Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Legionnaires' disease: evaluation of a quantitative microbial risk assessment model.

BACKGROUND: The quantities of Legionella vary considerably from natural waters to water in contaminated domestic hot water supplies, whirlpool spas and cooling towers, with the risk for LD rising as the Legionella counts grow. We currently report the results from our Quantitative Microbial Risk Assessment (QMRA) model evaluation. We developed the LD QMRA model to better understand Legionella exposure risks. METHODS: Using an animal data derived model for LD, we calculated risks from estimated exposures for a whirlpool spa outbreak, two hot spring spa outbreaks and compared the results to the reported LD risks. RESULTS: The QMRA model shows agreement (generally less than an order of magnitude discrepancy) with the reported Legionnaires' disease sub-clinical severity infection, clinical severity infection, and mortality risks. CONCLUSIONS: The LD QMRA model may lead to risk based limits to supplement the current guidance on Legionella control in cooling towers, whirlpool spas and other potential exposure sources. The verification of QMRA for LD also suggests the techniques, given suitable animal model data, may be useful in quantifying human response to other airborne pathogens.

Quantitative microbial risk assessment model for Legionnaires' disease: assessment of human exposures for selected spa outbreaks.

Evaluation of a quantitative microbial risk assessment (QMRA) model for Legionnaires' disease (LD) required Legionella exposure estimates for several well-documented LD outbreaks. Reports for a whirlpool spa and two natural spring spa outbreaks provided data for the exposure assessment, as well as rates of infection and mortality. Exposure estimates for the whirlpool spa outbreak employed aerosol generation, water composition, exposure duration data, and building ventilation parameters with a two-zone model. Estimates for the natural hot springs outbreaks used bacterial water to air partitioning coefficients and exposure duration information. The air concentration and dose calculations used input parameter distributions with Monte Carlo simulations to estimate exposures as probability distributions. The assessment considered two sets of assumptions about the transfer of Legionella from the water phase to the aerosol emitted from the whirlpool spa. The estimated air concentration near the whirlpool spa was 5 to 18 colony forming units per cubic meter (CFU/m(3)) and 50 to 180 CFU/m(3) for each of the alternate assumptions. The estimated 95th percentile ranges of Legionella dose for workers within 15 m of the whirlpool spa were 0.13-3.4 CFU and 1.3-34.5 CFU, respectively. The modeling for hot springs Spas 1 and 2 resulted in estimated arithmetic mean air concentrations of 360 and 17 CFU/m(3), respectively, and 95 percentile ranges for Legionella dose of 28 to 67 CFU and 1.1 to 3.7 CFU, respectively. The Legionella air concentration estimates fall in the range of limited reports on air concentrations of Legionella (0.33 to 190 CFU/m(3)) near showers, aerated faucets, and baths during filling with Legionella-contaminated water. These measurements may provide some indication that the estimates are of a reasonable magnitude, but they do not clarify the exposure estimates accuracy, since they were not obtained during LD outbreaks. Further research to improve the data used for the Legionella exposure assessment would strengthen the results. Several of the primary additional data needs include improved data for bacterial water to air partitioning coefficients, better accounting of time-activity-distance patterns and exposure potential in outbreak reports, and data for Legionella-containing aerosol viability decay instead of loss of capability for growth in culture.

Exposure assessment methods for a study of mortality and cancer morbidity in relation to specific petroleum industry exposures.

In 1987 a Canadian company implemented an exposure tracking and health information system. The exposure tracking method aligned closely with published concepts for describing workplace exposure, with over 1800 similar exposure groups being used to describe occupational exposures. The database has been actively maintained and is subject to a number of quality checks. Recently, the company initiated a cancer morbidity study, with one objective being to examine whether the exposure tracking data could be used to reconstruct exposure estimates for the cohort. Five agents--hydrogen sulfide, petroleum coke/spent catalyst, hydrocarbon solvents and fuels, hydrocarbon lubricants, and an index for exposure to operations derived from noise exposure--were selected for development of occupational exposure estimates for each cohort member. The cohort consisted of workers first employed between January 1964 and December 1994 and who were employed for at least 1 year. Work history records were associated with a similar exposure group, using human resources data and knowledge of local industrial hygienists. Only employees with >90% duration of their work history assigned were kept in the cohort (25,292 people out of a possible 25,617). For each similar exposure group inventory, the substances were identified that contributed to each of the five agents being studied. Exposure estimates before 1987 were modified using historic occupational exposure limits. Rules were created to sum the exposure from multiple substances found in any one similar exposure group. The validity of exposure estimates was tested via comparison with results documented in industrial hygiene survey reports. Industrial hygienists who were unaware of the derived exposure estimates evaluated several hundred industrial hygiene surveys and prepared benchmark information. The two lists were then evaluated for concordance, which was found to be significantly different from that occurring by chance. We conclude that the process described can create valid exposure estimates for use in epidemiology studies.

Short term and long term effects of enhanced auditory feedback on typing force, EMG, and comfort while typing.

Two studies were conducted to determine the effects of enhanced auditory feedback on typing force, electromyography (EMG) and subjective discomfort. The introduction of enhanced auditory feedback caused a 10-20% reduction in 90th percentile typing force, finger flexor EMG, and finger extensor EMG. Adaptation to the enhanced auditory feedback occurred in <3 min. After 1 week of intermittent enhanced auditory feedback there were no differences in typing force or EMG while subjects were typing with or without the enhanced auditory feedback. The continued use of auditory feedback did not further reduce the levels of typing force or EMG after 1 or 2 weeks of exposure.