The specific aims of the study were to evaluate the 2-year overall survival (OS) and progression-free survival (PFS), toxicity profile, and best objective response rate in patients with locally ...advanced, clinically unresectable esophageal cancer receiving cetuximab, cisplatin, irinotecan, and thoracic radiotherapy (TRT) within a multi-institutional cooperative-group setting.
Eligible patients (cT4 M0 or medically unresectable, biopsy proven, and noncervical esophageal cancer) were to receive four 21-day cycles of cetuximab 400 mg/m2 (day 1, cycle 1), cetuximab 250 mg/m2 (day 8, 15, cycle 1; then days 1, 8, and 15 for subsequent cycles), cisplatin 30 mg/m2 (days 1 and 8, all cycles), and irinotecan 65 mg/m2 (days 1 and 8, all cycles). TRT was administered at 1.8 Gy in 28 daily fractions to a total dose of 50.4 Gy, to begin with on day 1 of cycle 3. The primary endpoint was 2-year OS, with an accrual goal of 75 patients with adenocarcinoma.
The study was closed because of slow accrual, with 21 eligible patients (11 squamous, 10 adenocarcinoma) enrolled from May 2005 to September 2007. Two-year OS and PFS (95% confidence interval CI) were 33.3% (14.6–57.0%) and 23.8% (8.2–47.2%), respectively. Kaplan–Meier estimates of median (95% CI) OS and PFS were 11.2 (6.4–43.6) and 6.4 (3.7–12.0) months, respectively. The overall response rate (95% CI) among 17 evaluable patients was 17.6% (3.8–43.4%), including 6% confirmed complete responders and 12% unconfirmed partial responders. Two deaths resulted from protocol treatment (sudden death and gastrointestinal necrosis). Ten (47.6%) and 6 (28.6%) patients had grade-3 or -4 toxicity, respectively: 52.4% were hematologic, 23.8% had fatigue, 19.0% had nausea, 19.0% had dehydration, and 19.0% had anorexia.
Concomitant cetuximab, cisplatin, irinotecan, and TRT were poorly tolerated in the first North American cooperative group trial testing this regimen for locally advanced esophageal cancer as treatment-related mortality approached 10%. Single-institution phase-II cetuximab-based combined modality trials have yielded encouraging results in preliminary analyses. The SWOG GI Committee endorses enrollment to open clinical trials to clarify the therapeutic ratio of cetuximab-based combined modality approaches for esophageal cancer.
Transcontinental dispersals by organisms usually represent improbable events that constitute a major challenge for biogeographers. By integrating molecular phylogeny, historical biogeography and ...palaeoecology, we test a bold hypothesis proposed by Vladimir Nabokov regarding the origin of Neotropical Polyommatus blue butterflies, and show that Beringia has served as a biological corridor for the dispersal of these insects from Asia into the New World. We present a novel method to estimate ancestral temperature tolerances using distribution range limits of extant organisms, and find that climatic conditions in Beringia acted as a decisive filter in determining which taxa crossed into the New World during five separate invasions over the past 11 Myr. Our results reveal a marked effect of the Miocene–Pleistocene global cooling, and demonstrate that palaeoclimatic conditions left a strong signal on the ecology of present-day taxa in the New World. The phylogenetic conservatism in thermal tolerances that we have identified may permit the reconstruction of the palaeoecology of ancestral organisms, especially mobile taxa that can easily escape from hostile environments rather than adapt to them.
Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, ...phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival.
Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.8 Gy/d for 25 fractions; surgery was performed 28 to 42 days after neoadjuvant therapy. Chemotherapy was planned after surgery. Tumors were analyzed for mRNA expression and polymorphisms in genes involved in drug metabolism and DNA repair.
Ninety-three patients were evaluable. Two deaths (2.2%) were attributable to preoperative therapy, and two deaths (2.2%) were attributable to surgery. Grade 3 and 4 toxicities were recorded for 47.3% and 19.4% of patients, respectively. Seventy-nine patients (84.9%) underwent surgery; 67.7% of patients had R0 resections. Twenty-six patients (28.0%) had confirmed pCR (95% CI, 19.1% to 38.2%). At a median follow-up of 39.2 months, estimates of median and 3-year overall survival (OS) were 28.3 months and 45.1%, respectively. Intratumoral ERCC-1 gene expression was inversely related to progression-free survival and OS.
Neoadjuvant oxaliplatin, PI-FU, and EBRT for esophageal adenocarcinoma is active and tolerable. Because the regimen failed to meet the primary end point, it does not define a new standard. However, future trials can be built on this platform to validate the role of ERCC-1 in determining the best systemic regimen for individual patients.
