases), biological (neutrophil and platelet count) and treatment characteristics independently predict PFS and OS.

Constraining the Spatial Extent of Marine Oil Snow Sedimentation and Flocculent Accumulation Following the Deepwater Horizon Event Using an Excess 210Pb Flux Approach.

Following the Deepwater Horizon (DWH) event in 2010, there were several lines of evidence indicating the presence of marine oil snow sedimentation and flocculent accumulation (MOSSFA). A significant amount of marine oil snow formed in the water column of the northern Gulf of Mexico (nGoM), settled rapidly, and ultimately accumulated in the sediments of the nGoM. This study utilized a commonly used radioisotope tracer (excess 210Pb, 210Pbxs) from 32 sediment cores collected from 2010 to 2013 to characterize the spatial extent of MOSSFA on the seafloor. Relative to pre-DWH conditions, an increase in 210Pbxs flux occurred in two distinct regions: (1) in the western portion of the study area on an east-northeast to west-southwest axis, stretching 230 km southwest and 140 km northeast of the DWH wellhead, and (2) in the eastern portion of the study area on a 70 km northeast to southwest axis near the DeSoto Canyon. The total sedimentary spatial extent of MOSSFA, as calculated by increased 210Pbxs flux after 2010, ranged from 12 805 to 35 425 km2. 210Pbxs flux provides a valuable tool for documenting the spatial extent of MOSSFA following DWH and will continue to aid in the determination of advective transport and ultimate depocenters of MOSSFA material.

Sex differences in patients with gastrointestinal stromal tumours: do they exist and does it affect survival?

BACKGROUND: Sex differences in cancer have gained attention in recent years. The role of sex as a prognostic factor in gastrointestinal stromal tumours (GIST) has not been well established. The aim of this research was to elucidate potential sex differences in GIST patients and the influence of sex on disease-specific survival (DSS). METHODS: A review of the literature was carried out to obtain an overview of all literature with sex as a covariate on GIST survival analyses. Furthermore, in the Dutch GIST Registry, GIST characteristics between males and females were compared and the influence of sex on DSS was analysed. RESULTS: A total of 118 articles from the review of the literature met our selection criteria; 58% of the articles found no sex difference in survival and 42% did find a sex difference. All differences favoured female patients, although there was substantial overlap of individual patients in the various reported groups. The Dutch GIST Registry cohort consisted of 1425 patients (46% female). Compared with female patients, male patients had larger tumours (mean 9.0 cm versus 7.9 cm) and higher mitotic rates (34.4% versus 28.0% >5 mitoses/5 mm2). GIST in males was more often metastasized at diagnosis (21.3% versus 13.7%) and incurable (38.5% versus 31.0%). Male patients less often received surgery of the primary tumour (71.7% versus 78.9%), but did experience more tumour ruptures (18.2% versus 13.3%). Male patients had a worse DSS than females. This was not statistically significant when corrected for differences in GIST characteristics. CONCLUSIONS: In case of sex differences in GIST in the literature, male patients have a worse outcome. In our Dutch GIST cohort a similar finding was made, but sex was shown not to be an independent factor. Male patients more often had aggressive GISTs, with larger tumours, higher mitotic rates, more tumour ruptures, and metastases, which could explain the sex differences in DSS.

Priorities and preferences of advanced soft tissue sarcoma patients starting palliative chemotherapy: baseline results from the HOLISTIC study.

INTRODUCTION: Palliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions. PATIENTS AND METHODS: The prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher's exact tests were used to evaluate associations between patient characteristics and preferences. RESULTS: One hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%). CONCLUSIONS: Heterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care.

Mercury in sediment cores from the southern Gulf of Mexico: Preindustrial levels and temporal enrichment trends.

Spatial and temporal variability of mercury concentrations in sediments was evaluated in 210Pb-dated sediment cores from offshore and intertidal areas in the southern Gulf of Mexico. In offshore cores, mercury concentrations were comparable (11.2-69.2 ng g-1), and intermediate between concentrations in intertidal cores from the eastern (6.0-34.4 ng g-1) and the western (34.9-137.7 ng g-1) inlets of Términos Lagoon. The enrichment factor (EF) indicated minimal contamination (EF < 2) in most offshore cores, whereas in some intertidal cores steadily increasing mercury enrichment and fluxes were observed along the past century. No evidence of oil industry related mercury contamination was found, as the minor but increasing enrichment in intertidal cores is most likely related to land-derived sources such as catchment eroded soils and waste water runoff. Results highlight the importance to control catchment erosion and untreated sewage releases to reduce mercury loadings to the coastal zone.

