SNOT-22 in general population, a Spanish cohort study with an updated meta-analysis.

BACKGROUND: Olfactory loss (OL) has emerged as one of the most prevalent and debilitating symptoms of SARS-CoV-2 infection and long-COVID-19. The present prospective observational study aimed to evaluate the efficacy of olfactory training (OT) on orthonasal and retronasal olfactory function in a cohort of individuals with persistent post-COVID-19 OL. METHODOLOGY: Participants with post-COVID-19 olfactory impairment underwent 4 months of OT, self-assessing their smell perception and undergoing comprehensive psychophysical evaluation of orthonasal and retronasal olfaction at baseline and after training. Orthonasal olfactory function was assessed using the extended Sniffin' Sticks test battery. Retronasal olfactory function was tested with powdered aromas. RESULTS: Among 114 participants with post-COVID-19 olfactory loss, adherence to OT was 60%. In adherents, the average increase in composite TDI score was 6.0 points compared to 2.6 points in non-adherents. Fifty-seven percent of adherent participants achieved a clinically significant improvement in TDI score (≥5.5 points), compared to 22% of non-adherents. In retronasal olfactory identification, 56% of adherents achieved a clinically significant improvement (≥4 points), compared to 16% of non-adherents. CONCLUSION: Adherence to a 4-month OT regimen can yield clinically meaningful improvements in both orthonasal and retronasal olfactory function among individuals with persistent post-COVID-19 olfactory dysfunction.

Validation of Visual Analogue Scale for loss of smell as a quick test in chronic rhinosinusitis with nasal polyps.

BACKGROUND AND OBJECTIVE: Diagnostic criteria of chronic rhinosinusitis with nasal polyps (CRSwNP) include, among others, olfactory dysfunction (OD). We hypothesize that patients suffering with CRSwNP are good at self-assessing their sense of smell through visual analogue scale (VAS) compared to smell tests. METHODS: A controlled cross-sectional study was planned. Adults diagnosed with severe CRSwNP waiting for endoscopic sinus surgery were included. A cohort of healthy controls was also studied. All participants performed Barcelona smell test (BAST-24), sinonasal outcomes test 22 (SNOT-22), and VAS for loss of smell. CRSwNP underwent blood test (eosinophils count, total serum IgE), CT scan (Lund-Mackay Score), and nasal endoscopy. RESULTS: 138 severe CRSwNP and 40 controls subjects were included. The BAST-24 identification score was strongly correlated with the VAS score in the CRSwNP group (rho=-0.79, p<0.001) but not in the control group (rho=-0.14; p=0.39), this difference between groups being statistically significant (p<0.001). A significant correlation of SNOT-22 item 21 (loss of smell) was also found with BAST-24 identification (rho=-0.65, p<0.001), this difference being statistically significant (Z=-2.43; p=0.015). In the ROC curve, the area under the curve (AUC) was 0.85 with 72.5% sensitivity and 93.1% specificity. CONCLUSION: This study demonstrates a potential role of the VAS score for the screening of OD in severe CRSwNP in daily clinical practice.

Septoplasty and/or inferior turbinoplasty produce significant improvements of the sense of smell.

BACKGROUND: Patients with septal deviation and/or turbinal hypertrophy may experience olfactory disfunction (OD). The aim of this study was to analyse the effect of septoplasty and/or turbinoplasty on both lateralized and bilateral olfactory function. METHODOLOGY: Prospective study of 47 patients with nasal obstruction secondary to septal deviation and/or turbinal hypertrophy and 20 healthy controls. The Barcelona Olfactory test (BOT-8), a new supraliminal orthonasal subjective olfactometry, was applied 3 times in a row (in each nostril separately and in both simultaneously). The 8 items were applied randomly to minimize the possible risk of learning. The test has not established the minimal clinically important difference (MCID). Anterior rhinomanometry and acoustic rhinometry were performed. All participants self-assessed smell loss and nasal obstruction using a visual analogue scale (VAS) and completed questionnaires for nasal obstruction (Nasal Obstruction Symptom Evaluation, NOSE) and for quality of life (QoL), using disease-specific (SinoNasal Outcome Test-22, SNOT-22) and generic (Short Form-12 Health Survey, SF-12) questionnaires. Nasal measurements and questionnaires were performed preoperatively and 12 months after surgery. RESULTS: Before surgery, patients reported worse VAS on smell loss and on nasal obstruction compared to controls. Patients scored lower BOT-8 than controls. Lateralized preoperative olfactory function showed that all BOT-8 characteristics were lower at the narrow side than the wider one. Smell function and QoL improved significantly one year after surgery. CONCLUSIONS: Nasal septal deviation and turbinal hypertrophy lead to an olfactory impairment on the obstructed nostril. Nasal surgery provides a positive outcome on olfactory function, as well as on subjective and objective outcomes.

