A High-Resolution National-Scale Hydrologic Forecast System from a Global Ensemble Land Surface Model.

Warning systems with the ability to predict floods several days in advance have the potential to benefit tens of millions of people. Accordingly, large-scale streamflow prediction systems such as the Advanced Hydrologic Prediction Service or the Global Flood Awareness System are limited to coarse resolutions. This article presents a method for routing global runoff ensemble forecasts and global historical runoff generated by the European Centre for Medium-Range Weather Forecasts model using the Routing Application for Parallel computatIon of Discharge to produce high spatial resolution 15-day stream forecasts, approximate recurrence intervals, and warning points at locations where streamflow is predicted to exceed the recurrence interval thresholds. The processing method involves distributing the computations using computer clusters to facilitate processing of large watersheds with high-density stream networks. In addition, the Streamflow Prediction Tool web application was developed for visualizing analyzed results at both the regional level and at the reach level of high-density stream networks. The application formed part of the base hydrologic forecasting service available to the National Flood Interoperability Experiment and can potentially transform the nation's forecast ability by incorporating ensemble predictions at the nearly 2.7 million reaches of the National Hydrography Plus Version 2 Dataset into the national forecasting system.

100% Complete response rate in patients with cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid combination therapy: results of a case series.

BACKGROUND: Patients with cutaneous melanoma metastases have experienced excellent responses to intralesional interleukin (IL)-2. This has led to its recent inclusion into the US National Comprehensive Cancer Network guidelines for management of cutaneous melanoma metastases. Despite this, intralesional IL-2 has not been highlighted in the US literature nor have US physicians adopted it. OBJECTIVE: We sought to evaluate the effectiveness of intralesional IL-2 combined with topical imiquimod and retinoid for treatment of cutaneous metastatic melanoma. METHODS: A retrospective case series of 11 patients with cutaneous metastatic melanoma were treated with intralesional IL-2 combined with topical imiquimod and retinoid. RESULTS: A 100% complete local response rate with long-term follow-up (average of 24 months) was seen in all 11 patients treated with this proposed regimen. Biopsy specimens of treated sites confirmed absence of malignant cells. The most common treatment-related adverse event was rigors. LIMITATIONS: Small number of patients, retrospective review of charts, and lack of a comparison group were limitations. CONCLUSION: Intralesional IL-2 administered concomitantly with topical imiquimod and a retinoid cream is a promising therapeutic option for managing cutaneous melanoma metastases. The regimen was well tolerated and should be considered as a reasonable alternative to surgical excision.

Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity.

BACKGROUND: Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent. METHODS: For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). RESULTS: Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %). CONCLUSION: Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).

A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: a California Cancer Consortium trial.

BACKGROUND: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m(2) over 3 h on cycle 1, reduced to 45 mg/m(2) over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of ≥ 20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.

Influence of physician specialty on treatment recommendations in the multidisciplinary management of soft tissue sarcoma of the extremities.

IMPORTANCE: Although prospective randomized data are available to guide the multidisciplinary management of soft tissue sarcoma (STS) of the extremities, controversy exists regarding adjuvant chemotherapy and radiation therapy. OBJECTIVE: To determine if clinical specialty introduces bias in recommendations for multimodality treatment of STS. DESIGN: Electronic survey. SETTING: Database of active members of the American Society of Clinical Oncology, the Society of Surgical Oncology, and the Connective Tissue Oncology Society. PARTICIPANTS: Members of specialty oncology societies with an active interest in STS. EXPOSURE: Physician specialty. MAIN OUTCOMES AND MEASURES: Survey responses regarding the multidisciplinary management of STS were scored on a 5-point Likert scale and analyzed using analysis of variance. RESULTS: The questionnaire was completed by 320 of 490 potential respondents (65%), including medical (18%), radiation (8%), orthopedic (22%), and surgical oncologists (45%). Respondents concurred on the use of radiation therapy for margins positive for tumor, for high-grade tumors, for improvement in local control, for tumors larger than 10 cm, and for tumors in close proximity to a neurovascular bundle. Respondents diverged on the use of radiation therapy for tumors 5 to 10 cm in size, for low-grade tumors, for radiation-associated STS, and for survival benefit. Only radiation oncologists felt that radiation therapy was underutilized as a treatment modality (mean [SEM] Likert scale score, 2.44 [0.12]; P < .001). There was agreement on the use of chemotherapy for synovial sarcoma, for high-grade tumors, for tumors larger than 10 cm, for patients younger than 50 years of age, and for survival benefit. Medical oncologists were more likely to recommend chemotherapy for margins positive for tumor (mean [SEM] score, 3.12 [0.12]; P = .03) and for improvement in local control (mean [SEM] score, 2.91 [0.12] P = .08). Surgical oncologists placed the least emphasis on chemotherapy in the overall treatment plan (mean [SEM] score, 2.60 [0.07]; P = .001). CONCLUSIONS AND RELEVANCE: Specialty bias exists in adjuvant treatment recommendations for STS. This highlights the importance of multidisciplinary STS tumor boards and interdisciplinary care to facilitate consensus decision making for individual patients.

Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528.

PURPOSE: Everolimus, an oral inhibitor of mammalian target of rapamycin, can augment the efficacy of HER inhibitors in preclinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus and to describe its anti-tumor activity in the Phase I setting. METHODS: In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction. RESULTS: Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis, and fatigue. The MTD of the combination was 1,250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44 %, and mean clearance was decreased by 25 % when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response [thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months)]; 11 patients attained stable disease of at least 4 months. CONCLUSIONS: Lapatinib and everolimus are well tolerated at doses of 1,250 and 5 mg po daily, respectively. Stable disease ≥4 months/PR was achieved in 13 of 78 patients (17 %).

The acute effects of various types of stretching static, dynamic, ballistic, and no stretch of the iliopsoas on 40-yard sprint times in recreational runners.

BACKGROUND AND PURPOSE: The potential adverse effects of static stretching on athletic performance are well documented, but still appears to be controversial, especially as they relates to sprinting. The prevalence of this practice is demonstrated by the number of competitive and recreational athletes who regularly engage in stretching immediately prior to sprinting with the mindset of optimizing their performance. The purpose of this study was to examine the effects of acute static, dynamic, and ballistic stretching, and no stretching of the iliopsoas muscle on 40-yard sprint times in 18-37 year-old non-competitive, recreational runners. METHODS: Twenty-five healthy recreational runners (16 male and 9 female) between the ages of 24 and 35 (Mean = 26.76 yrs., SD = 2.42 yrs.) completed this study. A repeated measures design was used, which consisted of running a 40-yard sprint trial immediately following each of 4 different stretching conditions aimed at the iliopsoas muscle and lasting 1 minute each. The 4 conditions were completed in a randomized order within a 2-week time period, allowing 48-72 hours between each condition. Prior to each 40-yard sprint trial, a 5-minute walking warm-up was performed at 3.5 mph on a treadmill. The subject then ran a baseline 40-yard sprint. After a 10-minute self-paced walk, each subject performed one of the 4 stretching conditions (ballistic, dynamic, static, and no stretch) and then immediately ran a timed 40-yard sprint. RESULTS: There was a significant interaction between stretching conditions and their effects on sprint times, F(3,72) = 9.422, p<.0005. To break down this interaction, simple main effects were performed with 2 repeated measures ANOVAs and 4 paired t-tests using a Bonferroni corrected alpha (α = .0083). There were no significant differences between the 4 pre-condition times, p = 0.103 (Greenhouse-Geisser) or the post-condition times, p = 0.029. In the no stretch condition, subjects improved significantly from pre- to post- sprint times (p<0.0005). There were no statistically significant differences in pre- and post-stretch condition sprint times among the static (p = 0.804), ballistic (p = 0.217), and dynamic (p = 0.022) stretching conditions. CONCLUSIONS: Sprint performance may show greatest improvement without stretching and through the use of a walking generalized warmup on a treadmill. These findings have clinically meaningful implications for runners who include iliopsoas muscle stretching as a component of the warm-up. LEVEL OF EVIDENCE: Level 2.

A model for rural oncology.

Small rural hospitals in the United States have had challenging issues developing sustainable oncology programs. This is a report on the development of a successful rural oncology program. In 2006, the Tahoe Forest Health System in Truckee, CA, a remote mountain resort town, started a cancer program that was focused on addressing patient and family fears that are common to all cancer patients but more frightening in the rural setting. Four years later, it is a thriving program with significant community support, a creative academic affiliation, and a central focus of the future of the hospital. The Tahoe Forest Cancer Center developed a sustainable model for high quality cancer care that overcomes geographic, cultural and financial barriers. This structure may serve as a model for national rural health care.