Eran Nizri

Activation of the Cholinergic Anti-Inflammatory System by Nicotine Attenuates Neuroinflammation via Suppression of Th1 and Th17 Responses

The α7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of α7 nAChR activation by nicotine. Our results indicate that the α7 nAChR is expressed on the surface of CD4+ T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-α and IFN-γ) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, α7−/−-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-κB-mediated transcription as measured by IL-2 and IκB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis. α7−/− mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4+ and CD11b+ cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the α7 nAChR in immune modulation and suggest that α7 nAChR agonists may be effective in the treatment of inflammatory disorders.

Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine

In this study we determined the influence of cholinergic up-regulation by rivastigmine, an acetylcholinesterase inhibitor, on central nervous system inflammation. Neuroinflammation was induced in experimental autoimmune encephalomyelitis (EAE). Rivastigmine markedly ameliorated clinical symptoms of EAE and the spatial memory deficits induced by EAE. It also reduced demyelination, microglia activation and axonal damage. Rivastigmine decreased the reactivity of encephalitogenic T-cells and the production of pro-inflammatory cytokines (TNF-alpha, IFN-gamma and IL-17) without affecting IL-10 production. These effects were abolished by alpha7 nicotinic acetylcholine receptor antagonists. Antigen presentation was also affected by this treatment. Thus, rivastigmine treatment had immunomodulatory activity in EAE.

Modulation of inflammatory pathways by the immune cholinergic system.

Research done in the past years pointed to a novel function of cholinergic transmission. It has been shown that cholinergic transmission can modulate various aspects of the immune function, whether innate or adaptive. Cholinergic transmission affects immune cell proliferation, cytokine production, T helper differentiation and antigen presentation. Theses effects are mediated by cholinergic muscarinic and nicotinic receptors and other cholinergic components present in immune cells, such as acetylcholinesterase (AChE) and cholineacetyltransferase. The α7 nicotinic acetylcholine receptor was designated anti-inflammatory activity and has shown promise in pre-clinical models of inflammatory disorders. We herein describe the various components of the immune cholinergic system, and specifically the immune suppressive effects of α7 activation. This activation can be accomplished either by direct stimulation or indirectly, by inhibition of AChE. Thus, the presence of the immune cholinergic system can pave the way for novel immunomodulatory agents, or to the broadening of use of known cholinergic agents.

Current management practice of breast borderline lesions—need for further research and guidelines

BACKGROUND Breast borderline lesions are usually diagnosed on needle biopsies of imaging abnormalities. The natural history of these lesions is unclear, and the literature is divided on appropriate management. It was hypothesized that management varies among surgeons and may be associated with surgeon and practice characteristics. METHODS A survey of 477 members of the American Society of Breast Surgeons was completed. Results were analyzed according to various surgeon and practice characteristics. RESULTS Most respondents recommended routine excision for atypical ductal and lobular hyperplasia. Excision of radial scars and papillomas was much more variable, with only 50% recommending routine excision. Results differed by surgical dedication to breast surgery and fellowship training. Management of atypical ductal or lobular hyperplasia found at the margin varied significantly. The lack of a routine tumor board, low breast case volume, and low percentage of breast cases were associated with routine excision in these cases. CONCLUSIONS Breast borderline lesions pose a clinical dilemma, with practice varying greatly among surgeons.

Imaging the urinary pathways in mice by liposomal indocyanine green

UNLABELLED Intraoperative ureter identification can assist in the prevention of ureteral injury and consequently improve surgery outcomes. Our aim was to take advantage of the altered pharmacokinetics of liposomal indocyanine green (ICG), the only FDA-approved near-infrared (NIR) dye, for imaging of ureters during surgeries. ICG was passively adsorbed to liposomes. NIR whole mice body and isolated tissue imaging were used to study liposomal ICG properties vs. free ICG. In vivo, the urinary bladder could be clearly observed in most of the liposome-treated mice. Liposomal encapsulation of ICG enhanced ureteral emission up to 1.9 fold compared to free ICG (P<0.01). Increase in liposomal micropolarity and microviscosity and differential scanning calorimetry supported ICG localization within the liposomal bilayer. Our findings suggest that liposomal ICG could be utilized for ureteral imaging intra-operatively, thus potentially improving surgical outcomes. FROM THE CLINICAL EDITOR Iatrogenic ureteral injury is a serious complication of abdominal surgery and intra-operative recognition of the ureters is usually the best method of injury prevention. In this article, the authors developed liposomal indocyanine green, which could be excreted via the urinary system and investigated its in-vivo use in mice.

Optimal management of sarcomas of the breast: an update.

