Mapping the cancer surface proteome in search of target antigens for immunotherapy.

Immune-based therapeutic interventions recognizing proteins localized on the cell surface of cancer cells are emerging as a promising cancer treatment. Antibody-based therapies and engineered T cells are now approved by the Food and Drug Administration to treat some malignancies. These therapies utilize a few cell surface proteins highly expressed on cancer cells to release the negative regulation of immune activation that limits antitumor responses (e.g., PD-1, PD-L1, CTLA4) or to redirect the T cell specificity toward blood cancer cells (e.g., CD19 and B cell maturation antigen). One limitation preventing broader application of these novel therapeutic strategies to all cancer types is the lack of suitable target antigens for all indications owing in part to the challenges in identifying such targets. Ideal target antigens are cell surface proteins highly expressed on malignant cells and absent in healthy tissues. Technological advances in mass spectrometry, enrichment protocols, and computational tools for cell surface protein isolation and annotation have recently enabled comprehensive analyses of the cancer cell surface proteome, from which novel immunotherapeutic target antigens may emerge. Here, we review the most recent progress in this field.

A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.

The Antioxidant Effect of Dietary Bioactives Arises from the Interplay between the Physiology of the Host and the Gut Microbiota: Involvement of Short-Chain Fatty Acids.

The maintenance of redox homeostasis is associated with a healthy status while the disruption of this mechanism leads to the development of various pathological conditions. Bioactive molecules such as carbohydrates accessible to the microbiota (MACs), polyphenols, and polyunsaturated fatty acids (PUFAs) are food components best characterized for their beneficial effect on human health. In particular, increasing evidence suggests that their antioxidant ability is involved in the prevention of several human diseases. Some experimental data indicate that the activation of the nuclear factor 2-related erythroid 2 (Nrf2) pathway-the key mechanism in the maintenance of redox homeostasis-is involved in the beneficial effects exerted by the intake of PUFAs and polyphenols. However, it is known that the latter must be metabolized before becoming active and that the intestinal microbiota play a key role in the biotransformation of some ingested food components. In addition, recent studies, indicating the efficacy of the MACs, polyphenols, and PUFAs in increasing the microbial population with the ability to yield biologically active metabolites (e.g., polyphenol metabolites, short-chain fatty acids (SCFAs)), support the hypothesis that these factors are responsible for the antioxidant action on the physiology of the host. The underlying mechanisms through which MACs, polyphenols, and PUFAs might influence the redox status have not been fully elucidated, but based on the efficacy of SCFAs as Nrf2 activators, their contribution to the antioxidant efficacy of dietary bioactives cannot be excluded. In this review, we aimed to summarize the main mechanisms through which MACs, polyphenols, and PUFAs can modulate the host's redox homeostasis through their ability to directly or indirectly activate the Nrf2 pathway. We discuss their probiotic effects and the role played by the alteration of the metabolism/composition of the gut microbiota in the generation of potential Nrf2-ligands (e.g., SCFAs) in the host's redox homeostasis.

Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways.

Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.

Organic extract of Geodia cydonium induces cell cycle block in human mesothelioma cells.

The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species Geodia cydonium represents a potential source of these type of products with considerable biotechnological interest as pharmaceutical agents. The present study demonstrated the antiproliferative effect of an organic G. cydonium extract (GEOCYDO) against three human mesothelioma cell lines, MSTO-211H (MSTO), NCI-H2452 (NCI) and Ist-Mes2 (Mes2), which differ in their sensitivity (MSTO and NCI) and resistance (Mes2) to standard combined treatment with cisplatin and piroxicam. To this aim, the activity of the extract was evaluated by analyzing its effects on cell viability, cancer properties and cell cycle progression by means of colony formation assay, cell cycle analysis and protein expression analysis. The results revealed, in mesothelioma, this extract was able to reduce self-renewal, cell migration and it could induce cell cycle arrest in G0/G1 stage, thus blocking cell proliferation. In conclusion, to the best of our knowledge, the present results indicated for the first time that GEOCYDO can contain active compounds able to affect cell proliferation in mesothelioma, suggesting that it could be considered as a potential novel drug source for cancer treatment.

Bioactive Polyphenols and Neuromodulation: Molecular Mechanisms in Neurodegeneration.

