Ubiquitous atmospheric production of organic acids mediated by cloud droplets.

Atmospheric acidity is increasingly determined by carbon dioxide and organic acids1-3. Among the latter, formic acid facilitates the nucleation of cloud droplets4 and contributes to the acidity of clouds and rainwater1,5. At present, chemistry-climate models greatly underestimate the atmospheric burden of formic acid, because key processes related to its sources and sinks remain poorly understood2,6-9. Here we present atmospheric chamber experiments that show that formaldehyde is efficiently converted to gaseous formic acid via a multiphase pathway that involves its hydrated form, methanediol. In warm cloud droplets, methanediol undergoes fast outgassing but slow dehydration. Using a chemistry-climate model, we estimate that the gas-phase oxidation of methanediol produces up to four times more formic acid than all other known chemical sources combined. Our findings reconcile model predictions and measurements of formic acid abundance. The additional formic acid burden increases atmospheric acidity by reducing the pH of clouds and rainwater by up to 0.3. The diol mechanism presented here probably applies to other aldehydes and may help to explain the high atmospheric levels of other organic acids that affect aerosol growth and cloud evolution.

Biomechanical analysis of two runners who developed leg injuries during a six-week transition to maximal running shoes: A case series.

Achilles tendinopathy (AT) and medial tibial stress syndrome (MTSS) are two of the most common running-related injuries. In a previous study investigating running biomechanics before and after a six-week transition to maximal running shoes, two runners dropped out of this study due to Achilles pain and shin pain, respectively. The purpose of this case series was to investigate running biomechanics in those two runners, identifying potential causes for injury in relation to maximal shoe use. Running biomechanics were collected in a laboratory setting for these two runners wearing both a maximal running shoe and traditional running shoe before the six-week transition using an 8-camera motion capture system and two embedded force plates. Both runners displayed prolonged eversion in the maximal shoe, which has been previously cited as a potential risk factor for developing Achilles tendinopathy and medial tibial stress syndrome. Relatively high loading rates and impact forces were also observed in the runner with shin pain in the maximal shoe, which may have contributed to their pain. More prospective research on injury rates in individuals running in maximal shoes is needed.

Recent Northern Hemisphere stratospheric HCl increase due to atmospheric circulation changes.

The abundance of chlorine in the Earth's atmosphere increased considerably during the 1970s to 1990s, following large emissions of anthropogenic long-lived chlorine-containing source gases, notably the chlorofluorocarbons. The chemical inertness of chlorofluorocarbons allows their transport and mixing throughout the troposphere on a global scale, before they reach the stratosphere where they release chlorine atoms that cause ozone depletion. The large ozone loss over Antarctica was the key observation that stimulated the definition and signing in 1987 of the Montreal Protocol, an international treaty establishing a schedule to reduce the production of the major chlorine- and bromine-containing halocarbons. Owing to its implementation, the near-surface total chlorine concentration showed a maximum in 1993, followed by a decrease of half a per cent to one per cent per year, in line with expectations. Remote-sensing data have revealed a peak in stratospheric chlorine after 1996, then a decrease of close to one per cent per year, in agreement with the surface observations of the chlorine source gases and model calculations. Here we present ground-based and satellite data that show a recent and significant increase, at the 2σ level, in hydrogen chloride (HCl), the main stratospheric chlorine reservoir, starting around 2007 in the lower stratosphere of the Northern Hemisphere, in contrast with the ongoing monotonic decrease of near-surface source gases. Using model simulations, we attribute this trend anomaly to a slowdown in the Northern Hemisphere atmospheric circulation, occurring over several consecutive years, transporting more aged air to the lower stratosphere, and characterized by a larger relative conversion of source gases to HCl. This short-term dynamical variability will also affect other stratospheric tracers and needs to be accounted for when studying the evolution of the stratospheric ozone layer.

Bilateral movement asymmetries exist in recreational athletes during a 45° sidestep cut post-anterior cruciate ligament reconstruction.

