PURPOSE To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This multicenter, open-label, ...phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for < or = six cycles; cetuximab (400 mg/m(2) on day 1, 250 mg/m(2) weekly) was administered until progression or unacceptable toxicity. The primary end point was progression-free survival assessed by independent radiologic review committee (PFS-IRRC); overall response rate (ORR), overall survival (OS), quality of life (QoL), and safety were key secondary end points. PFS and ORR assessed by investigators were also evaluated. Results Median PFS-IRRC was 4.40 months with cetuximab/TC versus 4.24 months with TC (hazard ratio HR = 0.902; 95% CI, 0.761 to 1.069; P = .236). Median OS was 9.69 months with cetuximab/TC versus 8.38 months with TC (HR = 0.890; 95% CI, 0.754 to 1.051; P = .169). ORR-IRRC was 25.7% with cetuximab/TC versus 17.2% with TC (P = .007). The safety profile of this combination was manageable and consistent with its individual components. CONCLUSION The addition of cetuximab to TC did not significantly improve the primary end point, PFS-IRRC. There was significant improvement in ORR by IRRC. The difference in OS favored cetuximab but did not reach statistical significance.
The combination of vaccines and chemotherapy holds promise for cancer therapy, but the effect of cytotoxic chemotherapy on vaccine-induced antitumor immunity is unknown. This study was conducted to ...assess the effects of systemic chemotherapy on ALVAC-CEA/B7.1-induced T-cell immunity in patients with metastatic colorectal cancer.
Patients with metastatic colorectal cancer were treated with fluorouracil, leucovorin, and irinotecan and were also given ALVAC-CEA/B7.1 vaccine with or without tetanus toxoid adjuvant. Eligible patients were randomized to ALVAC followed by chemotherapy and booster vaccination (group 1), ALVAC and tetanus toxoid followed by chemotherapy (group 2), or chemotherapy alone followed by ALVAC in patients without disease progression (group 3). Humoral immune responses were measured by standard ELISA assay, and carcinoembryonic antigen (CEA)-specific T-cell responses were measured by IFN-gamma enzyme-linked immunospot assay.
One hundred eighteen patients were randomized to receive either ALVAC before and concomitantly with chemotherapy (n = 39), ALVAC with tetanus adjuvant before and concomitantly with chemotherapy (n = 40), or chemotherapy followed by ALVAC (n = 39). Serious adverse events were largely gastrointestinal (n = 30) and hematologic (n = 24). Overall, 42 patients (40.4%) showed objective clinical responses. All patients developed antibody responses against ALVAC, but increased anti-CEA antibody titers were detected in only three patients. Increases in CEA-specific T cells were detected in 50%, 37%, and 30% of patients in groups 1, 2, and 3, respectively. There were no differences in clinical or immune responses between the treatment groups.
The combination of ALVAC-CEA/B7.1 vaccine and systemic chemotherapy has an acceptable safety profile in patients with metastatic colorectal cancer. Systemic chemotherapy did not affect the generation of CEA-specific T-cell responses following vaccination.
In this study, we investigated the acquisition of affective dispositions towards neutral faces in patients with Alzheimer's disease and mixed dementia. Participants viewed four affectively neutral ...male faces from the International Affective Picture System. Biographical information about the depicted persons was presented, which described them in terms of positive or negative traits varying in intensity. Participants were asked to rate the pictures with respect to emotional valence, arousal, and preference prior to and after the presentation of the biographical information. Following a retention interval of 180
min, pictures were rated again and the biographical information was presented once more. Final ratings were obtained after another interval of 1300
min. As expected, healthy control participants identified the faces and recalled parts of the information in the delayed recall test. They showed pronounced changes in affective ratings. Patients did not recognize the faces in a recognition test after the retention intervals, but valence, arousal, and preference ratings were systematically altered by the affective content of biographies. The results suggest that acquisition and maintenance of implicit affective dispositions are preserved in dementia even when explicit memory is impaired.
