pN0(i+) and pN1mi Breast Cancer: Treatment and Outcomes in Comparison With pN0 and pN1a in the Modern Era.

PURPOSE: Locoregional recurrence risk and the role of locoregional radiation therapy (LRRT) in pN0(i+) and pN1mi breast cancer are unclear. This study compares locoregional relapse-free survival (LRRFS) in patients with pN0(i+) and pN1mi relative to pN0 and pN1a disease and evaluates LRRFS according to locoregional treatment. METHODS AND MATERIALS: We studied 10,271 patients referred between 2006 and 2011 with newly diagnosed pT1-T2, pN0, pN0(i+), pN1mi, or pN1a, M0 breast cancer. Outcomes were 10-year Kaplan-Meier LRRFS, relapse-free survival (RFS), distant relapse-free survival, and breast cancer-specific survival. Multivariable analysis of LRRFS and RFS was performed in pN0(i+) and pN1mi cohorts. RESULTS: Median follow-up was 9.3 years. In patients with pN0 (n = 7492), pN0(i+) (n = 305), pN1mi (n = 619), and pN1a (n = 1855) disease, LRRT was used in 1.1%, 24.3%, 45.7%, and 71.1%, respectively. Ten-year outcomes were LRRFS 96%, 92%, 97%, and 96% (P < .001), distant RFS 94%, 91%, 90%, and 84% (P < .001), and breast cancer-specific survival 95%, 90%, 93%, and 87% (P < .001), respectively. Ten-year LRRFS for patients treated with breast-conserving surgery alone, with breast RT, and with LRRT were 81%, 93%, and 91% for patients with pN0(i+) (P = .16) and 94%, 96%, and 100% for patients with pN1mi (P = .02), respectively. Among patients treated with mastectomy, 10-year LRRFS with surgery alone and with LRRT were 93% and 100% for patients with pN0(i+) (P = .12) and 95% and 99% for patients with pN1mi (P = .09). On multivariable analysis of patients with pN0(i+) and pN1mi, systemic therapy was associated with improved LRRFS in patients with pN0(i+) (hazard ratio [HR], 0.2; [0.06-0.6]; P = .005) and patients with pN1mi (HR, 0.1; [0.03-0.5]; P = .006). In patients with pN1mi, LRRT was associated with a trend toward increased LRRFS (HR, 0.2; [0.03-1.1]; P = .07). LRRT was not significantly associated with improved RFS in pN0(i+) or pN1mi disease. CONCLUSIONS: In the era of sentinel node staging and modern systemic therapy, patients with pN0(i+) and PN1mi treated with LRRT experienced 10-year LRR risks ≤10% after breast-conserving surgery or mastectomy and RT. LRRT was associated with a trend toward increased LRRFS in pN1mi but not pN0(i+) disease.

Controversies in locoregional management of breast cancer with low volume pN0(i+) and pN1mi nodal disease.

Introduction: The pathologic status of the axillary lymph nodes is an important prognostic factor in patients with breast cancer. With the transition from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB) for patients with clinically node negative breast cancer, there has been an increase in detection of pN0(i+) breast cancer with isolated tumor cells and pN1mi disease with micrometastatic nodal involvement. The prognostic impact of small volume nodal involvement and the role of locoregional radiotherapy, especially in the era of modern systemic therapy, are unclear. Areas covered: This review examines contemporary data evaluating the prognostic impact of pN0(i+) and pN1mi breast cancer on locoregional recurrence and survival outcomes, then discusses controversies related to the use of adjuvant locoregional radiation therapy in the presence of low volume nodal disease. Relevant papers were identified by searching multiple engines for articles published since 2000. Expert opinion: Sentinel lymph node biopsy without completion ALND is a standard surgical option for patients with pN0(i+) and pN1mi disease. The available evidence does not support routine use of adjuvant locoregional radiation therapy in patients with pN0i+ or pN1mi disease, but locoregional radiotherapy should be considered in the presence of concomitant high-risk features and patient factors.

The TEACHH model to predict life expectancy in patients presenting for palliative spine radiotherapy: external validation and comparison with alternate models.