Individuals post-ACL reconstruction (ACLR) are at elevated risk for ACL re-injury. While several studies have examined biomechanical asymmetries post-ACLR during landing, less is known about asymmetries during a sidestep cut. Therefore, the purpose of this study was to compare sagittal and frontal plane biomechanics at the hip and knee during a 45° sidestep cut in post-ACLR participants and healthy controls. Nineteen athletes post-ACLR and nineteen healthy controls performed a bilateral 45° sidestep cut while three-dimensional kinematics and kinetics were measured. Sagittal and frontal plane kinematics and kinetics were examined at the hip and knee during stance phase. A linear mixed model compared biomechanical differences between the limbs of ACLR and healthy control participants (α = 0.05). In the post-ACLR group, peak hip extension, peak knee flexion, sagittal hip and knee excursion, and the peak knee extensor moment were significantly lower in the ACLR surgical limb compared to the non-surgical limb (p < 0.05). The peak knee flexion angle and peak knee extensor moment were also lower in the ACLR surgical limb compared to the matched control limb (p < 0.05). In summary, post-ACLR participants exhibited altered sagittal plane movement in their surgical limb that was not demonstrated in the non-surgical limb or in control participants, which may suggest avoidance, or reduced utilization of the ACLR limb.

Influence of Footwear Selection on Youth Running Biomechanics: A Pilot Study.

BACKGROUND: The relationship of running biomechanics, footwear, and injury has been studied extensively in adults. There has been little research on the effects of footwear on running biomechanics in youth. HYPOTHESIS: Running biomechanics of youth will be significantly affected by changes in footwear. Minimal shoe running will demonstrate similarities to barefoot. STUDY DESIGN: Crossover study design: randomized trial. LEVEL OF EVIDENCE: Level 2. METHODS: A total of 14 active male youth (8-12 years old) participants with no previous exposure to minimalist shoes or barefoot running had running biomechanics (lower extremity sagittal plane kinematics and vertical ground reaction forces [vGRFs]) collected and analyzed in 3 footwear conditions (barefoot, traditional, and minimal shoe). RESULTS: The average vertical loading rate (AVLR) was significantly greater running barefoot (173.86 bodyweights per second [BW/s]) and in the minimal shoe (138.71 BW/s) compared with the traditional shoe (78.06 BW/s), (P < 0.01). There were significant differences between shoe conditions for knee flexion at initial contact (P < 0.01), knee sagittal plane excursion (P < 0.01), peak dorsiflexion (P < 0.01), and dorsiflexion at initial contact (P = 0.03). No participants displayed a forefoot-strike during this study. CONCLUSION: The introduction of barefoot and minimalist running in habitually shod youth significantly affected the running biomechanics of youth and caused immediate alterations in both lower extremity kinematics and vGRFs. Running barefoot or in minimal shoes dramatically increased the AVLR, which has been associated with injury, compared with a traditional shoe. CLINICAL RELEVANCE: This study evaluated the effects of footwear on overground running biomechanics, including AVLR, in pre- and early-adolescent youth males. Based on our findings, clinicians should exercise caution in barefoot or minimal shoe transition among young, habitually shod, runners due to the immediate and dramatic increases in AVLRs.

Comparing walking biomechanics of older females in maximal, minimal, and traditional shoes.

BACKGROUND: Knee osteoarthritis (OA) is a degenerative joint disease that affects millions of individuals each year. Several biomechanical variables during walking have been identified as risk factors for developing knee OA, including the peak external knee adduction moment (KAM) and the knee flexion angle at initial contact. Many interventions have been studied to help mitigate these risk factors, including footwear. However, it is largely unknown how varying shoe cushioning may affect walking biomechanics related to knee OA risk. RESEARCH QUESTION: What is the effect of maximally and minimally cushioned shoes on walking biomechanics compared to a traditionally cushioned shoe in older females? METHODS: Walking biomechanics in three shoes (maximal, traditional, minimal) were collected on 16 healthy females ages 50-70 using an 8-camera 3D motion capture system and two embedded force plates. Key biomechanical variables related to knee OA disease risk were compared between shoes using repeated measures ANOVAs. RESULTS: The KAM was significantly larger in the maximal shoe (p = 0.005), while the knee flexion angle at initial contact was significantly larger in both the maximal and minimal shoe compared to the traditional shoe (p = .000). Additionally, the peak knee flexion angle (p = .000) and the loading rates of the vertical ground reaction force were (instantaneous: p = 0.001; average: p = .010) were significantly higher in the minimal shoe. SIGNIFICANCE: While these results are specific to the shoes used in this study, clinicians should exercise caution in prescribing maximal or minimal shoes to females in this age group who may be at risk of knee OA given these results. Research is needed on the effect of these shoes in patients with knee OA.

Differences in running biomechanics between a maximal, traditional, and minimal running shoe.

