Serum NETosis expression and recurrence risk after regional or volatile anaesthesia during breast cancer surgery: A pilot, prospective, randomised single-blind clinical trial

Background: Some experimental and retrospective clinical studies signal an association between certain anaesthetic techniques and tumour metastasis following breast cancer surgery. Neutrophil Extracellular Trapping (NETosis) is an immunological process, whereby neutrophils engulf tumour antigen then degranulate, leaving a serologic marker. NETosis expression among breast cancer patients is associated with an increased risk of metastasis. We investigated the effect of two distinct anaesthetic techniques on the expression of NETosis in women who underwent potentially curative breast cancer surgery. Methods: In a parallel-group, randomised controlled trial, a subset of women (n = 40) undergoing breast cancer resection surgery, who were partaking in a larger trial (NCT00418457), were randomly assigned to receive volatile general anaesthesia (GA) or propofol GA combined with paravertebral regional anaesthesia (PPA) for their surgery. Serum was taken and stored before and 24 hours post-operatively. NETosis was measured by ELISA using Neutrophil Myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit) biomarkers, which were the co-primary end points. Results: Patient and breast cancer characteristics did not differ significantly between groups. Recurrence occurred in 7.5% patients. GA patients received more opioids and reported higher post-operative pain than PPA. There was no difference in post-operative MPO in GA vs PPA (10.5 ± 6.6 vs 11.5 ± 4.7 ng mL−1, P =.60). Regarding CitH3, there was no difference post-operatively in GA vs PPA (3.6 ± 2.3 vs 4.0 ± 5.9, P =.80). NET expression did not differ before or after anaesthesia and surgery in either group, for either biomarker. Conclusion: Anaesthetic technique did not affect NETosis expression in breast cancer patients, indicating that it is not a viable marker of the effect of anaesthetic technique on breast cancer recurrence

Heme as a Playmaker in the Regulation of the Nitric Oxide System

founding due to this factor. Our results are thus interpreted as the hazard ratio of recurrence for paravertebral versus general anesthesia for patients at the same histologic grade, and similarly for other factors in the model. This sort of multivariable analysis compensates for small, or even moderate, imbalances at baseline. We adjusted for this factor because of the retrospective nature of the study, even though we did not have evidence of it being a true confounder because it was not associated with the treatment groups (P ϭ 0.16) or the outcome (P ϭ 0.25), both of which are required by the classic definition of confounding. As specified in the article, a single surgeon performed all cases in both groups. And again as specified, all paravertebral anesthesia was performed by a single anesthesiologist (D.J.B.), who also performed some of general anesthesia alone cases. The remainder were performed by three other attending anesthesiologists. The cases were similar, and the primary determinant of anesthetic type was assignment to D.J.B., who was the only anesthesiologist in the group familiar with the paravertebral technique. The substantial limitations of observational studies are well known and were discussed in our article. For example, we specified: "Patients were not randomized and clinical care was not standardized, so that selection bias and the effects of unmeasured confounding variables cannot be excluded. For example, patients in the general anesthesia group had slightly larger tumors, smaller margins, and higher chemotherapy rates than patients in the paravertebral group, factors that could affect mortality, although these differences did not reach statistical significance. Relevant information such as the amount of morphine given and the type of chemotherapy used in each group was not available in the records." Under no circumstances should a small retrospective study be the basis for practice, and we suggested no such thing in our report. In contrast, the conclusion of our article was that "this study should be viewed as generating a hypothesis and an estimated effect size for future large randomized controlled trials, which are being planned and which will require several years for execution and analysis." A prospective trial is now in progress (ClinicalTrials.gov No. NCT00418457). Heme as a Playmaker in the Regulation of the Nitric Oxide System To the Editor:-We read with great interest the article by Tsai et al. The authors showed that lipopolysaccharide treatment resulted in a significant increase in type 2 cationic amino acid transporter expression and this effect was reversed by concomitant treatment with hemin ( 2,3 These observations may be consistent with previous work performed by the same authors 4 showing that propofol treatment resulted in a concomitant reduction of both the inducible isoform of nitric oxide synthase and type 2 cationic amino acid transporter expression. In this regard, we also showed that propofol may act as an inducer of HO-1 via activation of the nuclear factor-B pathway. 5 Another point that we believe needs to be raised is in regard to the authors' choice of adding hemin immediately after lipopolysaccharide stimulation, thus not permitting a strong preinduction of HO-1 activity, which would have allowed increased carbon monoxide levels and a reduction of the intracellular heme pool. Interestingly, the authors also showed that tin protoporphyrin, a strong inhibitor of HO activity, results in a significant increase of HO-1 protein (even though in the Results section it was indicated that tin protoporphyrin did not increase protein expression) and partial reversion of hemin effects. The molecular mechanism underlying this effect is still unclear, and several hypotheses may be carried out. One is that HO activity inhibition after tin protoporphyrin treatment results in increased intracellular heme level after strong HO activity inhibition, thus leading to increased HO-