INTRODUCTION: The TEACHH score was developed to identify patients with predicted short (< 3 months) and long (> 1 year) life expectancy. We aimed to validate this model in an independent group of patients presenting for palliative spine radiotherapy and to compare it to alternate prognostic models. METHODS: We retrospectively reviewed charts of 195 consecutive patients referred for palliative spine radiotherapy. Patients were grouped according to the number of risk factors from the TEACHH model, Chow model, and Oswestry Risk Index. RESULTS: One hundred and eighty patients with a median age of 65 years were included. Follow-up was 5.8 months in all patients and 31.8 months in living patients. For the TEACHH model, patients in groups 1, 2, and 3 had a median (95% CI) overall survival (OS) of 22.3 (15.7-36.1), 4.9 (3.8-6.6), and 1.5 (0.8-5.4) months, respectively. Wilcoxon pairwise comparisons showed statistically different survival between groups 1 and 2, and 1 and 3. In the Chow model, patients in groups 1, 2, and 3 had a median (95% CI) OS of 16.1 (10.0-22.3), 5.9 (3.8-9.2), and 1.9 (1.2-2.5) months, respectively. There was a significant difference between all groups. The Oswestry Risk Index identified five prognostic groups with median OS (95% CI) ranging from 22.2 (12.9-30.2) to 2.1 (0.8-4.0) months. Only group 1 was statistically different from the others. Although the effect of age was small, the TEACHH model performed best with the inclusion of all parameters. CONCLUSIONS: The TEACHH model is useful to identify patients with spinal metastases with predicted short, intermediate, and long LE. Its prognostic ability is similar to the Chow model.

Severe Late Toxicity After Adjuvant Breast Radiotherapy in a Patient with a Germline Ataxia Telangiectasia Mutated Gene: Future Treatment Decisions.

Ataxia telangiectasia mutated (ATM) gene mutations may confer increased sensitivity to ionizing radiation and increased risk of late toxicity for cancer patients. We present the case of a 55-year-old female treated with adjuvant breast and regional nodal radiation following lumpectomy and axillary lymph node dissection for stage II invasive ductal carcinoma of the breast. She developed severe telangiectasia, fibrosis, induration, chest wall pain (with evidence of rib fractures on imaging), and painful limitation in her range of motion at the shoulder. She was subsequently found to have a likely pathogenic germline ATM gene mutation. At relapse, she elected to pursue systemic therapy alone for intracranial metastases.

A vibro-tactile display for clinical monitoring: real-time evaluation.

BACKGROUND: Vibro-tactile displays use human skin to convey information from physiological monitors to anesthesiologists, providing cues about changes in the status of the patient. In this investigation, we evaluated, in a real-time clinical environment, the usability and wearability of a novel vibro-tactile display belt recently developed by our group, and determined its accuracy in identifying events when used by anesthesiologists. METHODS: A prospective observational study design was used. During routine anesthesia, a standard physiological monitor was connected to a software tool that used algorithms to automatically identify changing trends in mean noninvasive arterial blood pressure, expired minute ventilation, peak airway pressure, and end-tidal carbon dioxide partial pressure. The software was wirelessly interfaced to a vibro-tactile belt worn by the anesthesiologist. Each physiological variable was mapped to 1 of 4 tactor locations within the belt. The direction (increase/decrease) and 2 levels of change (small/large) were encoded in the stimulation patterns. A training session was completed by each anesthesiologist. The system was activated in real-time during anesthesia alongside routine physiological monitors. When the algorithms detected changes in the patient, the belt vibrated at the appropriate location with the pattern corresponding to the level and direction of change. Using a touch screen monitor the anesthesiologist was to enter the vibro-tactile message by first identifying the variable, then identifying the level and direction of change. Usability and wearability questionnaires were to be completed. The percentage of correct identification of the physiological trend, the direction of change, and the level of change were primary outcome variables. The mean usability score and wearability results were secondary outcome variables. We hypothesized that anesthesiologists would correctly identify the events communicated to them through the vibro-tactile belt 90% of the time, and that anesthesiologists would find the vibro-tactile belt usable and wearable. RESULTS: Seventeen anesthesiologists evaluated the display during 57 cases. The belt was operational for a mean (SD) duration of 75 (41) minutes per case. Seven cases were excluded from analysis because of technical failures. Eighty-one percent (confidence interval [CI], 77% to 84%) of all stimuli were decoded. The physiological trend, the direction of change, and the level of change were correctly identified for 97.7% (CI 96%-99%), 94.9% (CI 92%-97%), and 93.5% of these stimuli (CI, 91%-96%), respectively. Fourteen anesthesiologists completed the usability and wearability questionnaires. The mean usability score was 4.8 of a maximum usability score of 7. CONCLUSIONS: Anesthesiologists found a vibro-tactile belt to be wearable and usable and could accurately decode vibro-tactile messages in a real-time clinical environment.