The interest in dietary polyphenols in recent years has greatly increased due to their antioxidant bioactivity with preventive properties against chronic diseases. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and are able to neutralize the effects of oxidative stress, inflammation, and apoptosis. Interestingly, all these mechanisms are involved in neurodegeneration. Although polyphenols display differences in their effectiveness due to interindividual variability, recent studies indicated that bioactive polyphenols in food and beverages promote health and prevent age-related cognitive decline. Polyphenols have a poor bioavailability and their digestion by gut microbiota produces active metabolites. In fact, dietary bioactive polyphenols need to be modified by microbiota present in the intestine before being absorbed, and to exert health preventive effects by interacting with cellular signalling pathways. This literature review includes an evaluation of the literature in English up to December 2019 in PubMed and Web of Science databases. A total of 307 studies, consisting of research reports, review articles and articles were examined and 146 were included. The review highlights the role of bioactive polyphenols in neurodegeneration, with a particular emphasis on the cellular and molecular mechanisms that are modulated by polyphenols involved in protection from oxidative stress and apoptosis prevention.

Ginkgo biloba Prevents Oxidative Stress-Induced Apoptosis Blocking p53 Activation in Neuroblastoma Cells.

Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress-especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H2O2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H2O2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases.

Curcumin, Gut Microbiota, and Neuroprotection.

Curcumin, a nontoxic, naturally occurring polyphenol, has been recently proposed for the management of neurodegenerative and neurological diseases. However, a discrepancy exists between the well-documented pharmacological activities that curcumin seems to possess in vivo and its poor aqueous solubility, bioavailability, and pharmacokinetic profiles that should limit any therapeutic effect. Thus, it is possible that curcumin could exert direct regulative effects primarily in the gastrointestinal tract, where high concentrations of curcumin are present after oral administration. Indeed, a new working hypothesis that could explain the neuroprotective role of curcumin despite its limited availability is that curcumin acts indirectly on the central nervous system by influencing the "microbiota-gut-brain axis", a complex bidirectional system in which the microbiome and its composition represent a factor which preserves and determines brain "health". Interestingly, curcumin and its metabolites might provide benefit by restoring dysbiosis of gut microbiome. Conversely, curcumin is subject to bacterial enzymatic modifications, forming pharmacologically more active metabolites than curcumin. These mutual interactions allow to keep proper individual physiologic functions and play a key role in neuroprotection.

Curcumin C3 complex®/Bioperine® has antineoplastic activity in mesothelioma: an in vitro and in vivo analysis.

BACKGROUND: A major limitation in the treatment for malignant mesothelioma is related to serious side effects caused by chemotherapeutics and to the development of cancer-resistance. Advances in cancer therapies have been reached thanks to the introduction of alternative approaches, such as the use of phytochemicals. Curcumin-C3complex®/Bioperine® is a commercially standardized extract containing a ratio-defined mixture of three curcuminoids and piperine that greatly increase its bioavailability. Interestingly, the anticancer effect of this formulation has been described in different studies and several clinical trials have been started, but to our knowledge none refers to human mesothelioma. METHODS: Curcumin-C3complex®/Bioperine® anticancer effect was evaluated in vitro in different human mesothelioma cell lines analysing cell proliferation, colony-forming assay, wound healing assays, invasion assay and FACS analysis. In vivo anticancer properties were analysed in a mesothelioma xenograft mouse model in CD1 Nude mice. RESULTS: Curcumin-C3complex®/Bioperine® in vitro induced growth inhibition in all mesothelioma cell lines analysed in a dose- and time-depended manner and reduced self-renewal cell migration and cell invasive ability. Cell death was due to apoptosis. The analysis of the molecular signalling pathway suggested that intrinsic apoptotic pathway is activated by this treatment. This treatment in vivo delayed the growth of the ectopic tumours in a mesothelioma xenograft mouse model. CONCLUSIONS: Curcumin-C3complex®/Bioperine® treatment strongly reduces in vitro tumorigenic properties of mesothelioma cells by impairing cellular self-renewal ability, proliferative cell rate and cell migration and delays tumor growth in xenograft mouse model by reducing angiogenesis and increasing apoptosis. Considering that curcumin in vivo synergizes drug effects, its administration to treatment regimen may help to enhance drug therapeutic efficacy in mesothelioma. Our results suggest that implementation of standard pharmacological therapies with novel compounds may pave the way to develop alternative approaches to mesothelioma.

Polyphenols-gut microbiota interplay and brain neuromodulation.

