Analysis of trimodal and bimodal therapy in a selective-surgery paradigm for locally advanced oesophageal squamous cell carcinoma.

BACKGROUND: Long-term survival outcomes of trimodal therapy (TMT; chemoradiation plus surgery) and bimodal therapy (BMT; chemoradiation) have seldom been analysed. In a selective-surgery paradigm, the benefit of TMT in patients with a complete clinical response is controversial. Factors associated with survival in patients with a clinical complete response to chemoradiation were evaluated. METHODS: Patients with stage II-III oesophageal squamous cell carcinoma treated with TMT or BMT from 2002 to 2017 were evaluated. The BMT group consisted of patients who were otherwise eligible for surgery but underwent chemoradiation alone followed by observation. This group included patients who later had salvage oesophagectomy. Survival was evaluated and compared between TMT and BMT groups. Elastic net regularization was performed to select co-variables for Cox multivariable survival analysis in patients with a clinical complete response. RESULTS: Of 143 patients, 60 (41.9 per cent) underwent TMT and 83 (58.0 per cent) BMT. Patients who underwent TMT had longer median overall survival than those who had BMT (77 versus 33 months; P = 0.019). For patients with a clinical complete response, TMT achieved longer median overall survival than BMT (123 versus 55 months; P = 0.04). BMT had a high locoregional recurrence rate (48 versus 6 per cent; P < 0.001); 26 of 29 patients with locoregional recurrence in the BMT groupunderwent salvage resection. Cox multivariable analysis demonstrated that upper-mid oesophageal tumour location (hazard ratio (HR) 2.04; P = 0.024) and tumour length (HR 1.18; P = 0.046) were associated with worse survival. Although TMT was not associated with survival, it was a predictor of reduced recurrence (HR 0.28; P = 0.028). The maximum standardized uptake value after chemoradiation also predicted recurrence (HR 1.33; P < 0.001). CONCLUSION: In patients who achieve a clinical complete response, TMT reduces locoregional recurrence but may not prolong survival. The differences in survival outcomes may be due to patient selection; therefore, a selective-surgery strategy in oesophageal squamous cell carcinoma is a reasonable approach.

Morbidity following salvage esophagectomy for squamous cell carcinoma: the MD Anderson experience.

The survival advantage associated with the addition of surgical therapy in esophageal squamous cell carcinoma (ESCC) patients who demonstrate a complete clinical response to chemoradiotherapy is unclear, and many institutions have adopted an organ-preserving strategy of selective surgery in this population. We sought to characterize our institutional experience of salvage esophagectomy (for failure of definitive bimodality therapy) and planned esophagectomy (as a component of trimodality therapy) by retrospectively analyzing patients with ESCC of the thoracic esophagus and GEJ who underwent esophagectomy following chemoradiotherapy between 2004 and 2016. Of 76 patients who met inclusion criteria, 46.1% (35) underwent salvage esophagectomy. Major postoperative complications (major cardiovascular and pulmonary events, anastomotic leak [grade ≥ 2], and 90-day mortality) were frequent and occurred in 52.6% of the cohort (planned resection: 36.6% [15/41]; salvage esophagectomy: 71.4% [25/35]). Observed rates of 30- and 90-day mortality for the entire cohort were 7.9% (planned: 7.3% [3/41]; salvage: 8.6% [3/35]) and 13.2% (planned: 9.8% [4/41]; salvage: 17.1% [6/35]), respectively. In summary, esophagectomy following chemoradiotherapy for ESCC at our institution has been associated with frequent postoperative morbidity and considerable rates of mortality in both planned and salvage settings. Although a selective approach to surgery may permit organ preservation in many patients with ESCC, these results highlight that salvage esophagectomy for failure of definitive-intent treatment of ESCC may also constitute a difficult clinical undertaking in some cases.

Risk factors for local and regional recurrence in patients with resected N0-N1 non-small-cell lung cancer, with implications for patient selection for adjuvant radiation therapy.