PERIOPERATIVE MEDICINE Effect of Anesthetic Technique on Serum Vascular Endothelial Growth Factor C and Transforming Growth Factor ␤ in Women Undergoing Anesthesia and Surgery for Breast Cancer

ABSTRACT Background: In breast cancer, vascular endothelial growth factor C, transforming growth factor ␤, placental growth factor, and fibroblast growth factor (acidic and basic) promote angiogenesis and metastases. We tested the hypothesis that a propofol-paravertebral anesthetic (PPA) technique would attenuate postoperative changes in these angiogenic factors to a greater extent than balanced general anesthesia (GA) and morphine analgesia in women undergoing surgery for primary breast cancer. Method: Forty women with primary breast cancer undergoing surgical excision were randomized to receive either standard GA or PPA technique. Venous blood was sampled before and at 24 h after surgery and serum analyzed. The primary endpoint was a preoperative versus postoperative change in vascular endothelial growth factor C and transforming growth factor ␤ concentrations. Results: Using a visual analog scale (median [25-75% interquartile range]), PPA patients (1 [0 -2]) had less pain at 2 h (P ϭ 0.02) than did GA patients (3 [2-5]). The mean postoperative change in vascular endothelial growth factor C concentrations among GA patients was 733 versus 27 pg/ml for PPA patients (difference, 706 [97.5% CI,130] pg/ml, P ϭ 0.001). In contrast, the mean postoperative change in transforming growth factor ␤ concentration among GA patients was Ϫ163 versus 146 pg/ml for PPA patients (difference, 309 [97.5% CI, Ϫ474 to Ϫ143] pg/ml, P ϭ 0.005). Concentrations of placental growth factor and fibroblast growth factor, both acidic and basic, were undetectable in serum. Conclusion: Anesthetic technique influences serum concentrations of factors associated with angiogenesis in primary breast cancer surgery. B REAST cancer remains a leading cause of death among women and is second only to lung cancer as a cause of cancer mortality in western countries, most of which is attributable to recurrence and metastasis. Breast cancer also accounts for more new cases of cancer among women than any other cancer. 1 Initial treatment almost invariably involves surgical excision. However, tumor recurrence occurs in a significant number of patients. Even when the most experienced operator performs surgical resection, it is unavoidable that tumor cells are dispersed into the blood and lymphatic circulations.

Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006; 105: 660–664

Background: Regional anesthesia is known to prevent or attenuate the surgical stress response; therefore, inhibiting surgical stress by paravertebral anesthesia might attenuate perioperative factors that enhance tumor growth and spread. The authors hypothesized that breast cancer patients undergoing surgery with paravertebral anesthesia and analgesia combined with general anesthesia have a lower incidence of cancer recurrence or metastases than patients undergoing surgery with general anesthesia and patient-controlled morphine analgesia. Methods: In this retrospective study, the authors examined the medical records of 129 consecutive patients undergoing mastectomy and axillary clearance for breast cancer between September 2001 and December 2002. Results: Fifty patients had surgery with paravertebral anesthesia and analgesia combined with general anesthesia, and 79 patients had general anesthesia combined with postoperative morphine analgesia. The follow-up time was 32 ؎ 5 months (mean ؎ SD). There were no significant differences in patients or surgical details, tumor presentation, or prognostic factors. Recurrence-and metastasis-free survival was 94% (95% confidence interval, 87-100%) and 82% (74 -91%) at 24 months and 94% (87-100%) and 77% (68 -87%) at 36 months in the paravertebral and general anesthesia patients, respectively (P ‫؍‬ 0.012). Conclusions: This retrospective analysis suggests that paravertebral anesthesia and analgesia for breast cancer surgery reduces the risk of recurrence or metastasis during the initial years of follow-up. Prospective trials evaluating the effects of regional analgesia and morphine sparing on cancer recurrence seem warranted