The impact of obesity on receipt of adjuvant chemotherapy for breast cancer in the National Comprehensive Cancer Network (NCCN) centers.

Disparities in the receipt of adjuvant chemotherapy for early stage breast cancer is an important factor influencing mortality. We investigated whether greater body mass index (BMI) decreases receipt of adjuvant chemotherapy among women with operable breast cancer. In the NCCN breast cancer outcomes database, we identified women aged ≤ 70 with newly diagnosed stage I, II, or III breast cancer between 1997 and 2007, for whom use of adjuvant chemotherapy was classified as either standard-of-care or discretionary based on their clinical characteristics. Body mass index was assessed in categories (<18.5 kg/m(2) [underweight], 18.5 to <25 kg/m(2) [normal], 25 to <30 kg/m(2) [overweight], 30-39 kg/m(2) [obese], ≥ 40 kg/m(2) [extreme obese]). Multivariable logistic regression analysis was used to examine the association between BMI and receipt of chemotherapy in each classification group. 9,527 women were eligible for the study; 40% normal weight or less; 31% overweight; 24% obese; and 5% extremely obese. In multivariable analysis, there was no significant association between BMI and receipt of chemotherapy in either classification group. Among women for whom chemotherapy would be considered standard-of-care, older age (P < 0.001), comorbidity (P < 0.001), and non-Hispanic black ethnicity (P = 0.002) were associated with a lower likelihood of receipt of chemotherapy; however, the effect of ethnicity was not modified by obesity. Among women treated for operable breast cancer in the NCCN centers, BMI had no impact on receipt of adjuvant chemotherapy and did not modify the lower likelihood of chemotherapy among non-Hispanic black patients. Further investigation is needed into other factors that contribute to patient disparities in the receipt of chemotherapy in major academic centers.

Direct-to-consumer advertising for bleeding disorders: a content analysis and expert evaluation of advertising claims.

OBJECTIVE: In the United States, the Food and Drug Administration (FDA) requires that all direct-to-consumer advertising (DTCA) contain both an accurate statement of a medication's effects ('truth') and an even-handed discussion of its benefits and risks/adverse effects ('fair balance'). DTCA for medications to treat rare diseases such as bleeding disorders is unlikely to be given high priority for FDA review. METHODS: We reviewed all DTCA for bleeding disorder products appearing in the patient-directed magazine HemeAware from January 2004 to June 2006. We categorized the information presented in each advertisement as benefit, risk/adverse effect, or neither, and assessed the amount of text and type size devoted to each. We also assessed the readability of each type of text using the Flesch Reading Ease Score (FRES, where a score of >or=65 is considered of average readability), and assessed the accuracy of the advertising claims utilizing a panel of five bleeding disorder experts. RESULTS: A total of 39 unique advertisements for 12 products were found. On average, approximately twice the amount of text was devoted to benefits as compared with risks/adverse effects, and the latter was more difficult to read [FRES of 32.0 for benefits vs. 20.5 for risks/adverse effects, a difference of 11.5 (95% CI: 4.5-18.5)]. Only about two-thirds of the advertising claims were considered by a majority of the experts to be based on at least low-quality evidence. CONCLUSION: As measured by our methods, print DTCA for bleeding disorders may not reach the FDA's standards of truth and fair balance.

What do patients value in their hospital care? An empirical perspective on autonomy centred bioethics.

