Takamaru Ashikaga

Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial.

BACKGROUND Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects. METHODS NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤ 49 years, ≥ 50 years), clinical tumour size (≤ 2·0 cm, 2·1-4·0 cm, ≥ 4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1-126·7). This study is registered with ClinicalTrials.gov, number NCT00003830. FINDINGS 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96-1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4-93·3) in group 1 and 90·3% (88·8-91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90-1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5-84·4) in group 1 and 81·5% (79·6-83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye. INTERPRETATION Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. FUNDING US Public Health Service, National Cancer Institute, and Department of Health and Human Services.

Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial

BACKGROUND The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone. METHODS 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830. FINDINGS Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97.2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98.9% [5072 of 5128]). Only 1.4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65.1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3.9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97.1% (2544 of 2619; 95% CI 96.4-97.7), with a false-negative rate of 9.8% (75 of 766; 95% CI 7.8-12.2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0.7% (37 of 5588) of patients with data on toxic effects. INTERPRETATION The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

Effect of Occult Metastases on Survival in Node-Negative Breast Cancer

BACKGROUND Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking. METHODS We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension. RESULTS Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively. CONCLUSIONS Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003830.).

Morbidity results from the NSABP B‐32 trial comparing sentinel lymph node dissection versus axillary dissection

Three year post‐surgical morbidity levels were compared between patients with negative sentinel lymph node dissection alone (SLND) and those with negative sentinel node dissection and negative axillary lymph node dissection (ALND) in the NSABP B‐32 trial.

