5-Year Update of a Multi-Institution, Prospective Phase 2 Hypofractionated Postmastectomy Radiation Therapy Trial.

PURPOSE: Hypofractionation in the setting of postmastectomy radiation (PMRT) is not currently the standard of care in most countries. Here we present a 5-year update of our multi-institutional, phase 2 prospective trial evaluating a novel 15-day hypofractionated PMRT regimen. METHODS AND MATERIALS: Patients were enrolled to receive 3.33 Gy daily to the chest wall (or reconstructed breast) and regional lymphatics in 11 fractions with an optional 4-fraction mastectomy scar boost. The primary endpoint was freedom from grade 3 or higher late non-reconstruction-related radiation toxicities. Toxicities were scored using Common Terminology Criteria for Adverse Events v4.0. Secondary endpoints included local and locoregional recurrence rates, cosmesis, and reconstruction complications. RESULTS: After enrolling 69 patients with stage II-IIIa breast cancer, 67 women were eligible for analysis. At a median follow up of 54 months, there were no acute or late grade 3 and 4 nonreconstruction reported toxicities. The grade 2 or greater late toxicity rate was only 12% and comprised grade 2 pain, fatigue, and lymphedema that persisted beyond 6 months after completion of radiation therapy. Only 3 women (4.6%) experienced a chest wall or nodal recurrence as a first site of relapse. Freedom from local failure, including local failure after distant relapse, was 92% at 5 years, and the 5-year overall survival was 90%. CONCLUSIONS: This is the first prospective trial conducted in the United States to demonstrate the safe and effective use of hypofractionated PMRT. We have demonstrated a low complication rate while achieving excellent local control. Toxicity was better than anticipated based on previously published series of PMRT toxicities. Although our fractionation was novel, the radiobiological equivalent dose is similar to other hypofractionation schedules. This trial was the basis for the creation of Alliance A221505 (RT CHARM), which is currently accruing patients in a phase 3 randomized design.

Solar particle event storm shelter requirements for missions beyond low Earth orbit.

Protecting spacecraft crews from energetic space radiations that pose both chronic and acute health risks is a critical issue for future missions beyond low Earth orbit (LEO). Chronic health risks are possible from both galactic cosmic ray and solar energetic particle event (SPE) exposures. However, SPE exposures also can pose significant short term risks including, if dose levels are high enough, acute radiation syndrome effects that can be mission- or life-threatening. In order to address the reduction of short term risks to spaceflight crews from SPEs, we have developed recommendations to NASA for a design-standard SPE to be used as the basis for evaluating the adequacy of proposed radiation shelters for cislunar missions beyond LEO. Four SPE protection requirements for habitats are proposed: (1) a blood-forming-organ limit of 250 mGy-equivalent for the design SPE; (2) a design reference SPE environment equivalent to the sum of the proton spectra during the October 1989 event series; (3) any necessary assembly of the protection system must be completed within 30 min of event onset; and (4) space protection systems must be designed to ensure that astronaut radiation exposures follow the ALARA (As Low As Reasonably Achievable) principle.

A double-blind, placebo-controlled randomized trial of creatine for the cancer anorexia/weight loss syndrome (N02C4): an Alliance trial.

BACKGROUND: Multiple pilot studies, including one in colorectal cancer patients, suggest that creatine, an amino acid derivative, augments muscle, improves strength, and thereby could palliate the cancer anorexia/weight loss syndrome. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled trial, incurable patients with this syndrome were assigned creatine (20 g/day load×5 days followed by 2 g/day orally) versus identical placebo. Patients were weighed once a week for 1 month and then monthly. Patients were also assessed over 1 month for appetite and quality of life (validated questionnaires), fist grip strength, body composition (bioelectrical impedance), and adverse events. The primary endpoint was 10% or greater weight gain from baseline during the first month. RESULTS: Within this combined cohort of 263 evaluable patients (134 received creatine and 129 placebo), only 3 gained ≥10% of their baseline weight by 1 month: two creatine-treated and the other placebo-exposed (P = 1.00). Questionnaire data on appetite, quality of life, and activities of daily living showed no statistically significant differences between groups. Similarly, no statistically significant differences between groups were observed for fist-grip strength or body composition. Rates and severity of adverse events were comparable between groups. Finally, a median survival of 230 and 239 days were observed in the creatine and placebo groups, respectively (P = 0.70). CONCLUSION: Creatine, as prescribed in this trial, had no effect on the cancer anorexia/weight loss syndrome.

Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study.

BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population-based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high-radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7-10).

Physical dynamics controlling variability in nearshore fecal pollution: fecal indicator bacteria as passive particles.

We present results from a 5-h field program (HB06) that took place at California's Huntington State Beach. We assessed the importance of physical dynamics in controlling fecal indicator bacteria (FIB) concentrations during HB06 using an individual based model including alongshore advection and cross-shore variable horizontal diffusion. The model was parameterized with physical (waves and currents) and bacterial (Escherichia coli and Enterococcus) observations made during HB06. The model captured surfzone FIB dynamics well (average surfzone model skill: 0.84 {E. coli} and 0.52 {Enterococcus}), but fell short of capturing offshore FIB dynamics. Our analyses support the hypothesis that surfzone FIB variability during HB06 was a consequence of southward advection and diffusion of a patch of FIB originating north of the study area. Offshore FIB may have originated from a different, southern, source. Mortality may account for some of the offshore variability not explained by the physical model.

Factors controlling variability in nearshore fecal pollution: the effects of mortality.

A suite of physical-biological models was used to explore the importance of mortality and fluid dynamics in controlling concentrations of fecal indicator bacteria (FIB) at Huntington Beach, CA. An advection-diffusion (AD) model provided a baseline to assess improvements in model skill with the inclusion of mortality. Six forms of mortality were modeled. All mortality models performed better than the AD model, especially at offshore sampling stations, where model skill increased from <0.18 to >0.50 (Escherichia coli) or <-0.14 to >0.30 (Enterococcus). Models including cross-shore variable mortality rates reproduced FIB decay accurately (p<0.05) at more stations than models without. This finding is consistent with analyses that revealed cross-shore variability in Enterococcus species composition and solar dose response. No best model was identified for Enterococcus, as all models including cross-shore variable mortality performed similarly. The best model for E. coli included solar-dependent and cross-shore variable mortality.

Treatment profile and complications associated with cryotherapy for localized prostate cancer: a population-based study.

The aim of this study was to assess the treatment patterns and 3-12-month complication rates associated with receiving prostate cryotherapy in a population-based study. Men >65 years diagnosed with incident localized prostate cancer in Surveillance Epidemiology End Results (SEER)-Medicare-linked database from 2004 to 2005 were identified. A total of 21,344 men were included in the study, of which 380 were treated initially with cryotherapy. Recipients of cryotherapy versus aggressive forms of prostate therapy (ie, radical prostatectomy or radiation therapy) were more likely to be older, have one co-morbidity, low income, live in the South and be diagnosed with indolent cancer. Complication rates increased from 3 to 12 months following cryotherapy. By the twelfth month, the rates for urinary incontinence, lower urinary tract obstruction, erectile dysfunction and bowel bleeding reached 9.8, 28.7, 20.1 and 3.3%, respectively. Diagnoses of hydronephrosis, urinary fistula or bowel fistula were not evident. The rates of corrective invasive procedures for lower urinary tract obstruction and erectile dysfunction were both <2.9% by the twelfth month. Overall, complications post-cryotherapy were modest; however, diagnoses for lower urinary tract obstruction and erectile dysfunction were common.

Simultaneous magnetically directed drug convection and MR imaging.

Superparamagnetic iron oxide nanoparticles (IO NPs) are of interest for their usefulness in biomedical applications. In this work, we have synthesized iron oxide nanocomposites surface-modified with different biocompatible polymers. Bovine serum albumin (BSA) was physisorbed onto these IO NPs along with an excipient during freeze-drying. The mass transport of the protein attached to the iron oxide core-shell nanoparticles (IO cs-NPs) under a gradient magnetic field of an MRI instrument was observed in vitro and in an egg as a model system for a biological fluid. From the in vitro experiments in agarose gels, it was observed that the protein gets separated from the core during mass transport for some cs-IO, but co-migration was observed for PEG-modified IO cs-NPs. These experiments demonstrated proof-of-concept for the use of IO cs-NPs in magnetically directed drug convection.

Stroke surveillance in Manitoba, Canada: estimates from administrative databases.

