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Background/aim: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Patients eligible for surgery have better overall survival rate than patients who are not eligible. We investigated the prognostic value of p16 in patients who underwent surgery for lung cancer, in association with other factors such as PD-L1 and Ki-67., Materials and Methods: Expression of p16 was evaluated along with the presence of Ki-67 and PD-L1 in 256 NSCLC patients treated only surgically., Results: Adenocarcinoma was the prevalent histotype (56%) followed by squamous cell (29%) and differentiation grade of 3 was the most common (60%). p16 was detected in 83 patients (30%): low positivity (<10% cells) was observed in 30 samples (11%) and high positivity (>10 % cells) in 53 patients (20%). Ki-67 was detected in 89 patients (34%) with mild positivity in 46 patients (10-25% cells), moderate positivity (26-75% cells) in 30 patients (11%), and high positivity (>75% cells) in 13 patients (5%). An influence of p16 expression (p<0.05) along with grading and staging on overall survival (OS) was found. The average OS was 36 months, but the OS increased up to 54 months when patients were stratified according to p16 expression levels. The stratification by staging showed a significant prognostic value for p16 at an early stage (p<0.014)., Conclusion: p16 significantly influences prognosis, notably at an early stage, along with other variables such as grading and staging., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: For several years non-small cell lung cancer (NSCLC) has been considered non-immunogenic. Recent advances in antitumor immunity brought to the discovery of checkpoints that modulate immune response against cancer. One of them is programmed death receptor 1 (PD-1) and its ligand (PD-L1). Although PD-L1 expression seems predictive of response to anti-PD-1/PD-L1 agents, its prognostic value is unclear. In this study we investigated the prognostic value of PD-L1 expression and its correlation with clinical-pathological characteristics in a cohort of surgically resected NSCLC., Material and Methods: PD-L1 expression was evaluated in 289 surgically resected NSCLC samples by immunohistochemistry. Our cohort included patients not exposed to adjuvant chemotherapy. PD-L1 status was defined as: 1) PD-L1 high (tumor proportion score, TPS≥50%), PD-L1 low (TPS 1-49%), PD-L1 negative (TPS<1%); 2) PD-L1 positive (TPS≥50%) and negative (TPS<50%); 3) as a continuous variable., Results: Patients were mostly males (79%), former or current smokers (81%), with a median age of 67 years, non-squamous histology (67.5%) and high-grade tumors (55%). PD-L1 tumors were 18.7%. There was no significant association with sex, age, smoking status and histology. A strong correlation between high PD-L1 expression and tumor grade was detected. The difference in median OS in the different groups of patients was not statistically significant., Conclusion: PD-L1 is not prognostic in surgically resected NSCLC. The association with tumor differentiation suggests that grading could represent an easy-to-assess tool for selecting subjects potentially sensitive to immunotherapy warranting further investigations., Competing Interests: CONFLICTS OF INTEREST Dr Federico Cappuzzo: consultancy and advisory boards for Roche, Astrazeneca, BMS, MSD, Pfizer.

Purpose: Post-operative pain and swelling are frequently observed after sinus lift procedures. The aim of the present study was the clinical evaluation of swelling and pain of two different sinus flap lift techniques using a visual analogue scale (VAS), verbal rating scale (VRS), and infrared thermal imaging (i.e., thermography). Materials Methods : A randomized controlled trial was conducted with 15 patients (30 sinuses in total) randomly allocated into two groups. For the sinuses of Group I a trapezoidal flap was used, while for Group II a modified triangular flap without anterior release was utilized. Postoperative pain was scored by means of a 100-mm VAS ranging from 0 (no pain) to 100 (worst pain imaginable), and was recorded at 2, 4, 6 and 14 days after surgery. Swelling was recorded by a verbal rating scale (VRS) and was classified into four categories: a score of 1 referred the absence of swelling, patients with intra-oral swelling in the surgical zone scored 2, any extra-oral swelling in the surgical zone scored 3, and intense swelling exhibited by extra-oral swelling extending beyond the surgical zone scored 4. The facial temperature was recorded before and after sinus augmentation, and at 2, 4, 6, and 14 days post-surgery to check the course of healing. Results : In Group I pain intensity was recorded at 2 days after surgery with a mean score of 38.67 ± 6.4 mm. Swelling was greater at 2 and 4 days, and was absent at day 6. The facial temperature difference before and after the procedure was 4.737 &deg;C ± 0.37. In Group II the pain score were lower than in Group I ( p < 0.05). The score for swelling was 2 on the first and second days, and was reduced on day 4. After the second day the difference in temperature was significantly reduced as compared to the day of surgery (0.77 &deg;C); at 2 and 4 days no difference was registered. Conclusions : The results of this clinical study show the significant effectiveness of the modified triangular flap in the sinus lift procedure for reducing pain and swelling.