OBJECTIVE: Contemporary ethical accounts of the patient-provider relationship emphasise respect for patient autonomy and shared decision making. We sought to examine the relative influence of involvement in decisions, confidence and trust in providers, and treatment with respect and dignity on patients' evaluations of their hospital care. DESIGN: Cross-sectional survey. SETTING: Fifty one hospitals in Massachusetts. PARTICIPANTS: Stratified random sample of adults (N=27 414) discharged from a medical, surgical, or maternity hospitalisation between January and March, 1998. Twelve thousand six hundred and eighty survey recipients responded. MAIN OUTCOME MEASURE: Respondent would definitely be willing to recommend the hospital to family and friends. RESULTS: In a logistic regression analysis, treatment with respect and dignity (odds ratio (OR) 3.4, 99% confidence interval (CI) 2.8 to 4.2) and confidence and trust in providers (OR 2.5, CI 2.1 to 3.0) were more strongly associated with willingness to recommend than having enough involvement in decisions (OR 1.4, CI 1.1 to 1.6). Courtesy and availability of staff (OR 2.5, CI 2.1 to 3.1), continuity and transition (OR 1.9, CI 1.5 to 2.2), attention to physical comfort (OR 1.8, CI 1.5 to 2.2), and coordination of care (OR 1.5, CI 1.3 to 1.8) were also significantly associated with willingness to recommend. CONCLUSIONS: Confidence and trust in providers and treatment with respect and dignity are more closely associated with patients' overall evaluations of their hospitals than adequate involvement in decisions. These findings challenge a narrow emphasis on patient autonomy and shared decision making, while arguing for increased attention to trust and respect in ethical models of health care.

Cell culture of mechanoreceptor neurons innervating proleg sensory hairs in Manduca sexta larvae, and co-culture with target motoneurons.

The tip of each proleg in Manduca sexta larvae bears a dense array of mechanosensory hairs termed planta hairs (PHs), each innervated by a single sensory neuron (termed a PH-SN) located in the underlying epidermis. In the CNS, axon terminals of PH-SNs make direct, excitatory, nicotinic cholinergic synapses with proleg retractor motoneurons including the accessory planta retractor (APR). These synapses mediate a proleg withdrawal reflex, exhibit multiple forms of activity-dependent plasticity and weaken during the prepupal peak of ecdysteroids. In the present study we developed methods to dissociate PH-SNs from the epidermis and culture them alone or with APRs. The PH-SNs were fluorescently labeled in situ by introducing dye through the cut hair shaft or by retrograde axonal staining. Alternatively, unlabeled PH-SNs were utilized. The epidermis beneath the planta hair array was separated from the cuticle, enzymatically treated and mechanically dissociated into single cells. PH-SNs were cultured on glass coverslips coated with concanavalin A and laminin, in modified Leibovitz's IL-15 medium. Supplementation with medium conditioned by an insect cell line produced the best results. Dissociated PH-SNs had somatic diameters of ~10 micro m and typically bore a stout dendrite consisting of the inner and, occasionally, the outer dendritic segment. An axonal stump was sometimes retained. Viable PH-SNs typically extended new processes and often survived for 2-4 weeks. When co-cultured, PH-SNs and APRs exhibited robust growth and made close anatomical appositions. This culture system provides convenient experimental access to PH-SNs and may potentially permit sensorimotor synapses to be investigated in vitro.

Quality of informed consent in cancer clinical trials: a cross-sectional survey.

BACKGROUND: Investigators have to obtain informed consent before enrolling participants in clinical trials. We wanted to measure the quality of understanding among participants in clinical trials of cancer therapies, to identify correlates of increased understanding, and to assess providers' beliefs about clinical research. We also sought evidence of therapeutic misconceptions in participants and providers. METHODS: We sent a standard questionnaire to 287 adult patients with cancer who had recently enrolled in a clinical trial at one of three affiliated institutions, and surveyed the provider who obtained each patient's consent. FINDINGS: 207 of 287 (72%) patients responded. 90% (186) of these respondents were satisfied with the informed consent process and most considered themselves to be well informed. Nevertheless, many did not recognise non-standard treatment (74%), the potential for incremental risk from participation (63%), the unproven nature of the treatment (70%), the uncertainty of benefits to self (29%), or that trials are done mainly to benefit future patients (25%). In multivariate analysis, increased knowledge was associated with college education, speaking only English at home, use of the US National Cancer Institute consent form template, not signing the consent form at initial discussion, presence of a nurse, and careful reading of the consent form. Only 28 of 61 providers (46%) recognised that the main reason for clinical trials is benefit to future patients. INTERPRETATION: Misconceptions about cancer clinical trials are frequent among trial participants, and physician/investigators might share some of these misconceptions. Efforts to educate providers and participants about the underlying goals of clinical trials are needed.

The treating physician as active gatekeeper in the recruitment of research subjects.