The 8-Odorant Barcelona Olfactory Test (BOT-8): Validation of a New Test in the Spanish Population During the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVE: Most smell tests are difficult to implement in daily clinical practice owing to their long duration. The aim of the present study was to develop and validate a short, easy-to-perform, and reusable smell test to be implemented during the COVID-19 pandemic. METHODS: The study population comprised 120 healthy adults and 195 patients with self-reported olfactory dysfunction (OD). The 8-Odorant Barcelona Olfactory Test (BOT-8) was used for detection, memory/recognition, and forced-choice identification. In addition, a rose threshold test was performed, and a visual analog scale was applied. The Smell Diskettes Olfaction Test (SDOT) was used for correlation in healthy volunteers, and the University of Pennsylvania Smell Identification Test (UPSIT) was used for patients with OD to establish cut-offs for anosmia and hyposmia. In order to take account of the COVID-19 pandemic, disposable cotton swabs with odorants were compared with the original test. RESULTS: In healthy persons, the mean (SD) BOT-8 score was 100% for detection, 94.5% (1.07) for memory/recognition, and 89.6% (0.86) for identification. In patients with OD, the equivalent values were 86% (32.8), 73.2% (37.9), and 77.1% (34.2), respectively. BOT-8 demonstrated good test-retest reliability, with agreement of 96.7% and a quadratic k of 0.84 (P<.001). A strong correlation was observed between BOT-8 and SDOT (r=0.67, P<.001) and UPSIT (r=0.86, P<.001). Agreement was excellent for disposable cotton swabs, with a k of 0.79 compared with the original test. The cut-off point for anosmia was ≤3 (area under the curve, 0.83; sensitivity, 0.673; specificity, 0.993). CONCLUSION: BOT-8 offers an efficient and fast method for assessment of smell threshold, detection, memory, and identification in daily clinical practice. Disposable cotton swabs with odorants proved to be useful and safe during the COVID-19 pandemic.

Sinonasal mucosal melanomas: defining profiles for better survival outcomes.

BACKGROUND: Sinonasal mucosal melanoma is an aggressive malignancy with a 5-year survival rate ranging from 20% to 39%. Despite the evolving surgical and radiotherapy techniques, and introduction of immune-checkpoint inhibitor therapy, overall survival rates remain poor. METHODOLOGY: A retrospective cohort study was conducted at the Hospital Clinic de Barcelona and the Hospital de la Santa Creu i Sant Pau between 1984 and 2020; primary outcome measures were 3 and 5-year melanoma-specific survival (MSS). Kaplan-Meier survival analysis and Cox proportional hazards model were performed to identify predictors of survival. RESULTS: Fifty patients were included, the mean age was 70.4, MSS at 3 and 5 years was 51.2%, and 29.5%, respectively. The median follow-up was 39.6 months during which 46% presented locoregional recurrence and 36%, metastasis. The univariate and multivariate analyses found as survival predictors the N category, the treatment received, the surgical margins and the mitotic index. CONCLUSIONS: We found an overall 5-year MSS of 29.5%. Those patients with intention-to-cure (stages III and IVa) treated by surgery that were N0 at diagnosis, with < 10 mitoses per HPF showed a 5-year MSS rate of 74.1%. More studies will be needed to adequately define the patients' profiles that will benefit from a better survival outcome.

Functional Examination of the Upper and Lower Airways in Asthma and Respiratory Allergic Diseases: Considerations in the Post-SARS-CoV-2 Era.

Airway examination procedures can potentially transmit infectious diseases to patients and to the health care professionals who perform them via various mechanisms. The COVID-19 pandemic has halted most of the activity of the clinics and laboratories involved in assessment of lung and nasal function, and clear recommendations in this regard have been made. Today, we still do not know for sure what its consequences will be in the short or long term, since important gaps remain in our knowledge of aspects as fundamental as virus transmission mechanisms, pathophysiology, immune response, and diagnosis. In this review, we study the examination techniques used to assess patients with respiratory allergy, asthma, and associated diseases during this period and highlight their possible advantages and disadvantages. Therefore, we focus on exploring the entire upper and lower airways, from the perspective of the safety of both health professionals and patients and their specific characteristics. We also analyze the intrinsic value of these interventions in terms of diagnosis and patient management. The changing situation of COVID-19 may mean that some of the assertions presented in this review will have to be modified in the future. While we seek to ensure a consistently broad approach, some differences in operational details may apply owing to local regulations.