Increasing evidence suggests that food ingested polyphenols can have beneficial effects in neuronal protection acting against oxidative stress and inflammatory injury. Moreover, polyphenols have been reported to promote cognitive functions. Biotransformation of polyphenols is needed to obtain metabolites active in brain and it occurs through their processing by gut microbiota. Polyphenols metabolites could directly act as neurotransmitters crossing the blood-brain barrier or indirectly by modulating the cerebrovascular system. The microbiota-gut-brain axis is considered a neuroendocrine system that acts bidirectionally and plays an important role in stress responses. The metabolites produced by microbiota metabolism can modulate gut bacterial composition and brain biochemistry acting as neurotransmitters in the central nervous system. Gut microbiota composition can be influenced by dietary ingestion of natural bioactive molecules such as probiotics, prebiotics and polyphenol. Microbiota composition can be altered by dietary changes and gastrointestinal dysfunctions are observed in neurodegenerative diseases. In addition, several pieces of evidence support the idea that alterations in gut microbiota and enteric neuroimmune system could contribute to onset and progression of these age-related disorders. The impact of polyphenols on microbiota composition strengthens the idea that maintaining a healthy microbiome by modulating diet is essential for having a healthy brain across the lifespan. Moreover, it is emerging that they could be used as novel therapeutics to prevent brain from neurodegeneration.

New Therapeutic Drugs from Bioactive Natural Molecules: The Role of Gut Microbiota Metabolism in Neurodegenerative Diseases.

BACKGROUND: The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. METHOD: We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols - by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. RESULTS: Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. CONCLUSION: This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance.

Neuroendocrine stress response in gynecological laparoscopy: TIVA with propofol versus sevoflurane anesthesia.

STUDY OBJECTIVE: To compare intraoperative and postoperative neuroendocrine stress responses during total intravenous anesthesia (TIVA) using propofol and remifentanil versus sevoflurane anesthesia, during laparoscopic surgery. DESIGN: Prospective, randomized study. SETTING: Tertiary-care university hospital. PATIENTS: 46 ASA physical status I patients undergoing laparoscopic surgery for benign ovarian cysts. INTERVENTION: Patients were randomly allocated to two groups to receive either TIVA (Group A=23) or sevoflurane anesthesia (Group B=23). MEASUREMENTS: Perioperative plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), prolactin (PRL), and thyroid hormones (TSH, FT3, FT4) were measured. Blood samples were collected preoperatively, 30 minutes after the beginning of surgery, after extubation, and two and 4 hours after the end of surgery (times 0, 1, 2, 3, and 4). MAIN RESULTS: In Group A, perioperative levels of NE, E, ACTH, cortisol, and GH compared with preoperative values significantly decreased; in Group B they increased (Groups A vs. B: time 1, P<0.001 for all markers; time 2, P<0.001 for E, ACTH, cortisol, and GH; time 3, P<0.01 for cortisol, NE, and E, and P<0.05 for ACTH and GH). Perioperative PRL levels were significantly enhanced in both groups versus preoperative values. In both groups, TSH levels increased while FT3 levels decreased significantly relative to basal values. In both groups, perioperative FT4 levels significantly increased compared with preoperative values. CONCLUSIONS: TIVA inhibited the ACTH-cortisol axis and reduced NE, E, and GH levels, but it enhanced PRL and had a weak effect on thyroid hormone concentrations as compared to sevoflurane anesthesia.

Age does not hamper the response to pulmonary rehabilitation of COPD patients.

BACKGROUND: pulmonary rehabilitation (PR) improves health status and exercise tolerance, but not respiratory function in patients with chronic obstructive pulmonary disease (COPD). Our objective was to identify predictors of improvement in the 6-min walked distance (6'WD) in elderly COPD patients after PR. METHODS: this was a prospective observational study performed in an ambulatory rehabilitation setting. We enrolled 74 patients aged 65-83 years (mean: 74.2, SD: 4.4) with stable COPD in GOLD stage 3-4. About half (45.6%) of them had a basal O(2) saturation of 90% or less. After a baseline multi-dimensional assessment, patients underwent a 20-session rehabilitation cycle including training of the upper and lower extremities, and respiratory exercises, along with education sessions. The difference between final and basal 6'WD was expressed as a per cent of the basal value (6'WD gain). Patients were divided into two groups according to whether the 6'WD gain was above or under the 75th percentile, corresponding to 33% gain. RESULTS: patients whose 6'WD improved more had lower baseline forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) (46.0 versus 52.2%, P = 0.03) and baseline 6'WD, both as an absolute value (329.5 versus 408.9 m, P = 0.01) and as a per cent of the predicted (71.1 versus 93.5%, P = 0.002). After correction for potential confounders, baseline 6'WD was the only variable associated with the outcome (OR for 5% increments: 0.79; 95% CI 0.65-0.95). CONCLUSIONS: among elderly patients with COPD, a comprehensive rehabilitation programme can significantly improve the 6'WD even in the presence of chronic hypoxemia. The most physically impaired patients achieve the greatest benefit from rehabilitation, but we could not develop a model accurately predicting the response to rehabilitation.

