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Lucilla Piccari,1 Roberto Del Pozo,1 Isabel Blanco,1,2 Jessica García-Lucio,1 Yolanda Torralba,1,2 Olga Tura-Ceide,1,2 Jorge Moises,1,2 Marta Sitges,3,4 Víctor Ivo Peinado,1,2 Joan Albert Barberà1,2 1Department of Pulmonary Medicine, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; 2Biomedical Research Networking Centre on Respiratory Diseases (CIBERES), Madrid, Spain; 3Department of Cardiology, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Barcelona, Spain; 4Biomedical Research Networking Centre on Cardiovascular Diseases (CIBERCV), Madrid, SpainCorrespondence: Joan Albert BarberàDepartment of Pulmonary Medicine, Hospital Clínic, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, Barcelona 08036, SpainTel +34 932275779Email jbarbera@clinic.catIntroduction: In chronic obstructive pulmonary disease (COPD), endothelial dysfunction and stiffness of systemic arteries may contribute to increased cardiovascular risk. Pulmonary vascular disease (PVD) is frequent in COPD. The association between PVD and systemic vascular dysfunction has not been thoroughly evaluated in COPD.Methods: A total of 108 subjects were allocated into four groups (non-smoking controls, smoking controls, COPD without PVD and COPD with PVD). In systemic arteries, endothelial dysfunction was assessed by flow-mediated dilation (FMD) and arterial stiffness by pulse wave analysis (PWA) and pulse wave velocity (PWV). PVD was defined by a mean pulmonary artery pressure (PAP) ≥ 25 mmHg at right heart catheterization or by a tricuspid regurgitation velocity > 2.8 m/s at doppler echocardiography. Biomarkers of inflammation and endothelial damage were assessed in peripheral blood.Results: FMD was lower in COPD patients, with or without PVD, compared to non-smoking controls; and in patients with COPD and PVD compared to smoking controls. PWV was higher in COPD with PVD patients compared to both non-smoking and smoking controls in a model adjusted by age and the Framingham score; PWV was also higher in patients with COPD and PVD compared to COPD without PVD patients in the non-adjusted analysis. FMD and PWV correlated significantly with forced expiratory volume in the first second (FEV1), diffusing capacity for carbon monoxide (DLCO) and systolic PAP. FMD and PWV were correlated in all subjects.Discussion: We conclude that endothelial dysfunction of systemic arteries is common in COPD, irrespective if they have PVD or not. COPD patients with PVD show increased stiffness and greater impairment of endothelial function in systemic arteries. These findings suggest the association of vascular impairment in both pulmonary and systemic territories in a subset of COPD patients.Keywords: COPD, pulmonary circulation and pulmonary hypertension, emphysema, cardiovascular diseases

Karina Portillo,1 Yolanda Torralba,1,2 Isabel Blanco,1,2 Felip Burgos,1,2 Roberto Rodriguez-Roisin,1,2 Jose Rios,3 Josep Roca,1,2 Joan A Barberà1,21Department of Pulmonary Medicine, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain; 3Biostatistics and Data Management Core Facility, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Biostatistics Unit, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, SpainIntroduction: Few data are available in regards to the prevalence of pulmonary hypertension (PH) in the broad spectrum of COPD. This study was aimed at assessing the prevalence of PH in a cohort of COPD patients across the severity of airflow limitation, and reporting the hemodynamic characteristics at rest and during exercise.Methods: We performed a retrospective analysis on COPD patients who underwent right-heart catheterization in our center with measurements obtained at rest (n=139) and during exercise (n=85). PH was defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg and pulmonary capillary wedge pressure 3.Results: PH was present in 25 patients (18%). According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, PH prevalence in GOLD 2 was 7% (3 patients); 25% (14 patients) in GOLD 3; and 22% (8 patients) in GOLD 4. Severe PH (mPAP ≥35 mmHg) was identified in four patients (2.8%). Arterial partial oxygen pressure was the outcome most strongly associated with PH (r=-0.29, P

Intensive care unit discharge is an important transition that impacts a patient's wellbeing. Nurses can play an essential role in this scenario, potentiating patient empowerment. A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (the PRISMA Statement. Embase), PubMed/MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), CUIDEN Plus, and LILACS databases; these were evaluated in May 2021. Two independent reviewers analyzed the studies, extracted the data, and assessed the quality of evidence. Quality of the studies included was assessed using the Cochrane risk-of-bias tool. Of the 274 articles initially identified, eight randomized controlled trials that reported on nursing interventions had mainly focused on patients' ICU discharge preparation through information and education. The creation of ICU nurse-led teams and nurses' involvement in critical care multidisciplinary teams also aimed to support patients during ICU discharge. This systematic review provides an update on the clinical practice aimed at improving the patient experience during ICU discharge. The main nursing interventions were based on information and education, as well as the development of new nursing roles. Understanding transitional needs and patient empowerment are key to making the transition easier.