The treatment of non-small-cell lung cancer (NSCLC) has historically been based on platinum doublets- and taxan-based chemotherapy in the first- and second-line therapy, respectively. Although new agents have emerged for patients with driver mutations, treatment options for nononcogene addicted NSCLC have not changed for years. However, the last 5 years have seen the approval and introduction of new biological agents, such as immune checkpoint inhibitors and antiangiogenic drugs. The aim of this review is to give readers an update on the news in the treatment of nononcogene addicted NSCLC. As more and more therapeutic options are now available, we will delineate a potential therapeutic algorithm for the optimization of daily life treatment choice of NSCLC patients.

Background: This study aimed at investigating feasibility of programmed death ligand-1 (PD-L1) testing in plasma samples of advanced NSCLC patients receiving first-line treatment, assessing whether circulating (c)PD-L1 levels were modified by the therapy and whether baseline cPD-L1 levels were associated with patients' clinical responses and survival outcome., Methods: Peripheral blood samples were collected from 16 healthy volunteers and 56 newly diagnosed NSCLC patients before and at 12th week during the course of first-line therapy. The level of PD-L1 was measured in plasma samples using the human (PD-L1/CD274) ELISA kit (CUSABIO, MD, USA). The Mann Whitney test or Fisher's test were used for comparisons. Survival analysis was performed using Kaplan Meyer method, providing median and p -value., Results: Baseline median cPD-L1 was 42.21 pg/ml (range 12.00-143.49) in NSCLC patients and 37.81 pg/ml (range 9.73-90.21) in healthy control cohort ( p = 0.78). Median cPD-L1 increased in patients treated with first-line chemotherapy (63.20 pg/ml vs 39.34 pg/ml; p = 0.002), with no changes in patients exposed to non-chemotherapy drugs (42.39 pg/ml vs 50.67 pg/ml; p = 0.398). Time to progression and overall survival were 4.4 vs 6.9 months ( p = 0.062) and 8.8 vs 9.3 months ( p = 0.216) in cPD-L1 positive vs cPD-L1 negative patients. Baseline cPD-L1 levels increased with the ascending number of metastatic sites, even if the association was not statistically significant ( p = 0.063)., Conclusions: This study showed that cPD-L1 testing is feasible, with chemotherapy influencing PD-L1 plasma levels. The possibility of using such test for predicting or monitoring the effect of immunotherapy or combination of chemotherapy and immunotherapy warrant further investigations., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interests to declare

Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas G12D in mouse lung epithelial cells markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas G12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer., (© 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Cancer stem cells represent a population of immature tumor cells found in most solid tumors. Their peculiar features make them ideal models for studying drug resistance and sensitivity. In this study, we investigated whether cancer stem cells isolation and in vitro sensitivity assay are feasible in a clinical setting., Methods: Cancer stem cells were isolated from effusions or fresh cancer tissue of 23 patients who progressed after standard therapy failure. Specific culture conditions selected for immature tumor cells that express markers of stemness. These cells were exposed in vitro to chemotherapeutic and targeted agents., Results: Cancer stem cells were extracted from liver metastases in 6 cases (25%), lung nodules in 2 (8%), lymph node metastases in 3 (12.5%) and pleural/peritoneal/pericardial effusion in 13 (54%). Cancer stem cells were successfully isolated in 15 patients (63%), including 14 with lung cancer (93.3%). A sensitivity assay was successfully performed in 7 patients (30.4%), with a median of 15 drugs/combinations tested (range 5-28) and a median time required for results of 51 days (range 37-95)., Conclusion: The approach used for the STELLA trial allowed isolation of cancer stem cells in a consistent proportion of patients. The low percentage of cases completing the full procedure and the long median time for obtaining results highlights the need for a more efficient procedure., Trial Registration: ClinalTrials.gov NCT01483001.