Evidencing the nonlinearity independence of resolution in femtosecond laser ablation.

To overcome the resolution limits in laser processing technologies, it is highly attractive to translate concepts used in advanced optical microscopy. In this prospect, the nonlinear nature of absorption in dielectrics with femtosecond lasers is recurrently taken as a direct advantage in an analogous way to excitation in multiphoton microscopy. However, we establish that no direct benefit in resolution can be expected when laser ablation is observed. We explore widely different nonlinear regimes using ultrashort pulses at different wavelengths (1550 and 515 nm) and target materials of various bandgaps (3.8-8.8 eV). We find in the experiments that the shapes of all ablation features correspond to a one-to-one mapping of the beam contours at a strict threshold intensity. The nonlinearity-independent response shows that the incorporation of extreme UV should provide a direct route to the nanoscale resolutions routinely achieved in lithography.

Olfactory Dysfunction in the COVID-19 Outbreak.

The first cases of coronavirus 2019 disease (COVID-19) occurred in Wuhan, China, and the disease rapidly become a public health emergency of international proportions. COVID-19 can cause mild-to-severe acute respiratory syndrome (SARS) and is caused by the SARS-CoV-2 coronavirus. The clinical manifestations of COVID-19 include fever, dry cough, fatigue, sputum production, shortness of breath, sore throat, and headache. We performed this narrative review to analyze the current literature on postviral olfactory dysfunction related to the SARSCoV- 2 pandemic. Since the initial anecdotal reports from China, increasingly frequent international reports on COVID-19 indicate that 5% to 85% of affected patients lose their sense of smell, thus highlighting the very heterogeneous nature of the literature in this area. Therefore, we advise home isolation measures and/or social distancing, as well as tests to detect SARS-CoV-2 when possible, in patients with sudden and severe loss of smell who cannot be promptly evaluated.

Pediatric Barcelona Olfactory Test ̶ 6 (pBOT-6): Validation of a Combined Odor Identification and Threshold Screening Test in Healthy Spanish Children and Adolescents.

BACKGROUND AND OBJECTIVE: Few odor tests have been developed for children. Objectives: The aim of the present study was to develop and validate a simple and quick olfactory test to evaluate odor identification and threshold in a Spanish pediatric population. METHODS: The Pediatric Barcelona Olfactory Test-6 (pBOT-6) consisted of a set of 6 odorants for a forced choice identification test and a 6-dilution phenyl ethyl alcohol geometric series for the threshold test. The pBOT-6 was compared with the Universal Sniff test (a validated international pediatric smell test) in 131 healthy Spanish volunteers aged 6-17 years. A Bland-Altman plot was used to determine the agreement between the 2 tests. Reliability was analyzed in 15 volunteers using the intraclass correlation coefficient. Normative data were obtained, and 8 children diagnosed with subjective loss of smell were tested for validation. RESULTS: The Bland-Altman analysis demonstrated a minimal bias of -1.71% with upper and lower limits of agreement of -31.1% and 27.6%, respectively. The intraclass correlation coefficient was 0.83 (95%CI, 0.6-0.96) for the identification test and 0.73 (95%CI, 0.36-0.9) for the threshold test, with excellent and good consistency between measurements over time. Mean pBOT-6 scores were significantly higher in healthy volunteers than in patients with loss of smell. Discrimination between normosmia and loss of smell was achieved with a sensitivity of 96.9% and a specificity of 100%. CONCLUSIONS: pBOT-6 offers an effective and fast method that is useful in clinical routine to distinguish, with high sensitivity and specificity, between pediatric patients with normosmia and those with loss of smell.

Smell and Taste Dysfunction in COVID-19 Is Associated With Younger Age in Ambulatory Settings: A Multicenter Cross-Sectional Study.