Knowledge on the sequelae of Coronavirus Disease 2019 (COVID-19) remains limited due to the relatively recent onset of this pathology. However, the literature on other types of coronavirus infections prior to COVID-19 reports that patients may experience persistent symptoms after discharge. To determine the prevalence of respiratory symptoms in survivors of hospital admission after COVID-19 infection. A living systematic review of five databases was performed in order to identify studies which reported the persistence of respiratory symptoms in COVID-19 patients after discharge. Two independent researchers reviewed and analysed the available literature, and then extracted and assessed the quality of those articles. Of the 1,154 reports returned by the initial search nine articles were found, in which 1,816 patients were included in the data synthesis. In the pooled analysis, we found a prevalence of 0.52 (CI 0.38-0.66, p < 0.01, I 2 = 97%), 0.37 (CI 0.28-0.48, p < 0.01, I 2 = 93%), 0.16 (CI 0.10-0.23, p < 0.01, I 2 = 90%) and 0.14 (CI 0.06-0.24, p < 0.01, I 2 = 96%) for fatigue, dyspnoea, chest pain, and cough, respectively. Fatigue, dyspnoea, chest pain, and cough were the most prevalent respiratory symptoms found in 52%, 37%, 16% and 14% of patients between 3 weeks and 3 months, after discharge in survivors of hospital admission by COVID-19, respectively.

Introduction: The impact of pulmonary hypertension (PH) on exercise tolerance in chronic obstructive pulmonary disease (COPD) has not been fully elucidated. It is necessary to characterize pulmonary hemodynamics in patients with moderate to severe COPD in order to improve their management. The aim of the study was to determine whether in COPD the presence of PH is associated with reduced exercise tolerance in a cohort of stable COPD patients., Methods: Cross-sectional analysis of 174 COPD patients clinically stable: 109 without PH and 65 with PH (COPD-PH). We assessed socio-demographic data, lung function, quality of life, dyspnea, cardiopulmonary exercise testing (CPET), constant workload endurance time (CWET), and six-minute walk test (6MWT). We elaborated a logistic regression model to explore the impact of PH on exercise capacity in COPD patients., Results: COPD-PH patients showed lower exercise capacity both at maximal (CPET) (43(20) versus 68(27) Watts and 50(19)% versus 71(18)% predicted peak oxygen consumption (VO 2 peak), COPD-PH and COPD, respectively), and at submaximal tests (6MWT) (382(94) versus 486(95) m). In addition, the COPD-PH group had lower endurance time than the non-PH COPD group (265(113) s and 295(164) s, respectively)., Conclusions: The presence of PH is an independent factor that impairs exercise capacity in COPD., (Copyright © 2019 The Author(s). Publicado por Elsevier España, S.L.U. All rights reserved.)

Aim: We hypothesize that training-induced changes in muscle oxygen saturation (StO 2 ) assessed by near-infrared spectroscopy (NIRS) during constant work rate cycling exercise (CWRE) may be a useful marker of the effects of training at 'vastus medialis' of the quadriceps in patients with chronic obstructive pulmonary disease (COPD)., Methods: Incremental exercise [peak oxygen uptake (VO 2 )] and CWRE at 70% pretraining peak VO 2 , before and after 8-w training, were done in 10 healthy age-matched subjects (H) [80% men, 65(11) years, FEV 1 105(14)%] and 16 COPD patients [94% men, 70(5) years, FEV 1 46(11) %] encompassing the entire spectrum of disease severity, recruited in the outpatient clinics. NIRS was used to assess StO 2 in the 'vastus medialis' of the left quadriceps., Results: Pretraining CWRE decreased StO 2 (P<0·05) and generated marked StO 2 rebound (P<0·001) after unloading in the two groups. After training, VO 2 peak increased in H [253(204) ml min -1 ] (P<0·01) and in COPD [180(183) ml·min -1 ] (P = 0·01) and blood lactate fell [-4·4 (2·7) and -1·6(2·3) mmol·m -1 ] (P<0·05 each). Training generated a further fall in StO 2 during CWRE [-10(12)% and -10(10)%, P<0·05] and increased StO 2 rebound after unloading [8(7)% and 5(9)%, P<0·05] in both groups., Conclusion: Endurance training further decreased StO 2 during CWRE, similarly in both groups, likely due to training-induced enhancement of muscle O 2 transfer and utilization. Training-induced StO 2 fall during CWRE may be useful individual marker for non-invasive assessment of enhanced muscle aerobic post-training function., (© 2019 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Background: Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction., Methods: Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45 + cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively., Results: COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45 + cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = - 0.35, p < 0.05). In pulmonary arteries, the number of CD45 + cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = - 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels., Conclusion: In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD.