The development of targeted therapies has changed the approach to early oncological clinical trial design. Identification of patient populations most likely to derive benefit and the biologically effective dose are now as important as determination of the maximum tolerated dose. Completion of the 'pharmacological audit trail' highlights drugs most likely to progress through to license, so resources can be allocated appropriately. Key to the success of this changing model is the validation/qualification of circulating biomarkers. These might provide a readily accessible and dynamic picture of drug effect, tumor response and toxicity with minimum risk to patients. This review article examines circulating biomarkers currently used in early oncological clinical trials. It considers the evidence for their employment, limitations and challenges for future development.

The first targeted agents approved for non-small cell lung cancer (NSCLC) treatment, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, have an impressive activity in the presence of activating mutations of the EGFR gene. However, all patients develop acquired resistance principally through secondary mutations (T790M), HER2 amplification, MET amplification, and other molecular aberrations. An attempt to overcome EGFR TKI resistance has been through the development of irreversible blockers. Afatinib is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family. The pharmacologic properties of afatinib (formation of covalent bonds, inhibition of other family members, and in vitro and in vivo activity on T790M mutation positive tumors) made this drug particularly appealing to study in clinic. Therefore, an intense program of clinical research (LUX-Lung program) was started and clinical results have shown very encouraging activity profiles in patients harboring EGFR activating mutations and in those with acquired resistance to reversible TKIs.

In the last decade, new insights in molecular biology have changed the therapeutic landscape of non-small-cell lung cancer. Since 2004, when activating mutations of the EGFR were firstly identified, several genetic aberrations have been discovered, mainly in adenocarcinoma. EGFR mutations are a relatively frequent event in non-small-cell lung cancer, generally consisting of exon 19 deletion or exon 21 substitution. In adenocarcinoma, additional rare mutations are detectable in the EGFR gene, as well as in other genes, including ALK, ROS1, RET, HER2 and BRAF. Recent studies in squamous cell carcinoma identified TP53 as the most frequent mutation, followed by additional more rare mutations, including PI3KCA, PTEN, DDR2 and FGFR. The aim of the present review is to analyze the potential prognostic and predictive role of rare mutations.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths. In the last decade the EGF receptor (EGFR) signaling pathway has emerged as one of the most important molecular aberrations in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR-TKI), such as erlotinib or gefitinib, demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harboring activating mutations of the EGFR gene. Results of large Phase III randomized trials clearly demonstrated that an EGFR-TKI is the best front-line option for patients with classical EGFR mutations, while in the EGFR wild-type or EGFR unknown population platinum-based chemotherapy remains the gold standard. In pretreated patients, EGFR-TKIs are considered more effective than standard chemotherapy in the EGFR-mutated population, with no difference in EGFR wild-type NSCLC. Although EGFR-TKIs are certainly particularly effective in patients with EGFR mutations, at present no biomarker, including KRAS mutations, can be recommended in clinical practice for precluding the therapy to any pretreated patient. In this article, the authors analyzed data of erlotinib in NSCLC, focusing on its role in front-line therapy.