BACKGROUND: Institutional Review Boards vary in regard to the conditions imposed on investigators concerning contacting potential subjects to participate in health-services research studies. OBJECTIVE: The impact of more active involvement of the treating physician was examined in the approval process for recruiting study subjects. DESIGN: In recruiting subjects for a Massachusetts-based, multihospital (n = 17), health-services research study of treatment patterns for early stage breast cancer that required patient interviews, four hospitals stipulated that the treating surgeon provide written permission to the investigators to allow any contact with a potential study subject for the purpose of recruitment (active physician involvement group); the remaining 13 hospitals stipulated that the treating surgeon need only respond to the investigators if contact with a potential subject was forbidden (passive physician involvement group). SUBJECTS: Of the 1401 potential subjects treated for early stage breast cancer, 697 were in the active physician involvement group and 704 were in the passive physician involvement group. MEASURES: The percentages of patients for whom contact was allowed for recruitment purposes and who enrolled in the study were determined for the active physician involvement group and the passive physician involvement group, respectively. Logistic regression models were used to assess the independent effect of physician involvement on study enrollment. RESULTS: Of the 697 patients in the active physician involvement group, contact was approved by the treating surgeon for 72% (n = 505), compared with 91% (n = 638) of the passive physician involvement group (P <0.001). After adjustment for a variety of patient, physician, and hospital-level variables, patients in the passive physician involvement group were found to be significantly more likely to be enrolled in the study (adjusted OR 2.61; 95% CI, 1.53-4.45). However, among those patients approved for investigator contact, there were no significant differences between patients who were enrolled and patients who were not enrolled in the study with regard to physician involvement in the recruitment process (adjusted OR 1.13; 95% CI, 0.70-1.81). CONCLUSION: Our findings demonstrate that more stringent IRB requirements on health services researchers to verify permission from the treating physician to access patients for recruitment purposes adversely impact on the enrollment of patients even in noninterventional research studies. Current procedures for involving the treating physician as a gatekeeper in the recruitment of research subjects may limit access to patient participation in research studies from the perspectives of both researchers and potential subjects.

Habituation of the proleg withdrawal reflex in Manduca sexta does not involve changes in motoneuron properties or depression at the sensorimotor synapse.

Larvae of the hawkmoth, Manduca sexta, exhibit a defensive proleg withdrawal reflex in which deflection of mechanosensory hairs on the proleg tip (the planta) evokes retraction of the proleg. A previous behavioral study showed that this reflex habituates in response to repeated planta hair deflection and exhibits several other defining features of habituation. In a semi-intact preparation consisting of a proleg and its associated segmental ganglion, repeated deflection of a planta hair or electrical stimulation of its sensory neuron causes a neural correlate of habituation, manifested as a decrease in the number of action potentials evoked in the proleg motor nerve. Monosynaptic connections from planta hair sensory neurons to the principal planta retractor motoneuron exhibit several forms of activity-dependent plasticity. In the present study we recorded intracellularly from this motoneuron during repetitive electrical stimulation of a planta hair sensory neuron. The number of action potentials evoked in the motoneuron decreased significantly, representing a neural correlate of habituation. The motoneuron's resting membrane potential, input resistance. and spike threshold measured before and after repetitive stimulation did not differ between the stimulated group and a control group. Furthermore, the amplitude of the monosynaptic excitatory postsynaptic potential, as well as the magnitude of paired-pulse facilitation, evoked in the motoneuron by the sensory neuron did not change after repetitive stimulation. These results suggest that depression at the sensorimotor synapse does not contribute to reflex habituation. Rather, other mechanisms in the ganglion of the stimulated segment, such as changes in polysynaptic reflex pathways, appear to be responsible.

Discussion of treatment options for early-stage breast cancer: effect of provider specialty on type of surgery and satisfaction.