Background
Significant heterogeneity exists regarding patient reported outcome measures (PROMs) used in total hip (THA) and knee (TKA) arthroplasty randomized controlled trials (RCTs). This study ...investigates the PROMs used as primary and secondary outcomes in contemporary arthroplasty RCTs.
Methods
A literature search identified THA and TKA RCTs that were published in top ten impact factor orthopaedic journals from 2017 to 2021. Screening identified 241 trials: 76 THA, 157 TKA, and eight combined. Data were extracted to identify PROMs utilized as either primary or secondary outcomes and the time period of measurement.
Results
Visual Analog Scale (VAS) Pain was the most reported primary PROM in THA (9.2%) and TKA (22.9%) trials. This was followed by Numeric Rating Scale (NRS) Pain (7.9%) and the Harris Hip score (6.6%) in THA trials and NRS Pain (4.5%) and the Knee Society score (4.5%) in TKA trials. Many THA (37.0%) and TKA (52.1%) trials did not clearly specify primary outcome time points. Only pain scales were reported at time points less than one week, while various joint-specific functional outcomes were reported at later time points. As secondary outcomes, the Harris Hip score (28.9%) was most common in THA trials and the Knee Society score (26.1%) was most common in TKA trials. Indeterminate primary or secondary outcomes were reported in 18.2% of studies.
Conclusions
Contemporary THA and TKA trials exhibit heterogeneity of PROMs as study outcomes after the first postoperative week. Our findings highlight the need for consensus in PROM reporting and better methodological reporting to improve the interpretability of RCT outcomes.
PROSPERO registration number
CRD42022337255.
Molybdenum (Mo) is an essential micronutrient for biological assimilation of nitrogen gas and nitrate because it is present in the cofactors of nitrogenase and nitrate reductase enzymes. Although Mo ...is the most abundant transition metal in seawater (107 nM), it is present in low concentrations in most freshwaters, typically <20 nM. In 1960, it was discovered that primary productivity was limited by Mo scarcity (2-4 nM) in Castle Lake, a small, meso-oligotrophic lake in northern California. Follow up studies demonstrated that Mo also limited primary productivity in lakes in New Zealand, Alaska, and the Sierra Nevada. Research in the 1970s and 1980s showed that Mo limited primary productivity and nitrate uptake in Castle Lake only during periods of the growing season when nitrate concentrations were relatively high because ammonium assimilation does not require Mo. In the years since, research has shifted to investigate whether Mo limitation also occurs in marine and soil environments. Here we review studies of Mo limitation of nitrogen assimilation in natural microbial communities and pure cultures. We also summarize new data showing that the simultaneous addition of Mo and nitrate causes increased activity of proteins involved in nitrogen assimilation in the hypolimnion of Castle Lake when ammonium is scarce. Furthermore, we suggest that meter-scale Mo and oxygen depth profiles from Castle Lake are consistent with the hypothesis that nitrogen-fixing cyanobacteria in freshwater periphyton communities have higher Mo requirements than other microbial communities. Finally, we present topics for future research related to Mo bioavailability through time and with changing oxidation state.
Determining the factors that control food web interactions is a key issue in ecology. The empirical relationship between nutrient loading (total phosphorus) and phytoplankton standing stock ...(chlorophyll a) in lakes was described about 30 years ago and is central for managing surface water quality. The efficiency with which biomass and energy are transferred through the food web and sustain the production of higher trophic levels (such as fish) declines with nutrient loading and system productivity, but the underlying mechanisms are poorly understood. Here we show that in seston (fine particles in water) during summer, specific ω3-polyunsaturated fatty acids (ω3-PUFAs), which are important for zooplankton, are significantly correlated to the trophic status of the lake. The ω3-PUFAs octadecatetraenoic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid, but not α-linolenic acid, decrease on a double-logarithmic scale with increasing total phosphorus. By combining the empirical relationship between EPA-to-carbon content and total phosphorus with functional models relating EPA-to-carbon content to the growth and egg production of daphnids, we predict secondary production for this key consumer. Thus, the decreasing efficiency in energy transfer with increasing lake productivity can be explained by differences in ω3-PUFA-associated food quality at the plant-animal interface.
Although the study of lakes has traditionally focused on pelagic production pathways, recent stable isotope and diet evidence indicates that benthic algal production is an important contributor to ...fish production. This has led to the suggestion that energy may be more efficiently passed along benthic food chains relative to their pelagic counterparts. To test this idea, we combined stable isotope based assessments of energy flow pathways with estimates of pelagic- and benthic-based primary and secondary production in Castle Lake, California. Approximately 50% of whole-lake primary production and 30% of whole-lake secondary production occurred in benthic habitats. Stable carbon isotopes and dietary data indicated that fish were predominantly supported by benthic (63%) and terrestrial (24%) secondary production. Ecological efficiencies (algal production / invertebrate production) were low in Castle Lake (<3%), though zoobenthic production was more efficiently passed to fish than was zooplankton production. The larger size of benthic prey relative to pelagic prey may affect fish prey selection and foraging efficiency, resulting in differences in ecological efficiency between pelagic and benthic trophic pathways.