BACKGROUND: The purpose of this study was to evaluate the actuarial risk of local and regional failure in patients with completely resected non-small-cell lung cancer (NSCLC), and to assess surgical and pathological factors affecting this risk. PATIENTS AND METHODS: Between January 1998 and December 2009, 1402 consecutive stage I-III (N0-N1) NSCLC patients underwent complete resection without adjuvant radiation therapy. The median follow-up was 42 months. RESULTS: Local-regional recurrence was identified in 9% of patients, with local failure alone in 3% of patients, regional failure alone in 4% of patients, and both local and regional failure simultaneously in 2% of patients. Patients who had local failure were found to be at increased risk of mortality. By multivariate analyses, three variables were shown to be independently significant risk factors for local [surgical procedure (single/multiple wedges+segmentectomy versus lobectomy+bilobectomy+pneumonectomy), tumor size>2.7 cm, and visceral pleural invasion] and regional (pathologic N1 stage, visceral pleural invasion, and lymphovascular space invasion, LVI) recurrence, respectively. CONCLUSION: Patients with N0-N1 disease have low rates of locoregional recurrence after surgical resection. However, several prognostic factors can be identified that increase this risk and identify patients who may benefit from adjuvant treatment.

Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort.

BACKGROUND: Chemoradiation followed by surgery is the preferred treatment of localized gastroesophageal cancer (GEC). Surgery causes considerable life-altering consequences and achievement of clinical complete response (clinCR; defined as postchemoradiation [but presurgery] endoscopic biopsy negative for cancer and positron emission tomographic (PET) scan showing physiologic uptake) is an enticement to avoid/delay surgery. We examined the association between clinCR and pathologic complete response (pathCR). PATIENTS AND METHODS: Two hundred eighty-four patients with GEC underwent chemoradiation and esophagectomy. The chi-square test, Fisher exact test, t-test, Kaplan-Meier method, and log-rank test were used. RESULTS: Of 284 patients, 218 (77%) achieved clinCR. However, only 67 (31%) of the 218 achieved pathCR. The sensitivity of clinCR for pathCR was 97.1% (67/69), but the specificity was low (29.8%; 64/215). Of the 66 patients who had less than a clinCR, only 2 (3%) had a pathCR. Thus, the rate of pathCR was significantly different in patients with clinCR than in those with less than a clinCR (P < 0.001). CONCLUSIONS: clinCR is not highly associated with pathCR; the specificity of clinCR for pathCR is too low to be used for clinical decision making on delaying/avoiding surgery. Surgery-eligible GEC patients should be encouraged to undergo surgery following chemoradiation despite achieving a clinCR.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation.

BACKGROUND: Patients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: Approximately 25% of patients with esophageal cancer (EC) who undergo preoperative chemoradiation, achieve a pathologic complete response (pathCR). We hypothesized that a model based on clinical parameters could predict pathCR with a high (≥60%) probability. PATIENTS AND METHODS: We analyzed 322 patients with EC who underwent preoperative chemoradiation. All the patients had baseline and postchemoradiation positron emission tomography (PET) and pre- and postchemoradiation endoscopic biopsy. Logistic regression models were used for analysis, and cross-validation via the bootstrap method was carried out to test the model. RESULTS: The 70 (21.7%) patients who achieved a pathCR lived longer (median overall survival [OS], 79.76 months) than the 252 patients who did not achieve a pathCR (median OS, 39.73 months; OS, P = 0.004; disease-free survival, P = 0.003). In a logistic regression analysis, the following parameters contributed to the prediction model: postchemoradiation PET, postchemoradiation biopsy, sex, histologic tumor grade, and baseline (EUS)T stage. The area under the receiver-operating characteristic curve was 0.72 (95% confidence interval [CI] 0.662-0.787); after the bootstrap validation with 200 repetitions, the bias-corrected AU-ROC was 0.70 (95% CI 0.643-0.728). CONCLUSION: Our data suggest that the logistic regression model can predict pathCR with a high probability. This clinical model could complement others (biomarkers) to predict pathCR.

Patients with high body mass index tend to have lower stage of esophageal carcinoma at diagnosis.