BACKGROUND AND OBJECTIVE: Since the initial anecdotal reports of coronavirus disease 2019 (COVID-19) from China, a growing number of studies have reported on smell and/or taste dysfunction (STD). Objective: The aim of our study was to investigate the frequency and severity of STD in COVID-19 patients and to evaluate the association with demographic characteristics, hospital admission, symptoms, comorbidities, and blood biomarkers. METHODS: We performed a multicenter cross-sectional study on patients who were positive for SARS-CoV-2 (n=846) and controls (n=143) from 15 Spanish hospitals. Data on STD were collected prospectively using an in-person survey. The severity of STD was categorized using a visual analog scale. We analyzed time to onset, recovery rate, time to recovery, hospital admission, pneumonia, comorbidities, smoking, and symptoms. RESULTS: STD was at least 2-fold more common in COVID-19-positive patients than in controls. COVID-19-positive hospitalized patients were older, with a lower frequency of STD, and recovered earlier than outpatients. Analysis stratified by severity of STD showed that more than half of COVID-19 patients presented severe loss of smell (53.7%) or taste (52.2%); both senses were impaired in >90%. In the multivariate analysis, older age (>60 years), being hospitalized, and increased C-reactive protein were associated with a better sense of smell and/or taste. COVID-19-positive patients reported improvement in smell (45.6%) and taste (46.1%) at the time of the survey; in 90.6% this was within 2 weeks of infection. CONCLUSION: STD is a common symptom in COVID-19 and presents mainly in young and nonhospitalized patients. More studies are needed to evaluate follow-up of chemosensory impairment.

Adjuvant sunitinib in patients with high-risk renal cell carcinoma: safety, therapy management, and patient-reported outcomes in the S-TRAC trial.

Background: Adjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial. Patients and methods: Patients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Results: Patients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases. Conclusions: In S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects. Clinical trial registration: ClinicalTrials.gov, NCT00375674.

Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial.

Background: The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy. Patients and methods: In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted. Results: A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660-1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468-0.879; P = 0.0051), and by IRC (0.735; 0.525-1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo. Conclusions: ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported. Trial registration number: NCT01599754.

Training working memory updating in young adults.

Working memory updating (WMU) is a core mechanism in the human mental architecture and a good predictor of a wide range of cognitive processes. This study analyzed the benefits of two different WMU training procedures, near transfer effects on a working memory measure, and far transfer effects on nonverbal reasoning. Maintenance of any benefits a month later was also assessed. Participants were randomly assigned to: an adaptive training group that performed two numerical WMU tasks during four sessions; a non-adaptive training group that performed the same tasks but on a constant and less demanding level of difficulty; or an active control group that performed other tasks unrelated with working memory. After the training, all three groups showed improvements in most of the tasks, and these benefits were maintained a month later. The gain in one of the two WMU measures was larger for the adaptive and non-adaptive groups than for the control group. This specific gain in a task similar to the one trained would indicate the use of a better strategy for performing the task. Besides this nearest transfer effect, no other transfer effects were found. The adaptability of the training procedure did not produce greater improvements. These results are discussed in terms of the training procedure and the feasibility of training WMU.

Acute toxicity of anionic and non-ionic surfactants to aquatic organisms.

The environmental risk of surfactants requires toxicity measurements. As different test organisms have different sensitivity to the toxics, it is necessary to establish the most appropriate organism to classify the surfactant as very toxic, toxic, harmful or safe, in order to establish the maximum permissible concentrations in aquatic ecosystems. We have determined the toxicity values of various anionic surfactants ether carboxylic derivatives using four test organisms: the freshwater crustacean Daphnia magna, the luminescent bacterium Vibrio fischeri, the microalgae Selenastrum capricornutum (freshwater algae) and Phaeodactylum tricornutum (seawater algae). In addition, in order to compare and classify the different families of surfactants, we have included a compilation of toxicity data of surfactants collected from literature. The results indicated that V. fischeri was more sensitive to the toxic effects of the surfactants than was D. magna or the microalgae, which was the least sensitive. This result shows that the most suitable toxicity assay for surfactants may be the one using V. fischeri. The toxicity data revealed considerable variation in toxicity responses with the structure of the surfactants regardless of the species tested. The toxicity data have been related to the structure of the surfactants, giving a mathematical relationship that helps to predict the toxic potential of a surfactant from its structure. Model-predicted toxicity agreed well with toxicity values reported in the literature for several surfactants previously studied. Predictive models of toxicity is a handy tool for providing a risk assessment that can be useful to establish the toxicity range for each surfactant and the different test organisms in order to select efficient surfactants with a lower impact on the aquatic environment.

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

BACKGROUND: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. METHODS: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. RESULTS: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). CONCLUSION: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Role of executive functions in the relations of state- and trait-math anxiety with math performance.