Breath analysis holds the promise of a non-invasive technique for the diagnosis of diverse respiratory conditions including chronic obstructive pulmonary disease (COPD) and lung cancer. Breath contains small metabolites that may be putative biomarkers of these conditions. However, the discovery of reliable biomarkers is a considerable challenge in the presence of both clinical and instrumental confounding factors. Among the latter, instrumental time drifts are highly relevant, as since question the short and long-term validity of predictive models. In this work we present a methodology to counter instrumental drifts using information from interleaved blanks for a case study of GC-MS data from breath samples. The proposed method includes feature filtering, and additive, multiplicative and multivariate drift corrections, the latter being based on component correction. Biomarker discovery was based on genetic algorithms in a filter configuration using Fisher's ratio computed in the partial least squares-discriminant analysis subspace as a figure of merit. Using our protocol, we have been able to find nine peaks that provide a statistically significant area under the ROC curve of 0.75 for COPD discrimination. The method developed has been successfully validated using blind samples in short-term temporal validation. However, the attempt to use this model for patient screening six months later was not successful. This negative result highlights the importance of increasing validation rigor when reporting biomarker discovery results.

Background and Aim: Both interval (IT) and continuous (CT) exercise training results in an improvement of aerobic capacity in patients with chronic obstructive pulmonary disease (COPD); however, their effects on cardiac autonomic function remains unclear. The aim of our study was to evaluate the effect of a supervised CT vs IT on autonomic cardiac function in COPD patients., Methods: COPD patients were divided into two different groups according to training modality (IT or CT). Autonomic cardiac dysfunction (ACD) was defined as a heart rate recovery lower than 12 bpm heart rate after the first minute of maximal exercise (HRR1 ) and an abnormal chronotropic response (CR) to exercise (<80%)., Results: A total of 29 patients {mean [standard deviation (SD)] age: 68 (8) years, %FEV1 : 42 (13) predicted} were trained (15 subjects in the CT group, 14 subjects in the IT group). After training, both groups increased peak oxygen consumption [mean difference ΔVO2 peak: 156 mL/min (P = 0.04) on IT; and 210 mL/min (P = 0.01) on CT], HRR1 [IT, from 10.4 (5) to 13.8 (5) bpm (P = 0.04); and CT, from 14.3 (5) to 17.7 (5) bpm (P = 0.04)] and CR [IT, from 57% (22) to 81% (9) (P = 0.001); and CT, from 48% (28) to 73% (17) (P = 0.001)]. Sixteen patients showed ACD. Among these patients, HRR1 (P = 0.01 for IT and P = 0.04 for CT) and CR (P = 0.001 for IT and P = 0.002 for CT) were enhanced after training., Conclusions: Both IT and CT exercise training improve heart rate recovery and CR in COPD patients. These benefits could help to individualize exercise training., (© 2014 John Wiley & Sons Ltd.)

Background and Objective: Non-anaemic iron deficiency (NAID) might alter the oxygen pathway in health and disease. The current study aims at assessing the impact of NAID on aerobic capacity in patients with chronic obstructive pulmonary disease (COPD)., Methods: A prospective sample of 70 non-anaemic COPD patients candidate to participate in an 8-week pulmonary rehabilitation (PR) programme was studied. Incremental cycling exercise to peak oxygen uptake (V'O2peak ) and constant work-rate exercise at 80% V'O2peak to exhaustion were assessed pre- and post-PR. Training-induced increase of endurance time (ET) ≥33%, which represented the minimal clinically important difference, classified patients as responders to exercise training., Results: The prevalence of NAID was 48% (n = 34) showing no relationship with the Global Initiative for Chronic Obstructive Lung Disease stages (P = 0.209). Patients with NAID showed lower pre-training ET (P = 0.033) and V'O2peak (P = 0.007) than normal iron status (NIS) patients after adjustment for potential covariates. Significant training-induced physiological changes were seen in the NIS group (ΔV'O2peak 68(132) mL/min; P = 0.009), but not in the NAID group (ΔV'O2peak 26 (126) mL/min; P = 0.269). The NAID group showed lower percentage of responders to training (56%) than the NIS group (78%) (P = 0.041)., Conclusions: COPD patients with NAID showed lower pre-training aerobic capacity and reduced training-induced response than NIS patients after adjusting for potential confounding variables., (© 2015 Asian Pacific Society of Respirology.)