Natural and anthropogenic oil impacts on benthic foraminifera in the southern Gulf of Mexico.

The Campeche Sound is the major offshore oil producing area in the Southern Gulf of Mexico (SGoM). To evaluate the impact of oil related activities in the ocean floor sediments, we analyzed the geochemical (major and trace element, organic carbon and hydrocarbon concentrations) and biological (benthic foraminifera) composition of 62 superficial sediment samples, from 13 to 1336 m water depth. Cluster and Factor analysis of all the variables indicate that their distribution patterns are mainly controlled by differences between the terrigenous and carbonate platforms in the SGoM. Benthic foraminiferal assemblages were abundant and diverse, and their distribution patterns are mainly determined by water depth and sedimentary environment. However, most of the abundant species are opportunistic and/or low-oxygen tolerant, and many of their tests show oil stains and infillings, characteristic of oil polluted locations, suggesting the environment has been modified by natural seepage or oil-related activities. To determine if these conditions are natural or anthropogenic in origin, pre - industrial settings should be studied. Organic carbon (Corg) content (0.6-2.9%) and total hydrocarbon concentrations (PAHs 1.0-29.5 µg kg-1) were usually higher around the oil platforms area, the natural hydrocarbon seeps ("chapopoteras") area and offshore rivers, but there is no accumulation of oil related trace elements in these areas. However, the comparison with international sediment quality benchmarks indicates that Cd, Cr and Ni concentrations are above the threshold effect level, and also As, Ba and Cu are above the probable effect level benchmarks, which indicate that these element concentrations might be of potential ecological concern. Comprehensive studies involving different proxies, and assessing pre-industrial conditions, must be undertaken before assessing environmental health of marine benthic ecosystems.

Prostaglandin protection of human isolated gastric glands against indomethacin and ethanol injury. Evidence for direct cellular action of prostaglandin.

Isolated human gastric glands from surgical specimens were preincubated in an oxygenated medium with placebo or 16,16 dimethyl prostaglandin E2 (dmPGE2) and incubated at 37 degrees C in either medium alone, medium containing 4.43 mM indomethacin or medium containing 8% ethanol. We assessed the viability of gland cells with fast green exclusion, release of lactate dehydrogenase (LDH) into the medium, and ultrastructural damage by scanning and transmission electron microscopy. Both indomethacin and ethanol significantly reduced the viability of placebo-pretreated glands, increased LDH release into the medium, and produced prominent ultrastructural damage. DmPGE2 significantly reduced both indomethacin and ethanol-induced injury, increased the number of viable cells, reduced LDH release, and diminished the extent of ultrastructural damage. These studies indicate that PG protection of gastric mucosal cells has a direct cellular action that is not limited to replacement of depleted endogenous PGs. PG protection in our experiments did not depend on PG's previously described systemic actions, such as protection of the microvessels, preservation of the mucosal blood flow, or stimulation of bicarbonate and mucus secretion.

Characterizing the variability of benthic foraminifera in the northeastern Gulf of Mexico following the Deepwater Horizon event (2010-2012).

Following the Deepwater Horizon (DWH) event in 2010 subsurface hydrocarbon intrusions (1000-1300 m) and an order of magnitude increase in flocculent hydrocarbon deposition caused increased concentrations of hydrocarbons in continental slope sediments. This study sought to characterize the variability [density, Fisher's alpha (S), equitability (E), Shannon (H)] of benthic foraminifera following the DWH event. A series of sediment cores were collected at two sites in the northeastern Gulf of Mexico from 2010 to 2012. At each site, three cores were utilized for benthic faunal analysis, organic geochemistry, and redox metal chemistry, respectively. The surface intervals (∼0-10 mm) of the sedimentary records collected in December 2010 at DSH08 and February 2011 at PCB06 were characterized by significant decreases in foraminiferal density, S, E, and H, relative to the down-core intervals as well as previous surveys. Non-metric multidimensional scaling (nMDS) analysis suggested that a 3-fold increase in polycyclic aromatic hydrocarbon (PAH) concentration in the surface interval, relative to the down-core interval, was the environmental driver of benthic foraminiferal variability. These records suggested that the benthic foraminiferal recovery time, following an event such as the DWH, was on the order of 1-2 years.