Weight Training Improves Walking Endurance in Healthy Elderly Persons

Physical disability is common among older persons living within the community. The Framingham Disability Study [1, 2] reported that, among community-dwelling persons older than 70 years of age, 49% of women and 27% of men have substantial mobility or work limitations. More recently, a 4-year prospective trial of healthy elderly persons with no disability at baseline showed that lower-extremity physical performance at baseline was highly predictive for the subsequent development of disability [3]. Muscle mass, strength, and endurance decrease with age, and a close correlation between short-course walking speed and the size and strength of leg muscles has been shown in institutionalized nonagenarians [4]. Furthermore, resistance training in this population has been shown to result in increased measures of physical performance and corresponding increases in muscle strength, size, and short-course walking speed [4, 5]. Our goal was to determine whether resistance training would improve walking endurance and lower-limb strength in nondisabled, community-dwelling elderly persons. Methods Twenty-four sedentary, healthy persons (11 men and 13 women) were randomly assigned within sex groups either to a 12-week resistance-training program or to sedentary control status. The mean age of the participants was 70.4 4 years (range, 65 to 79 years), and no differences in mean age were seen between groups (69.9 4 years in the resistance-training group; 70.7 5 years in the control group [P > 0.2]). The resistance-training group was composed of 6 men and 6 women; the control group consisted of 5 men and 7 women. Participants did symptom-limited treadmill stress tests at baseline, and we collected expired gas to determine peak aerobic capacity. We used a Horizon Metabolic Measurement Cart (Sensormedics, Yorba Linda, California) to analyze expired air. Participants were excluded if they had angina or electrocardiographic ischemia (defined as ST-segment depression more than 1 mm) during the exercise test (n = 2), if their resting blood pressure was higher than 160/90 mm Hg (n = 4), or if they had a noncardiopulmonary limitation of exercise capacity, such as claudication, arthritis, or cerebrovascular disease (n = 1). We tested 29 participants to arrive at the final study sample of 24 persons. No participants were receiving calcium- or -blocking medications or estrogen-replacement therapy, and none had diabetes. We determined body composition by using underwater weighing and correcting for residual volume [6]. Leg-muscle mass was determined by dual-energy x-ray absorptiometry [7]. Strength was evaluated on a Universal Gym apparatus (Universal, Cedar Rapids, Iowa) by measuring the single repetition maximal lift for leg extension, leg flexion, and bench press. We measured submaximal endurance capacity on the treadmill by first having participants walk for 5 minutes at an intensity of 50% of their previously determined peak aerobic capacity. Participants then gradually increased their walking intensity to 80% of peak aerobic capacity by 10 minutes of the continuous protocol and proceeded until exhaustion (n = 24) or 45 minutes, at which time the test was terminated. Because none of the participants had angina, claudication, or exercise-limiting arthritis, exhaustion was defined as a combination of leg fatigue, dyspnea, and overall body fatigue. During endurance testing, heart rate, blood pressure, oxygen uptake, and perceived exertion [8] were measured at 5-minute intervals until exhaustion. After 12 weeks, variables were measured again, and walking endurance was measured at the same absolute workload as before conditioning. The weight-training regimen consisted of three sets of eight repetitions of seven exercises done using a Universal Gym apparatus 3 days per week. The exercises (and primary muscles exercised) were leg extension (quadriceps), leg curl (hamstrings), arm extension (triceps), arm curl (biceps), lateral pull-down (latissimus dorsi and biceps), bench press (pectoralis major and triceps), and squat (gluteals and quadriceps). A rest period of 1 to 2 minutes was taken between sets. The participants began at a resistance of 50% of their single repetition maximum. The resistance was then increased progressively until participants were exercising at 80% of their single repetition maximum by week 9. Strength was retested intermittently, and the training loads were adjusted as required. The participants did not train aerobically. Controls were instructed not to alter their home activity habits. A two-factor analysis of variance was done on baseline measures, with sex and training groups as the factors [9]. Women differed from men in baseline measures of fitness, strength, and body composition, but no sex-group interactions were seen. Pre- to postconditioning measures were analyzed using repeated-measure analysis of variance with results separated by sex. Data collected during the submaximal endurance study were analyzed for perceived exertion, heart rate, and systolic blood pressure (excluding rest and exhaustion values) by repeated-measure analysis of variance. Relations between variables were studied by linear regression analysis. Data are presented as mean SD. Analyses were done using BMDP New System for Windows, Version 1.0 (BMDP Statistical Software, Los Angeles, California). Results After the 12-week resistance-training program, strength increased substantially in the resistance-training group. The single repetition maximums increased by 29% 24% for leg extension, 65% 79% for leg flexion, and 29% 15% for bench press. When results were analyzed separately by sex and compared with results in controls, single repetition maximums for leg extension increased significantly among women (P < 0.01) but not among men (P = 0.12) (Table 1). Similarly, single repetition maximums for bench press increased significantly among women (P < 0.01) but not among men (P = 0.12). Both women and men had increased single repetition maximums for leg flexion compared with controls (P < 0.01 for women and P < 0.05 for men). It should be noted that the study was not designed to fully address sex-specific outcomes. The control group showed no change in strength measures over the 12-week period, and the strength changes for each of the exercises in the intervention group when sexes were combined were significantly greater than the measures in the controls (P < 0.005) (Table 1). Table 1. Resistance-Training and Control Groups at Baseline and 12 Weeks Women in our study had lower measures of peak aerobic capacity at baseline than men (21.5 1.1 mL/kg min1 compared with 28.8 1.5 mL/kg min1; P = 0.03) and lower measures of strength as measured by single repetition maximum for leg extension (23.5 1.0 kg compared with 42.8 4 kg; P = 0.001), leg curl (5.3 0.4 kg compared with 14.4 1.5 kg; P = 0.003), and bench press (20.9 1.1 kg compared with 31.3 2.2 kg; P = 0.008). Neither women nor men showed changes in peak aerobic capacity after resistance training. No participant had significant changes in body weight, percentage of body fat, fat mass, or fat-free mass as measured by underwater weighing (Table 1). Analysis of regional body composition measured by dual-energy x-ray absorptiometry scanning showed an increased lean mass of the leg with weight training when compared with controls (P = 0.02) (Table 1). This was due to an increase among women (P < 0.02); no increase was seen among men (P> 0.2). Peak aerobic capacity was unaltered in both groups, regardless of sex. The primary outcome variable of interest was walking endurance time. After the resistance-training program, mean walking time until exhaustion for the resistance-training group increased by 38%, from 25 4 minutes to 34 9 minutes. In contrast, no change was seen in the control group (20 5 minutes to 19 10 minutes; P = 0.005 for comparison between groups). The increase in endurance time was due primarily to increases seen among men (P < 0.02) rather than among women (P> 0.2). Mean exercise intensity, measured at 10 minutes of the endurance protocol at baseline, was 82% of peak aerobic capacity in both the training group and the control group (P> 0.2 between groups). Before the study intervention, none of the 24 participants completed the full 45-minute endurance protocol. After conditioning, 3 of the 12 participants who received resistance training and 1 of 12 controls completed the entire protocol. After conditioning, mean scores for perceived exertion for all submaximal data points from 10 minutes until the end of the walking endurance protocol (not including the exhaustion point) were lower in the resistance-training group than in the control group (P = 0.03) (Figure 1). Mean submaximal heart rate and systolic blood pressure measures were lower after conditioning; however, when groups were compared by repeated-measure analysis of variance, differences between groups were not significant (Figure 1). Submaximal or peak exercise oxygen consumption did not change during the endurance testing. Figure 1. Conditioning data in the resistance-training group. For all 24 participants, significant relations were seen between change in walking endurance and change in strength measures for leg extension (r = 0.48 [95% CI, 0.10 to 0.74]; P = 0.02) and leg flexion (r = 0.46 [CI, 0.07 to 0.73]; P = 0.03). Baseline peak aerobic capacity (r = 0.10 [CI, 0.48 to 0.3]; P > 0.2) and baseline endurance time (r = 0.41 [CI, 0.22 to 0.73]; P = 0.13) were not significantly related to change in endurance capacity in the resistance-training group of 12 participants. Discussion We show that healthy, community-dwelling elders can improve walking endurance and leg strength by participating in a resistance-training program. This finding is relevant to persons at risk for disability because walking endurance and leg strength are important components of physical functioning [3]. Resistance training improves walking endurance in at lea

Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma

Axillary lymph node status is a powerful prognostic factor in breast carcinoma; however, complications after axillary lymph node dissection are common. Sentinel lymph node biopsy is an alternative staging procedure. The sentinel lymph node postulate is that tumor cells migrating from the primary tumor colonize one or a few lymph nodes before colonizing subsequent lymph nodes. To validate this hypothesis, the distribution of occult and nonoccult metastases in sentinel and nonsentinel lymph nodes was evaluated.

Internet delivered behavioral obesity treatment

OBJECTIVES To evaluate the efficacy of an Internet behavioral weight loss program; and determine if adding periodic in-person sessions to an Internet intervention improves outcomes. METHODS 481 healthy overweight adults (28% minority) were randomized to one of 3 delivery methods of a behavioral weight loss program with weekly meetings: Internet (n=161), InPerson (n=158), or Hybrid (Internet+InPerson, n=162). Outcome variables were weight at baseline and 6 months and percent of subjects achieving a 5 and 7% weight loss. The study took place in two centers in Vermont and Arkansas from 2003 to 2008. RESULTS Conditions differed significantly in mean weight loss [8.0 (6.1) kg vs. 5.5 (5.6) kg vs. 6.0 (5.5) kg], for InPerson, Internet, and Hybrid respectively, p<0.01, n=462). Weight loss for InPerson was significantly greater than the Internet and Hybrid conditions (p<0.05). Although the proportion reaching a 5% weight loss did not differ, the proportion losing 7% did differ significantly (56.3% vs. 37.3% vs. 44.4% for InPerson, Internet, and Hybrid respectively, p<0.01). CONCLUSIONS These results demonstrate that the Internet is a viable alternative to in-person treatment for the delivery and dissemination of a behavioral weight-control intervention. The addition of periodic in-person sessions did not improve outcomes.