Background: The relationship between airway hyperresponsiveness (AHR) and obesity, a low-grade systemic inflammatory condition, remains largely unknown. It is established that AHR to indirect stimuli is associated with active airway inflammation. The objectives were to investigate the rate of AHR to mannitol in obese subjects and its changes 1 year after bariatric surgery (BS)., Methods: We enrolled 58 candidates to BS severely obese (33 nonsmokers and 25 smokers) without history of asthma and 20 healthy, nonobese participants and related AHR to functional findings and serum and exhaled biomarkers., Results: Before surgery, AHR was observed in 16 (28 %) obese with the provocation doses of mannitol to induce a 15 % fall in FEV1 (PD15) of (geometric mean [95 % CI]) 83 (24-145) mg. Compared to control participants, obese participants had lower spirometric values and higher serum and exhaled biomarkers (p < 0.05 each). After surgery, AHR was abolished (p < 0.01) in all but four obese subjects., Conclusions: Weight loss induced by BS was the key independent factor associated to AHR improvement. AHR to mannitol is highly prevalent in obesity, and it is largely abolished by BS.

Background: In healthy subjects, Nordic walking (NW) generates higher oxygen uptake (V˙O2) than standard walking at an equal rate of perceived exertion (RPE). The feasibility and positive outcomes of NW in patients with chronic obstructive pulmonary disease (COPD) have been reported., Objectives: The aim of the current study is to assess the physiological responses and RPE during NW in COPD patients., Methods: In 15 COPD patients [mean (SD) age 67 (9) years] with a forced expiratory volume in the 1st s of 55% (15)], V˙O2, minute ventilation and heart rate were measured with a portable system during the 6-min walking test (6MWT), incremental shuttle walking test (SWT), 6-min NW on solid ground (6mNWground) and 6-min NW on soft dry beach sand (6mNWsand). The RPE using a modified Borg scale was assessed after each test., Results: 6mNWground and 6mNWsand showed a higher V˙O2 plateau compared with the 6MWT and peak V˙O2 measured during SWT [mean (SD) V˙O2 21 (3), 22 (4), 18 (4) and 19 (5) ml·kg(-1)·min(-1), respectively; p < 0.05 each]. However, no differences in RPE were observed among 6mNWground, 6MWT and SWT [modified Borg scale score for dyspnea 4.2 (2.0), 4.1 (1.8) and 4.3 (1.7), respectively; nonsignificant]. However, RPE in 6mNWsand was significantly higher than in all the other exercise protocols [modified Borg scale score for dyspnea 5.2 (2.2); p < 0.05]., Conclusions: In COPD patients, the use of Nordic poles generates higher V˙O2 than standard walking with no differences in the dyspnea score. The results indicate the potential to enhance community-based training programs in these patients. © 2015 S. Karger AG, Basel.

Background: In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown., Objectives: To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function., Methods: 62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45(+)CD34(+)CD133(+) labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects., Results: Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries., Conclusions: Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.

Background: Abnormalities of autonomic function have been reported in patients with chronic obstructive pulmonary disease. The effect of the exercise training in heart rate recovery (HRR) has not been established in patients with COPD., Objective: To assess the effects of 8-weeks' endurance training program on parasympathetic nervous system response measured as heart rate recovery in a sample of moderate-to-severe COPD patients., Methods: We recruited a consecutive sample of patients with COPD candidates to participate in a pulmonary rehabilitation program from respiratory outpatient clinics of a tertiary hospital. HRR was calculated, before and after training, as the difference in heart rate between end-exercise and one minute thereafter (HRR1) in a constant-work rate protocol., Results: A total of 73 COPD patients were included: mean (SD) age 66 (8) years, median (P25-P75) post-bronchodilator FEV1 39 (29-53)%. The prevalence of slow HRR1 (≤12 beats) at baseline was 63%, and was associated with spirometric severity (mean FEV1 35% in slow HRR1 vs 53 in normal HRR1, p < 0.001). After 8-weeks training, HRR1 improved from mean (SD) 10 (7) to 12 (7) beats (p = 0.0127). Multivariate linear regression models showed that the only variable related to post-training HRR1 was pre-training HRR1 (p < 0.001)., Conclusions: These results suggest that training enhances HRR in patients with moderate-to-severe COPD. HRR is an easy tool to evaluate ANS such that it may be a useful clinical marker of parasympathetic nervous system response in patients with COPD.