Uptake of riboflavin by intestinal basolateral membrane vesicles: a specialized carrier-mediated process.

The mechanism of riboflavin (RF) uptake by intestinal basolateral membrane vesicles (BLMV) was examined in this study. BLMV were isolated by an established Percoll-gradient methodology from rabbit small intestine. Uptake of riboflavin was mainly the result of transport of the substrate into an osmotically active intravesicular space with less binding to membrane surfaces. Uptake of RF with time was similar in the presence of a Na+ and a K+ gradient (out > in) and was not significantly influenced by changes in incubation buffer pH. The initial rate of uptake of riboflavin as a function of concentration was saturable in both jejunal and ileal BLMV and occurred with apparent Km values of 5.0 microM and 4.4 microM and Vmax values of 91.6 and 60.8 pmol/mg protein per 5 s, respectively. Unlabeled riboflavin and the structural analogues lumiflavin, isoriboflavin and 8-aminoriboflavin all caused significant inhibition (but to different degrees) in the uptake of [3H]riboflavin. On the other hand, 8-hydroxyriboflavin, lumichrome, lumazine and D-ribose failed to inhibit [3H]riboflavin uptake. Trans-stimulation of [3H]riboflavin efflux from preloaded BLMV by unlabeled riboflavin or lumiflavin was also observed. Altering transmembrane electrical potential by anion substitution and valinomycin-induced K+ diffusion did not affect the riboflavin uptake process. These results demonstrate the existence of a specialized carrier-mediated mechanism for riboflavin uptake by intestinal BLMV. Furthermore, the system appears to transport the vitamin by a process which is Na(+)- and pH-independent, and electroneutral in nature.

Absorption of 5-methyltetrahydrofolate in rat jejunum with intact blood and lymphatic vessels.

UNLABELLED: Transport results from in vitro studies may not be applicable to in vivo situations. In this study, we extended our previous in vitro observations regarding the intestinal transport of 5-methyltetrahydrofolate to in vivo studies in the unanesthetized rat and examined the effect of the unstirred water layer on the absorption process. We used a well defined intestinal perfusion technique. Absorption of 0.5 and 5 microM 5-methyltetrahydrofolate proceeded in a linear manner for 40 min of perfusion at 0.31 and 1.74 nmol/100 cm per min, respectively. Absorption of 0.5 microM 5-methyltetrahydrofolate increased with increasing perfusate flow-rate from 0.5 to 2 to 4 ml/min, indicating an unstirred water layer influence on the absorption rate. Absorption of the substrate was saturable with an apparent Kt of 5.7 microM and Vmax of 3.45 nmol/100 cm per min. Absorption was pH-dependent, and was inhibited by structural analogues. In contrast to the in vitro data, addition of glucose (20 mM) to the perfusate was unnecessary for in vivo absorption to proceed. Unconjugated cholic (5 mM) and deoxycholic (1 mM) acids and the organic anion rose bengal (0.1 mM) inhibited the absorption of 0.5 microM 5-methyltetrahydrofolate when added to the perfusate. CONCLUSIONS: the results of previous in vitro studies of 5-methyltetrahydrofolate intestinal transport are applicable to in vivo situations, except that luminal glucose was found to be unnecessary in the latter. The unstirred water layer modulated the absorption of 5-methyltetrahydrofolate, while unconjugated bile acids and rose bengal inhibited it.

Severe blunt thoracic trauma: differences between adults and children in a level I trauma centre.