The nature of upright and inverted face representations: an adaptation-transfer study of configuration.

It is considered that whole-face processing of spatial structure may only be possible in upright faces, with only local feature processing in inverted faces. We asked whether this was due to impoverished representations of inverted faces. We performed two experiments. In the first, we divided faces into segments to create 'exploded' faces with disrupted second-order structures, and 'scrambled' faces with altered first-order relations; in the second we shifted features within intact facial outlines to create equivalent disruptions of spatial structure. In both we assessed the transfer of adaptation between faces with altered structure and intact faces. Scrambled adaptors did not adapt upright or inverted intact faces, indicating that a whole-face configuration is required at either orientation. Both upright and inverted faces showed a similar decline in aftereffect magnitude when adapting faces had altered second-order structure, implying that this structure is present in both upright and inverted face representations. We conclude that inverted faces are not represented simply as a collection of features, but have a whole-face configuration with second-order structure, similar to upright faces. Thus the qualitative impairments induced by inversion are not due to degraded inverted facial representations, but may reflect limitations in perceptual mechanisms.

Pharmacodynamic modeling of propofol-induced tidal volume depression in children.

OBJECTIVE: This investigation aimed to develop a pediatric pharmacodynamic model of propofol-induced tidal volume depression towards an ultimate goal of developing a dosing schedule that would preserve spontaneous breathing following a loading dose of propofol. METHODS: Fifty two ASA 1 and 2 children aged 6-15 year presenting for gastrointestinal endoscopy were enrolled. Subjects were administered a loading dose of 4 mg/kg of propofol intravenously at a constant infusion rate determined by a randomization schedule. Respiratory parameters including tidal volume, respiratory rate, minute volume, and end-tidal CO(2) were recorded at 5 s intervals. Using the predicted plasma concentration, based on the Paedfusor pharmacokinetic model, propofol-induced tidal volume depression was modeled by 3 different approaches (2-stage, pooled, and mixed effects) and results were compared using prediction residual, median percentage errors, median absolute percentage errors, and root-mean-squared normalized errors. The effects of age and body weight as covariates were examined. RESULTS: Respiratory rate and end-tidal CO(2) did not show clear dependence on the predicted plasma concentration. The pharmacodynamic models for tidal volume derived from different modeling approaches were highly consistent. The 2-stage, pooled, and mixed effects approaches yielded k(e0) of 1.06, 1.24, and 0.72 min(-1); γ of 1.10, 0.83, and 0.93; EC50 of 3.18, 3.44, and 3.00 mcg/ml. Including age and body weight as covariates did not significantly improve the predictive performance of the models. CONCLUSIONS: A pediatric pharmacodynamic model of propofol-induced tidal volume depression was developed. Models derived from 3 different approaches were shown to be consistent with each other; however, the individual pharmacodynamic parameters exhibited significant inter-individual variability without strong dependence on age and body weight. This would suggest the desirability of adapting the pharmacodynamic model to each subject in real time.

Monitor-decoupled pharmacodymamics of propofol in children using State Entropy as the clinical end point.