This study investigated the use of population-based administrative databases for stroke surveillance. First, a meta-analysis was conducted of four studies, identified via a PubMed search, which estimated the sensitivity and specificity of hospital data for ascertaining cases of stroke when clinical registries or medical charts were the gold standard. Subsequently, case-ascertainment algorithms based on hospital, physician and prescription drug records were developed and applied to Manitoba's administrative data, and prevalence estimates were obtained for fiscal years 1995/96 to 2003/04 by age group, sex, region of residence and income quintile. The meta-analysis results revealed some over-ascertainment of stroke cases from hospital data when the algorithm was based on diagnosis codes for any type of cerebrovascular disease (Mantel-Haenszel Odds-Ratio [OR] - 1.70 [95% confidence interval (CI): 1.53 - 1.88]). Analyses of Manitoba administrative data revealed that while the total number of stroke cases varied substantially across the algorithms, the trend in prevalence was stable regardless of the algorithm adopted.

Species distribution and antimicrobial resistance of enterococci isolated from surface and ocean water.

AIMS: The species identification and antimicrobial resistance profiles were determined for enterococci isolated from Southern California surface and ocean waters. METHODS AND RESULTS: Species identification was determined for 1413 presumptive Enterococcus isolates from urban runoff, bay, ocean and sewage water samples. The most frequently isolated species were Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus casseliflavus and Enterococcus mundtii. All five of these species were isolated from ocean and bay water with a frequency ranging from 7% to 36%. Enterococcus casseliflavus was the most frequently isolated species in urban runoff making up 36-65% of isolates while E. faecium was the most frequently isolated species in sewage making up 53-78% of isolates. The similar distribution of species in urban runoff and receiving water suggests that urban runoff may be the source of Enterococcus. No vancomycin or high level gentamycin resistance was detected in E. faecalis and E. faecium isolates. CONCLUSIONS: Enterococcus faecalis, E. faecium, E. casseliflavus and E. mundtii are the most commonly isolated Enterococcus species from urban runoff and receiving waters in Southern California. SIGNIFICANCE AND IMPACT OF THE STUDY: Determination of the Enterococcus species isolated from receiving waters and potential pollution sources may assist in determining the sources of pollution.

Using strain typing to characterise a fluoroquinolone-resistant Neisseria gonorrhoeae transmission network in southern California.

OBJECTIVE: We investigated the initial outbreak of fluoroquinolone-resistant Neisseria gonorrhoeae (QRNG) in southern California with analysis of transmission using strain typing. METHODS: Surveillance for QRNG was conducted between 2000 and 2002 in southern California, including epidemiology and strain typing by a combination of antibiogram, auxotype, serovar, Lip type and amino acid alteration patterns in the quinolone-resistance determining region of GyrA and ParC. Combining epidemiological data with strain typing, we describe the emergence of QRNG outbreak strains using risk factor analysis and transmission networks. RESULTS: Two outbreak strains accounted for 82% of isolates. Both strains required proline, were Lip type 17c, had amino acid alterations 91> Phe in GyrA and 87> Arg in ParC, but they differed by their serovar, IB-3C8 versus IB-2H7, 2G2. Outbreak strains were positively associated with men who have sex with men (MSM), adjusted odds ratio (AOR) 23.9 (95% confidence interval (CI) 2.2 to 261) and negatively associated with travel history: AOR 0.05, (95% CI 0.0 to 0.6). Network analysis demonstrated that 17 cases were connected by sexual contacts and/or public venues including bars, bathhouses/sex clubs, and internet sites. CONCLUSIONS: QRNG may have become established among Californian MSM through an identified transmission network of southern Californian bars, bathhouses and internet sites.

Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease.

Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.

Myeloperoxidase predicts risk of vasculopathic events in hemizgygous males with Fabry disease.

Fabry disease results in a global vasculopathy leading to early-onset stroke and renal and cardiac failure. We found that random myeloperoxidase in serum and plasma was significantly elevated in 73 consecutive male patients with Fabry disease. Random serum myeloperoxidase level in men predicted the risk of a Fabry vasculopathy-related event in subsequent years. Long-term enzyme replacement therapy did not reduce myeloperoxidase level or eliminate the risk of vasculopathic events.

Comparison of 16S rRNA sequencing with conventional and commercial phenotypic techniques for identification of enterococci from the marine environment.