Data collected over a 3-year study of a high arctic watershed and lake are used to understand the fate of organochlorine compounds (OCs) and form the basis of a mass balance contaminant fate model. ...The model uses the fugacity/aquivalence approach to describe OC dynamics between air, stream inflows and outflow, the water column, and surficial sediments. The steady-state model results indicate that stream inflows contributed from 96 to >99% of total chemical loadings, but 57−98% of total loadings were lost from the lake via the outlet, the percentage of which is controlled by the hydrologic regime of the high arctic lake. Conversely, only 0.4−3.4% of loadings were retained within the sediments due to the high export rate, minimal scavenging from the water column and low organic carbon fraction of the sediments. Using the unsteady-state model, which includes year-round processes, degradation was estimated to account for losses of 7−32% for the more persistent OCs and 42−50% for the less persistent OCs (α-HCH, γ-HCH, and endosulfan I). If loadings were eliminated, water column concentrations would decline with half-lives <1 year for less persistent OCs and 1−2 years for the more persistent OCs, whereas the half-lives for OCs in sediment are 8−25 years.
Climate Assessment for 2000 Lawrimore, Jay H.; Halpert, Michael S.; Bell, Gerald D. ...
Bulletin of the American Meteorological Society,
06/2001, Letnik:
82, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The global climate in 2000 was again influenced by the long-running Pacific cold episode (La Niña) that began in mid-1998. Consistent with past cold episodes, enhanced convection occurred across the ...climatologically convective regions of Indonesia and the western equatorial Pacific, while convection was suppressed in the central Pacific. The La Niña was also associated with a well-defined African easterly jet located north of its climatological mean position and low vertical wind shear in the tropical Atlantic and Caribbean, both of which contributed to an active North Atlantic hurricane season. Precipitation patterns influenced by typical La Niña conditions included 1) above-average rainfall in southeastern Africa, 2) unusually heavy rainfall in northern and central regions of Australia, 3) enhanced precipitation in the tropical Indian Ocean and western tropical Pacific, 4) little rainfall in the central tropical Pacific, 5) below-normal precipitation over equatorial east Africa, and 6) drier-than-normal conditions along the Gulf coast of the United States.
Although no hurricanes made landfall in the United States in 2000, another active North Atlantic hurricane season featured 14 named storms, 8 of which became hurricanes, with 3 growing to major hurricane strength. All of the named storms over the North Atlantic formed during the August–October period with the first hurricane of the season, Hurricane Alberto, notable as the third-longest-lived tropical system since reliable records began in 1945. The primary human loss during the 2000 season occurred in Central America, where Hurricane Gordon killed 19 in Guatemala, and Hurricane Keith killed 19 in Belize and caused $200 million dollars of damage.
Other regional events included 1) record warm January–October temperatures followed by record cold November–December temperatures in the United States, 2) extreme drought and widespread wildfires in the southern and western Unites States, 3) continued long-term drought in the Hawaiian Islands throughout the year with record 24-h rainfall totals in November, 4) deadly storms and flooding in western Europe in October, 5) a summer heat wave and drought insouthern Europe, 6) monsoon flooding in parts of Southeast Asia and India, 7) extreme winter conditions in Mongolia, 8) extreme long-term drought in the Middle East and Southwest Asia, and 9) severe flooding in southern Africa.
Global mean temperatures remained much above average in 2000. The average land and ocean temperature was 0.39°C above the 1880–1999 long-term mean, continuing a trend to warmer-than-average temperatures that made the 1990s the warmest decade on record. While the persistence of La Niña conditions in 2000 was associated with somewhat cooler temperatures in the Tropics, temperatures in the extratropics remained near record levels. Land surface temperatures in the high latitudes of the Northern Hemisphere were notably warmer than normal, with annually averaged anomalies greater than 2°C in parts of Alaska, Canada, Asia, and northern Europe.
The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation; however, instances of CD133
− cells exhibiting ...similar properties have also been reported. Here, we show that some
PTEN-deficient GBM tumors produce a series of CD133
+ and CD133
− self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stemlike cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage.
► GBM PTEN deficiency correlates with successfully expandable neurosphere culture ► Identification of self-renewing CD133
− cell type generating CD133
+ and CD133
− progeny ► Evidence for lineage hierarchy of self-renewing, tumor-initiating cells in GBM ► GBM cell lineage with graded spectrum of cancer stem cell competencies
Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat ...shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis.
This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed.
Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 76% male and 36 24% female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 77% and 70 90%, respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (–3·26, 95% CI –4·15 to –2·36 in the arimoclomol group vs –2·26, –3·11 to –1·41 in the placebo group; mean difference –0·99 95% CI –2·23 to 0·24; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group.
Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design.
US Food and Drug Administration Office of Orphan Products Development and Orphazyme.
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination ...with chemotherapy.
Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life.
The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed.
The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
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