This paper presents two alternative approaches to characterize the pharmacodynamics of propofol anesthesia in children, using State Entropy as a clinical end point. The first approach is the traditional approach where the pharmacodynamic model is described in terms of an effect-site equilibration rate constant and the Hill equation. In the second approach (the monitor-decoupled approach) the dynamics of the Entropy monitor is identified and added to the traditional pharmacodynamic model. The traditional approach resulted in mean k(e0) values of 2.08min(-1) and 1.27min(-1) for the Paedfusor and Kataria pharmacokinetic models, respectively. The monitor-decoupled approach resulted in significantly larger values (mean k(e0) values of 2.57min(-1) and 1.71min(-1)) than the traditional approach. The differences between k(e0) values suggest that the dynamic effect of the Entropy monitor must be accounted for when identifying the "true" pharmacodynamics of the patient, without the bias caused by the monitor's processing characteristics. The values of k(e0) obtained in this study were larger than those values previously published for the Bispectral Index. This is likely due to the different processing characteristics of the Entropy and Bispectral Index monitors, as well as the use of different pharmacokinetic models.

Slower administration of propofol preserves adequate respiration in children.

BACKGROUND: Propofol is a versatile anesthetic agent used in pediatric practice to facilitate investigational and interventional procedures. Propofol can cause significant respiratory depression, the management of which may require advanced airway management skills. This investigation aimed to increase the safety of propofol administration by developing a dosing schedule that would preserve spontaneous respiration in at least 95% of subjects. METHODS: With Research Ethics Board approval and informed consent, American Society of Anesthesiologists' Status I and II children aged 6-15 years presenting for upper or lower gastrointestinal endoscopy were enrolled. An intravenous loading dose of propofol (4 mg·kg(-1) ) was administered at a rate determined by a randomization schedule in a two-phased study. Following the loading dose, additional propofol was infused at 200 mcg·kg(-1) ·min(-1) for 5 min or until respiratory insufficiency was observed. In Phase I, the infusion rate was modified by 100 mcg·kg(-1) ·min(-1) increments depending upon the respiratory response of the previous subject. In Phase II, the duration of infusion was randomized according to a Biased Coin Design principle to determine the 95% threshold for respiratory insufficiency. RESULTS: Fifty subjects were included in the analysis. Infusion rates ranged from 1000 to 2300 mcg·kg(-1) ·min(-1) . Seven subjects experienced respiratory insufficiency. The mean (sd) time to respiratory insufficiency was 104 (36) s and duration was 93 (51) s. A propofol loading dose administered over 3.0 min (CI = 1.9-3.4 min) maintained spontaneous respiration in 95% of subjects. CONCLUSIONS: The respiratory response to propofol is highly variable in children. Slower infusion of propofol will result in a lower risk of respiratory depression.

Defining the reliability of sonoanatomy identification by novices in ultrasound-guided pediatric ilioinguinal and iliohypogastric nerve blockade.

BACKGROUND: The ilioinguinal (II)/iliohypogastric (IH) nerve block is a safe, frequently used block that has been improved in efficacy and safety by the use of ultrasound guidance. We assessed the frequency with which pediatric anesthesiologists with limited experience with ultrasound-guided regional anesthesia could correctly identify anatomical structures within the inguinal region. Our primary outcome was to compare the frequency of correct identification of the transversus abdominis (TA) muscle with the frequency of correct identification of the II/IH nerves. We used 2 ultrasound machines with different capabilities to assess a potential equipment effect on success of structure identification and time taken for structure identification. METHODS: Seven pediatric anesthesiologists with <6 mo experience with ultrasound-guided regional anesthesia performed a total of 127 scans of the II region in anesthetized children. The muscle planes and the II and IH nerves were identified and labeled. The ultrasound images were reviewed by a blinded expert to mark accuracy of structure identification and time taken for identification. Two ultrasound machines (Sonosite C180plus and Micromaxx, both from Sonosite, Bothell, WA) were used. RESULTS: There was no difference in the frequency of correct identification of the TA muscle compared with the II/IH nerves (chi(2) test, TA versus II, P = 0.45; TA versus IH, P = 0.50). Ultrasound machine selection did show a nonsignificant trend in improving correct II/IH nerve identification (II nerve chi(2) test, P = 0.02; IH nerve chi(2) test, P = 0.04; Bonferroni corrected significance 0.17) but not for the muscle planes (chi(2) test, P = 0.83) or time taken (1-way analysis of variance, P = 0.07). A curve of improving accuracy with number of scans was plotted, with reliability of TA recognition occurring after 14-15 scans and II/IH identification after 18 scans. CONCLUSIONS: We have demonstrated that although there is no difference in the overall accuracy of muscle plane versus II/IH nerve identification, the muscle planes are reliably identified after fewer scans of the inguinal region. We suggest that a reliable end point for the inexperienced practitioner of ultrasound-guided II/IH nerve block may be the TA/internal oblique plane where the nerves are reported to be found in 100% of cases.