OBJECTIVES: To describe the physicians with whom breast cancer patients discuss treatment options and assess whether discussing surgical options with a medical oncologist is associated with type of surgery and satisfaction. RESEARCH DESIGN: Medical record abstraction and survey. SUBJECTS: Women with early-stage breast cancer numbering 2,426 in two states-Massachusetts, where the rate of breast-conserving surgery is high, and Minnesota, where it is lower. MEASURES: Receipt of breast-conserving surgery and satisfaction. RESULTS: Women in Massachusetts discussed breast cancer treatments with more physicians than women in Minnesota (mean 3.5 vs. 2.8; P <0.001) and more often discussed surgical options with a medical oncologist (52% vs. 28%; P <0.001). Using propensity score analyses, in Massachusetts, discussing surgical options with a medical oncologist was not related to type of surgery (adjusted difference in rate of breast-conserving surgery: 3.9%, 95% CI -3.6% to 11.5%) but was associated with greater satisfaction (adjusted difference: 8.1, 95% CI 2.0% to 14.2%). In Minnesota, discussing surgical options with a medical oncologist was associated with breast-conserving surgery (adjusted difference: 12.6%, 95% CI 5.6% to 19.7%) with no difference in satisfaction (adjusted difference: -1.5%, 95% CI -6.8% to 3.8%). CONCLUSIONS: Outcomes associated with discussing surgical treatments with a medical oncologist vary with local care patterns. Where breast-conserving surgery is standard care, seeing a medical oncologist is not related to type of surgery, but is associated with greater satisfaction. Where it is not the standard, seeing a medical oncologist is associated with more breast-conserving surgery and equivalent satisfaction. These findings suggest that collaborative care may benefit women with respect to treatment selection or satisfaction.

Costs and effectiveness of staging and treatment options in early-stage Hodgkin's disease.

PURPOSE: Using a cost-effectiveness analysis, to weigh the costs and benefits of the different staging and treatment options in early-stage Hodgkin's disease. METHODS: We constructed a decision-analytic model for a hypothetical cohort of 25-year-old patients with early-stage Hodgkin's disease. Markov models were used to simulate the lifetime costs and prognosis of each staging and treatment strategy. Baseline probabilities and cost estimates were derived from published studies and bills of relevant patient cohorts. RESULTS: Among the six management strategies considered, the incremental cost-effectiveness ratio of laparotomy and tailored treatment compared with mantle and para-aortic-splenic radiation therapy in all clinical stage I-II patients was $24,100/quality-adjusted life year, while that of the strategy of combined modality therapy in all clinical stage I-II patients compared with laparotomy was $61,700/quality-adjusted life year. All the remaining strategies were dominated by one of these three strategies. Sensitivity analysis showed that the cost-effectiveness ratios were driven predominantly by the effectiveness rather than the cost of each strategy. In particular, the analysis was heavily influenced by the utility of the post-laparotomy health state. CONCLUSIONS: In considering the various alternative management strategies in early-stage Hodgkin's disease, even very small gains in effectiveness were enough to justify the additional costs of more expensive treatment options.

Developmental change in the steroid hormone signal for cell-autonomous, segment-specific programmed cell death of a motoneuron.

During metamorphosis of the hawkmoth, Manduca sexta, accessory planta retractor (APR) motoneurons undergo a segment-specific pattern of programmed cell death (PCD): e.g., APRs from abdominal segment six [APR(6)s] die at pupation in direct response to the prepupal rise in 20-hydroxyecdysone (20E), whereas APR(4)s survive through the pupal stage and die at eclosion (adult emergence). The hypothesis that the death of APR(4)s is triggered by the decline in 20E at eclosion was supported by findings that injection of 20E into developing pupae to delay the fall in 20E delayed APR(4) death. Furthermore, abdomen isolation to advance the fall in 20E caused precocious APR(4) death. In other experiments, APR(4)s were placed in primary cell culture 4 days before eclosion in medium containing 1 microg/ml 20E. A switch to hormone-free medium induced PCD in a significant proportion of APR(4)s, compared to APR(4)s that remained in 20E. Process fragmentation was a reliable early indicator of PCD. These results show that a decline in 20E triggers cell-autonomous PCD of APR(4)s, in contrast to the rise in 20E that triggers cell-autonomous PCD of APR(6)s. Thus, the PCD of homologous motoneurons in different body segments at different developmental times is triggered by different steroid hormone signals.

Discrepancies between patient and physician estimates for the success of stem cell transplantation.