OBJECTIVES: Previous studies comparing shoes based on the amount of midsole cushioning have generally used shoes from multiple manufacturers, where factors outside of stack height may contribute to observed biomechanical differences in running mechanics between shoes. Therefore, the purpose of this study was to compare ground reaction forces and ankle kinematics during running between three shoes (maximal, traditional, and minimal) from the same manufacturer that only varied in stack height. DESIGN: Within-participant repeated measures METHODS: Twenty recreational runners ran overground in the laboratory in three shoe conditions (maximal, traditional, minimal) while three-dimensional kinematic and kinetic data were collected using a 3D motion capture system and two embedded force plates. Repeated measures ANOVAs (α=.05) compared biomechanical data between shoes. RESULTS: While the loading rate was significantly greater in the minimal shoe compared to the maximal shoe, no other differences were seen for the ground reaction force variables. Peak eversion was greater in the maximal and minimal shoe compared to the traditional shoe, while eversion duration and eversion at toe-off were greater in the maximal shoe. CONCLUSIONS: Previously cited differences in ground reaction force parameters between maximal and traditional footwear may be due to factors outside of midsole stack height. The eversion mechanics in the maximal shoes from this study may place runners at a greater risk of injury. Disagreement between previous studies indicates that more research on maximal running shoes is needed.

A 6-Week Transition to Maximal Running Shoes Does Not Change Running Biomechanics.

BACKGROUND: A recent study suggested that maximal running shoes may increase the impact force and loading rate of the vertical ground-reaction force during running. It is currently unknown whether runners will adapt to decrease the impact force and loading rate over time. PURPOSE: To compare the vertical ground-reaction force and ankle kinematics between maximal and traditional shoes before and after a 6-week acclimation period to the maximal shoe. STUDY DESIGN: Controlled laboratory study. METHODS: Participants ran in a traditional running shoe and a maximal running shoe during 2 testing sessions 6 weeks apart. During each session, 3-dimensional kinematics and kinetics were collected during overground running. Variables of interest included the loading rate, impact peak, and active peak of the vertical ground-reaction force, as well as eversion and dorsiflexion kinematics. Two-way repeated measures analyses of variance compared data within participants. RESULTS: No significant differences were observed in any biomechanical variable between time points. The loading rate and impact peak were higher in the maximal shoe. Runners were still everted at toe-off and landed with less dorsiflexion, on average, in the maximal shoe. CONCLUSION: Greater loading rates and impact forces were previously found in maximal running shoes, which may indicate an increased risk of injury. The eversion mechanics observed in the maximal shoes may also increase the risk of injury. A 6-week transition to maximal shoes did not significantly change any of these measures. CLINICAL RELEVANCE: Maximal running shoes are becoming very popular and may be considered a treatment option for some injuries. The biomechanical results of this study do not support the use of maximal running shoes. However, the effect of these shoes on pain and injury rates is unknown.

Sex differences in lower extremity coordinative variability during running.

BACKGROUND: Differences in coordinative variability have been previously reported between healthy and injured runners. Many running-related injuries have a sex bias, particularly patellofemoral pain (PFP), as female runners are approximately twice as likely to develop PFP compared to males. However, very little is currently known regarding sex differences in coordinative variability during running. RESEARCH QUESTION: Are there sex differences in continuous relative phase (CRP) variability for pelvis-thigh and thigh-shank couplings during the stance phase of running? METHODS: Pelvis, thigh, and shank segment kinematics were collected on 15 female and 15 male subjects during overground running at a self-selected easy pace (2.39-3.56 m/s) using a 10-camera 3D motion capture system. Continuous relative phase (CRP) variability was calculated between the pelvis-thigh and thigh-shank, and averaged during four distinct stance sub-phases. A mixed effects linear model compared CRP variability between sexes at each stance sub-phase. RESULTS: Compared to males, females displayed significantly lower pelvis-thigh CRP variability in the transverse plane during the loading response phase, and significantly lower thigh-shank CRP variability in the sagittal plane during the loading response and pre-swing phases. SIGNIFICANCE: Lower coordinative variability in females during the loading response for two couplings may provide additional insight into the sex bias for developing certain running-related injuries. However, any injury implications from these results are speculative and should be interpreted with caution.

Atmospheric implications of large C2-C5 alkane emissions from the U.S. oil and gas industry.