Functional status and factors influencing the rehabilitation outcome of people affected by above-knee amputation and hemiparesis.

OBJECTIVES: To evaluate the functional status of people with transfemoral amputation and hemiparesis and to identify the factors that influence rehabilitation outcome after inpatient treatment. DESIGN: Retrospective study. SETTING: Rehabilitation hospital. PARTICIPANTS: Forty-five patients (30 men, 15 women; mean age, 69+/-9y) with intact mental status affected by unilateral transfemoral amputation for vascular disease and mild or moderate hemiparesis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Barthel Index, Barthel Index effectiveness, and Locomotor Capabilities Index (LCI) scores were measured. The following factors were studied: side and cause of amputation, side and severity of hemiparesis, sequence and laterality of dual impairment, time interval between impairments, and hospital length of stay. RESULTS: At discharge, mean Barthel Index and LCI scores +/-1 standard deviation were 79+/-12 and 15+/-5.6, respectively; Barthel Index effectiveness was 55+/-23.8. Only 2 patients ambulated without walking aids. Barthel Index effectiveness was better in patients with mild hemiparesis than in patients with more severe impairment. Ipsilateral localization of dual impairment increased the probability of higher LCI scores. CONCLUSIONS: Selected patients with dual impairment can recover the ability to walk. Severity of hemiparesis and laterality were the 2 clinical factors that had the greatest influence on functional measures.

Inflammatory response to cardiac bypass in ewe fetuses: effects of steroid administration or continuous hemodiafiltration.

OBJECTIVES: We sought to investigate the effectiveness of glucocorticoid administration or continuous venovenous hemodiafiltration on endothelin and corticotropin-releasing factor release or clearance during prolonged fetal cardiac bypass and on the overall performance of fetuses. METHODS: Circulating endothelin 1, 2, and 3 and corticotropin-releasing factor levels were measured in fetal ewes during a 60-minute cardiac bypass period performed with an inline axial flow pump. Blood samples were collected before, during, and 90 minutes after cardiac bypass. Animals were divided into 4 groups. The betamethasone group (n = 6) received maternal treatment with 12 mg of betamethasone 1 and 2 days before the experiment. The methylprednisolone group (n = 5) received fetal treatment with 40 mg/kg intravenous methylprednisolone at the beginning of cardiac bypass. The continuous venovenous hemodiafiltration group (n = 4) underwent continuous venovenous hemodiafiltration with a 0.3-m(2) polysulfone filter during cardiac bypass. The final group was the control group (n = 4). RESULTS: Maternal steroid pretreatment failed to decrease endothelin or corticotropin-releasing factor production when compared with levels in the control animals. Fetal treatment with methylprednisolone produced a significant decrease in endothelin 2 production during cardiac bypass (P <.02) and endothelin 1 production at the end of the experiment (P <.02). Continuous venovenous hemodiafiltration blocked completely the increase of endothelin and corticotropin-releasing factor levels during cardiac bypass (P <.02), which was maintained 90 minutes after cardiac bypass. Acid-base balance was preserved during cardiac bypass by the continuous venovenous hemodiafiltration but worsened after disconnection of the extracorporeal circuit, whereas animals treated with methylprednisolone had better pH, Paco(2), and bicarbonate levels by the end of the experiment. The overall tolerance of the procedure was better in the continuous venovenous hemodiafiltration group during cardiac bypass and in the methylprednisolone group at the end of the experiment. CONCLUSIONS: Continuous venovenous hemodiafiltration provides sustained stability of endothelin levels during fetal cardiac bypass. This technique might help, in association with fetal steroid treatment, to contain the inflammatory response leading to postbypass placental dysfunction.

Neuroendocrine stress response in patients undergoing benign ovarian cyst surgery by laparoscopy, minilaparotomy, and laparotomy.