CONTEXT: Stem cell transplantation is associated with considerable morbidity and mortality. The extent to which patients and their physicians correctly estimate these risks is unknown. OBJECTIVE: To measure the expectations of patients and physicians prior to stem cell transplantation and correlate them with actual outcomes after transplantation. DESIGN: Prospective cohort study with baseline questionnaire administered July 1996 through November 1999 and follow-up to May 2000. SETTING: Tertiary care transplant center in the United States. PARTICIPANTS: Of 458 surveys mailed, evaluable returned surveys were included for 313 autologous and allogeneic stem cell transplantation patients and their physicians. MAIN OUTCOME MEASURES: Patient and physician expectations prior to transplantation (measured on 6-point Likert scales) of treatment-related mortality, cure with transplantation, and cure without transplantation; actual treatment-related mortality and disease-free survival among patients with at least 1 year of follow-up after transplantation (n = 263). RESULTS: Both patients and physicians were fairly accurate in estimating treatment-related mortality when actual mortality was less than 30%. However, in situations in which mortality was higher than 30%, such as with allogeneic transplantation for intermediate or advanced disease, physician expectations were lower, while patients remained optimistic. Similarly, physicians provided lower estimates of disease-free survival in cases of intermediate or advanced disease while patient expectations remained high and constant regardless of disease stage. CONCLUSIONS: Patients and their physicians have the most concordant and accurate expectations when the outcome of stem cell transplantation is likely to be favorable. However, patients with more advanced disease fail to recognize the higher risks associated with their situations.

Patient preferences for adjuvant interferon alfa-2b treatment.

PURPOSE: Although trials of adjuvant interferon alfa-2b (IFN alpha-2b) in high-risk melanoma patients suggest improvement in disease-free survival, it is unclear whether treatment offers improvement in overall survival. Widespread use of adjuvant IFN alpha-2b has been tempered by its significant toxicity. To quantify the trade-offs between IFN alpha-2b toxicity and survival, we assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a particular health state on a scale of 0 (death) to 1 (perfect health). PATIENTS AND METHODS: We assessed utilities for health states associated with adjuvant IFN among 107 low-risk melanoma patients using the standard gamble technique. Health states described four IFN alpha-2b toxicity scenarios and the following three posttreatment outcomes: disease-free health and melanoma recurrence (with or without IFN alpha-2b) leading to cancer death. We also asked patients the improvement in 5-year disease-free survival they would require to tolerate IFN. RESULTS: Utilities for melanoma recurrence with or without IFN alpha-2b were significantly lower than utilities for all IFN alpha-2b toxicities but were not significantly different from each other. At least half of the patients were willing to tolerate mild-moderate and severe IFN alpha-2b toxicity for 4% and 10% improvements, respectively, in 5-year disease-free survival. CONCLUSION: On average, patients rate quality of life with melanoma recurrence much lower than even severe IFN alpha-2b toxicity. These results suggest that recurrence-free survival is highly valued by patients. The utilities measured in our study can be applied directly to quality-of-life determinations in clinical trials of adjuvant IFN alpha-2b to measure the net benefit of therapy.

Quality of informed consent: a new measure of understanding among research subjects.

BACKGROUND: The informed consent of participants is ethically and legally required for most research involving human subjects. However, standardized methods for assessing the adequacy of informed consent to research are lacking. METHODS AND RESULTS: We designed a brief questionnaire, the Quality of Informed Consent (QuIC), to measure subjects' actual (objective) and perceived (subjective) understanding of cancer clinical trials. The QuIC incorporates the basic elements of informed consent specified in federal regulations, assesses the therapeutic misconception (the belief that all aspects of a clinical trial are designed to directly benefit the subject), and employs the language and structure of the new National Cancer Institute template for informed consent documents. We modified the QuIC after receiving feedback from pilot tests with cancer research subjects, as well as validation from two independent expert panels. We then sent the QuIC to 287 adult cancer patients enrolled on phase I, II, or III clinical trials. Two hundred seven subjects (72%) completed the QuIC. To assess test-retest reliability, a random sample of 32 respondents was selected, of whom 17 (53%) completed the questionnaire a second time. The test-retest reliability was good with intraclass correlation coefficients of.66 for tests of objective understanding and.77 for tests of subjective understanding. The current version of the QuIC, which consists of 20 questions for objective understanding and 14 questions for subjective understanding, was tested for time and ease of administration in a sample of nine adult cancer patients. The QuIC required an average of 7.2 minutes to complete. CONCLUSIONS: The QuIC is a brief, reliable, and valid questionnaire that holds promise as a standardized way to assess the outcome of the informed consent process in cancer clinical trials.