Emissions of C2-C5 alkanes from the U.S. oil and gas sector have changed rapidly over the last decade. We use a nested GEOS-Chem simulation driven by updated 2011NEI emissions with aircraft, surface and column observations to 1) examine spatial patterns in the emissions and observed atmospheric abundances of C2-C5 alkanes over the U.S., and 2) estimate the contribution of emissions from the U.S. oil and gas industry to these patterns. The oil and gas sector in the updated 2011NEI contributes over 80% of the total U.S. emissions of ethane (C2H6) and propane (C3H8), and emissions of these species are largest in the central U.S. Observed mixing ratios of C2-C5 alkanes show enhancements over the central U.S. below 2 km. A nested GEOS-Chem simulation underpredicts observed C3H8 mixing ratios in the boundary layer over several U.S. regions and the relative underprediction is not consistent, suggesting C3H8 emissions should receive more attention moving forward. Our decision to consider only C4-C5 alkane emissions as a single lumped species produces a geographic distribution similar to observations. Due to the increasing importance of oil and gas emissions in the U.S., we recommend continued support of existing long-term measurements of C2-C5 alkanes. We suggest additional monitoring of C2-C5 alkanes downwind of northeastern Colorado, Wyoming and western North Dakota to capture changes in these regions. The atmospheric chemistry modeling community should also evaluate whether chemical mechanisms that lump larger alkanes are sufficient to understand air quality issues in regions with large emissions of these species.

Influence of Maximal Running Shoes on Biomechanics Before and After a 5K Run.

BACKGROUND: Lower extremity injuries are common among runners. Recent trends in footwear have included minimal and maximal running shoe types. Maximal running shoes are unique because they provide the runner with a highly cushioned midsole in both the rearfoot and forefoot. However, little is known about how maximal shoes influence running biomechanics. PURPOSE: To examine the influence of maximal running shoes on biomechanics before and after a 5-km (5K) run as compared with neutral running shoes. STUDY DESIGN: Controlled laboratory study. METHODS: Fifteen female runners participated in 2 testing sessions (neutral shoe session and maximal shoe session), with 7 to 10 days between sessions. Three-dimensional kinematic and kinetic data were collected while participants ran along a 10-m runway. After 5 running trials, participants completed a 5K treadmill run, followed by 5 additional running trials. Variables of interest included impact peak of the vertical ground-reaction force, loading rate, and peak eversion. Differences were determined by use of a series of 2-way repeated-measures analysis of variance models (shoe × time). RESULTS: A significant main effect was found for shoe type for impact peak and loading rate. When the maximal shoe was compared with the neutral shoe before and after the 5K run, participants exhibited an increased loading rate (mean ± SE: pre-maximal shoe, 81.15 body weights/second [BW/s] and pre-neutral shoe, 60.83 BW/s [P < .001]; post-maximal shoe, 79.10 BW/s and post-neutral shoe, 61.22 BW/s [P = .008]) and increased impact peak (pre-maximal shoe, 1.76 BW and pre-neutral shoe, 1.58 BW [P = .004]; post-maximal shoe, 1.79 BW and post-neutral shoe, 1.55 BW [P = .003]). There were no shoe × time interactions and no significant findings for peak eversion. CONCLUSION: Runners exhibited increased impact forces and loading rate when running in a maximal versus neutral shoe. Because increases in these variables have been associated with an increased risk of running-related injuries, runners who are new to running in a maximal shoe may be at an increased risk of injury. CLINICAL RELEVANCE: Understanding the influence of running footwear as an intervention that affects running biomechanics is important for clinicians so as to reduce patient injury.

Region-dependent alterations in glutamate and GABA measured by high-resolution magnetic resonance spectroscopy following acute binge inhalation of toluene in juvenile rats.

Little is known about the neurochemical effects accompanying the high-concentration inhalant exposures characteristic of binge solvent abuse. In adult animals, prior studies with other patterns of exposure indicate that toluene, a commonly abused household and industrial solvent, has significant effects on the glutamatergic and GABAergic neurotransmitter systems and on other neurotransmitter systems as well. In the current investigation, high-resolution "magic angle" spinning proton magnetic resonance spectroscopy (HR-MAS (1)H-MRS) was used to assess the effect of acute binge toluene inhalation on regional brain concentrations of various neurochemicals including glutamate (GLU), GABA, and glutamine (GLN) in juvenile male and female rats. Acute toluene (8000 ppm or 12,000 ppm) significantly reduced levels of hippocampal GABA (-12%) and GLU (-8%), and the GLU/GLN ratio, an index of glutamatergic tone, was significantly reduced (-22%) in the dorsal anterior striatum, driven largely by a 28% increase in GLN. Significant increases in alanine and lactate in several brain regions after acute toluene may be indicative of altered oxygen-dependent metabolism associated with the inhalation of higher concentrations of toluene (e.g., >5000 ppm). Other components of the MR-visible neurochemical profile, such as N-acetylaspartate (NAA), myo-inositol, creatine, and various choline containing compounds, were unchanged by acute toluene. The results are consistent with the notion that binge toluene exposure affects juvenile neurochemistry in systems mediating the rewarding and emotional aspects of substance abuse. Moreover the results provide a framework to understand further (1)H-MRS studies in clinical populations.