High body mass index (H-BMI; ≥25 kg/m(2) ) is common in US adults. In a small cohort of esophageal cancer (EC) patients treated with surgery, H-BMI and diagnosis of early stage EC appeared associated. We evaluated a much larger cohort of EC patients. From a prospectively maintained database, we analyzed 925 EC patients who had surgery with or without adjunctive therapy. Various statistical methods were used. Among 925 patients, 69% had H-BMI, and 31% had normal body mass index (<25 kg/m(2) ; N-BMI). H-BMI was associated with men (P<0.001), Caucasians (P=0.064; trend), lower esophageal localization (P<0.001), adenocarcinoma histology (P<0.001), low baseline cT-stage (P=0.003), low baseline overall clinical stage (P=0.003), coronary artery disease (P=0.036), and diabetes (P<0.001). N-BMI was associated with weight loss (P<0.001), alcohol abuse (P=0.056; trend), ever/current smoking (P=0.014), and baseline cN+ (P=0.018). H-BMI patients with cT1 tumors (n=110) had significantly higher rates of gastresophageal reflux disease symptoms (P<0.001), gastresophageal reflux disease history (P<0.001), and Barrett's esophagus history (P<0.001) compared with H-BMI patients with cT2 tumors (n=114). Median survival of N-BMI patients was 36.66 months compared with 53.20 months for H-BMI patients (P=0.005). In multivariate analysis, older age (P<0.001), squamous histology (P=0.002), smoking (P=0.040), weight loss (P=0.002), high baseline stage (P<0.001), high number of ypN+ (P=0.005), high surgical stage (P<0.001), and American Society of Anesthesia scores, three out of four (P<0.001) were independent prognosticators for poor overall survival. We were able to perform propensity-based analysis of surgical complications between H-BMI and N-BMI patients. A comparison of fully matched 376 patients (188 with H-BMI and 188 with N-BMI) found no significant differences in the rate of complications between the two groups. This larger data set confirms that a fraction of H-BMI patients with antecedent history is diagnosed with early baseline EC. Upon validation of our data in an independent cohort, refinements in surveillance of symptomatic H-BMI patients are warranted and could be implemented. Our data also suggest that H-BMI patients do not experience higher rate of surgical complications compared with N-BMI patients.

Early chronic low-level methylmercury poisoning in monkeys impairs spatial vision.

Five monkeys were treated from birth with oral doses of mercury as methylmercury (50 micrograms per kilogram of body weight per day); concentrations in the blood peaked at 1.2 to 1.4 parts per million; and declined after weaning from infant formula to a steady level of 0.6 to 0.9 part per million. There were no overt signs of toxicity. When tested between 3 and 4 years of age under conditions of both high and low luminance, treated monkeys exhibited spatial vision that was impaired compared with that of control monkeys.

Neurotoxicity of lead, methylmercury, and PCBs in relation to the Great Lakes.

There is ample evidence identifying lead, methylmercury, and polychlorinated biphenyls (PCBs) as neurotoxic agents. A large body of data on the neurotoxicity of lead, based on both epidemiologic studies in children and animal models of developmental exposure, reveals that body burdens of lead typical of people in industrialized environments produce behavioral impairment. Methylmercury was identified as a neurotoxicant in both adults and the developing organism based on episodes of human poisoning: these effects have been replicated and extended in animals. High-dose PCB exposure was recognized as a developmental toxicant as a result of several episodes of contamination of cooking oil. The threshold for PCB neurotoxicity in humans is less clear, although research in animals suggests that relatively low-level exposure produces behavioral impairment and other toxic effects. Tissue levels in fish below which human health would not be adversely affected were estimated for methylmercury and PCBs based on calculated reference doses (RfDs) and estimated fish intake. Present levels in fish tissue in the Great Lakes exceed these levels for both neurotoxicants. Great Lakes fish and water do not pose a particular hazard for increased lead intake. However, the fact that the present human body burden is in a range at which functional deficits are probable suggests that efforts should be made to eliminate point sources of lead contamination in the Great Lakes basin.

Parallels between attention deficit hyperactivity disorder and behavioral deficits produced by neurotoxic exposure in monkeys.

