Ten-Year Results of FAST: A Randomized Controlled Trial of 5-Fraction Whole-Breast Radiotherapy for Early Breast Cancer.

PURPOSE: Previous studies of hypofractionated adjuvant whole-breast radiotherapy for early breast cancer established a 15- or 16-fraction (fr) regimen as standard. The FAST Trial (CRUKE/04/015) evaluated normal tissue effects (NTE) and disease outcomes after 5-fr regimens. Ten-year results are presented. METHODS: Women ≥ 50 years of age with low-risk invasive breast carcinoma (pT1-2 pN0) were randomly assigned to 50 Gy/25 fr (5 weeks) or 30 or 28.5 Gy in 5 once-weekly fr of 6.0 or 5.7 Gy. The primary end point was change in photographic breast appearance at 2 and 5 years; secondary end points were physician assessments of NTE and local tumor control. Odds ratios (ORs) from longitudinal analyses compared regimens. RESULTS: A total of 915 women were recruited from 18 UK centers (2004-2007). Five-year photographs were available for 615/862 (71%) eligible patients. ORs for change in photographic breast appearance were 1.64 (95% CI, 1.08 to 2.49; P = .019) for 30 Gy and 1.10 (95% CI, 0.70 to 1.71; P = .686) for 28.5 Gy versus 50 Gy. α/ß estimate for photographic end point was 2.7 Gy (95% CI, 1.5 to 3.9 Gy), giving a 5-fr schedule of 28 Gy (95% CI, 26 to 30 Gy) estimated to be isoeffective with 50 Gy/25 fr. ORs for any moderate/marked physician-assessed breast NTE (shrinkage, induration, telangiectasia, edema) were 2.12 (95% CI, 1.55 to 2.89; P < .001) for 30 Gy and 1.22 (95% CI, 0.87 to 1.72; P = .248) for 28.5 Gy versus 50 Gy. With 9.9 years median follow-up, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) have occurred. CONCLUSION: At 10 years, there was no significant difference in NTE rates after 28.5 Gy/5 fr compared with 50 Gy/25 fr, but NTE were higher after 30 Gy/5 fr. Results confirm the published 3-year findings that a once-weekly 5-fr schedule of whole-breast radiotherapy can be identified that appears to be radiobiologically comparable for NTE to a conventionally fractionated regimen.

Intraosseous Pressure Monitoring in Healthy Volunteers.

STUDY OBJECTIVE: Invasively monitoring blood pressure through the IO device has not been thoroughly demonstrated. This study attempted to establish baseline values of IO pressure in a healthy human population. METHODS: This was a prospective, healthy volunteer, observational study. Participants had two IO devices placed (humerus and tibia), and participant IO pressures, vital signs, and pain scores were monitored for up to 60 minutes. Participants were contacted at 24-hours and 7 days post-testing to assess for adverse events. Summary statistics were calculated for systolic, diastolic, and mean humeral and tibial IO pressure. The ratio of IO to non-invasive blood pressure was calculated, and Bland Altman plots were created. The slope (linear) of the mean humeral and the tibial IO pressures were also calculated. RESULTS: Fifteen subjects were enrolled between April and July 2015. Fourteen of 15 humeral IOs were placed successfully (93.3%) and all 15 of the tibial IOs were placed successfully. Mean tibial systolic, diastolic, and mean IO pressure were 55.8 ± 27.9, 49.3 ± 27.1, and 48.4 ± 29.4 mm Hg, respectively. Humeral systolic, diastolic, and mean IO pressure were 32.9 ± 16.0, 27.4 ± 15.2, and 24.5 ± 14.3 mm Hg. The mean tibial IO pressure was 52.5% ± 32.0% of external cuff pressure ratio. The mean humeral IO pressure was 26.5% ± 15.2% of the external mean blood pressure. The Bland Altman plots showed an inconsistent relationship between the systolic and diastolic cuff pressure and the IO pressures. We observed a 1% per minute decrease in IO pressure from the initial placement until the final reading. CONCLUSIONS: Intraosseous pressure readings can be obtained in healthy human volunteers. However, absolute IOP values were not consistent between subjects. Future research may determine how IO pressure can be used to guide therapy in ill and injured patients.

Evaluation of intraosseous pressure in a hypovolemic animal model.