Breast sarcomas are rare mesenchymal-derived breast tumors. The small number of patients, the different histological subtypes, and the variation in clinical practice impairs the ability to draw firm practice recommendations. Patient management is often extrapolated from other soft tissue sarcomas, mostly of the extremities in which more clinical data is available. Surgical resection with negative margins is the goal of treatment, irrespective of the surgical procedure; the implication of radiation and chemotherapy is variable. Further advances in treatment should follow the assembly of breast sarcoma patients in specific cancer networks in specialized sarcoma referral centers. The characterization of molecular pathways active in tumorogenesis of these tumors may pave the way for the application of novel therapeutic agents.

Analysis of histological and immunological parameters of metastatic lymph nodes from colon cancer patients reveals that T-helper 1 type immune response is associated with improved overall survival

AbstractLymph node (LN) involvement in colonic carcinoma (CC) is a grave prognostic sign and mandates the addition of adjuvant treatment. However, in light of the histological variability and outcomes observed, we hypothesized that patients with LN metastases (LNM) comprise different subgroups.We retrospectively analyzed the histological sections of 82 patients with CC and LNM. We studied various histological parameters (such as tumor grade, desmoplasia, and preservation of LN architecture) as well as the prevalence of specific peritumoral immune cells (CD8+, CD20+, T-bet+, and GATA-3+). We correlated the histological and immunological data to patient outcome.Tumor grade was a significant prognostic factor even in patients with LNM. So was the number of LN involved (N1/N2 stage). From the morphological parameters tested (LN extracapsular invasion, desmoplasia in LN, LN architecture preservation, and mode of metastases distribution), none was found to be significantly associated with overall survival (OS). The mean OS of CD8+ low patients was 66.6 ± 6.25 versus 71.4 ± 5.1 months for CD8+ high patients (P = 0.79). However, T-helper (Th) 1 immune response skewing (measured by Th1/Th2 ratio >1) was significantly associated with improved OS. For patients with low ratio, the median OS was 35.5 ± 5 versus 83.5 months for patients with high Th1/Th2 ratio (P = 0.001).The histological presentation of LNM does not entail specific prognostic information. However, the finding of Th1 immune response in LN signifies a protective immune response. Future studies should be carried to verify this marker and develop a strategy that augments this immune response during subsequent adjuvant treatment.

Intraoperative Localization of Rectal Tumors Using Liposomal Indocyanine Green

Background: Tumor localization may pose a significant challenge during minimally invasive rectal resection. Near-infrared (NIR) imaging can penetrate biological tissue and afford tumor localization from the external surface of the rectum. Our aim was to develop an NIR-based tool for rectal tumor imaging that can be administered intravenously. Methods: We prepared indocyanine-green (ICG)–loaded liposomes by sonication. Liposomes were evaluated for their size and morphology. We then used an endoscopically induced rectal cancer in mice as a model for rectal cancer. After intravenous administration, tumors were evaluated for their fluorescence intensity. Tumor intensity was expressed in relation to the background signal, that is, tumor to background ratio (TBR). Results: Liposomes in various sizes could be prepared by adjusting sonication time. We selected 100-nm-sized liposomes for further experiments. Transmission electron microscopy showed spherical particles and confirmed the size measurements. The liposomes could be lyophilized and then rehydrated again before use without compromising their structure or signal. Fluorescence intensity was kept for 24 hours after solubilization. Testing the optimal time course for rectal tumor imaging revealed that early time course (up to 3 hours) yielded nonspecific imaging, whereas after long time course (24 hours), a very weak signal remained in the tissue. The optimal time window for imaging was after 12 hours from injection, with TBR = 8.1 ± 3.6 (P = .002). Free ICG could not achieve similar results. Conclusions: The liposomal ICG can be reproducibly prepared and kept in lyophilized form. Liposomal ICG could serve as a tool for intraoperative tumor localization.

Learning Curve, Training Program, and Monitorization of Surgical Performance of Peritoneal Surface Malignancies Centers

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is a complex procedure with high cost and significant morbidity and mortality. The associated learning curve is steep and could reliably be evaluated using specific statistics. Risk-adjusted sequential probability ratio test is an effective and robust method to monitor surgical performance in the learning and audit phase of a peritoneal surface malignancies center development. The most critical factor associated with surgical performance is mentoring of the trainee by an expert. A well-structured tutor-based training program has been implemented in Europe. This initiative will improve the standardization of the combined procedure and improve quality of services across the continent.

2018 ESMO Sarcoma and GIST Symposium: ‘take-home messages’ in soft tissue sarcoma

The 7th edition of the ‘ESMO Sarcoma and GIST Symposium’ was held in Milan in February 2018. For the first time, the Symposium brought together representatives from the European Reference Network on rare adult solid cancer (EURACAN) joined by sarcoma experts from the USA, Japan and patient advocacy groups, to share insights and discuss future directions in this rare condition. This commentary will summarise the highlights in soft tissue sarcomas.