BACKGROUND: Trauma is a leading cause of death in the developing world. Blunt thoracic trauma represents a major burden of disease in both adults and children. Few studies have investigated the differences between these two patient groups. OBJECTIVE: To compare mechanism of injury, presentation, management and outcome in children and adults with blunt thoracic trauma. METHODS: Patients were identified from the database of the trauma intensive care unit at Inkosi Albert Luthuli Central Hospital, Durban, South Africa. Demographics and relevant data were extracted from a pre-existing database. RESULTS: Of 415 patients admitted to the unit, 331 (79.7%) were adults and 84 (20.2%) children aged < 18 years. The median injury severity score (ISS) was similar for both age groups (32 v. 34; p = 0.812). Adults had a higher lactate level at presentation (3.94 v. 2.60 mmol/L; p = 0.001). Of the children, 96.4% were injured in motor vehicle collisions, 75.0% as pedestrians. Compared with adults, children had significantly fewer rib fractures (20.2% v. 42.0%; p < 0.001), flail chests (2.4% v. 26.3%; p<0.001) and.blunt cardiac injuries (BCIs) (9.5% v. 23.6%; p = 0.004), but sustained more lung contusions (79.8% v. 65.6%; p = 0.013). Mortality in children was significantly lower than in adults (16.7% v. 27.8%; p = 0.037). CONCLUSION: Thoracic injuries in children are the result of pedestrian collisions more often than in adults. They suffer fewer rib fractures and BCIs, but more lung contusions. Despite similar ISSs, children have significantly lower mortality than adults. More effort needs to be concentrated on child safety and preventing pedestrian injury.

Immunologic and structural relatedness of the integrin beta 7 complex and the human intraepithelial lymphocyte antigen HML-1.

We recently cloned the newest human integrin beta subunit, termed beta 7, from a cDNA library constructed from SEA-activated T lymphocytes. In this communication, we report on the structure of the human integrin beta 7 protein complex determined using a rabbit anti-beta 7 peptide antibody raised to an N-terminal 22 amino acid residue sequence deduced from the human beta 7 subunit cDNA. The beta 7 subunit (Mr 116,000) expressed on PHA lymphoblasts associates with a single major alpha subunit (alpha H) that is distinct from the prominent T cell marker, integrin alpha 4. The alpha H subunit (Mr 180,000 nonreduced) displays a distinctive shift in size on reduction to an apparent Mr of 150,000. We show that these structural properties of the integrin beta 7 complex are shared with the cell surface antigen HML-1 found highly expressed on T cells which populate the intestinal epithelium and are proposed to be involved in mucosal immunity. Sequential immunoprecipitation and Western blotting demonstrate identity or close homology between the alpha H beta 7 and HML-1 proteins.

Mechanism and site of small intestinal uptake of vitamin D3 in pharmacological concentrations.

The site and mechanism of initial uptake of 1,2-3H vitamin D3 pharmacological concentrations was investigated using everted rat small bowel sacs incubated in a micellar medium. The mean +/- SE uptake rates of the vitamin at 300 muM incubation solution concentration by proximal, medial, and distal small bowel segments were 6.7 +/- 0.26, 7.8 +/- 0.54, and 3.3 +/- 0.20 nmole/min/100 mg tissue, respectively. Incubation with the addition of 10(-3) M 2,4-dinitrophenol, or 10(-3) M KCN, or under nitrogen atmosphere did not change (P greater than 0.05) the above rates of absorption. Incremental increases in the concentration of vitamin D in the incubation medium up to 1200 muM resulted in a linear increase in the uptake rate indicating lack of saturation kinetics. In all the above experiments, greater rate of uptake of the vitamin occurred in the proximal and medial small bowel than the distal small bowel (P less than 0.01). The above experiments indicate that vitamin D3 in this range of concentrations is taken up by enterocytes by a nonsaturable passive diffusion mechanism showing no evidence for carrier mediation. The rate of intestinal uptake is highest in the proximal and medial segments of the small bowel.

Impaired intestinal absorption of vitamin D3 in azotemic rats.

Changes in vitamin D metabolism and their effect on calcium and bone metabolism in uremia have been extensively studied. However, the possible effect of uremia on intestinal absorption of vitamin D has not been investigated. We determined the rate of intestinal absorption of vitamin D3 in uremic and normal rats using a well-defined in vivo perfusion technique under identical experimental conditions. The rate of jejunal absorption of vitamin D3 in uremic animals (5.09 +/- 1.87 pmol/100 cm/h) was significantly less (p less than 0.001) than that found in the control animals (11.5 +/- 1.6 pmol/100 cm/h). While the underlying mechanism(s) of the observed reduction in vitamin D absorption in uremia is not known, its recognition adds another dimension to the previously recognized abnormalities of vitamin D metabolism in uremia.

Eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan: muscle biopsy findings in 4 patients.

Muscle biopsies of 4 patients with the eosinophilia-myalgia syndrome associated with ingestion of L-tryptophan showed lymphocytic infiltrates with occasional eosinophils largely restricted to interstitial fibrous tissue and perivascular areas. There was inflammation and fibrosis of muscle spindle capsules in 3 patients. In the 2 sickest patients, there was profound muscle atrophy, affecting both muscle fiber types.