STUDY OBJECTIVE: To quantify and compare neuroendocrine stress responses during and immediately after surgery by laparoscopy, minilaparotomy, and laparotomy for benign ovarian cysts. DESIGN: Prospective study (Canadian Task Force classification II-1). SETTING: Tertiary care university hospital. PATIENTS: Thirty healthy women with no major diseases and without endocrine disorders. INTERVENTIONS: Surgery for benign ovarian cysts performed by laparoscopy (10), minilaparotomy (10), or laparotomy (10). MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected at fixed times as follows: at 8 A.M. in the ward before transferring the patient to the operating room (time 0), 30 minutes after the beginning of surgery (time 1), at the end of surgery after extubation with the patient awake (time 2), and 2 and 4 hours after the end of surgery (times 3 and 4). We evaluated intraoperative and postoperative variations of the following stress-related markers: norepinephrine (NE), epinephrine (E), adrenocorticotropic hormone (ACTH), human growth hormone (hGH), prolactin (PRL), and cortisol, and postoperative pain. No differences were present in demographic characteristics and operating times in the three groups. No anesthesiologic or surgical complications occurred. Postoperative pain was similar in the laparoscopy and minilaparotomy group but significantly higher in the laparotomy group (p <0.001). Serum levels of markers were not significantly different among the groups at baseline. In the laparoscopy group the increase of hGH was limited to intraoperative time (p <0.05); increases in NE, E, ACTH, and PRL were limited to intraoperative and early postoperative time after extubation (p <0.01), with only PRL persisting with significantly higher levels after the end of surgery (p <0.05). In the minilaparotomy group no increase was detected for hGH, a significant intraoperative increase in cortisol was present (p <0.05), and NE, E, ACTH, and PRL were significantly higher even after the end of surgery (p <0.01). In this group levels of NE, E, and hGH were significantly higher than in the laparoscopy group 2 and 4 hours after the end of surgery (p <0.05). In the laparotomy group significant intraoperative increases were present for all stress markers and persisted until after extubation for ACTH (p <0.01) and to the postoperative period for NE (p <0.01), E (p <0.01), cortisol (p <0.01), PRL (p <0.05), and hGH (p <0.01). In this group levels of NE, E, ACTH, and hGH were significantly higher than those in the laparoscopy group from the beginning (NE p <0.05, E p <0.01, ACTH p <0.05, hGH p <0.01) until after the end of surgery. Comparison of laparotomy and minilaparotomy groups showed the former to have significantly higher plasma levels of E, cortisol, and hGH in intraoperative and postoperative times (p <0.001); significantly higher NE at sampling times 1 and 2 (p <0.001) and time 4 (p <0.01), and no difference at sampling time 3; and ACTH significantly higher only during surgery (p <0.01). CONCLUSION: Laparoscopic surgery causes minimal activation of stress hormones, which in some instances is confined to the intraoperative period. Minilaparotomy may be a valid alternative to laparoscopy in high-risk patients who cannot tolerate abdominal distention.

Sevoflurane improves the neuroendocrine stress response during laparoscopic pelvic surgery.

PURPOSE: Stress response to surgery is modulated by several factors, including magnitude of the injury, type of procedure (e.g., laparoscopy vs laparotomy) and type of anesthesia. Our purpose was to compare intra- and postoperative hormonal changes during isoflurane vs sevoflurane anesthesia, in a clinical model of well defined operative stress (laparoscopic pelvic surgery). METHOD: In this prospective randomized clinical study, 20 women requiring laparoscopic pelvic surgery for benign ovarian cysts received either a standard isoflurane plus fentanyl (Group A) or sevoflurane plus fentanyl anesthesia (Group B). Blood samples were collected preoperatively, 30 min after the beginning of surgery, at the end of surgery after extubation, and two and four hours after the end of surgery. Intra- and postoperative plasma levels of norepinephrine, epinephrine, adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH) and prolactin (PRL) were measured. RESULTS: Catecholamine levels and postoperative pain were similar in both groups. Nonetheless, in comparison to Group A, Group B showed a significant decrease of ACTH, cortisol and GH levels (A vs B at the end of surgery: ACTH 160 +/- 45 vs 100 +/- 40 pg.mL(-1); cortisol 45 +/- 8 vs 23 +/- 7 microg.dL(-1); GH 3 +/- 2 vs 0.8 +/- 0.4 ng.mL(-1); P < 0.001 for all), but enhanced PRL levels (A vs B, at 30 min after the beginning of surgery: 139 +/- 54 vs 185 +/- 22 ng.mL(-1); at the end of surgery: 100 +/- 27 vs 141 +/- 45 ng.mL(-1); P < 0.001 for both). CONCLUSIONS: In the clinical setting of low stress laparoscopic surgery, the type of volatile anesthetic significantly affected the stress response; the changes associated with sevoflurane suggested a more favourable metabolic and immune response compared to isoflurane.