The detrimental effect of math anxiety on math performance is thought to be mediated by executive functions. Previous studies have primarily focused on trait-math anxiety rather than state-math anxiety and have typically examined a single executive function rather than comprehensively evaluating all of them. Here, we used a structural equation modeling approach to concurrently determine the potential mediating roles of different executive functions (i.e., inhibition, switching, and updating) in the relationships between both state- and trait-math anxiety and math performance. A battery of computer-based tasks and questionnaires were administered to 205 university students. Two relevant results emerged. First, confirmatory factor analysis suggests that math anxiety encompassed both trait and state dimensions and, although they share substantial variance, trait-math anxiety predicted math performance over and above state-math anxiety. Second, working memory updating was the only executive function that mediated the relationship between math anxiety and math performance; neither inhibition nor switching played mediating roles. This calls into question whether some general proposals about the relationship between anxiety and executive functions can be extended specifically to math anxiety. We also raise the possibility that working memory updating or general cognitive difficulties might precede individual differences in math anxiety.

Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer.

BACKGROUND: We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). METHODS: Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. RESULTS: Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively. CONCLUSIONS: At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

A phase I, dose-finding study of sunitinib combined with cisplatin and 5-fluorouracil in patients with advanced gastric cancer.

Background This phase I, open-label, dose-escalation study examined the safety, maximum tolerated dose (MTD), and pharmacokinetics of sunitinib plus chemotherapy in patients with advanced gastric cancer. Patients and methods Sunitinib (25 or 37.5 mg/day, Schedule 2/1: 2 weeks on treatment/1 week off) plus chemotherapy (fixed starting doses of cisplatin 80 mg/m(2) and 5-fluorouracil [5-FU] 4,000 mg/m(2)) was administered to patients with advanced gastric cancer who had not received prior therapy for metastatic disease. Results Thirty-four patients were enrolled and received sunitinib 25 mg/day (n = 24) or 37.5 mg/day (n = 10) plus chemotherapy. No dose-limiting toxicity (DLT) was reported in the sunitinib 37.5 mg cohort. However, repeated patterns of myelosuppression beyond the first cycle led to investigation of sunitinib 25 mg/day. This was the MTD, and one DLT (grade 3 mucosal inflammation) was reported. The combination had an acceptable adverse event profile; generally of grade 1/2. There was no evidence of a pharmacokinetic drug-drug interaction between sunitinib and 5-FU. Six patients (26 %) receiving the MTD had a partial response and eight patients experienced stable disease ≥3 months. Conclusions Sunitinib plus cisplatin 80 mg/m(2) and 5-FU 4,000 mg/m(2) were combinable and adverse events were manageable. The MTD of sunitinib was established as 25 mg/day on Schedule 2/1.

Acute toxicity of alkylpolyglucosides to Vibrio fischeri, Daphnia magna and microalgae: a comparative study.

In this paper, toxicity values of alkylpolyglucosides have been determined by applying the 24-h immobilization test with Daphnia magna, the LumiStox(®) 300 test which employs the luminescent bacteria Photobacterium phosphoreum and the test with Selenastrum capricornutum. Three alkylpolyglucosides with different alkyl chain and degree of polymerisation have been tested. For all tests, the results indicated that Vibrio fischeri was more sensitive to toxic effects from alkylpolyglucosides than was D. magna or S. capricornutum. The results demonstrate considerable variation in toxicity responses within structurally related glucose-based surfactants regardless of the species tested. The toxicity increased as the critical micelle concentration decreased, and as the alkyl chain length and resultant hydrophobicity increased.

Effect of concentration on the primary and ultimate biodegradation of alkylpolyglucosides in aerobic biodegradation tests.

This study examines the primary and ultimate biodegradation of a non-ionic surfactant, an alkylpolyglucoside, in ready biodegradability tests. The surfactant concentration was tested by the anthrone method, while the ultimate biodegradation (mineralization) was analyzed by the total organic carbon determinations. The influence of the concentration on the extent of primary and ultimate biodegradation and the kinetics of degradation also were determined. The primary and ultimate biodegradation was studied at different initial concentrations-15, 25, 50, 75, and 100 mg/L. The increasing concentration of test chemical from 15 to 100 mg/L resulted in a decrease in the relative maximum mineralization rate and longer estimated lag times by a factor of approximately 4.3. During the degradative process, two different stages were noted; these are better described with Quiroga and first-order kinetic models, respectively. For the study of the influence of concentration, the parameters characteristic of the biodegradation profiles in the different biodegradation assays were evaluated.