Spontaneous respiration during intravenous anesthesia in children.

PURPOSE OF REVIEW: Maintaining spontaneous respiration during intravenous anesthesia for investigative and surgical procedures may avoid the need for airway instrumentation and reduce the risk of desaturation. In addition, when performing airway endoscopic procedures in children, maintaining spontaneous respiration while using intravenous anesthesia can reduce the need for endotracheal intubation. This facilitates improved access to the smaller airway, allows assessment of the dynamic function of the airway, and reduces exposure of personnel to inhaled anesthetic agents. RECENT FINDINGS: Anesthetic hypnotic and analgesic agents are potent dose-dependent depressants of respiration. Infants have historically been considered to be at a higher risk of respiratory depression, especially from opioid analgesics. However, recent evidence suggests that infants and younger children outside the neonatal period are more resistant to the effects of remifentanil, even when combined with propofol. Spontaneous respiration can be maintained at doses adequate to suppress somatic responses to painful procedures. The large inter-individual variation in respiratory depressant effects necessitates individualized dose titration. The drug dose is more linearly related to variation in the respiratory rhythm and respiratory rate than to minute volume or end-tidal carbon dioxide. Apneic episodes are less likely when respiratory depressant drugs are administered slowly, as this allows time for the end-tidal carbon dioxide level to rise to a new apneic threshold. Hypnotic anesthetics and opioid analgesics act synergistically to cause respiratory depression and suppression of the somatic response. SUMMARY: Spontaneous respiration can be maintained when anesthetizing children using intravenous anesthesia.

Defining rules for the identification of critical ventilatory events.

PURPOSE: The automated recognition of critical clinical events by physiological monitors is a challenging task exacerbated by a lack of standardized and clinically relevant threshold criteria. The objective of this investigation was to develop consensus for such criteria regarding the identification of three ventilatory events: disconnection or significant leak in the anesthesia circuit, decreased lung compliance or increased resistance, and anesthetic overdose from inhaled anesthetics. METHODS: We individually administered a structured interview to five expert anesthesiologists to gain insight into the cognitive processes used by clinicians to diagnose ventilatory events and to determine the common heuristics (rules of thumb) used in clinical practice. We then used common themes, identified from analysis of the structured interviews, to generate questions for a series of web-based questionnaires. Using a modified Delphi technique, iterative questionnaire administration facilitated rapid consensus development on the thresholds for the specific rules used to identify ventilatory events. RESULTS: A threshold for 75% agreement was described for each scenario in a healthy ventilated adult. A disconnection or significant leak in the anesthesia circuit is diagnosed with peak airway pressure (< 5 cm H2O or change of 15 cm H2O), ETCO2 (0 mmHg, 40% drop, or value below 10 mmHg for a duration of 20 sec), and inspired-expired volume difference (300 mL). Increased resistance or decreased lung compliance is diagnosed with high peak airway pressure (40 cm H2O or a 20 cm H2O change), asymmetry of capnogram, and changes in measured compliance or resistance. Anesthetic overdose from inhaled anesthetics is diagnosed with high end-tidal anesthetic agent concentration (2 MAC in a patient less than 60 yr of age or 1.75 MAC in a patient over 60 yr of age), low systolic blood pressure (below 60 mmHg), and low modified electroencephalogram (bispectral index or entropy). CONCLUSION: This investigation has provided a set of consensus-based criteria for developing rules for the identification of three critical ventilatory events and has presented insight into the decision heuristics used by clinicians.