AIMS: To compare accuracy of genus and species level identification of presumptive enterococci isolates from the marine environment using conventional biochemical testing, four commercial identification systems and 16S rRNA sequence analysis. METHODS AND RESULTS: Ninety-seven environmental bacterial isolates identified as presumptive enterococci on mEI media were tested using conventional and Enterococcus genus screen biochemical tests, four commercial testing systems and 16S rRNA sequencing. Conventional and Enterococcus genus screen biochemical testing, 16S rRNA sequencing and two commercial test systems achieved an accuracy of > or = 94% for Enterococcus genus confirmation. Conventional biochemical testing and 16S rRNA sequencing achieved an accuracy of > or = 90% for species level identification. CONCLUSIONS: For confirmation of Enterococcus genus from mEI media, conventional or genus screen biochemical testing, 16S rRNA sequencing and the four commercial systems were correct 79-100% of the time. For speciation to an accuracy of 90% or better, either conventional biochemical testing or 16S rRNA sequencing is required. SIGNIFICANCE AND IMPACT OF THE STUDY: Accurate identification of presumptive environmental Enterococcus isolates to genus and species level is an integral part of laboratory quality assurance and further characterization of Enterococcus species from pollution incidents. This investigation determines the ability of six different methods to correctly identify environmental isolates.

Enumeration and speciation of enterococci found in marine and intertidal sediments and coastal water in southern California.

AIMS: To determine the levels and species distribution of enterococci in intertidal and marine sediments and coastal waters at two beaches frequently in violation of bacterial water standards. METHODS AND RESULTS: Faecal indicator bacteria were extracted from sediment and enumerated using membrane filtration. High levels of enterococci were detected in intertidal sediments in a seasonal river and near a storm drain outlet. Low levels were found in marine sediments at 10 m depths and in surf zone sand. Bacterial isolates presumptively identified as Enterococcus on mEI media were speciated. The predominant species found in both water and sediment included Enterococcus faecalis, Enterococcus faecium, Enterococcus hirae, Enterococcus casseliflavus and Enterococcus mundtii. A number of isolates (11-26%) from regulatory water samples presumptively identified as enterococci on mEI media were subsequently identified as species other than Enterococcus. At both study sites, the distribution of species present in water was comparable with those in sediments and the distribution of species was similar in water samples passing and exceeding bacterial indicator standards. CONCLUSIONS: High levels of Enterococcus in intertidal sediments indicate retention and possible regrowth in this environment. SIGNIFICANCE AND IMPACT OF THE STUDY: Resuspension of enterococci that are persistent in sediments may cause beach water quality failures and calls into question the specificity of this indicator for determining recent faecal contamination.

Evaluation of antibiotic resistance analysis and ribotyping for identification of faecal pollution sources in an urban watershed.

AIMS: The accuracy of ribotyping and antibiotic resistance analysis (ARA) for prediction of sources of faecal bacterial pollution in an urban southern California watershed was determined using blinded proficiency samples. METHODS AND RESULTS: Antibiotic resistance patterns and HindIII ribotypes of Escherichia coli (n = 997), and antibiotic resistance patterns of Enterococcus spp. (n = 3657) were used to construct libraries from sewage samples and from faeces of seagulls, dogs, cats, horses and humans within the watershed. The three libraries were analysed to determine the accuracy of host source prediction. The internal accuracy of the libraries (average rate of correct classification, ARCC) with six source categories was 44% for E. coli ARA, 69% for E. coli ribotyping and 48% for Enterococcus ARA. Each library's predictive ability towards isolates that were not part of the library was determined using a blinded proficiency panel of 97 E. coli and 99 Enterococcus isolates. Twenty-eight per cent (by ARA) and 27% (by ribotyping) of the E. coli proficiency isolates were assigned to the correct source category. Sixteen per cent were assigned to the same source category by both methods, and 6% were assigned to the correct category. Addition of 2480 E. coli isolates to the ARA library did not improve the ARCC or proficiency accuracy. In contrast, 45% of Enterococcus proficiency isolates were correctly identified by ARA. CONCLUSIONS: None of the methods performed well enough on the proficiency panel to be judged ready for application to environmental samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Most microbial source tracking (MST) studies published have demonstrated library accuracy solely by the internal ARCC measurement. Low rates of correct classification for E. coli proficiency isolates compared with the ARCCs of the libraries indicate that testing of bacteria from samples that are not represented in the library, such as blinded proficiency samples, is necessary to accurately measure predictive ability. The library-based MST methods used in this study may not be suited for determination of the source(s) of faecal pollution in large, urban watersheds.

Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study.

BACKGROUND: This study was performed to determine the efficacy of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients with previously untreated advanced or metastatic disease were enrolled in a phase II study of gemcitabine and oxaliplatin. Oxaliplatin was given i.v. on day 1 and gemcitabine i.v. on days 1 and 8 of a 3-week cycle. The primary end point of the trial was 6-month survival. Secondary end points included response rate, overall survival, median time to progression and toxicity. RESULTS: A total of 47 patients were enrolled, 46 of whom were evaluable. Of those patients assessed for the primary end point 50% lived for > or =6 months. The median time to progression was 4.53 months. Five confirmed responses were seen with a median duration of response of 2.7 months. Overall, the treatment was well tolerated. However, one patient died as a result of treatment-related hemolytic uremic syndrome. CONCLUSIONS: Gemcitabine and oxaliplatin, at doses of 1000 mg/m(2) and 100 mg/m(2), respectively, showed moderate activity in patients with pancreatic ACA. Based on the results of this study further evaluation of this combination is warranted.

Comparison of total coliform, fecal coliform, and enterococcus bacterial indicator response for ocean recreational water quality testing.

In July 1999, California's ocean recreational bacterial water quality standards were changed from a total coliform (TC) test to a standard requiring testing for all three bacterial indicators: TC, fecal coliforms (FC), and enterococci (EC). To compare the relationship between the bacterial indicators, and the effect that changing the standards would have on recreational water regulatory actions, three regional studies were conducted along the southern California shoreline from Santa Barbara to San Diego, California. Two studies were conducted during dry weather and one following a large storm event. In each study, samples were collected at over 200 sites which were selected using a stratified random design, with strata consisting of open beach areas and rocky shoreline, and areas near freshwater outlets that drain land-based runoff. During the dry weather studies, samples were collected once per week for 5 weeks. For the storm event study, sampling occurred on a single day about 24 h following the storm. The three indicator bacteria were measured at each site and the results were compared to the single sample standards (TC > 10,000; FC > 400 and EC > 104 MPN or cfu/100 ml). EC was the indicator that failed the single sample standards most often. During the wet weather study, 99% of all standard failures were detected using EC, compared with only 56% for FC, and 40% for TC. During the Summer Study, EC was again the indicator that failed the single sample standards most often, with 60% of the failures for EC alone. The increased failure of the EC standard occurred consistently regardless of whether the sample was collected at a beach or rocky shoreline site, or at a site near a freshwater outlet. Agreement among indicators was better during wet weather than during dry weather. During dry weather, agreement among indicators was better near freshwater outlets than along open shoreline. Cumulatively, our results suggest that replacement of a TC standard with an EC standard will lead to a five-fold increase in failures during dry weather and a doubling of failures during wet weather. Replacing a TC standard with one based on all three indicators will lead to an eight-fold increase in failures. Changes in the requirements for water quality testing have strong implications for increases in beach closures and restrictions.

The neurogenetics of mucolipidosis type IV.

BACKGROUND: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. OBJECTIVE: To comprehensively characterize the clinical and genetic abnormalities of MLIV. METHODS: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. RESULTS: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. CONCLUSIONS: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.

Gemcitabine and oxaliplatin for patients with advanced or metastatic pancreatic cancer: a North Central Cancer Treatment Group (NCCTG) phase I study.

BACKGROUND: The study was performed to determine the maximum tolerated dose (MTD) of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients, with previously untreated advanced or metastatic disease, were enrolled in a dose escalation study of gemcitabine and oxaliplatin. Oxaliplatin was given intravenously on day 1 and gemcitabine intravenously on days 1 and 8 of a 3-week cycle. Doses of both drugs were increased with sequential cohorts of patients until dose-limiting toxicity (DLT) was observed. RESULTS: A total of 18 patients were enrolled to three dose levels. DLT of neutropenia and a severe infection was noted at a dose of gemcitabine 1250 mg/m2 and oxaliplatin 130 mg/m2. Hematological toxicity and nausea and vomiting were the most common grade 3/4 toxicities. The MTD, gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2, was well tolerated. Three confirmed responses were seen. CONCLUSIONS: The MTD of gemcitabine and oxaliplatin in patients with pancreatic ACA was determined. A phase II study of this combination is ongoing and will be reported separately at a later date.