Role of caspases and mitochondria in the steroid-induced programmed cell death of a motoneuron during metamorphosis.

Accessory planta retractor (APR) motoneurons of the hawk moth, Manduca sexta, undergo a segment-specific pattern of programmed cell death (PCD) 24 to 48 h after pupal ecdysis (PE). Cell culture experiments show that the PCD of APRs in abdominal segment 6 [APR(6)s] is a cell-autonomous response to the steroid hormone 20-hydroxyecdysone (20E) and involves mitochondrial demise and cell shrinkage. Twenty-four hours before PE, at stage W3-noon, APR(6)s require further 20E exposure and protein synthesis (as tested with cycloheximide) to undergo PCD, and death can be blocked by a broad-spectrum caspase inhibitor. By PE, death is 20E- and protein synthesis-independent and the caspase inhibitor blocks cell shrinkage but not loss of mitochondrial function. Thus, the commitment to mitochondrial demise precedes the commitment to execution events. The phenotype of necrotic cell death induced by a mitochondrial electron transfer inhibitor differs unambiguously from 20E-induced PCD. By inducing PCD pharmacologically, the readiness of APR(6)s to execute PCD was found to increase during the final larval instar. These data suggest that the 20E-induced PCD of APR(6)s includes a premitochondrial phase which includes 20E-induced synthetic events and apical caspase activity, a mitochondrial phase which culminates in loss of mitochondrial function, and a postmitochondrial phase during which effector caspases are activated and APR(6) is destroyed.

Effectiveness of chemotherapy for advanced lung cancer in the elderly: instrumental variable and propensity analysis.

PURPOSE: To compare the effectiveness of chemotherapy given to elderly patients in routine practice for stage IV non-small-cell lung cancer (NSCLC) with the efficacy observed in randomized trials. PATIENTS AND METHODS: We used instrumental variable analysis (IVA) and propensity scores (PS) to simulate the conditions of a randomized trial in a retrospective cohort of patients over age 65 from the Survival, Epidemiology, and End Results (SEER) tumor registry. Geographic variation in chemotherapy use served as the instrument for the IVA analysis, and propensity scores were calculated with a logistic model based on patient disease and sociodemographic characteristics. RESULTS: Among 6,232 elderly patients, the instrumental variable estimate indicated an increase in median survival of 33 days and an improvement in 1-year survival of 9% attributable to chemotherapy. In a Cox regression model, chemotherapy administration was associated with a hazard ratio of 0.81 (95% confidence interval, 0.76 to 0.85). When survival was analyzed separately within propensity score quintiles, the hazard ratios were all similar, ranging from 0.78 to 0.85. These results are comparable with those of a large meta-analysis, which found a hazard ratio of 0.87 in the subgroup of patients over age 65. CONCLUSION: Chemotherapy for stage IV NSCLC seems to have effectiveness for elderly patients and those with comorbid conditions that is similar to the efficacy seen in randomized trials containing mostly younger, highly selected patients. All suitable patients should be given the opportunity to consider palliative chemotherapy for metastatic NSCLC.

Defensive responses of larval Manduca sexta and their sensitization by noxious stimuli in the laboratory and field.