Rationale: The wreckage of the oil tanker Prestige in November 2002 produced heavy contamination off the coast of Galicia, Spain., Objectives: To evaluate the prevalence of respiratory symptoms in local fishermen more than 1 year after having participated in clean-up work., Methods: Questionnaires including qualitative and quantitative information about clean-up activities and respiratory symptoms were distributed among associates of 38 fishermen's cooperatives. Both postal and telephone follow-up was performed. The association between participation in clean-up work and respiratory symptoms was evaluated using multiple logistic regression analyses, adjusted for sex, age, and smoking status., Measurements and Main Results: Between January 2004 and February 2005, data were obtained from 6,780 fishermen (response rate, 76%). Sixty-three percent had participated in clean-up operations. Lower respiratory tract symptoms (LRTS) were more prevalent in clean-up workers: odds ratio (OR), 1.73; 95% confidence interval (CI), 1.54-1.94. This association was consistent for men and women, for different fishermen's cooperatives, and for different types of respiratory symptoms, and remained after excluding those who reported anxiety or believed that the oil spill had affected their health (OR, 1.57; 95% CI, 1.37-1.80). The risk of LRTS increased with the number of exposed days, exposed hours per day, and number of activities (linear trend, P < 0.0001). The excess risk of LRTS decreased when more time had elapsed since last exposure: OR, 2.33, 1.69, and 1.24 for less than 14 months, 14-20 months, and more than 20 months, respectively., Conclusions: Participation in clean-up work of oil spills may result in prolonged respiratory symptoms that last 1 to 2 years after exposure.

A transplanted mammary fibroadenoma was found to grow in 95 per cent of intact adult female rats and the increment of tumor weights was progressive and logarithmic. The growth of the tumor was retarded by ovariectomy and still more when this was combined with adrenalectomy. In ovariectomized rats the growth of the tumor was stimulated by phenolic estrogens, this increase being enhanced when progesterone was added. In these responses to hormonal changes the mammary gland and the tumor resembled each other. Yet there are many differences between the growth of the fibroadenoma and that of the mammary gland. In contrast to the progressive growth which occurred in intact adult females there was a prolonged period of indolent growth of transplants in hypophysectomized rats; but after many weeks active growth began and the tumors eventually reached large size. During the period of quiescent growth the tumor was cytologically atrophic but after the growth spurt had started the microscopic appearance of the fibroadenoma resembled that of tumors growing in normal adult females. The mammary gland remained atrophic during both the slow and the accelerated phases of tumor growth, and so too with the other secondary sex expressions. In hypophysectomized rats estrone and progesterone, when combined, stimulated the growth of the tumor, and this growth was accelerated by the additional administration of lactogenic or growth hormones. None of these hormones, separately, stimulated the growth of the tumor. In ovariectomized rats other differences were demonstrated between the growth of the mammary gland and the fibroadenoma. Progesterone, injected alone, accelerated the growth of the tumor but not that of the mammary glands. The administration of phenolic estrogens exerted a biphasic effect on the growth of the tumor whilst that on the breast of its hosts was monophasic. With progressively increasing doses of these phenols there occurred primarily an augmentation of the rate of growth of the tumor until a peak was achieved; an increase of the dose above the optimal amount depressed the growth of the tumor. The stage of depression of growth was not observed in the mammary glands of these tumor-bearing rats. Many steroids which induced gestational changes in the mammary gland accelerated the growth of the tumor. Among these were estrone and progesterone in combination and 17alpha-ethinyl-19-nor-testosterone administered alone. But gestational changes developed in the mammary gland of rats treated with 4-androstene-3alpha,17beta-diol, without growth of the tumor. The evidence which we have presented proves that the mammary fibroadenoma tested had some of the functional properties of a normal mammary gland, and neoplastic traits as well. In its response to hormones it had characteristics which set it apart from all other endocrine targets of the rat.