Prenatal toluene exposure impairs performance in the Morris Water Maze in adolescent rats.

Volatile organic solvent abuse continues to be a worldwide health problem, including the neurobehavioral teratogenic sequelae of toluene abuse during pregnancy. Although abuse levels of prenatal toluene exposure can lead to a Fetal Solvent Syndrome, there is little research examining these effects on memory. Consumption of toluene can have detrimental effects on the developing hippocampus which could lead to specific spatial learning and memory deficits. This study used a rat model to determine how prenatal exposure to abuse levels of toluene would affect performance in a spatial learning and memory task, the Morris Water Maze (MWM). Pregnant Sprague-Dawley rats were exposed to 0, 8000 or 12,000ppm (ppm) of toluene for 15min twice daily from gestation day 8 (GD8) through GD20. Male and female offspring (N=104) were observed in the MWM for 5days beginning on postnatal day (PN) 28 and again on PN44. While prenatal toluene-exposed animals did not differ in initial acquisition in the MWM, rats prenatally exposed to 12,000ppm toluene displayed performance deficits during a probe trial and in reversal learning on PN44. Overall, this study indicates that prenatal exposure to repeated inhaled abuse patterns of high concentrations of toluene can impair spatial memory function that persists into adolescence.

A hemispherical, high-solid-angle optical micro-cavity for cavity-QED studies.

We report a novel hemispherical micro-cavity that is comprised of a planar integrated semiconductor distributed Bragg reflector (DBR) mirror, and an external, concave micro-mirror having a radius of curvature 50 microm. The integrated DBR mirror containing quantum dots (QD), is designed to locate the QDs at an antinode of the field in order to maximize the interaction between the QD and cavity. The concave micro-mirror, with high-reflectivity over a large solid-angle, creates a diffraction-limited (sub-micron) mode-waist at the planar mirror, leading to a large coupling constant between the cavity mode and QD. The half-monolithic design gives more spatial and spectral tuning abilities, relatively to fully monolithic structures. This unique micro-cavity design will potentially enable us to both reach the cavity quantum electrodynamics (QED) strong coupling regime and realize the deterministic generation of single photons on demand.

Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen.

Between October 1985 and March 1987, 92 patients were registered on a phase II study of the Northern California Oncology Group investigating the importance of dose intensity in the treatment of advanced non-small cell lung cancer (NSCLC). Treatment consisted of high-dose cisplatin in hypertonic saline (200 mg/m2 on a 28-day cycle) given in a divided day 1 and day 8 schedule. The response rate among 76 assessable patients was 36% (27/76), with complete response (CR) in 8% (6/76) and partial response (PR) in 28% (21/76). If all patients receiving any drug therapy were considered, the overall response rate was 31% (27/87), with CR in 7% (6/87) and PR in 24% (21/87). Median survival times for all assessable patients and all patients receiving any therapy were 37 and 35 weeks, respectively. With the use of a protocol design specifying dose delays rather than dose reduction for toxicity, the mean dose intensity delivered was 47.2 mg/m2 per week, or 94% of projected. Compared with other dose-intensive regimens of cisplatin, this day 1 and day 8 schedule was relatively well tolerated, with peripheral neuropathy as the dose-limiting toxicity. The data on response and median survival times among patients receiving this single-agent therapy are encouraging. They support the potential importance of cisplatin dose intensity in the treatment of NSCLC. Whether these results represent a positive dose-response effect in NSCLC will be tested in a randomized comparative trial of high-dose versus standard-dose cisplatin therapy.

Cardiotoxicity of epirubicin and doxorubicin: assessment by endomyocardial biopsy.