Attention deficit hyperactivity disorder (ADHD) is a disability that affects between 3 and 7% of children, with a significant number of individuals continuing to be affected into adolescence and adulthood. ADHD is characterized in part by an inability to organize complex sequences of behavior, to persist in the face of distracting stimuli, and to respond appropriately to the consequences of past behavior. There are some parallels between the features of ADHD and the behavior of monkeys exposed developmentally to lead or polychlorinated biphenyls (PCBs), as evidenced by research from our laboratory. Both lead and PCB exposure produce deficits on discrimination reversal and spatial delayed alternation performance; treated monkeys exhibit deficits in their ability to change an already established response strategy and inhibit inappropriate responses. Monkeys exposed developmentally to lead or PCBs also perform differently from control monkeys on a fixed interval schedule of reinforcement, which requires the temporal organization of behavior using only internal cues. Whereas the etiology of ADHD is multifactorial, the possibility that neurotoxic agents in the environment contribute to the incidence of ADHD warrants attention.

Behavioral effects of lead: commonalities between experimental and epidemiologic data.

Enormous effort has been focused over the last decade and a half on characterizing the behavioral effects of lead in the developing organism. While age-appropriate standardized measures of intelligence (IQ) have been the dependent variable most often used to assess lead-induced cognitive impairment in epidemiologic studies, researchers have also used a variety of other methods designed to assess specific behavioral processes sensitive to lead. Increased reaction time and poorer performance on vigilance tasks associated with increased lead body burden suggest increased distractibility and short attention span. Assessment of behavior on teachers' rating scales identified increased distractibility, impulsivity, nonpersistence, inability to follow sequences of directions, and inappropriate approach to problems as hallmarks of lead exposure. Robust deficits in learned skills such as reading, spelling, math, and word recognition have also been found. Spatial organizational perception and abilities seem particularly sensitive to lead-induced impairment. Assessment of complex tasks of learning and memory in both rats and monkeys has revealed overall deficits in function over a variety of behavioral tasks. Exploration of behavioral mechanisms responsible for these deficits identified increased distractibility perseveration, inability to inhibit inappropriate responding, and inability to change response strategy as underlying deficits. Thus, there is remarkable congruence between the epidemiologic and experimental literatures with regard to the behavioral processes identified as underlying the deficits inflicted by developmental lead exposure. However, careful behavioral analysis was required from researchers in both fields for such understanding to emerge.

Lessons for neurotoxicology from selected model compounds: SGOMSEC joint report.

The ability to identify potential neurotoxicants depends upon the characteristics of our test instruments. The neurotoxic properties of lead, methylmercury, polychlorinated biphenyls, and organic solvents would all have been detected at some dose level by tests in current use, provided that the doses were high enough and administered at an appropriate time such as during gestation. The adequacy of animal studies, particularly rodent studies, to predict intake levels at which human health can be protected is disappointing, however. It is unlikely that the use of advanced behavioral methodology would alleviate the apparent lack of sensitivity of the rodent model for many agents.

Workshop to identify critical windows of exposure for children's health: neurobehavioral work group summary.

This paper summarizes the deliberations of a work group charged with addressing specific questions relevant to risk estimation in developmental neurotoxicology. We focused on eight questions. a) Does it make sense to think about discrete windows of vulnerability in the development of the nervous system? If it does, which time periods are of greatest importance? b) Are there cascades of developmental disorders in the nervous system? For example, are there critical points that determine the course of development that can lead to differences in vulnerabilities at later times? c) Can information on critical windows suggest the most susceptible subgroups of children (i.e., age groups, socioeconomic status, geographic areas, race, etc.)? d) What are the gaps in existing data for the nervous system or end points of exposure to it? e) What are the best ways to examine exposure-response relationships and estimate exposures in vulnerable life stages? f) What other exposures that affect development at certain ages may interact with exposures of concern? g) How well do laboratory animal data predict human response? h) How can all of this information be used to improve risk assessment and public health (risk management)? In addressing these questions, we provide a brief overview of brain development from conception through adolescence and emphasize vulnerability to toxic insult throughout this period. Methodological issues focus on major variables that influence exposure or its detection through disruptions of behavior, neuroanatomy, or neurochemical end points. Supportive evidence from studies of major neurotoxicants is provided.