Regional Responses of Hemlock Woolly Adelgid (Homoptera: Adelgidae) to Low Temperatures

Abstract Hemlock woolly adelgid, Adelges tsugae Annand, is an exotic forest pest threatening the health of New England’s eastern hemlock, Tsuga canadensis (L.) Carrière. Research indicates that the northern spread of this insect may be slowed or prevented by cold temperature. We conducted laboratory studies to assess the coldhardiness of A. tsugae, collected at sites within plant hardiness zones 5a (Northern), 6a (Central), and 6b (Southern) in January, February, and March. Adelgids were exposed to −15, −20, −25, −30, and −35°C for 2, 4, or 8 h, and comparisons in survival were made with insects held at 0°C. For all months and sites, mortality increased as temperature decreased, and no survival occurred among those from the Central and Southern sites exposed to −30 and −35°C. In January and February, ≤3% of the adelgids collected from the Northern site survived −30°C, and none survived −35°C in January or March. Adelgids from all sites entered the winter with similar levels of coldhardiness, but those from the Central and Southern sites lost their tolerance to cold earlier in the season than those from the Northern site. In January and February, −25°C was a critical temperature at which significant reduction in coldhardiness was observed. Despite the evidence that adelgids in the Northern site possessed greater tolerance to cold temperatures than the other sites, only 14% survived exposure to −15°C in March. In all sites the actual percentage of adelgids that survived after exposure to −15°C decreased 50–60% from January to March. Our results show that adelgid coldhardiness differs depending on geographical location and time of year, and further confirm that cold temperature has a significant impact on their survival.

Comparative Decellularization and Recellularization of Normal versus Emphysematous Human Lungs

Acellular whole human lung scaffolds represent a unique opportunity for ex vivo tissue engineering. However, it remains unclear whether lungs from individuals with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) can be appropriately decellularized and recellularized. To assess this, cadaveric human lungs from normal (non-smoking) patients and from patients with COPD (smoking history) were decellularized and found by histochemical and immunohistochemical staining, electron microscopy, and mass spectrometry to retain characteristic histological architecture and extracellular matrix components (ECM) reflecting either normal or COPD, particularly emphysematous, origin. Inoculation of human bronchial epithelial cells, endothelial progenitor cells, bone marrow-derived mesenchymal stem cells, and lung fibroblasts via airway or vascular routes into small, excised segments of the decellularized lungs demonstrated that normal lung scaffolds robustly supported initial engraftment and growth of each cell type for up to one month. In contrast, despite initial binding, all cell types inoculated into decellularized emphysematous lungs did not survive beyond one week. However, cell attachment and proliferation on solubilized ECM homogenates of decellularized normal and emphysematous lungs coated onto tissue culture plates was comparable and not impaired, suggesting that the 3-dimensional decellularized emphysematous scaffolds may lack the necessary ECM architecture to support sustained cell growth.

Prerandomization Surgical Training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 Trial: A Randomized Phase III Clinical Trial to Compare Sentinel Node Resection to Conventional Axillary Dissection in Clinically Node-Negative Breast Cancer

Objective:To train surgeons in a standardized technique of sentinel lymph node biopsy and to prepare them for the requirements of a prospective randomized surgical trial. Summary Background Data:The NSABP B32 trial opened to accrual in May 1999. A significant component of this trial was a prerandomization training phase of surgeons performed by a group of core surgical trainers. The goals of this training phase were to expeditiously instruct surgeons in a standardized technique of sentinel lymph node biopsy and to educate those same surgeons in complete and accurate data collection and source documentation for the trial. Methods:This study is a description of the training data collected in a prospective fashion for the training component for surgeon entry into the B32 trial, evaluating the effectiveness of the training program in regards to surgical outcomes and protocol compliance. Results:Two hundred twenty-six registered surgeons underwent site visit training by a core surgical trainer and 187 completed training and were approved to randomize patients on the trial. The results of 815 training (nontrial) cases demonstrated a technical success rate for identifying sentinel nodes at 96.2% with a false negative rate of 6.7%. A protocol compliance analysis, which included the evaluation of 94 separate fields, showed mean protocol compliance of 98.6% for procedural fields, 95.5% for source documentation fields and 95.0% for data entry fields. Conclusions:This training and quality control program has resulted in a large number of surgeons capable of performing sentinel lymph node biopsy in a standardized fashion with a high degree of protocol compliance and pathologic accuracy. This will ensure optimal results for procedures performed on the randomized phase of the trial.