Sensitization of defensive responses following noxious stimulation occurs in diverse species, but no demonstration of nociceptive sensitization in insects has been reported. A set of defensive behavior patterns in larval Manduca sexta is described and shown to undergo sensitization following noxious mechanical stimulation. The striking response is a rapid bending that accurately propels the head towards sharply poking or pinching stimuli applied to most abdominal segments. The strike is accompanied by opening of the mandibles and, sometimes, regurgitation. The strike may function to dislodge small attackers and startle larger predators. When the same stimuli are applied to anterior segments, the head is pulled away in a withdrawal response. Noxious stimuli to anterior or posterior segments can evoke a transient withdrawal (cocking) that precedes a strike towards the source of stimulation and may function to maximize the velocity of the strike. More intense noxious stimuli evoke faster, larger strikes and may also elicit thrashing, which consists of large, cyclic, side-to-side movements that are not directed at any target. These are sometimes also associated with low-amplitude quivering cycles. Striking and thrashing sequences elicited by obvious wounding are sometimes followed by grooming-like behavior. Very young larvae also show locomotor responses to noxious stimuli. Observations in the field of attacks on M. sexta larvae by Cardinalis cardinalis, an avian predator, suggest that thrashing decreases the success of a bird in biting a larva. In the laboratory, noxious stimulation was found to produce two forms of sensitization. Repeated pinching of prolegs produces incremental sensitization, with later pinches evoking more strikes than the first pinch. Brisk pinching or poking of prolegs also produces conventional sensitization, in which weak test stimuli delivered to another site evoke more strikes following noxious stimulation. The degree and duration of sensitization increase with more intense noxious stimulation. The most intense stimulus sequences were found to enhance strike frequency for approximately 60 min. Nociceptive sensitization generalizes to sites distant from sites of noxious stimulation, suggesting that it involves a general, but transient, arousal of defensive responses. http://www.biologists.com/JEB/movies/jeb3271.html

Measuring the incremental cost of clinical cancer research.

PURPOSE: To summarize evidence on the costs of treating patients in clinical trials and to describe the Cost of Cancer Treatment Study, an ongoing effort to produce generalizable estimates of the incremental costs of government-sponsored cancer trials. METHODS: A retrospective study of costs will be conducted with 1,500 cancer patients recruited from a randomly selected sample of institutions in the United States. Patients accrued to either phase II or phase III National Cancer Institute-sponsored clinical trials during a 15-month period will be asked to participate in a study of their health care utilization (n = 750). Costs will be measured approximately 1 year after their trial enrollment from a combination of billing records, medical records, and an in-person survey questionnaire. Similar data will be collected for a comparable group of cancer patients not in trials (n = 750) to provide an estimate of the incremental cost. RESULTS: Evidence suggests insurers limit access to trials because of cost concerns. Public and private efforts are underway to change these policies, but their permanent status is unclear. Previous studies found that treatment costs in clinical trials are similar to costs of standard therapy. However, it is difficult to generalize from these studies because of the unique practice settings, insufficient sample sizes, and the exclusion of potentially important costs. CONCLUSION: Denials of coverage for treatment in a clinical trial limit patient access to trials and could impede clinical research. Preliminary estimates suggest changes to these policies would not be expensive, but these results are not generalizable. The Cost of Cancer Treatment Study is an ongoing effort to provide generalizable estimates of the incremental treatment cost of phase II and phase III cancer trials. The results should be of great interest to insurers and the research community as they consider permanent ways to finance cancer trials.

Recovery after stem-cell transplantation for hematologic diseases.

PURPOSE: Although the number of autologous and allogeneic stem-cell transplantations (SCT) is increasing, relatively little information about recovery after transplantation is available. Quantitative information appropriate for patient counseling is difficult to discern from the literature. We sought to suggest reasonable expectations for recovery and symptoms after SCT for hematologic malignancies and other disorders using the following measures: (1) objective measures of health status, such as frequency of clinic visits, need for rehospitalization, medication usage, work status, and overall and event-free survival; (2) qualitative assessment of quality of life, such as returning to a normal life, resumption of normal activities, satisfaction with appearance, and whether recovery has occurred; and (3) quantification of specific bothersome symptoms. PATIENTS AND METHODS: Autologous and allogeneic SCT recipients at a tertiary-care transplant center participated in the prospective, longitudinal questionnaire study. RESULTS: Three hundred twenty patients were studied. Questionnaire response rates at 6, 12, and 24 months range from 85% to 88% among survivors. Although autologous patients had better event-free and overall survival, fewer symptoms, and more complete recovery at 6 months, these advantages had largely equalized by 12 months. Specific bothersome symptoms were reported by less than 24% of patients after transplantation, except for fatigue and financial and sexual difficulties, which were more prevalent. CONCLUSION: These findings may help counsel patients considering transplantation and educate them about reasonable expectations for recovery. Overall, the low level of bothersome symptoms and continued recovery through the first year after transplantation are encouraging.