The natural history of amyotrophic lateral sclerosis and the use of natural history controls in therapeutic trials.

We analyzed the natural history of amyotrophic lateral sclerosis in 277 patients. Our goal was to develop a better understanding of the clinical disease and thus improve the design of therapeutic trials. The Tufts Quantitative Neuromuscular Exam (TQNE) was used as the primary assessment instrument. Our analysis suggested that although more observations are desirable, six monthly TQNEs were adequate to establish the rate of disease progression. We observed a spectrum of deterioration rates without definable subgroups. The striking linearity of deterioration was confirmed. We found a high correlation between deterioration rates in arm and leg strength for individual patients, but a wide range between different patients. Sex and the age at clinical onset did not affect the deterioration rate. As compared with patients without a positive family history, those with other affected family members had a slower loss in arm but not leg strength. We propose that natural history controls can be used effectively in the design of ALS therapeutic trials.

Nonvasculitic, steroid-responsive mononeuritis multiplex.

We report two patients with mononeuritis multiplex, both of whom had focal inflammation of the perineurium and endoneurium on sural nerve biopsy without necrosis of blood vessel walls, histologic evidence of lymphoid malignancy, or mycobacterial infection. The predominant early sensory symptoms were asymmetric pain and paresthesias; subsequently, muscle weakness developed. Electrophysiologic studies showed an asymmetric sensorimotor axon loss radiculoneuropathy with denervation of limb and paraspinal muscles. Spinal fluid protein was elevated in one patient. There was no cause or underlying systemic disease. Marked improvement occurred with steroid therapy.

Intrathecal thyrotropin-releasing hormone does not alter the progressive course of ALS: experience with an intrathecal drug delivery system.

Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. Since TRH crosses the blood-brain barrier poorly, if at all, we postulated that the negative parenteral clinical trials could be a result of insufficient drug-receptor interaction. We thus carried out a blinded, placebo-controlled, crossover study of intrathecal TRH in 36 patients by delivery through an implanted, constant infusion pump achieving a steady-state CSF level comparable with that shown to be effective in tissue culture experiments. Utilizing a quantitative measurement technique to assess motor unit loss, we did not observe any alteration of the progressive course during 6 months on TRH and 6 months on saline placebo. However, the implanted pump delivery system proved to be safe, reliable, and well tolerated.

A multicenter, randomized, double-blinded trial of pyridostigmine in postpolio syndrome.

BACKGROUND: Postpoliomyelitis syndrome (PPS) is likely due to degeneration and dysfunction of terminal axons of enlarged postpolio motor units. Age-related decline in growth hormone and insulin-like growth factor (IGF-I) may be a contributing factor. Neuromuscular junction abnormalities and decreased IGF-I levels may respond to the anticholinesterase pyridostigmine, with consequent improvement in strength, fatigue, and quality of life. OBJECTIVES: To determine the effect of pyridostigmine in PPS on health-related quality of life, isometric muscle strength, fatigue, and serum IGF-I levels; and to assess the safety of pyridostigmine in PPS. METHODS: The study was a multicenter, randomized, double-blinded, placebo-controlled trial of a 6-month course of pyridostigmine 60 mg three times per day in 126 PPS patients. The primary data analysis compared mean changes of outcomes between treatment and control groups at 6 months using an intention to treat approach. Secondary analyses included a comparison of outcomes at 6 and 10 weeks, and in compliant patients. RESULTS: The study showed no significant differences in pyridostigmine and placebo-treated patients with regard to changes in quality of life, isometric strength, fatigue, and IGF-I serum levels at 6 months in the primary analysis and in compliant patients. There were no differences in outcomes at 6 and 10 weeks between groups. However, very weak muscles (1 to 25% predicted normal at baseline) were somewhat stronger (p = 0.10, 95% CI of difference -9.5 to 73.3%), and in compliant patients IGF-I was somewhat increased (p = 0.15, 95% CI of difference -6.4 to 44.8 ng/mL) at 6 months with the medication. Pyridostigmine was generally well tolerated. CONCLUSIONS: This study showed no significant differences between pyridostigmine and placebo-treated PPS patients on measures of quality of life, isometric strength, fatigue, and serum IGF-I.