BACKGROUND: In emergent situations, access to the vascular bed is frequently required for fluid and medication administration. Central venous catheter placement is associated with risk and may slow resuscitation in the unstable patient. The purpose of this study was to determine whether intraosseous pressure (IOP) could be consistently recorded and how similar this pressure was to central venous and arterial pressure in a porcine hemorrhagic shock model. MATERIALS AND METHODS: After sedation, eight female swine had catheters placed in the femoral vein, aorta via femoral artery, and superior vena cava. IOP lines were placed in the proximal humerus, distal femur, and proximal tibia. Pressure readings were recorded continuously through the five stages of progressive hypovolemia. Pressure data were descriptively summarized, with the percent of change of IOP at each stage compared with arterial pressure using a multilevel mixed effects linear model with log transformation. RESULTS: The IOP baseline values were between 16 and 18 mm Hg, approximately 22% of baseline arterial pressure. The intraosseous (IO) waveform mostly closely resembled the arterial pressure waveform, including the presence of a dichroitic notch. Pressure variations caused by ventilation (respiratory variability) were also identified in all the tracings. The rate of pressure change in the humeral IO most closely matched the change in arterial pressure rate. IO blood gas analysis showed gas composition to most closely match venous blood. CONCLUSIONS: IOP was reliably obtained in this porcine model and suggests potential for clinical application in humans.

The chemical interactions underlying tomato flavor preferences.

Although human perception of food flavors involves integration of multiple sensory inputs, the most salient sensations are taste and olfaction. Ortho- and retronasal olfaction are particularly crucial to flavor because they provide the qualitative diversity so important to identify safe versus dangerous foods. Historically, flavor research has prioritized aroma volatiles present at levels exceeding the orthonasally measured odor threshold, ignoring the variation in the rate at which odor intensities grow above threshold. Furthermore, the chemical composition of a food in itself tells us very little about whether or not that food will be liked. Clearly, alternative approaches are needed to elucidate flavor chemistry. Here we use targeted metabolomics and natural variation in flavor-associated sugars, acids, and aroma volatiles to evaluate the chemistry of tomato fruits, creating a predictive and testable model of liking. This nontraditional approach provides novel insights into flavor chemistry, the interactions between taste and retronasal olfaction, and a paradigm for enhancing liking of natural products. Some of the most abundant volatiles do not contribute to consumer liking, whereas other less abundant ones do. Aroma volatiles make contributions to perceived sweetness independent of sugar concentration, suggesting a novel way to increase perception of sweetness without adding sugar.

First results of the randomised UK FAST Trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015).

BACKGROUND AND PURPOSE: Randomised trials testing 15- or 16-fraction regimens of adjuvant radiotherapy in women with early breast cancer have reported favourable outcomes compared with standard fractionation. To evaluate hypofractionation further, two 5-fraction schedules delivering 1 fraction per week have been tested against a 25-fraction regimen. MATERIALS AND METHODS: Women aged ⩾50years with node negative early breast cancer were randomly assigned after microscopic complete tumour resection to 50Gy in 25 fractions versus 28.5 or 30Gy in 5 once-weekly fractions of 5.7 or 6.0Gy, respectively, to the whole breast. The primary endpoint was 2-year change in photographic breast appearance. RESULTS: Nine hundred and fifteen women were recruited from 2004 to 2007. Seven hundred and twenty-nine patients had 2-year photographic assessments. Risk ratios for mild/marked change were 1.70 (95% CI 1.26-2.29, p<0.001) for 30Gy and 1.15 (0.82-1.60, p=0.489) for 28.5Gy versus 50Gy. Three-year rates of physician-assessed moderate/marked adverse effects in the breast were 17.3% (13.3-22.3%, p<0.001) for 30Gy and 11.1% (7.9-15.6%, p=0.18) for 28.5Gy compared with 9.5% (6.5-13.7%) after 50Gy. With a median follow-up in survivors of 37.3months, 2 local tumour relapses and 23 deaths have occurred. CONCLUSIONS: At 3years median follow-up, 28.5Gy in 5 fractions is comparable to 50Gy in 25 fractions, and significantly milder than 30Gy in 5 fractions, in terms of adverse effects in the breast.

Evaluation of implanted gold seeds for breast radiotherapy planning and on treatment verification: a feasibility study on behalf of the IMPORT trialists.