Age-related increase in auditory impairment in monkeys exposed in utero plus postnatally to methylmercury.

Hearing impairment and deafness have been reported as a result of developmental and adult exposure to methylmercury; however, objective assessment of auditory function is generally lacking. This study extends previous research in our laboratory in which monkeys exposed to methylmercury from birth to adulthood exhibited high-frequency hearing impairment. Monkeys (Macaca fascicularis) were exposed throughout gestation and postnatally until 4 years of age to 0, 10, 25, or 50 micrograms/kg/day mercury as methylmercuric chloride. When they were 11 and 19 years of age, pure-tone detection thresholds for six frequencies between 0.125 and 31.5 kHz were determined by means of a psychophysical (behavioral) procedure. At 19 years of age, all five methylmercury-exposed monkeys exhibited elevated pure-tone thresholds compared with controls. Impairment was generally observed across the full range of frequencies. Comparisons of performance at 11 and 19 years revealed relatively greater deterioration in function in treated compared with control monkeys. These results extend previously reported evidence of deficits in auditory function produced by postnatal methylmercury exposure, and describe a pattern of deficit across frequencies different than that observed in the previous study. This study also provides evidence for development or acceleration of impairment of auditory function during aging as a consequence of developmental methylmercury exposure.

Silicone thorax: a complication of tube thoracostomy in the presence of mammary implants.

Rupture of silicone breast implants is usually either iatrogenic or due to trauma. We present a case of blunt chest wall trauma in a patient with bilateral breast implants. Emergency chest tube thoracostomy resulted in rupture of one of the prostheses and caused subsequent migration of silicone into the chest cavity, where it led to empyema. The patient ultimately required a thoracotomy to evacuate the silicone and decorticate the lung. Review of the literature and methods to avoid this complication are described.

Effect of cystoscopy, prostate biopsy, and transurethral resection of prostate on serum prostate-specific antigen concentration.

To assess the effect of cystoscopy, prostate biopsy, and transurethral resection of the prostate (TURP) on the serum prostate-specific antigen (PSA) concentration, 101 patients were evaluated. For cystoscopic examination, 69 men were randomized in a prospective manner to one of three groups: flexible cystoscopy, rigid cystoscopy, and a control cohort. The median change in serum PSA was 0.1 ng/mL following flexible cystoscopy, 0.05 ng/mL after rigid cystoscopy, and 0.05 ng/mL for the control group, in which two serum PSA determinations were obtained without an intervening cystoscopy. The differences between the three groups were not statistically significant. The effect of prostate biopsy and TURP was examined in 32 men. Prostate biopsy caused an immediate elevation in the serum PSA level, with a median increase of 7.9 ng/mL (p < 0.0001). Similarly, TURP produced an elevation in the serum PSA concentration, with a median change of 5.9 ng/mL (p < 0.001). The median time required for the serum PSA value to return to a stable level after prostate biopsy was fifteen days (range: 5-21 days) for men with prostate cancer and seventeen days (range: 3-30+ days) for men without cancer, and eighteen days (range: 12-30+ days) for men who underwent TURP. These findings indicate that a serum PSA determination after either a flexible or a rigid cystoscopy is accurate and reliable. Both biopsy and TURP cause an immediate increase in the serum PSA level, which usually returns to a stable, baseline level within three weeks. However, because in some patients the serum PSA still remained elevated after four weeks, it is recommended that a serum PSA determination not be obtained for at least six weeks after either a prostate biopsy or TURP.

Long-term consequences of intraoperative spillage of bile and gallstones during laparoscopic cholecystectomy.

