Conservative Versus Surgical Management of Elbow Medial Ulnar Collateral Ligament Injury: A Systematic Review

Objective: Several studies have been published regarding the treatment of medial ulnar collateral ligament (MUCL) injuries for professional overhead athletes. However, there is a paucity of data regarding non-professional athletes. The aim of this systematic review was to compare the rate of outcome scores and complications of conservative versus operative treatments both in non-professional athletes and in non-sport-related trauma patients with MUCL lesions. Methods: A systematic review of the published literature was performed by applying the PRISMA guidelines. A search was conducted using three databases: Medline, Science Direct, and Web of Science. The keywords used were \u201culnar collateral ligament injury,\u201d \u201celbow,\u201d \u201csurgery,\u201d and \u201cconservative treatment\u201d. Patients were divided into three groups: patients who underwent conservative treatment (C-group), surgical treatment (S-group), and surgery after a failed conservative treatment (C&S-group). Clinical outcomes were analyzed: Disability of Arm, Shoulder and Hand (DASH), Conway scale, Carson score, and Kerlan\u2013Jobe Orthopaedic Clinic score (KJOC). Results: A total of 15 studies were included, evaluating 513 patients. Although good and excellent outcomes were found for most patients during daily and/or sport activities, independently of the type of treatment, the C-group had better results. Excellent results were found in 98.8% of the C-group, in 88.1% of the S-group, and in 87.7% of the C&S-group. The complication rate in the C-group was statistically higher compared to the S and C&S groups (P < 0.001). However, its complication rate was higher with lower patient satisfaction. Conclusions: There is insufficient evidence to establish statistically significant differences in the effects of conservative versus surgical treatments on the functional outcomes of patients with MUCL lesions. However, a period of rehabilitation therapy and the functional request of the single injured subject are useful to discern which patients genuinely require MUCL surgical repair

Classification of current anticancer immunotherapies

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches

the Role of the immunogenetic Profile of patients in response to chemotherapy

L'immunité antitumorale induite par les cellules dendritiques intratumorales contribue à l'efficacité de la chimiothérapie à base d'anthracycline dans le cancer. Nous avons identifié un allèle de perte de fonction du gène codant pour le récepteur formyl peptide 1 (FPR1) qui était associé à une faible survie sans métastases et à une survie globale chez les patientes atteintes d'un cancer du sein et colorectal recevant une chimiothérapie adjuvante.Les effets thérapeutiques des anthracyclines ont été abrogés chez les souris Fpr1 (-/-) porteuses de tumeurs en raison d'une immunité antitumorale altérée. Les cellules dendritiques déficientes en Fpr1 ne parvenaient pas à s'approcher des cellules cancéreuses mourantes et, en conséquence, ne pouvaient pas déclencher l'immunité des cellules T antitumorales.Des expériences réalisées dans un dispositif microfluidique ont confirmé que FPR1 et son ligand, l'annexine-1, favorisaient des interactions stables entre les cellules cancéreuses mourantes et les leucocytes humains ou murins.Nous avons également étudié la contribution possible de FPR1 à l'efficacité d'une combinaison de mitoxantrone (MTX) et cyclophosphamide (CTX) pour le traitement du cancer du sein induit par l'hormone.Le cancer du sein induit par une combinaison d'acétate de médroxyprogestérone (MPA) et de 7,12-diméthylbenz [a] anthracène (DMBA) a pu être traité avec succès avec MTX plus CTX dans la mesure où la croissance tumorale était retardée et la survie globale augmentée (par rapport à commandes traitées uniquement avec un véhicule).Toutefois, l'efficacité thérapeutique de la thérapie combinée a été complètement abolie lorsque les récepteurs FPR1 ont été bloqués au moyen de la cyclosporine H (CSH). Des études génétiques futures sur les cancers du sein traités par chimiothérapie néoadjuvante sont nécessaires pour valider ces résultats au niveau clinique.L'ensemble de ces résultats mettent en évidence l'importance de FPR1 dans les réponses immunitaires anti-cancéreux induites par la chimiothérapie.Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy.The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity.Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes.We investigated also the possible contribution of FPR1 to the efficacy of a combination of mitoxantrone (MTX) and cyclophosphamide (CTX) for the treatment of hormone-induced breast cancer.Breast cancer induced by a combination of medroxyprogesterone acetate (MPA) and 7,12-Dimethylbenz[a]anthracene (DMBA) could be successfully treated with MTX plus CTX in thus far that tumor growth was retarded and overall survival was extended (as compared to vehicle-only treated controls).However, the therapeutic efficacy of the combination therapy was completely abolished when FPR1 receptors were blocked by means of cyclosporin H (CsH). Future genetic studies on neoadjuvant chemotherapy-treated breast cancers are warranted to validate these findings at the clinical level.Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses

Autophagy induction for the treatment of cancer

Cancer can be viewed in 2 rather distinct ways, namely (i) as a cell-autonomous disease in which malignant cells have escaped control from cell-intrinsic barriers against proliferation and dissemination or (ii) as a systemic disease that involves failing immune control of aberrant cells. Since macroautophagy/autophagy generally increases the fitness of cells as well as their resistance against endogenous or iatrogenic (i.e., relating to illness due to medical intervention) stress, it has been widely proposed that inhibition of autophagy would constitute a valid strategy for sensitizing cancer cells to chemotherapy or radiotherapy. Colliding with this cell-autonomous vision, however, we found that immunosurveillance against transplantable, carcinogen-induced or genetically engineered cancers can be improved by pharmacologically inducing autophagy with caloric restriction mimetics. This positive effect depends on autophagy induction in cancer cells and is mediated by alterations in extracellular ATP metabolism, namely increased release of immunostimulatory ATP and reduced adenosine-dependent recruitment of immunosuppressive regulatory T cells into the tumor bed. The combination of autophagy inducers and chemotherapeutic agents is particularly efficient in reducing cancer growth through the stimulation of CD8(+) T lymphocyte-dependent anticancer immune responses

A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice

International audienceWe have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents

Metabolic effects of fasting on human and mouse blood in vivo

Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes ∼20% weight loss) or starvation of human volunteers for up to 4 d (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes. White blood cells from mice and human volunteers responded to fasting with a marked reduction in protein lysine acetylation, affecting both nuclear and cytoplasmic compartments. In circulating leukocytes from mice that underwent 48-h fasting, an increase in LC3B lipidation (as assessed by immunoblotting and immunofluorescence) only became detectable if the protease inhibitor leupeptin was injected 2 h before drawing blood. Consistently, measurement of an enhanced autophagic flux was only possible if white blood cells from starved human volunteers were cultured in the presence or absence of leupeptin. Whereas all murine leukocyte subpopulations significantly increased the number of LC3B(+) puncta per cell in response to nutrient deprivation, only neutrophils from starved volunteers showed signs of activated autophagy (as determined by a combination of multi-color immunofluorescence, cytofluorometry and image analysis). Altogether, these results suggest that white blood cells are suitable for monitoring autophagic flux. In addition, we propose that the evaluation of protein acetylation in circulating leukocytes can be adopted as a biochemical marker of organismal energetic status

Chemical activation of SAT1 corrects diet-induced metabolic syndrome.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis,&nbsp;but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects&nbsp;relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N1-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of&nbsp;SAT. All the positive&nbsp;effects of TETA on high-fat diet-induced metabolic syndrome&nbsp;were lost in SAT1-deficient&nbsp;mice.&nbsp;Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity

Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell–mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-α and IFN-β receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN–related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy

Cancer cell–autonomous contribution of type I interferon signaling to the efficacy of chemotherapy

International audienceThe immune system is routinely confronted with cell death resulting from the physiological turnover of renewable tissues, as well as from pathological insults of several types. We hypothesize the existence of a mechanism that allows the immune system to discriminate between physiological and pathological instances of cell death, but the factors that determine whether cellular demise is perceived as a neutral, tolerogenic or immunogenic event remain unclear 1. Infectious insults are accompanied by so-called microbe-associated molecular patterns (MAMPs), i.e., viral or bacterial products that activate immune cells through a panel of pattern-recognition receptors (PRRs) 2. Moreover, intracellular pathogens generally trigger adaptive mechanisms aimed toward the re-establishment of homeosta-sis, including the unfolded protein response (UPR) and autophagy 3,4. In mammals, MAMPs coupled to the activation of stress responses Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN- and IFN- receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We surmise that such 'viral mimicry' constitutes a hallmark of successful chemotherapy. np