BACKGROUND AND PURPOSE: We describe a feasibility study testing the use of gold seeds for the identification of post-operative tumour bed after breast conservation surgery (BCS). MATERIALS AND METHODS: Fifty-three patients undergoing BCS for invasive cancer were recruited. Successful use was defined as all six seeds correctly positioned around the tumour bed during BCS, unique identification of all implanted seeds on CT planning scan and ≥ 3 seeds uniquely identified at verification to give couch displacement co-ordinates in 10/15 fractions. Planning target volume (PTV) margin size for four correction strategies were calculated from these data. Variability in tumour bed contouring was investigated with five radiation oncologists outlining five CT datasets. RESULTS: Success in inserting gold seeds, identifying them at CT planning and using them for on-treatment verification was recorded in 45/51 (88%), 37/38 (97%) and 42/43 (98%) of patients, respectively. The clinicians unfamiliar with CT breast planning consistently contoured larger volumes than those already trained. Margin size ranged from 10.1 to 1.4mm depending on correction strategy. CONCLUSION: It is feasible to implant tumour bed gold seeds during BCS. Whilst taking longer to insert than surgical clips, they have the advantage of visibility for outlining and verification regardless of the ionising radiation beam quality. Appropriate correction strategies enable margins of the order of 5mm as required by the IMPORT trials however, tackling clinician variability in contouring is important.

Flavour compounds in tomato fruits: identification of loci and potential pathways affecting volatile composition.

The unique flavour of a tomato fruit is the sum of a complex interaction among sugars, acids, and a large set of volatile compounds. While it is generally acknowledged that the flavour of commercially produced tomatoes is inferior, the biochemical and genetic complexity of the trait has made breeding for improved flavour extremely difficult. The volatiles, in particular, present a major challenge for flavour improvement, being generated from a diverse set of lipid, amino acid, and carotenoid precursors. Very few genes controlling their biosynthesis have been identified. New quantitative trait loci (QTLs) that affect the volatile emissions of red-ripe fruits are described here. A population of introgression lines derived from a cross between the cultivated tomato Solanum lycopersicum and its wild relative, S. habrochaites, was characterized over multiple seasons and locations. A total of 30 QTLs affecting the emission of one or more volatiles were mapped. The data from this mapping project, combined with previously collected data on an IL population derived from a cross between S. lycopersicum and S. pennellii populations, were used to construct a correlational database. A metabolite tree derived from these data provides new insights into the pathways for the synthesis of several of these volatiles. One QTL is a novel locus affecting fruit carotenoid content on chromosome 2. Volatile emissions from this and other lines indicate that the linear and cyclic apocarotenoid volatiles are probably derived from separate carotenoid pools.

Identification of loci affecting flavour volatile emissions in tomato fruits.

Fresh tomato fruit flavour is the sum of the interaction between sugars, acids, and a set of approximately 30 volatile compounds synthesized from a diverse set of precursors, including amino acids, lipids, and carotenoids. Some of these volatiles impart desirable qualities while others are negatively perceived. As a first step to identify the genes responsible for the synthesis of flavour-related chemicals, an attempt was made to identify loci that influence the chemical composition of ripe fruits. A genetically diverse but well-defined Solanum pennellii IL population was used. Because S. pennellii is a small green-fruited species, this population exhibits great biochemical diversity and is a rich source of genes affecting both fruit development and chemical composition. This population was used to identify multiple loci affecting the composition of chemicals related to flavour. Twenty-five loci were identified that are significantly altered in one or more of 23 different volatiles and four were altered in citric acid content. It was further shown that emissions of carotenoid-derived volatiles were directly correlated with the fruit carotenoid content. Linked molecular markers should be useful for breeding programmes aimed at improving fruit flavour. In the longer term, the genes responsible for controlling the levels of these chemicals will be important tools for understanding the complex interactions that ultimately integrate to provide the unique flavour of a tomato.

Characteristics of demand oxygen delivery systems: maximum output and setting recommendations.

BACKGROUND: Demand oxygen delivery systems (DODS) allot oxygen by interrupting the oxygen flow during exhalation, when it would mostly be wasted. Because DODS conserve oxygen by various methods, there are important performance differences between DODS. We studied certain performance factors that have not previously been carefully examined. METHODS: A bench model was constructed to simulate a nose, airway, and alveolar chamber. A breathing simulator generated 4 respiratory patterns, at frequencies of 15, 20, 25, and 30 breaths/min. Eighteen models of DODS were tested at 4 settings, each up to the maximum output, and compared to continuous-flow oxygen. The variable of interest was the fraction of inspired oxygen (F(I)O(2)) in the alveolar chamber, which was measured for each condition. RESULTS: The DODS differed from continuous-flow oxygen, delivering 0.5-2.1 times (mean = 1.13 times) the F(I)O(2) increase at similar settings. During maximum output the DODS showed a wide range of F(I)O(2), from 0.27 to 0.46. There was a direct relationship between volume output per pulse in the first 0.6 s of inhalation and the delivered F(I)O(2). CONCLUSIONS: DODS settings were not equivalent to continuous-flow oxygen in a bench model assessment; with equivalent settings the DODS tended to deliver greater F(I)O(2) than did continuous-flow oxygen. The maximum output capacity differed markedly among the DODS, and the user should know the device's capacity. A volume-referenced setting system for DODS should be adopted that would allow more predictable oxygen prescription and delivery via DODS.