Laparoscopic cholecystectomy is associated with a higher incidence of iatrogenic perforation of the gallbladder than open cholecystectomy. The long-term consequences of spilled bile and gallstones are unknown. Data were collected prospectively from 1059 consecutive patients undergoing laparoscopic cholecystectomy over a 3-year period. Details of the operative procedures and postoperative course of patients in whom gallbladder perforation occurred were reviewed. Long-term follow-up (range 24 to 59 months) was available for 92% of patients. Intraoperative perforation of the gallbladder occurred in 306 patients (29%); it was more common in men and was associated with increasing age, body weight, and the presence of omental adhesions (each P < 0.001). There was no increased risk in patients with acute cholecystitis (P = 0.13). Postoperatively pyrexia was more common in patients with spillage of gallbladder contents (18% vs. 9%; P < 0.001). Of the patients with long-term follow-up, intra- abdominal abscess developed in 1 (0.6%) of 177 with spillage of only bile, and in 3 (2.9%) of 103 patients with spillage of both bile and gallstones, whereas no intra- abdominal abscesses occurred in the 697 patients in whom the gallbladder was removed intact ( P < 0.001). Intraperitoneal spillage of gallbladder contents during laparoscopic cholecystectomy is associated with an increased risk of intra-abdominal abscess. Attempts should be made to irrigate the operative field to evacuate spilled bile and to retrieve all gallstones spilled during the operative procedure.

Identification of functional domains affected by developmental exposure to methylmercury: Faroe islands and related studies.

The Faroe Islands study is a prospective study designed to assess the neurological and behavioral consequences of in utero exposure to methylmercury (meHg). Maternal exposure to meHg was through consumption of fish and intermittent higher-level exposure through pilot whale meat, while consumption of pilot whale blubber resulted in maternal exposure to PCBs. Analysis of the neurobehavioral domains affected revealed impairment in attention, memory, and auditory processing, impairment in primary auditory function, and to a lesser extent motor impairment. For four of the eight endpoints affected by meHg exposure atp < .10, impairment was also correlated (p < .10) with in utero PCB exposure as measured by cord tissue PCB levels. Further analyses provide evidence for an independent effect of PCBs and meHg on these endpoints. Cross-sectional studies in a smaller number of children in the Amazon and Madeira by the same group of investigators, in which average meHg maternal hair levels were about twice as high those in the Faroe Islands, identified auditory, visual, and/or motor deficits, with little or no evidence of deficits in attention or memory. However, the results of the cross-sectional studies must be interpreted with caution, due to limited statistical power as well as a lack of opportunity to correlate effects to in utero exposure.

Lead exposure during different developmental periods produces different effects on FI performance in monkeys tested as juveniles and adults.

Monkeys (Macaca fascicularis) were dosed with 0 or 1500 micrograms/kg/day of lead as lead acetate according to one of four regimens: Group 1, vehicle continuously from birth; Group 2, lead continuously from birth; Group 3, lead from birth to 400 days of age and vehicle thereafter; Group 4, vehicle from birth to 300 days of age and lead thereafter. Blood lead values of the three treated groups were approximately 20-35 micrograms/dl, depending on age. Performance on a multiple fixed interval-fixed ratio (mult FI-FR) schedule of reinforcement was assessed when monkeys were three years of age, and again at 7-8 years of age following exposure to other behavioral tasks. Results of the first assessment were largely negative, with lead-treated monkeys failing to exhibit the rate increases on the FI observed in previous groups of monkeys tested at the same age. The second assessment revealed increased run rates and decreased average IRTs on the FI in all three treated groups. Effects on the FR component were minimal and transient during both assessment periods, which is consistent with previous results. Monkeys in previous studies had a history of tasks with trials procedures, in which every correct response was reinforced, before being tested on the mult FI-FR. The monkeys in the present study had no such history before the first assessment, but extensive exposure to trials procedures between the first and second assessment. It may be that the negative results of the first assessment and positive results of the second are the result of an interaction of lead with such a behavioral history. This suggestion is especially compelling in view of the results from Group 3, dosed only during infancy. These monkeys were unaffected during the first assessment, performed two years after cessation of dosing, but performed differently from controls on the second assessment, performed 5-6 years after cessation of dosing. This finding, combined with data from previous experiments, suggests that the greater total dose of lead accumulated by Groups 2 and 4 between the first and second assessment is not an explanation for the difference in results. These results also indicate that exposure to lead during infancy is not necessary for FI performance to be affected, and that exposure only during infancy is sufficient to produce effects.