Purpose of Review: Treatment of advanced nonsmall cell lung cancer (NSCLC) has rapidly changed over the last decade. On the basis of the progress made in cancer biology, the old-fashioned 'one size fits all' chemotherapeutic approach is shifting to a novel approach in which treatment choice is mainly based on the tumor's biological genotype. The aim of the present review is to describe the anaplastic lymphoma kinase (ALK) translocation as a prominent molecular driver aberration in NSCLC, its prognostic and predictive role, and the new available treatment options., Recent Findings: Crizotinib is a tyrosine kinase inhibitor of MET, ALK and ROS1. Its impressive clinical activity shown in a phase IB trial led to accelerated approval for patients with ALK-positive advanced NSCLC. More recently, a phase III trial confirmed the high activity of crizotinib in this subset of lung tumors. Many new-generation ALK inhibitors are currently also in clinical development., Summary: ALK-positive NSCLC has emerged as a distinct, well defined subset of lung malignancies. The use of ALK inhibitors deeply impacts the therapy of patients harboring such translocation. Nevertheless, to date, several issues remain open, such as the most suitable screening and diagnostic method for the detection of ALK gene rearrangement and expression and particularly the mechanisms of acquired resistance for further clinical development of these agents.

Lung cancer treatment has rapidly changed in the last few years thanks to novel insights into cancer biology. Several biomarkers and signaling pathways have been recognized as conceivable targets for treatment, and among them is the mesenchymal-epithelial transition/hepatocyte growth factor (c-MET/HGF) axis. Alterations in the c-MET gene and aberrations of MET and HGF expression impact on lung cancer prognosis and are involved in resistance to epidermal growth factor receptor (EGFR) inhibitors in non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Several anti-MET and anti-HGF strategies are currently under investigation, including monoclonal antibodies. Ficlatuzumab is a monoclonal antibody directed against HGF that is currently under investigation in NSCLC. The aim of the present review is to critically review available data on HGF and ficlatuzumab in NSCLC.

The epidermal growth factor receptor (EGFR) mutation is the first recognized molecular target in non-small cell lung cancer that makes personalized therapy feasible. This molecular alteration has been demonstrated to be more frequent in Asians, non-smokers and patients with adenocarcinoma histology. Several retrospective and subgroup analyses of phase III trials have shown the single agent, erlotinib, to be associated with higher response rates and longer progression-free survival in patients harbouring an EGFR mutation. Two prospective randomized phase III studies from China and Europe have confirmed the role of first-line erlotinib in patients with the mutations. Erlotinib has also been evaluated in combination with chemotherapy in either a concurrent or intercalated regimen. Earlier trials were limited by little information on the EGFR mutational status of the enrolled patients, and an ongoing phase III trial with translational biomarker analysis will provide more comprehensive data on the combination.

Non-small-cell lung cancer (NSCLC) is a heterogeneous disease due to the presence of different clinically relevant molecular subtypes. Until today, several biological events have been identified in lung adenocarcinoma, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, offering new hopes to patients with metastatic disease. Unfortunately, in approximately 50% of adenocarcinoma and for those harbouring K-RAS mutations, the most frequent mutation in Caucasian lung adenocarcinoma, so far no specific drug demonstrated efficacy. The rat sarcoma (RAS) genes, including H-RAS, K-RAS, and N-RAS, encode a family of proteins regulating cell growth, differentiation, and apoptosis. K-RAS mutations are present in 20-30% of NSCLC and occur most commonly, but not exclusively, in adenocarcinoma histology and life-long smokers. Although in colorectal cancer patients K-RAS mutations represent a validated negative predictive biomarker for treatment with anti-EGFR monoclonal antibodies, their role in selecting specific treatment for NSCLC patients remains undefined. Aim of the present paper is to critically analyze the prognostic and predictive value of K-RAS mutations in NSCLC.