The factors that regulate energy transfer between primary producers and consumers in aquatic ecosystems have been investigated for more than 50 years (refs 1,2,3). Among all levels of the food web ...(plants, herbivores, carnivores), the plant-animal interface is the most variable and least predictable link. In hypereutrophic lakes, for example, biomass and energy transfer is often inhibited at the phytoplankton-zooplankton link, resulting in an accumulation of phytoplankton biomass instead of sustaining production at higher trophic levels, such as fish. Accumulation of phytoplankton (especially cyanobacteria) results in severe deterioration of water quality, with detrimental effects on the health of humans and domestic animals, and diminished recreational value of water bodies. We show here that low transfer efficiencies between primary producers and consumers during cyanobacteria bloom conditions are related to low relative eicosapentaenoic acid (20:5ω3) content of the primary producer community. Zooplankton growth and egg production were strongly related to the primary producer 20:5ω3 to carbon ratio. This indicates that limitation of zooplankton production by this essential fatty acid is of central importance at the pelagic producer-consumer interface.
To assess whether improvements in cognitive and behavioral development seen in preschool educational programs persist, we compared those in a multisite randomized trial of such a program over the ...first 3 years of life (INT) to those with follow-up only (FUO) at 18 months of age.
This was a prospective follow-up of the Infant Health and Development Program at 8 sites heterogeneous for sociodemographic characteristics. Originally 985 children were randomized to the INT (n = 377) or FUO (n = 608) groups within 2 birth weight strata: heavier low birth weight (HLBW; 2001-2499 g) and lighter low birth weight (LLBW; < or = 2000 g). Primary outcome measures were the Peabody Picture Vocabulary Test (PPVT-III), reading and mathematics subscales of the Woodcock-Johnson Tests of Achievement, youth self-report on the Total Behavior Problem Index, and high-risk behaviors on the Youth Risk Behavior Surveillance System (YRBSS). Secondary outcomes included Weschler full-scale IQ, caregiver report on the Total Behavior Problem Index, and caregiver and youth self-reported physical health using the Medical Outcome Study measure. Assessors were masked as to study status.
We assessed 636 youths at 18 years (64.6% of the 985, 72% of whom had not died or refused at prior assessments). After adjusting for cohort attrition, differences favoring the INT group were seen on the Woodcock-Johnson Tests of Achievement in math (5.1 points), YRBSS (-0.7 points), and the PPVT-III (3.8 points) in the HLBW youth. In the LLBW youth, the Woodcock-Johnson Tests of Achievement in reading was higher in the FUO than INT group (4.2).
The findings in the HLBW INT group provide support for preschool education to make long-term changes in a diverse group of children who are at developmental risk. The lack of observable benefit in the LLBW group raises questions about the biological and educational factors that foster or inhibit sustained effects of early educational intervention.
We conducted a series of experiments feeding Daphnia pulex nine different phytoplankton monocultures with widely varying fatty acid composition and nutritional values to test the extent to which ...Daphnia fatty acid composition was affected by diet. In general, Daphnia fatty acid composition matched that of their diet much more closely than it did the fatty acid composition of Daphnia consuming other diets. However, Daphnia had consistently less saturated fatty acids and more arachidonic acid than did their diet, and Daphnia consuming cyanobacteria had substantially less saturated fatty acids and more monounsaturated fatty acids than their diets. Daphnia that consumed cryptophytes, which are rich in ω 3 polyunsaturated fatty acids (PUFAs), had on average$47% \pm 8%$($\pm 1 SD$) ω 3 PUFAs within their fatty acid pool, whereas Daphnia that consumed ω 3 PUFA-poor cyanophytes only had$6% \pm 3% \omega 3$PUFAs. The ratio of ω 3 to ω 6 fatty acids in Daphnia was also strongly dependent on diet, and averaged$\approx 10:1$, 2:1, and 1:1 for Daphnia that consumed cryptophytes, chlorophytes, and cyanophytes, respectively. Furthermore, the sum of C20and C22ω 3 and ω 6 fatty acids in Daphnia was highly correlated with that of their diet (r2= 0.94). These results suggest analyses of Daphnia fatty acid composition may be a powerful means of inferring diet in the field. These results also suggest the nutritional benefits of consuming$\omega 3-rich$phytoplankton will transfer up the food web, making Zooplankton both more efficient at converting phytoplankton biomass to their own biomass as well as much more nutritious for the zooplanktivorous fish that consume them.
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