Forty-two evaluable endomyocardial biopsies were obtained from 29 patients treated with epirubicin, the 4'-epimer of doxorubicin in cumulative doses ranging from 147 mg/m2 to 888 mg/m2. In this study of the Northern California Oncology Group, myofibrillar loss and sarcoplasmic vacuolization were identified and shown to be identical to those previously described for doxorubicin. However, when these biopsies were compared to 119 biopsies obtained from 98 patients treated with doxorubicin, milligram for milligram, epirubicin caused less endomyocardial injury than doxorubicin (P = 0.0013). Age, sex, type of primary malignancy, prior cardiac disease, and hypertension did not influence the degree of histologically demonstrated anthracycline injury induced by epirubicin.

Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study.

Thirty-five patients with superficial transitional carcinoma of the bladder were treated intravesically with escalating doses of recombinant alpha-2-interferon administered weekly for 8 weeks. Of the 19 patients with high-grade intraepithelial neoplasia (17 carcinoma in situ [CIS], two severe dysplasia, all cytology positive), six (32%) had complete resolution of all histologic and cytologic evidence of disease (complete response). An additional three patients (16%) had complete resolution of CIS, but the interval appearance of a low-grade transitional cell neoplasm. Five (26%) had a partial response (complete resolution of all evidence of CIS on multiple bladder biopsies but persistently positive cytologic preparations). Sixteen patients with recurrent papillary tumors and extensive prior therapy were also treated. Four (25%) had a complete response. Twenty-three of the 35 patients had prior intravesical therapy. Seven of the 23 (30%) patients with prior intravesical chemotherapy or immunotherapy had a complete or partial response to interferon, while eight of the 12 patients (67%) without prior intravesical treatment responded. These responses were achieved with minimal local and systemic toxicity. Of the ten complete responders, five remain in continuous unmaintained remission for 18+ to 37+ months. Intracavitary alpha-2-interferon is an effective new treatment for some patients with bladder cancer.

Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study.

Fifty-eight patients with metastatic transitional cell carcinoma of the urinary tract received cisplatin, methotrexate, and vinblastine (CMV) combination chemotherapy. Complete responses (CRs) were noted in 14 of the 50 (28%) evaluable patients and partial responses (PRs) in 14 patients for an overall response rate of 56% (95% confidence limits of 42% to 70%). The median duration of the 14 CRs was 9 months. Six of the 14 CRs (43%) remain in unmaintained remission from 6 + to 35 + months from onset of treatment. The median survival of evaluable patients receiving CMV was 8 months. Median survival for CRs was 11 months v 7 months for PRs (P less than .05) and 6 months for nonresponders. Renal and hematologic toxicities with this regimen were moderate. CMV is an effective regimen for patients with metastatic transitional cell carcinoma of the bladder. Prolonged disease-free survival may result from a CR to this regimen.

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial.

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.

Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group.

We compared the effectiveness of fluorouracil (5-FU) alone (arm A), high-dose leucovorin plus 5-FU (arm B), and sequential methotrexate, 5-FU, and leucovorin (arm C) for treatment of patients with advanced colorectal carcinomas who had not received prior chemotherapy. Arm A consisted of infusions of 5-FU at 12 mg/kg/d intravenously (IV) for 5 days followed by weekly infusions of 5-FU at 15 mg/kg; arm B consisted of leucovorin infusions at 200 mg/m2/d IV plus infusions of 5-FU at 400 mg/m2/d IV on days 1 through 5 of a 28-day cycle; arm C consisted of methotrexate at 50 mg/m2 orally every 6 hours for five doses followed by infusions of 5-FU, 500 mg/m2 IV, and leucovorin, 10 mg/m2 orally, every 6 hours for five doses every other week. A total of 265 patients were entered into the trial, of whom 249 (94%) were fully evaluable. The objective response rate (complete [CR] plus partial [PR] responses) was 17.3% on arm A, 18.8% on arm B, and 19.8% on arm C (log-rank test, P greater than .4). The median time to failure was 138 days on arm A, 166 days on arm B, and 182 days on arm C (log-rank test, P values of arm A v B = .06; arm A v arm C = .04). Median survival was 345 days on arm A, 324 days on arm B, and 356 days on arm C (log-rank test, P greater than .4). Treatment with 5-FU alone was significantly more dose intensive and more toxic than either of the experimental combinations. The rates of grade 3 or greater nonhematologic toxicity were 42.3% on arm A, 24.3% on arm B, and 14.3% on arm C. Hematologic toxicity was milder but had the same pattern. This study indicates that these regimens of high-dose leucovorin plus 5-FU and sequential methotrexate, 5-FU, and leucovorin are not more effective than is 5-FU alone for treatment of patients with colorectal carcinomas when 5-FU is administered at high-dose intensity.