The use of a compensator library to reduce dose inhomogeneity in tangential radiotherapy of the breast.

BACKGROUND AND PURPOSE: The dose variation throughout the volume of the breast from tangential fields can exceed 20% for large breasts. This is postulated to result in poor cosmesis [Radiother Oncol 16 (1989) 253], particularly at the inframammary fold, where the dose is highest. Compensators may be used to reduce this variation, but at the cost of the time to manufacture each unique compensator for the individual patients. This paper outlines the implementation and routine use of a library of reusable compensators. MATERIALS AND METHODS: For the period of December 1999 to May 2001, 94 patients attending for breast radiotherapy received treatment using breast compensators calculated from multiple outlines measured using the Osiris system. The compensators manufactured for the early patients were added to a library for possible reuse by later patients. Of the 94 patients, 28 patients' compensators formed the library and 66 subsequent patients have been treated using compensators derived from the library. Selection of the most appropriate library compensator was determined from the analysis of the distribution of the calculated dose-volume histogram for the whole breast, excluding lung, penumbra and build-up regions. Once the library was complete, approximately 50% of all subsequent breast patients were treated with compensators (46% from the library and 4% with individual compensators). This represented a usage rate of 92% for the library compensators for those patients requiring compensation. RESULTS: In all cases the compensators reduced the variation in the dose distribution. For example, the group treated with a library compensator demonstrated a mean reduction from 29 to 9% for the volume of breast tissue receiving more than 5% greater than the reference dose. If the same patients had been treated using their own individual compensators, the corresponding value would have been 7%. There is a small systematic, but negligible, difference in the two populations of dose variation for individual versus library compensators, but this difference (P=0.20) did not reach the level of statistical significance of P=0.05). CONCLUSION: The method of creation and selection of library compensators has proved to be simple and reliable in practice. Every patient receiving radiotherapy for breast cancer is currently investigated under full software control to ascertain whether the use of a library compensator would be advantageous.

Tracheal gas insufflation during late exhalation efficiently reduces PaCO(2) in experimental acute lung injury.

OBJECTIVE: Tracheal gas insufflation (TGI) reduces PaCO(2) by flushing the tracheal and mechanical deadspace, and may have its maximum benefit when TGI gas is unopposed by significant expiratory gas flow. Thus, limiting TGI to the late expiratory period may diminish tracheal exposure to TGI gas while preserving the efficacy of TGI. This study examined the gas exchange consequences of such late-expiratory TGI. DESIGN AND SETTING: Randomized controlled trial, animal study. MATERIALS: Eleven pigs. INTERVENTIONS: After stable lung injury was established using oleic acid 11 pigs were ventilated using a standardized lung protective strategy. Phasic expiratory TGI was applied for 30 min stages during the last 20%, 40%, 60%, and 100% of expiration in random sequence. PaCO(2) was continuously measured via an indwelling blood gas analysis system. MEASUREMENTS AND RESULTS: PaCO(2) at baseline was 86.1+/-4.7 mmHg, and decreased progressively with increasing TGI duration of 20%, 40%, and 60%, but not 100%, of expiration (PaCO(2)=75.7+/-5.2, 68.8+/-3.6, 65.1+/-5.3 and 65.2+/-5.2 mmHg, respectively). For all stages the reduction in PaCO(2) relative to baseline was significant. Trends of increasing PaO(2) and airway pressure with increasing TGI duration were noted and most likely associated with a TGI-induced increase in lung volume. CONCLUSIONS: Under these conditions confining TGI to the final 60% of expiration achieved effective PaCO(2) reduction, not significantly different from panexpiratory TGI, while limiting exposure of the trachea to TGI gas, and reducing the potential for TGI-induced hyperinflation. These findings suggest that TGI is most effectively applied in a phasic manner in late expiration, with its duration titrated to effect.