First- and second-order theory of mind (ToM) abilities seem to form a hierarchy of mind states within the same construct. If so, no ability in higher comprehension of intentionality would be possible when the previous one is failing. The purpose of the study is to investigate this hierarchy in a sample of schizophrenic subjects. Insofar as ToM defines processes involved in a multi-level social cognitive processing, they could be part of a scenario of specialized areas performing different parallel computations. Therefore, we further investigated the relationship of ToM scores to metacognitive indexes, widely demonstrated to be involved in social cognition, symptomatology and global functionality, in two independent samples of subjects with schizophrenia. Thirty-eight subjects with schizophrenia were preliminarily examined for first- and second-order ToM, using only one story in each order. Cross-tabulation of subjects according to their answers revealed that 13.2% of subjects gave incorrect answers to ToM I but correct answers to ToM II. A more extensive examination of first- and second-order ToM in a sample of 42 subjects with schizophrenia was then performed. The results confirmed the existence of a group of subjects (11.9%) scoring incorrectly at ToM I but correctly at ToM II, which is unexplainable if the hierarchical hypothesis were true. While both ToM scores were highly correlated with metacognitive scores on the Positive and Negative Syndrome Scale (PANSS), for both positive and negative clusters, and only second-order ToM was correlated with scores on the Global Assessment of Function (GAF). On the other hand, meta-cognitive indexes were correlated with both PANSS and GAF scores. First-order ToM was found to play an essential role in determining clinical severity. ToM I and II order scores share a minor part of variance. Instead of hierarchically ordered mind states, first- and second-order intentionality can represent different constructs. The ability to 'understand others', i.e. ToM, can be dissociable, suggesting the existence of an interconnected network of different constructs deputed to an adequate understanding and management of the social world complexity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The paradigm for first-line treatment of relapsed or metastatic non-small cell lung cancer (NSCLC) is changing. Large phase III trials demonstrated that, in 2010, we cannot select a therapy without an accurate definition of tumor histology and epidermal growth factor receptor (EGFR) status. Patients harboring an EGFR-activating mutation have a better prognosis and certainly are extremely sensitive to EGFR-tyrosine kinase inhibitors, while other agents, such as bevacizumab or pemetrexed, are more effective and less toxic in patients with non-squamous histology. Moreover, data from large phase III trials demonstrated that maintenance therapy with pemetrexed, docetaxel or erlotinib is an effective strategy against metastatic NSCLC. Overall, the changing paradigm in first-line treatment of NSCLC inevitably is changing the second-line strategy. In addition, the emerging role of maintenance therapy is leading to early use of all agents potentially active in a second- or third-line setting, with the consequence that very few options are available at disease progression. The aim of this article is to discuss the consequences of targeted treatments for second-line therapy in metastatic NSCLC.

Purpose: The aims of the present study were to evaluate the clinical activity and the pharmacodynamic profile of the novel schedule of a single i.v. standard dose of cyclophosphamide (CTX) immediately followed by an oral metronomic CTX regimen with celecoxib (CXB) and dexamethasone (DEX) in advanced hormone-refractory prostate cancer patients., Experimental Design: Twenty-eight patients (68% docetaxel-resistant) received 500 mg/m2 CTX i.v. bolus on day 1 and, from day 2, 50 mg/day CTX p.o. plus 200 mg/twice a day CXB p.o. and 1 mg/day DEX p.o. until disease progression. Plasma vascular endothelial growth factor (VEGF) and thrombospondin-1 were detected by ELISA, and real-time reverse transcription-PCR of VEGF and thrombospondin-1 gene expression on peripheral blood mononuclear cell and of VE-cadherin (VE-C) in blood samples was done., Results: A confirmed prostate-specific antigen decrease of > or =50% from baseline was observed in 9 of 28 patients (32%). Median progression-free survival and overall survival were 3 months (95% confidence interval, 2.2-4.2 months) and 21 months (95% confidence interval, 12.4-29.4 months), respectively. Toxicity was mild and no grade 3 to 4 toxicities occurred. A significant relationship was found between plasma VEGF and prostate-specific antigen values (r = 0.4223; P < 0.001). VEGF levels significantly increased in nonresponders, whereas the responder patients maintained significantly lower levels of VE-C gene expression after the beginning of the treatment if compared with nonresponder ones., Conclusion: Metronomic CTX plus CXB and DEX showed favorable toxicity and activity profile in patients. VE-C gene expression and VEGF levels represent potentially useful pharmacodynamic markers for the clinical response.

The long-term results of a technique for correction of syndactyly are reported. The technique consists of a dorsal omega flap and a palmar anchor forming two palmar and lateral flaps. A long-term review was made of 50 patients with a minimum of 8 years follow-up operated over a period of 10 years. A total of 122 web spaces in simple, complex and syndromic syndactyly were operated on. Most patients achieved satisfactory reconstruction of the web spaces, resulting in a web of good shape. At long-term review, web creep was recorded in eight webs, and skin contractures in three fingers. This study shows the technique to be effective in reconstructing web spaces and in minimizing the prevalence of complications.