Understanding of prognosis among parents of children who died of cancer: impact on treatment goals and integration of palliative care.

CONTEXT: Parents' understanding of prognosis or decision making about palliative care for children who die of cancer is largely unknown. However, a more accurate understanding of prognosis could alter treatment goals and expectations and lead to more effective care. OBJECTIVES: To evaluate parental understanding of prognosis in children who die of cancer and to assess the association of this factor with treatment goals and the palliative care received by children. DESIGN, SETTING, AND PARTICIPANTS: Survey, conducted between September 1997 and August 1998, of 103 parents of children who received treatment at the Dana-Farber Cancer Institute and Children's Hospital, Boston, Mass, and who died of cancer between 1990 and 1997 (72% of those eligible and those located) and 42 pediatric oncologists. MAIN OUTCOME MEASURE: Timing of parental understanding that the child had no realistic chance for cure compared with the timing of physician understanding of this prognosis, as documented in the medical record. RESULTS: Parents first recognized that the child had no realistic chance for cure a mean (SD) of 106 (150) days before the child's death, while physician recognition occurred earlier at 206 (330) days before death. Among children who died of progressive disease, the group characterized by earlier recognition of this prognosis by both parents and physicians had earlier discussions of hospice care (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01-1.06; P =.01), better parental ratings of the quality of home care (OR, 3.31; 95% CI, 1.15-9.54; P =.03), earlier institution of a do-not-resuscitate order (OR, 1.03; 95% CI, 1.00-1.06; P =.02), less use of cancer-directed therapy during the last month of life (OR, 2.80; 95% CI, 1.05-7.50; P =.04), and higher likelihood that the goal of cancer-directed therapy identified by both physician and parent was to lessen suffering (OR, 5.17; 95% CI, 1.86-14.4; P =.002 for physician and OR, 6.56; 95% CI, 1.54-27.86; P =.01 for parents). CONCLUSION: Considerable delay exists in parental recognition that children have no realistic chance for cure, but earlier recognition of this prognosis by both physicians and parents is associated with a stronger emphasis on treatment directed at lessening suffering and greater integration of palliative care. JAMA. 2000;284:2469-2475.

Patient preferences for axillary dissection in the management of early-stage breast cancer.

BACKGROUND: Recent data on the value of adjuvant therapy in lymph node-negative breast cancer and promising early data on less invasive strategies for managing the axilla have raised questions about the appropriate role of axillary lymph node dissection (ALND) in the management of early-stage breast cancer. We sought to evaluate how women weigh potential benefits of ALND-prognostic information, enhanced local control, and tailored therapy-against the risks of long-term morbidity that are associated with the procedure. METHODS: We used hypothetical scenarios to survey 82 randomly selected women with invasive breast cancer who had been treated with ALND and 62 women at risk for invasive breast cancer by virtue of a history of ductal carcinoma in situ (DCIS) who had not undergone ALND. RESULTS: Women in both the invasive cancer and the DCIS groups required substantial improvements in local control of the cancer (5% and 15%, respectively) and overall survival (3% and 10%, respectively) before they would opt for this procedure. Women with invasive cancer would choose ALND if it had only a 1% chance of altering treatment recommendations, whereas DCIS subjects required a 25% chance. Sixty-eight percent and 29% of women in the invasive cancer and DCIS groups, respectively, would accepted a 40% risk of arm dysfunction to gain prognostic information that would not change treatment. CONCLUSIONS: For most subjects treated previously for invasive breast cancer and almost half those at risk of the disease, the potential benefits of ALND, particularly the value of prognostic information, were sufficient to outweigh the risks of morbidity. However, women varied considerably in their preferences, highlighting the need to tailor decisions regarding management of the axilla to individual patients' values.