Tissue expansion has been advocated as a method of obtaining enough skin to correct syndactyly without using skin grafts. However, results have been disappointing, indications are unclear, and complication rates are still relatively high. We review the published cases of syndactyly treated with tissue expansion, acknowledging the lack of data and guidelines for its use in such condition. After more than 10 years since its introduction in the treatment of syndactyly, its use is still not as widespread as one would have been led to expect.

Many fingertip injuries in childhood involve the nail bed. Deformities of the nail are a frequent result of failure to repair the nail bed at the time of injury. Secondary correction of nail deformities seldom achieves good results. We present the results of our experience in the management of 19 children with 22 injuries involving the nail bed. All achieved normal nail growth and the overall result of the repair was good in 91%. Complications were few and parental satisfaction with the management was high. Every effort should be made to perform a meticulous primary repair of all nail bed injuries.

A case of partial traumatic division of a Dupuytren's band in a 56-year-old man with known Dupuytren's disease is described. Management consisted of exploration of the wound and limited fasciectomy, with excision of the diseased fascia, the pretendinous band, the lateral cord and the spiral cord. Postoperative recovery was uneventful, and the patient returned to work. He remains well two years after the injury.

The authors examined prospectively 100 patients with lung diseases--50 of them benign and 50 malignant. The mean value of all lesions was measured with a constant region of interest (ROI); the muscle was considered as the reference tissue. Histopathology was the gold standard for the patients who underwent CT-guided needle biopsy and/or surgery; clinical-radiologic follow-up (average time: 2 years) was the gold standard for nonsurgical patients. A superconductive 1.5-T magnet with circular polarization body coil was used; T1- and T2-weighted spin echo images were acquired on the coronal and axial planes, respectively. The mean values with the constant ROI were measured both on the lesions and on the reference tissue to calculate and compare the T1-lesion/T1-muscle and T2-lesion/T2-muscle ratios in benign and malignant conditions. The t-test, the linear regression and correlation test and the analysis of variance were used to analyze the data. T1 benign lung disease/T1 muscle ratio was 1.21, while T1 malignant lung disease/T1 muscle ratio was 1.27, with no statistically significant difference. T2 benign lung disease/T2 muscle ratio was 2.63, while T2 malignant lung disease/T2 muscle ratio was 4.80: the difference was statistically significant (p < 0.001). To conclude, in chest diseases, the measurement of mean values in T2 allowed malignancy-indicative values (> 4 ratio) and positively benign values (< 2.5 ratio) to be identified.

Muscular exercise is accompanied by evident and perfectly matched cardiovascular and respiratory adjustments to avoid changes in arterial blood gases. The mechanisms responsible for this perfect regulation have not yet been defined. Our previous experimental investigations have shown that a consistent rate of cardiorespiratory reflex responses to exercise is caused by chemosensitive muscular receptors activation. The 2 different types of classical muscular exercise (rhythmic and isometric exercise) are joined with the 2 different patterns of cardiorespiratory reflex responses attributed in our opinion to the activation of 2 different kinds of muscle receptors (K and P). It has been observed that the increase in ventilation (VE), elicited by activation of both types of chemoreceptors during muscular experimental exercise is not accompanied by significant variations of partial pressure of CO2 (PaCO2) in the arterial blood (isocapnic hyperpnea). This suggest that muscular chemoreceptor activation during physical exercise determines an adequate cardiopulmonary matching. The main purpose of the present study has been to verify, in anesthetized rabbits, if also the chemical activation of muscular receptors was able to evoke reflexly an adequate degree of cardiopulmonary matching. The ventilation reflex changes and the concomitant variations of PaCO2 induced by injection of bradikinin (BK 250 ng) and hypertonic solutions (NaCl 10% 1 ml) in femoral artery have been evaluated in 10 anesthetized rabbits. The PaCO2 modifications observed during reflex hyperpnea have been compared with those recorded during hyperpnea induced by artificial ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)